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Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in PregnantHIV-1-Infected Women for Maternal Health and Interventions toReduce Perinatal HIV Transmission in the United StatesDownloaded from http://aidsinfo.nih.gov/guidelines on...  
Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in PregnantHIV-1-Infected Women for Maternal Health and Interventions toReduce Perinatal HIV Transmission in the United StatesDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Visit the AIDSinfo website to access the most up-to-date guideline.Register for e-mail notification of guideline updates at http://aidsinfo.nih.gov/e-news.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugsin Pregnant HIV-1-Infected Women for MaternalHealth and Interventions to Reduce Perinatal HIVTransmission in the United StatesDeveloped by the HHS Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission —A Working Group of the Office of AIDS Research Advisory Council (OARAC)How to Cite the Perinatal Guidelines:Panel on Treatment of HIV-Infected Pregnant Women and Prevention of PerinatalTransmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIVTransmission in the United States. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed (insert date) [include page numbers, table number, etc. if applicable] It is emphasized that concepts relevant to HIV management evolve rapidly. The Panel has amechanism to update recommendations on a regular basis, and the most recent informa-tion is available on the AIDSinfo website (http://aidsinfo.nih.gov).access AIDSinfomobile siteDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States iWhat’s New in the Guidelines? (Last updated July 31, 2012; last reviewedJuly 31, 2012)Key changes made to update the September 14, 2011, version of the guidelines are summarized below.Throughout the revised guidelines, significant updates are highlighted and discussed. The addendum to theguidelines—Supplement: Safety and Toxicity of Individual Antiretroviral Agents in Pregnancy—includes updated information from the Antiretroviral Pregnancy Registry and updates on recent studies ofvarious antiretroviral agents in human pregnancy. Lessons from Clinical Trials of Antiretroviral Interventions to Reduce PerinatalTransmission of HIVand Table 3, Results of Major Studies on Antiretroviral Prophylaxisto Prevent Mother-to-Child Transmission of HIV:• Table 3updated to include data on 48-week results of the Breastfeeding and Nutrition (BAN) studyin Malawi.Preconception Counseling and Care for HIV-Infected Women of Childbearing AgeandTable 4, Drug Interactions Between Hormonal Contraceptives and Antiretroviral Agents:• Table 4updated to include data on hormonal contraceptive interactions with rilpivirine and raltegravir.• Reproductive Options for HIV-Concordant and Serodiscordant Couples:oFor serodiscordant couples who want to conceive, use of antiretroviral therapy is nowrecommended for the HIV-infected partner, with the strength of the recommendation differingbased on the CD4-cell count of the infected partner:- AIfor CD4 T-lymphocyte (CD4-cell) count ≤550 cells/mm3, BIIIfor CD4-cell count >550cells/mm3). If therapy is initiated, maximal viral suppression is recommended beforeconception is attempted (AIII).oAdded discussion of the pre-exposure prophylaxis (PrEP) studies in heterosexual couples, with anew recommendation regarding PrEP in discordant couples who wish to conceive. Discussionincludes information on counseling, laboratory testing, and monitoring of individuals on PrEP andimportance of reporting uninfected women who become pregnant on PrEP to the AntiretroviralPregnancy Registry:- Periconception administration of antiretroviral PrEP for HIV-uninfected partners may offer anadditional tool to reduce the risk of sexual transmission (CIII). The utility of PrEP of the uninfectedpartner when the infected partner is receiving antiretroviral therapy has not been studied.Antepartum Care• General Principles Regarding Use of Antiretroviral Drugs During Pregnancy:oInitial assessment for HIV-infected pregnant women expanded to include screening for hepatitis Cvirus and tuberculosis infection, as well as history of side effects or toxicities from priorantiretroviral drug regimens.oAdditional benefit of antiretroviral drug regimens expanded to include benefits of therapy forreducing sexual transmission to discordant partners when viral suppression is maintained, withDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States iidiscussion of the HPTN 052 trial results.• Recommendations for Use of Antiretroviral Drugs During Pregnancy and Table 5,Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Datain Human Pregnancy and Recommendations for Use in Pregnancy:oModified recommendations regarding categorization of various antiretroviral agents in categoriesof drugs that are preferred, alternative, or use in special circumstances. oNucleoside reverse transcriptase inhibitors:- Didanosine and stavudine moved from alternativeNRTI category to use in specialcircumstancescategory because they have more toxicity than the preferred and alternativeNRTI drugs.oProtease inhibitors:- Atazanavir with low-dose ritonavir boosting moved from an alternativeprotease inhibitor to apreferredprotease inhibitor for use in antiretroviral-naive pregnant women, along withlopinavir/ritonavir, because of increased information on safety in pregnancy.- Darunavir moved from insufficient data to recommend useto an alternativeproteaseinhibitor for use in antiretroviral-naive pregnant women.oIntegrase inhibitors:- Raltegravir moved from insufficient data to recommend useto use in specialcircumstancesfor antiretroviral-naive pregnant women when preferred or alternative agentscannot be used.• HIV-Infected Pregnant Women Who Have Never Received Antiretroviral Drugs(Antiretroviral Naive):oIncreased discussion on when to initiate an antiretroviral drug regimen in pregnant women:- The decision as to whether to start the regimen in the first trimester or delay until 12 weeks’gestation will depend on CD4-cell count, HIV RNA levels, and maternal conditions such asnausea and vomiting (AIII). Earlier initiation of a combination antiretroviral regimen may bemore effective in reducing transmission, but benefits must be weighed against potential fetaleffects of first-trimester drug exposure.• HIV-Infected Pregnant Women Who Are Currently Receiving Antiretroviral Therapy:oDiscussion of efavirenz use in the first trimester:- Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy andpregnancy is rarely recognized before 4 to 6 weeks of pregnancy, and unnecessaryantiretroviral drug changes during pregnancy may be associated with loss of viral control andincreased risk of perinatal transmission, efavirenz can be continued in pregnant womenreceiving an efavirenz-based regimen who present for antenatal care in the first trimester,provided the regimen produces virologic suppression (CIII).• Special Situations - Failure of Viral Suppression:oUse of raltegravir in late pregnancy in women with high viral loads to decrease viral loaddiscussed but not endorsed. The efficacy and safety of this approach have not been evaluated andDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.only anecdotal reports are available. In the setting of a failing regimen related to nonadherenceand/or resistance, there are concerns that the addition of a single agent may further increase risk ofresistance and potential loss of future effectiveness with raltegravir. Until more data becomeavailable on the safety of raltegravir use in pregnancy, this approach cannot be recommended.Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-InfectedPregnant Women and Their Infants• Combination Antiretroviral Drug Regimens and Pregnancy Outcome:oAddition of a new table—Table 7– Results of Studies Assessing Association BetweenAntiretroviral Regimens and Preterm Delivery—that summarizes the results of studies assessingthe association between antiretroviral regimens and preterm delivery.Intrapartum Care• Intrapartum Antiretroviral Therapy/Prophylaxis:oDiscussion of use of intravenous (IV) zidovudine during labor and maternal viral load:- IV zidovudine is no longer required for HIV-infected women receiving combinationantiretroviral regimens who have HIV RNA - HIV-infected women with HIV RNA ≥400 copies/mL (or unknown HIV RNA) near deliveryshould be administered IV zidovudine during labor, regardless of antepartum regimen or modeof delivery (AI).- Based on pharmacokinetic data, in women with HIV RNA ≥400 copies/mL near delivery forwhom zidovudine is recommended, IV would be preferred to oral administration in the UnitedStates; in situations where IV administration is not possible, oral administration can be considered.Postpartum Care• Infant Antiretroviral Prophylaxis and Table 9, Recommended Neonatal Dosing for Preventionof Mother-to-Child Transmission of HIV:oTable 9revised to reflect neonatal dosing only of zidovudine (in term and preterm infants) andnevirapine in the regimen used in the NICHD-HPTN 040 study.oChoice of neonatal antiretroviral drug prophylaxis includes discussion of the NICHD-HPTN 040study and concerns regarding use of lopinavir/ritonavir in neonates.oAddition of new pharmacokinetic data on nevirapine in preterm infants.• Initial Postnatal Management of the HIV-Exposed Neonate:oBecause of the potential for enhanced hematologic toxicity in infants receiving azidovudine/lamivudine-containing prophylaxis regimen, a recheck of hemoglobin and neutrophilcounts is recommended 4 weeks after initiation of prophylaxis (AI).oNew recommendation that health care providers should routinely inquire about premastication offoods fed to infants, instruct HIV-infected caregivers to avoid this practice, and advise on saferfeeding options (AII).Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States iiiDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States ivTable of ContentsWhat’s New in the Guidelines?...............................................................................................................iGuidelines Panel Members...................................................................................................................viiFinancial Disclosure.................................................................................................................................ixIntroduction..............................................................................................................................................A-1Table 1. Outline of the Guidelines Development Process........................................................................A-2Table 2. Rating Scheme for Recommendations........................................................................................A-3Lessons From Clinical Trials of Antiretroviral Interventions to Reduce Perinatal Transmission of HIV....................................................................................B-1Overview..................................................................................................................................................B-1Mechanisms of Action of Antiretroviral Prophylaxis in Reducing Perinatal Transmission of HIV.................................................................................................................B-3Lessons from International Clinical Trials of Short-Course Antiretroviral Regimensfor Prevention of Perinatal Transmission of HIV....................................................................................B-5Table 3. Results of Major Studies on Antiretroviral Prophylaxis to Prevent Mother-to-Child Transmission of HIV...............................................................................................B-7Perinatal Transmission of HIV and Maternal HIV RNA Copy Number................................................B-19Preconception Counseling and Care for HIV-Infected Women of Childbearing Age.......C-1Overview..................................................................................................................................................C-1Table 4. Drug Interactions Between Antiretroviral Agents and Hormonal Contraceptives..............C-3Reproductive Options for HIV-Concordant and Serodiscordant Couples...............................................C-6Antepartum Care.....................................................................................................................................D-1General Principles Regarding Use of Antiretroviral Drugs During Pregnancy.......................................D-1Table 5.Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy and Recommendations for Use in Pregnancy...................D-5Table 6.Clinical Scenario Summary Recommendations for Antiretroviral Drug Use by Pregnant HIV-Infected Women and Prevention of Perinatal Transmission of HIV-1 in the United States.....D-24HIV-Infected Pregnant Women Who Have Never Received Antiretroviral Drugs (Antiretroviral Naive)..D-33HIV-Infected Pregnant Women Who Are Currently Receiving Antiretroviral Therapy........................D-38HIV-Infected Pregnant Women Who Have Previously Received Antiretroviral Treatment or Prophylaxis but Are Not Currently Receiving Any Antiretroviral Medications...............................D-40Special Situations – HIV/Hepatitis B Virus Coinfection ......................................................................D-44Special Situations – HIV/Hepatitis C Virus Coinfection.......................................................................D-48Special Situations – HIV-2 Infection and Pregnancy.............................................................................D-52Special Situations – Acute HIV Infection..............................................................................................D-56Special Situations – Stopping Antiretroviral Drugs During Pregnancy.................................................D-60Special Situations – Failure of Viral Suppression..................................................................................D-63Monitoring of the Woman and Fetus During Pregnancy.......................................................................D-65Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States vSpecial Considerations Regarding the Use of Antiretroviral Drugs byHIV-Infected Pregnant Women and their Infants......................................................................E-1Overview..................................................................................................................................................E-1Pharmacokinetic Changes........................................................................................................................E-2Teratogenicity...........................................................................................................................................E-4Combination Antiretroviral Drug Regimens and Pregnancy Outcome....................................................E-8Table 7. Results of Studies Assessing Association Between Antiretroviral Regimens and Preterm Delivery.......................................................................................................................E-10Nevirapine and Hepatic/Rash Toxicity...................................................................................................E-15Nucleoside Reverse Transcriptase Inhibitor Drugs and Mitochondrial Toxicity...................................E-18Protease Inhibitor Therapy and Hyperglycemia.....................................................................................E-25Antiretroviral Drug Resistance and Resistance Testing in Pregnancy...............................F-1Intrapartum Care...................................................................................................................................G-1Intrapartum Antiretroviral Therapy/Prophylaxis.....................................................................................G-1Transmission and Mode of Delivery........................................................................................................G-5Table 8. Clinical Scenarios and Recommendations Regarding Mode of Delivery to Reduce Perinatal Transmission of HIV..........................................................................................................G-8Other Intrapartum Management Considerations....................................................................................G-12Postpartum Care......................................................................................................................................H-1Postpartum Follow-Up of HIV-Infected Women.....................................................................................H-1Infants Born To Mothers with Unknown HIV Infection Status...............................................................H-6Infant Antiretroviral Prophylaxis.............................................................................................................H-7Table 9.Recommended Neonatal Dosing for Prevention of Mother-to-Child Transmission of HIV...H-12Initial Postnatal Management of the HIV Exposed Neonate.................................................................H-19Long-Term Follow-Up of Antiretroviral Drug-Exposed Infants...........................................................H-24Appendix A: Supplement: Safety and Toxicity of Individual Antiretroviral Agents in Pregnancy...................................................................................................I-1Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors.........................................................I-1Abacavir (Ziagen, ABC)............................................................................................................................I-1Didanosine (Videx, ddI)............................................................................................................................I-2Emtricitabine (Emtriva, FTC)...................................................................................................................I-3Lamivudine (Epivir, 3TC).........................................................................................................................I-5Stavudine (Zerit, d4T)...............................................................................................................................I-6Tenofovir disoproxil fumarate (Viread, TDF)...........................................................................................I-8Zalcitabine (HIVID, ddC)........................................................................................................................I-11Zidovudine (Retrovir, AZT, ZDV)..........................................................................................................I-11Non-Nucleoside Reverse Transcriptase Inhibitors........................................................................................I-15Delavirdine (Rescriptor, DLV)................................................................................................................I-15Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Efavirenz (Sustiva, EFV)........................................................................................................................I-15Etravirine (Intelence, ETR).....................................................................................................................I-18Nevirapine (Viramune, NVP)..................................................................................................................I-19Rilpivirine (Edurant, RPV)......................................................................................................................I-23Protease Inhibitors........................................................................................................................................I-25Amprenavir (Agenerase, APV)...............................................................................................................I-25Atazanavir (Reyataz, ATV).....................................................................................................................I-25Darunavir (Prezista, DRV)......................................................................................................................I-28Fosamprenavir (Lexiva, FPV).................................................................................................................I-30Indinavir (Crixivan, IDV)........................................................................................................................I-31Lopinavir + Ritonavir (Kaletra, LPV/r)..................................................................................................I-33Nelfinavir (Viracept, NFV).....................................................................................................................I-35Ritonavir (Norvir, RTV)..........................................................................................................................I-37Saquinavir (Invirase [Hard Gel Capsule], SQV).....................................................................................I-38Tipranavir (Aptivus, TPV)......................................................................................................................I-40Entry Inhibitors..............................................................................................................................................I-42Enfuvirtide (Fuzeon, T-20)......................................................................................................................I-42Maraviroc (Selzentry, MVC)...................................................................................................................I-43Integrase Inhibitors.......................................................................................................................................I-45Raltegravir (Isentress).............................................................................................................................I-45Antiretroviral Pregnancy Registry.................................................................................................................I-47Appendix B: Acronyms..........................................................................................................................J-1TablesTable 1. Outline of the Guidelines Development Process.......................................................................A-2Table 2. Rating Scheme for Recommendations.......................................................................................A-3Table 3. Results of Major Studies on Antiretroviral Prophylaxis to Prevent Mother-to-Child Transmission of HIV................................................................................................................................B-7Table 4. Drug Interactions Between Antiretroviral Agents and Hormonal Contraceptives.....................C-3Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy and Recommendations for Use in Pregnancy...............................................D-5Table 6. Clinical Scenario Summary Recommendations for Antiretroviral Drug Use by Pregnant HIV-Infected Women and Prevention of Perinatal Transmission of HIV-1 in the United States..........D-24Table 7. Results of Studies Assessing Association Between Antiretroviral Regimens and Preterm Delivery..............................................................................................................................E-10Table 8.Clinical Scenarios and Recommendations Regarding Mode of Delivery to ReducePerinatal Transmission of HIV.................................................................................................................G-8Table 9. Recommended Neonatal Dosing for Prevention of Mother-to-Child Transmission of HIV...H-12Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States viDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States viiMembers of the Panel on Treatment of HIV-Infected Pregnant Womanand Prevention of Perinatal Transmission (Last updated July 31, 2012;last reviewed July 31, 2012)Revisions to the September 14, 2011, Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health andInterventions to Reduce Perinatal Transmission in the UnitedStates have been made by the Department of Health and Human Services (HHS) Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission (a Working Group of the Office of AIDSResearch Advisory Council).Members of the PanelErika Aaron, MSN, ANP, RNP Drexel University College of Medicine, Philadelphia, PAElaine J. Abrams, MD Columbia University, New York, NYJean Anderson, MD Johns Hopkins University School of Medicine, Baltimore, MDDawn Averitt Bridge, BIS The Well Project, Charlottesville, VARana Chakraborty, MD, MS, PhD Emory University School of Medicine, Atlanta, GASusan E. Cohn, MD, MPH Northwestern University Feinberg School of Medicine, Chicago, ILSusan Cu-Uvin, MD The Miriam Hospital, Brown University, Providence, RIJudith Feinberg, MD University of Cincinnati College of Medicine, Cincinnati, OHPatricia M. Flynn, MD St. Jude Children’s Research Hospital, Memphis, TNMary Glenn-Fowler, MD, MPH Johns Hopkins University School of Medicine, Baltimore, MDRobert Maupin, MD Louisiana State University Health Sciences Center, New Orleans, LAHoward Minkoff, MD Maimonides Medical Center, State University of New York Brooklyn, Brooklyn, NYMark Mirochnick, MD Boston Medical Center, Boston, MAFatima Y. Prioleau, MA Brooklyn, NYStephen A. Spector, MD University of California, San Diego, La Jolla, CA and Rady Childrens Hospital, San Diego, CAKathleen E. Squires, MD Thomas Jefferson University, Philadelphia, PAMeg Sullivan, MD Boston Medical Center, Boston, MARuth Tuomala, MD Brigham and Women’s Hospital, Harvard Medical School, Boston, MAGeoffrey A. Weinberg, MD University of Rochester School of Medicine and Dentistry, Rochester, NYPanel Executive SecretaryLynne Mofenson, MD National Institutes of Health, Rockville, MD Ex Officio MemberJess Waldura, MD National Perinatal HIV Hotline, San Francisco, CADownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States viiiMembers from the Department of Health and Human ServicesSonghai Barclift, MD Health Resources and Services Administration, Rockville, MDBrian Feit, MPA Health Resources and Services Administration, Rockville, MDEdward Handelsman, MD* National Institutes of Health, Rockville, MDDenise Jamieson, MD, MPH Centers for Disease Control and Prevention, Atlanta, GASteve Nesheim, MD Centers for Disease Control and Prevention, Atlanta, GAAlan Shapiro, MD, PhD Food and Drug Administration, Rockville, MDD. Heather Watts, MD National Institutes of Health, Rockville, MDNonvoting Observers from the Francois-Xavier Bagnound CenterCarolyn Burr, RN, EdD François-Xavier Bagnoud Center, School of Nursing, University of Medicine and Dentistry of New Jersey, Newark, NJDeborah Storm, MSN, PhD François-Xavier Bagnoud Center, School of Nursing, University of Medicine and Dentistry of New Jersey, Newark, NJ* Dr. Handelsman died suddenly on March 4, 2012. He is remembered as a leader in and advocate ofpediatric and perinatal HIV research. Panel members hope to honor Dr. Handelsman’s legacy by continuinghis work to save the lives of women and children worldwide.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States ixFinancial Disclosure List for Members of the HHS Panel on Treatmentof HIV-Infected Pregnant Women and Prevention of PerinatalTransmission (Last updated July 31, 2012; last reviewed July 31, 2012)NamePanelStatusCompany RelationshipAaron, Erika M None N/AAbrams, Elaine J. M None N/AAnderson, Jean M None N/AAveritt Bridge, Dawn M MerckBristol-Myers SquibbAdvisory BoardSpeakers’ BureauHonorariaConsultantAdvisory BoardHonorariaConsultantBarclift, Songhai HHS None N/AChakraborty, Rana M None N/ACohn, Susan E. M Tibotec Therapeutics Advisory BoardCu-Uvin, Susan M Global Microbicide Project Advisory BoardFeinberg, Judith M AbbottBristol-Myers SquibbBoehringer-IngelheimGlaxoSmithKline/ViiVRocheMerckJanssenPfizerTobiraSpeakers’ BureauResearch SupportSpeakers’ BureauResearch SupportAdvisory BoardResearch SupportSpeakers’ BureauResearch SupportAdvisory BoardSpeakers’ BureauAdvisory BoardResearch SupportSpeakers’ BureauResearch SupportResearch SupportFeit, Brian HHS None N/AFlynn, Patricia M. M Bristol-Myers SquibbJohnson and Johnson (formerly Tibotec)Merck Research SupportResearch SupportDSMB MemberGlenn-Fowler, Mary M None N/AJamieson, Denise HHS None N/AMaupin, Robert M None N/AMinkoff, Howard M None N/ADownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States xFinancial Disclosure List for Members of the HHS Panel on Treatmentof HIV-Infected Pregnant Women and Prevention of PerinatalTransmission (Last updated July 31, 2012; last reviewed July 31, 2012)NamePanelStatusCompany RelationshipMirochnick, Mark M Abbott Advisory BoardMofenson, Lynne ES None N/ANesheim, Steve HHS None N/APrioleau, Fatima Y. M None N/AShapiro, Alan HHS None N/ASpector, Stephen A. M Abbott Advisory BoardSquires, Kathleen E. M BioCrystGilead SciencesGlaxoSmithKlineMerckTibotec TherapeuticsTobiraViiVAbbottPfizerResearch SupportAdvisory BoardResearch SupportHonorariaResearch SupportConsultantAdvisory BoardResearch SupportConsultantAdvisory BoardResearch SupportAdvisory BoardConsultantAdvisory BoardAdvisory BoardDSMB MemberStorm, Deborah NVO MerckLillyRocheStock holderStock holderStock holder Sullivan, Meg M None N/ATuomala, Ruth M None N/AWaldura, Jess ExOM None N/AWatts, D. Heather HHS None N/AWeinberg, Geoffrey A. M MerckGlaxoSmithKlineSanofi Pasteur VaccinesSpeakers’ BureauSpeakers’ BureauSpeakers’ BureauDSMB = Data Safety Monitoring Board, ES = Executive Secretary, ExOM = Ex Officio Member, HHS = Member from HHS, M = Member, N/A = Not applicable, NVO = Nonvoting ObserverDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States A-1Introduction (Last updated July 31, 2012; last reviewed July 31, 2012)Recommendations regarding HIV screening and treatment of pregnant women and prophylaxis for perinataltransmission of HIV have evolved considerably in the United States over the last 25 years, reflecting changesin the epidemic and the science of prevention.1, 2With the implementation of recommendations for universalprenatal HIV counseling and testing, antiretroviral (ARV) prophylaxis, scheduled cesarean delivery, andavoidance of breastfeeding, the rate of perinatal transmission of HIV has dramatically diminished to less than2% in the United States and Europe.3-6These guidelines update the September 14, 2011, Recommendations for Use of Antiretroviral Drugs inPregnant HIV-1-Infected Women for Maternal Health andInterventions to Reduce Perinatal HIVTransmission in the United States. The Department of Health and Human Services Panel on Treatment ofHIV-Infected Pregnant Women and Prevention of Perinatal Transmission, a working group of the Office ofAIDS Research Advisory Council, develops these guidelines. The guidelines provide health care providerswith information for discussion with HIV-infected pregnant women to enable the patient/provider team tomake informed decisions regarding the use of ARV drugs during pregnancy and use of scheduled cesareandelivery to reduce perinatal transmission of HIV. The recommendations in the guidelines are accompanied bydiscussion of various circumstances that commonly occur in clinical practice and the factors influencingtreatment considerations. The Panel recognizes that strategies to prevent perinatal transmission and conceptsrelated to management of HIV disease in pregnant women are rapidly evolving and will consider newevidence and adjust recommendations accordingly. The updated guidelines are available from the AIDSinfowebsite (http://aidsinfo.nih.gov).Health care providers considering the use of ARV agents for HIV-infected women during pregnancy musttake into account two separate but related issues:1. ARV treatment of maternal HIV infection and2. ARV chemoprophylaxis to reduce the risk of perinatal transmission of HIV.The benefits of ARV drugs for a pregnant woman must be weighed against the risks of adverse events to thewoman, fetus, and newborn. Combination drug regimens are considered the standard of care both fortreatment of HIV infection and for prevention of perinatal transmission of HIV.2, 7After provider counselingand discussion on ARV drug use during pregnancy, a pregnant woman’s informed choice on whether to takeARV drugs for her treatment, for prevention of mother-to-child transmission, and/or to follow other medicalrecommendations intended to reduce perinatal transmission of HIV should be respected. Coercive andpunitive policies are potentially counterproductive; they may undermine provider-patient trust and coulddiscourage women from seeking prenatal care and adopting health care behaviors that optimize fetal andneonatal well-being.The current guidelines have been structured to reflect the management of an individual mother-child pair andare organized into a brief discussion of preconception care followed by principles for management of awoman and her infant during the antepartum, intrapartum, and postpartum periods. Although perinataltransmission of HIV occurs worldwide, these recommendations have been developed for use in the UnitedStates. Alternative strategies may be appropriate in other countries. Policies and practices in other countriesregarding the use of ARV drugs for reduction of perinatal transmission of HIV may differ from therecommendations in these guidelines and will depend on local considerations, including availability and costof ARV drugs, accessibility of facilities for safe intravenous infusions during labor, and localrecommendations regarding breastfeeding by HIV-infected women.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States A-2Topic CommentGoal of the guidelines Provide guidance to HIV care practitioners on the optimal use of antiretroviral (ARV) agents inpregnant women for treatment of HIV infection and for prevention of mother-to-child transmission(PMTCT) of HIV in the United States.Panel members The Panel is composed of approximately 30 voting members who have expertise in management ofpregnant HIV-infected women (such as training in either obstetrics/gynecology or women’s health)and interventions for PMTCT (such as specialized training in pediatric HIV infection) as well ascommunity representatives with knowledge of HIV infection in pregnant women and interventions forPMTCT. The U.S. government representatives, appointed by their agencies, include at least 1representative from each of the following Department of Health and Human Services agencies: theCenters for Disease Control and Prevention, the Food and Drug Administration (FDA), the HealthResources and Services Administration (HRSA), and the National Institutes of Health (NIH).Members who do not represent U.S. government agencies are selected by Panel members after anopen announcement to call for nominations. Each member serves on the Panel for a 3-year period,with an option for reappointment. A list of all Panel members can be found in the Panel Roster.Financial disclosures All members of the Panel submit a written financial disclosure annually reporting any associationwith manufacturers of ARV drugs or diagnostics used for management of HIV infections. A list ofthe latest disclosures is available on the AIDSinfowebsite (http://aidsinfo.nih.gov).Users of the guidelines Providers of care to HIV-infected pregnant women and to HIV-exposed infantsDeveloper Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission—a working group of OARACFunding source Office of AIDS Research, NIHEvidence forrecommendationsThe recommendations in these guidelines are generally based on studies published in peer-reviewed journals. On some occasions, particularly when new information may affect patient safety,unpublished data presented at major conferences or prepared by the FDA and/or manufacturers aswarnings to the public may be used as evidence to revise the guidelines.RecommendationgradingSee Table 2.Method of synthesizingdataEach section of the guidelines is assigned to a small group of Panel members with expertise in thearea of interest. A structured literature search is conducted by staff from the HIV/AIDS NationalResource Center at the Francois-Xavier Bagnoud Center (through funding from HRSA) and providedto the Panel working group. The members review and synthesize the available data and proposerecommendations to the entire Panel. The Panel discusses and votes on all proposals during monthlyteleconferences. Proposals receiving endorsement from a consensus of members are included in theguidelines as official Panel recommendations. Other guidelines These guidelines focus on HIV-infected pregnant women and their infants. Other guidelines outlinethe use of ARV agents in non-pregnant HIV-infected adults and adolescents, HIV-infected children,and people who experience occupational or nonoccupational exposure to HIV. The guidelinesdescribed are also available on the AIDSinfowebsite (http://aidsinfo.nih.gov). Preconceptionmanagement for non-pregnant women of reproductive age is briefly discussed in this document.However, for more detailed discussion on issues of treatment of non-pregnant adults, the WorkingGroup defers to the designated expertise offered by Panels that have developed those guidelines.Guidelines Development ProcessTable 1. Outline of the Guidelines Development ProcessDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States A-3Topic CommentUpdate plan The Panel meets monthly by teleconference to review data that may warrant modification of theguidelines. Updates may be prompted by new drug approvals (or new indications, new dosingformulations, or changes in dosing frequency), significant new safety or efficacy data, or otherinformation that may have a significant impact on the clinical care of patients. In the event ofsignificant new data that may affect patient safety, the Panel may issue a warning announcementand accompanying recommendations on the AIDSinfowebsite until the guidelines can be updatedwith appropriate changes. Updated guidelines are available at the AIDSinfowebsite(http://aidsinfo.nih.gov).Public comments A 2-week public comment period follows release of the updated guidelines on the AIDSinfowebsite.The Panel reviews comments received to determine whether additional revisions to the guidelinesare indicated. The public may also submit comments to the Panel at any time atcontactus@aidsinfo.nih.gov.Guidelines Development ProcessTable 1. Outline of the Guidelines Development Process, cont’dBasis for RecommendationsRecommendations in these guidelines are based on scientific evidence and expert opinion. Eachrecommended statement is rated with a letter of A, B, or Cthat represents the strength of therecommendation and with a numeral I, II, or III, according to the quality of evidence.Table 2. Rating Scheme for RecommendationsReferences1. Centers for Disease Control and Prevention. Achievements in public health. Reduction in perinatal transmission of HIVinfection—United States, 1985-2005. MMWR Morb Mortal Wkly Rep. Jun 2 2006;55(21):592-597. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16741495.2. Jamieson DJ, Clark J, Kourtis AP, et al. Recommendations for human immunodeficiency virus screening, prophylaxis,and treatment for pregnant women in the United States. Am J Obstet Gynecol. Sep 2007;197(3 Suppl):S26-32. Availableat http://www.ncbi.nlm.nih.gov/pubmed/17825647.3. Birkhead GS, Pulver WP, Warren BL, Hackel S, Rodriguez D, Smith L. Acquiring human immunodeficiency virusduring pregnancy and mother-to-child transmission in New York: 2002-2006. Obstet Gynecol. Jun 2010;115(6):1247-1255. Available at http://www.ncbi.nlm.nih.gov/pubmed/20502297.4. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. Apr 152002;29(5):484-494. Available at http://www.ncbi.nlm.nih.gov/pubmed/11981365.Strength of Recommendation Quality of Evidence for RecommendationA:Strong recommendation for the statementB:Moderate recommendation for the statementC:Optional recommendation for the statementI:One or more randomized trials with clinical outcomes and/or validatedlaboratory endpointsII:One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomesIII:Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.5. Townsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-childtransmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS.May 11 2008;22(8):973-981. Available at http://www.ncbi.nlm.nih.gov/pubmed/18453857.6. Birkhead GS, Pulver WP, Warren BL, et al. Progress in prevention of mother-to-child transmission of HIV in New YorkState: 1988-2008. J Public Health Manag Pract. Nov-Dec 2010;16(6):481-491. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20885177.7. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed June 15, 2012.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States A-4Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-1Lessons from Clinical Trials of Antiretroviral Interventions toReduce Perinatal Transmission of HIV (Last updated July 31, 2012; lastreviewed July 31, 2012)OverviewOne of the major achievements in HIV research was the demonstration by the Pediatric AIDS Clinical TrialsGroup 076 (PACTG 076) clinical trial that administration of zidovudine to pregnant women and their infantscould reduce risk of perinatal transmission by nearly 70%.1Following the results of PACTG 076, in theUnited States and in other resource-abundant countries, implementation of the zidovudine regimen coupledwith increased antenatal HIV counseling and testing rapidly resulted in significant declines in transmission.2-5Subsequent clinical trials and observational studies demonstrated that combination antiretroviral (ARV)prophylaxis (initially dual- and then triple-combination therapy) given to a mother antenatally was associatedwith further declines in transmission to less than 2%.2, 6, 7Current estimates indicate that fewer than 200 HIV-infected infants are now born each year in the United States.4, 8, 9Each individual birth of an infected infant is a sentinel event representing missed opportunities and barriersto prevention.10, 11Important obstacles to elimination of perinatal transmission in the United States includethe continued increase in HIV infection in women of childbearing age;12absent or delayed prenatal care,particularly in women using illicit drugs; acute (primary) infection in late pregnancy and in women who arebreastfeeding; poor adherence to prescribed ARV regimens in pregnant women; and lack of fullimplementation of routine, universal prenatal HIV counseling and testing.9, 11, 13Following the results of PACTG 076, researchers began to explore the development of shorter, lessexpensive prophylactic regimens more applicable to resource-constrained settings. Clinical trials initiallyfocused on shortened zidovudine-alone prophylaxis regimens and moved to evaluating whether combinationARV regimens, such as short-course zidovudine combined with lamivudine, might have improved efficacyover zidovudine alone. Studies also evaluated whether even simpler, less expensive, single-drug regimens,such as single-dose intrapartum/neonatal nevirapine, would be effective and whether combining suchregimens with other short-course regimens might result in improved efficacy. These studies have providedimportant insights into the mechanisms of action of ARV drugs in reducing perinatal transmission and indetermining optimal regimens for use in the United States and other resource-rich countries.References1. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virustype 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. Nov3 1994;331(18):1173-1180. Available at http://www.ncbi.nlm.nih.gov/pubmed/7935654.2. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. Apr 152002;29(5):484-494. Available at http://www.ncbi.nlm.nih.gov/pubmed/11981365.3. Wortley PM, Lindegren ML, Fleming PL. Successful implementation of perinatal HIV prevention guidelines. Amultistate surveillance evaluation. MMWR Recomm Rep. May 11 2001;50(RR-6):17-28. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15580801.4. Centers for Disease Control and Prevention. Achievements in public health. Reduction in perinatal transmission of HIVinfection--United States, 1985-2005. MMWR Morb Mortal Wkly Rep. Jun 2 2006;55(21):592-597. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16741495.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-25. European Collaborative Study. HIV-infected pregnant women and vertical transmission in Europe since 1986. Europeancollaborative study. AIDS. 2001;15(6):761-770. Available athttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11371691.6. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudine-zidovudine combination for prevention ofmaternal-infant transmission of HIV-1. JAMA. Apr 25 2001;285(16):2083-2093. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11311097.7. Dorenbaum A, Cunningham CK, Gelber RD, et al. Two-dose intrapartum/newborn nevirapine and standardantiretroviral therapy to reduce perinatal HIV transmission: a randomized trial. JAMA. Jul 10 2002;288(2):189-198.Available at http://www.ncbi.nlm.nih.gov/pubmed/12095383.8. McKenna MT, Hu X. Recent trends in the incidence and morbidity that are associated with perinatal humanimmunodeficiency virus infection in the United States. Am J Obstet Gynecol. Sep 2007;197(3 Suppl):S10-16. Availableat http://www.ncbi.nlm.nih.gov/pubmed/17825639.9. Rogers MF, Taylor AW, Nesheim SR. Preventing perinatal transmission of HIV: the national perspective. J PublicHealth Manag Pract. Nov-Dec 2010;16(6):505-508. Available at http://www.ncbi.nlm.nih.gov/pubmed/20885179.10. Peters V, Liu KL, Gill B, et al. Missed opportunities for perinatal HIV prevention among HIV-exposed infants born1996-2000, pediatric spectrum of HIV disease cohort. Pediatrics. Sep 2004;114(3):905-906. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15342884.11. Whitmore SK, Taylor AW, Espinoza L, Shouse RL, Lampe MA, Nesheim S. Correlates of mother-to-child transmissionof HIV in the United States and Puerto Rico. Pediatrics. Jan 2012;129(1):e74-81. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22144694.12. Whitmore SK, Zhang X, Taylor AW, Blair JM. Estimated number of infants born to HIV-infected women in the UnitedStates and five dependent areas, 2006. J Acquir Immune Defic Syndr. Jul 1 2011;57(3):218-222. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21372725.13. Whitmore SK, Patel-Larson A, Espinoza L, Ruffo NM, Rao S. Missed opportunities to prevent perinatal humanimmunodeficiency virus transmission in 15 jurisdictions in the United States during 2005-2008. Women Health. Jul2010;50(5):414-425. Available at http://www.ncbi.nlm.nih.gov/pubmed/20853217.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-3Mechanisms of Action of Antiretroviral Prophylaxis in Reducing Perinatal Transmissionof HIV (Last updated July 31, 2012; last reviewed July 31, 2012)Antiretroviral (ARV) drugs can reduce perinatal transmission through a number of mechanisms. Antenataldrug administration decreases maternal viral load in blood and genital secretions, which is a particularlyimportant mechanism of action in women with high viral loads. Even among women with HIV RNA levels1In addition, thelevel of HIV RNA at delivery and receipt of antenatal ARV drugs are independently associated with risk oftransmission, suggesting that reduction in viral load is not solely responsible for the efficacy of ARVprophylaxis.2, 3Another mechanism of protection is infant pre-exposure prophylaxis achieved by administering ARV drugsthat cross the placenta from mothers to infants and produce adequate systemic drug levels in the infants. Thismechanism of protection likely is particularly important during passage through the birth canal, a time wheninfants receive intensive exposure to maternal genital-tract virus. Infant post-exposure prophylaxis isachieved by administering drugs to infants after birth. This intervention provides protection from cell-free orcell-associated virus that may have entered the fetal/infant systemic circulation through maternal-fetaltransfusion associated with uterine contractions during labor or systemic dissemination of virus swallowedduring infant passage through the birth canal.The efficacy of ARV drugs in reducing perinatal transmission likely is multifactorial, and each of themechanisms previously described may make a contribution. The importance of the pre- and post-exposurecomponents of prophylaxis in reducing perinatal transmission is demonstrated by the efficacy ofinterventions that involve administration of ARVs only during labor and/or to the newborns, discussed in thenext section.4-10References1. Ioannidis JP, Abrams EJ, Ammann A, et al. Perinatal transmission of human immunodeficiency virus type 1 by pregnantwomen with RNA virus loads http://www.ncbi.nlm.nih.gov/pubmed/11170978.2. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. Apr 152002;29(5):484-494. Available at http://www.ncbi.nlm.nih.gov/pubmed/11981365.3. Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment, and the risk of transmission ofhuman immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 StudyGroup. N Engl J Med. Nov 28 1996;335(22):1621-1629. Available at http://www.ncbi.nlm.nih.gov/pubmed/8965861.Panel’s Recommendation• Antiretroviral (ARV) drugs reduce perinatal transmission by several mechanisms, including lowering maternal antepartumviral load and providing infant pre- and post-exposure prophylaxis. Therefore, combined antepartum, intrapartum, andinfant ARV prophylaxis is recommended to prevent perinatal transmission of HIV (AI).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.4. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine forprevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012randomised trial. Lancet. Sep 13 2003;362(9387):859-868. Available athttp://www.ncbi.nlm.nih.gov/pubmed/13678973.5. Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and latetransmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial. Lancet. Apr 6 2002;359(9313):1178-1186. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11955535.6. Moodley D, Moodley J, Coovadia H, et al. A multicenter randomized controlled trial of nevirapine versus a combinationof zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of humanimmunodeficiency virus type 1. J Infect Dis. Mar 1 2003;187(5):725-735. Available athttp://www.ncbi.nlm.nih.gov/pubmed/12599045.7. Taha TE, Kumwenda NI, Gibbons A, et al. Short postexposure prophylaxis in newborn babies to reduce mother-to-childtransmission of HIV-1: NVAZ randomised clinical trial. Lancet. Oct 11 2003;362(9391):1171-1177. Available athttp://www.ncbi.nlm.nih.gov/pubmed/14568737.8. Gaillard P, Fowler MG, Dabis F, et al. Use of antiretroviral drugs to prevent HIV-1 transmission through breast-feeding:from animal studies to randomized clinical trials. J Acquir Immune Defic Syndr. Feb 1 2004;35(2):178-187. Available athttp://www.ncbi.nlm.nih.gov/pubmed/14722452.9. Gray GE, Urban M, Chersich MF, et al. A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers. AIDS. Aug 12 2005;19(12):1289-1297. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16052084.10. Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIVinfection. N Engl J Med. Jun 21 2012;366(25):2368-2379. Available at http://www.ncbi.nlm.nih.gov/pubmed/22716975.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-4Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-5Lessons from International Clinical Trials of Short-Course Antiretroviral Regimens forPrevention of Perinatal Transmission of HIV (Last updated July 31, 2012; last reviewed July 31, 2012)A number of regimens have been identified that are effective in reducing perinatal transmission in resource-limited countries (see Table 3). In many cases, direct comparison of results from trials of these regimens isnot possible because the studies involved diverse patient populations residing in different geographiclocations, infected with diverse viral subtypes, and with different infant feeding practices. However, somegeneralizations are relevant to understanding use of antiretroviral (ARV) drugs for prevention of perinataltransmission in both resource-limited and resource-rich countries.Combination antenatal prophylaxis taken over a longer duration is more effective than a short-course single-drug regimen in reducing perinatal transmission.The use of ARV drugs to prevent transmission is highly effective, even in HIV-infected women withadvanced disease.1, 2Efficacy has been demonstrated for a number of short-course ARV regimens, includingthose with zidovudine alone; zidovudine plus lamivudine; single-dose nevirapine; and single-dose nevirapinecombined with either short-course zidovudine or zidovudine/lamivudine.3-12In general, combinationregimens are more effective than single-drug regimens in reducing perinatal transmission. In addition, forprevention of perinatal transmission, administration of ARV drugs during the antepartum, intrapartum, andpostpartum periods is superior to administration of ARV drugs only during the antepartum and intrapartumperiods or intrapartum and postpartum periods.4, 13, 14Almost all trials in resource-limited countries have included oral intrapartum prophylaxis, with varyingdurations of maternal antenatal and/or infant (and sometimes maternal) postpartum prophylaxis. Perinataltransmission is reduced by regimens with antenatal components starting as late as 36 weeks’ gestation andlacking an infant prophylaxis component.9-11However, longer duration antenatal ARV prophylaxis (startingat 28 weeks’ gestation) is more effective than shorter duration ARV prophylaxis (starting at 36 weeks’gestation), suggesting that a significant proportion of in uterotransmission occurs between 28 and 36 weeks’gestation.12Analyses from the European National Study of HIV in Pregnancy and Childhood have shownthat efficacy is increased with even longer duration antenatal ARV prophylaxis (starting before 28 weeks’gestation), with each additional week of a triple-drug regimen corresponding to a 10% reduction in risk oftransmission after adjustment for viral load, mode of delivery, and sex of the infant.15More prolonged infantpost-exposure prophylaxis does not appear to substitute for longer duration maternal ARV prophylaxis.12No trials have directly compared the efficacy of zidovudine plus single-dose nevirapine with a triple-drugARV regimen for prevention of in uterotransmission in women with higher CD4 T-lymphocyte (CD4-cell)counts. In African women with CD4-cell counts ranging from 200 to 500 cells/mm3, the Kesho Bora trialcompared a triple-ARV drug prophylaxis regimen with zidovudine plus single-dose nevirapine prophylaxis,both started at 28 weeks’ gestation or later. The women in the triple-drug arm continued the drugs untilbreastfeeding ceased, but those in the zidovudine/single-dose nevirapine arm did not receive postnatalprophylaxis. Although the rate of postnatal transmission was significantly lower in the triple-drug arm than inthe zidovudine/single-dose nevirapine arm without postnatal prophylaxis, the rates of transmission at birthwere similar in women randomized to a triple-drug regimen (1.8%) and women randomized to antepartumzidovudine/single-dose nevirapine (2.5%); for women with CD4-cell counts from 350 to 500 cells/mm3, therate of infection at birth was 1.7% in each arm.16However, the study was not powered to address equivalencebetween regimens in preventing in uteroinfection in women with higher CD4-cell counts and the drugs inboth arms were administered antepartum for only 6 weeks.Regimens that do not include maternal ARV prophylaxis during pregnancy have been evaluated becausesome women may lack antenatal care and present for prenatal care for the first time when they go into labor.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Regimens that include only intrapartum and postpartum drug administration also have been shown to beeffective in reducing perinatal transmission.3-5However, without continued infant post-exposure prophylaxis,intrapartum pre-exposure prophylaxis alone with nucleoside reverse transcriptase inhibitor drugs(zidovudine/lamivudine) is not effective in reducing transmission.4The SAINT trial demonstrated thatintrapartum/postpartum zidovudine/lamivudine and single-dose intrapartum/newborn nevirapine are similarin efficacy and safety.5Combination infant ARV prophylaxis is recommended in the United States for infants whose mothers havenot received antenatal ARV drugs.In some situations, it may be impossible to administer maternal antepartum and intrapartum therapy and onlyinfant prophylaxis may be an option. In the absence of maternal therapy, the standard infant prophylaxisregimen of 6 weeks of zidovudine was effective in reducing HIV transmission compared with noprophylaxis, based on epidemiologic data in resource-rich countries.17A trial in Malawi in breastfeedinginfants demonstrated that adding 1 week of zidovudine therapy to infant single-dose nevirapine reduced riskof transmission by 36% compared with infant single-dose nevirapine alone.6To define the optimal infant prophylaxis regimen in the absence of maternal antepartum ARV drugadministration in a formula-fed population of infants such as in the United States, the NICHD-HPTN040/P1043 (NCT00099359) multicountry (Argentina, Brazil, South Africa, and the United States) clinicaltrial enrolled 1,735 formula-fed infants born to HIV-infected mothers who did not receive ARV drugs duringthe current pregnancy before labor (if women presented early enough, intravenous intrapartum zidovudinewas given).18The study compared 3 infant ARV regimens: standard 6 weeks of zidovudine alone versus 6weeks of zidovudine plus 3 doses of nevirapine given in the first week of life (first dose birth to 48 hours;second dose 48 hours after first dose; third dose 96 hours after second dose) versus 6 weeks of zidovudineplus lamivudine and nelfinavir given from birth through age 2 weeks. The study demonstrated that thecombination regimens reduced risk of intrapartum transmission by approximately 50% compared with infantprophylaxis with zidovudine alone (see Table 3). Based on these data, combination ARV prophylaxis is nowrecommended in the United States for infants whose mothers have not received antenatal ARV drugs (seeInfant Antiretroviral Prophylaxis).Adding single-dose intrapartum nevirapine is not recommended for women in the United States who arereceiving standard recommended antenatal ARV prophylaxis.Several studies in formula-fed and breastfed populations in resource-limited countries have found that addingmaternal/infant single-dose nevirapine to a maternal short-course zidovudine or zidovudine/lamivudineregimen increased efficacy compared with the short-course regimen alone.14, 19, 20Whether single-dosenevirapine provides any additional efficacy when combined with the standard recommended combinationARV prophylaxis regimens used in the United States was evaluated in PACTG 316, a clinical trial conductedin the United States, Europe, Brazil, and the Bahamas. This study demonstrated that for nonbreastfeedingwomen in resource-rich countries, the addition of single-dose nevirapine did not offer significant benefit inthe setting of combination ARV prophylaxis throughout pregnancy and very low viral load at the time ofdelivery.21Thus, adding single-dose intrapartum nevirapine is not recommended for women in the UnitedStates who are receiving standard recommended antenatal ARV prophylaxis (see Intrapartum Care).Breastfeeding by HIV-infected women is not recommended in the United States.Breastfeeding by HIV-infected women (including those receiving ARV drugs) is not recommended in theUnited States where replacement feeding is affordable, feasible, acceptable, sustainable, and safe and the riskof infant mortality due to diarrheal and respiratory infections is low. A number of studies have evaluated theuse of maternal or infant ARV prophylaxis during breastfeeding to reduce postnatal transmission (see Table3). Observational data and randomized clinical trials have demonstrated that infant prophylaxis (primarilyRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-6Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.using daily infant nevirapine) during breastfeeding significantly decreases risk of postnatal transmission inbreast milk and that maternal triple-drug prophylaxis during breastfeeding likewise decreases postnatalinfection.1, 16, 22-27Maternal prophylaxis with triple-drug regimens may be less effective than infantprophylaxis when the maternal triple regimen is first started postpartum or late in pregnancy because it takesseveral weeks to months before full viral suppression in breast milk is achieved.26, 28Importantly, althoughsignificantly lowering the risk of postnatal infection, neither infant nor maternal postpartum ARVprophylaxis completely eliminates the risk of HIV transmission through breast milk. Therefore, breastfeedingis not recommended for HIV-infected women in the United States (including those receiving combinationARV drug regimens). Finally, both infant nevirapine prophylaxis and maternal triple-drug prophylaxis duringbreastfeeding may be associated with development of ARV drug resistance in infants who become infecteddespite prophylaxis.29-32Three studies have found multiclass drug resistance in breastfeeding infants whobecame infected despite maternal triple-drug prophylaxis.30-33Table 3. Results of Major Studies on Antiretroviral Prophylaxis to Prevent Mother-to-ChildTransmission of HIV (page 1 of 9)Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-7Study Location(s)Mode of Infant FeedingAntiretroviral(ARV) DrugsAntepartum andIntrapartumPostpartumMother-to-ChildTransmission (MTCT) Rateand EfficacyPACTG 076United States, France34Formula feedingZDV vs. placebo Long (from 14 weeks)IV IPLong (6 weeks),infant only• MTCT at 18 months was8.3% in ZDV arm vs. 25.5%in placebo arm (68%efficacy).CDC short-course ZDV trialThailand11Formula feeding ZDV vs. placebo Short (from 36 weeks)Oral IP None • MTCT at 6 months was 9.4%in ZDV arm vs. 18.9% inplacebo arm (50% efficacy).DITRAME (ANRS 049a) trialIvory Coast, Burkina Faso10, 35BreastfeedingZDV vs. placebo Short (from 36 weeks)Oral IPShort (1 week),mother only• MTCT was 18.0% in ZDV armvs. 27.5% in placebo arm at 6months (38% efficacy) and21.5% vs. 30.6% at 15months (30% efficacy).• MTCT was 22.5% in ZDV armvs. 30.2% in placebo arm inpooled analysis at 24 months(26% efficacy).CDC short-course ZDV trialIvory Coast9, 10BreastfeedingZDV vs. placebo Short (from 36 weeks)Oral IPNone • MTCT was 16.5% in ZDV armvs. 26.1% in placebo arm at 3months (37% efficacy).• MTCT was 22.5% in ZDV armvs. 30.2% in placebo arm inpooled analysis at 24 months(26% efficacy).Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-8Study Location(s)Mode of Infant FeedingAntiretroviral(ARV) DrugsAntepartum andIntrapartumPostpartumMother-to-ChildTransmission (MTCT) Rateand EfficacyPETRA trialSouth Africa, Tanzania, andUganda4Breastfeeding and formulafeedingAP/IP/PP ZDV +3TC vs. IP/PPZDV + 3TC vs. IP-only ZDV + 3TCvs. placeboShort (from 36 weeks)Oral IPShort (1 week),mother andinfant• MTCT was 5.7% at 6 weeksfor AP/IP/PP ZDV + 3TC,8.9% for IP/PP ZDV + 3TC,14.2% for IP-only ZDV + 3TC,and 15.3% for placebo(efficacy compared withplacebo: 63%, 42%, and 0%,respectively).• MTCT was 14.9% at 18months for AP/IP/PP ZDV +3TC, 18.1% for IP/PP ZDV +3TC, 20.0% for IP-only ZDV +3TC, and 22.2% for placebo(efficacy compared withplacebo: 34%, 18%, and 0%,respectively).HIVNET 012 trial Uganda3BreastfeedingsdNVP vs. ZDV No AP ARVOral IP: sdNVP vs. oralZDVsdNVP within72 hours ofbirth, infantonly vs. ZDV (1week), infantonly• MTCT was 11.8% in NVP armvs. 20.0% in ZDV arm at 6–8weeks (42% efficacy); 15.7%in NVP arm vs. 25.8% in ZDVarm at 18 months (41%efficacy).SAINT trialSouth Africa5Breastfeeding and formulafeedingsdNVP vs. ZDV +3TCNo AP ARVOral IP: sdNVP vs. ZDV + 3TCsdNVP within48 hours ofbirth, motherand infant vs.ZDV + 3TC (1week), motherand infant• MTCT was 12.3% in sdNVParm vs. 9.3% in ZDV + 3TCarm at 8 weeks (differencenot statistically significant, P = 0.11).Perinatal HIV PreventionTrial (PHPT-1)Thailand12Formula feedingFour ZDVregimens withdifferentdurations of APand infant PPadministration, noplaceboLong (from 28 weeks),short (from 36 weeks)Oral IPLong (6 weeks),short (3 days),infant only• Short-short arm stopped atinterim analysis (10.5%).MTCT was 6.5% in long-longarm vs. 4.7% in long-shortarm and 8.6% in short-longarm at 6 months (nostatistical difference). In uterotransmission wassignificantly higher with shortvs. long maternal therapyregimens (5.1% vs. 1.6%).Table 3. Results of Major Studies on Antiretroviral Prophylaxis to Prevent Mother-to-ChildTransmission of HIV (page 2 of 9)Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-9Study Location(s)Mode of Infant FeedingAntiretroviral(ARV) DrugsAntepartum andIntrapartumPostpartumMother-to-ChildTransmission (MTCT) Rateand EfficacyPACTG 316 trial Bahamas,Belgium, Brazil, France,Germany, Italy, Spain,Sweden, Switzerland,United Kingdom, UnitedStates21Formula feedingsdNVP vs. placeboamong womenalready receivingZDV alone (23%)or ZDV + otherARV drugs (77%combinationtherapy)Nonstudy ARVregimenOral IP: placebo vs.sdNVP + IV ZDVPlacebo vs.sdNVP within72 hours ofbirth +nonstudy ARVdrugs (ZDV),infant only• 77% of women received dual-or triple-combination ARVregimens during pregnancy.• Trial stopped early because ofvery low MTCT in both arms:1.4% in sdNVP arm vs. 1.6%in placebo arm (53% of MTCTwas in utero).Perinatal HIV PreventionTrial (PHPT-2)Thailand19Formula feedingZDV alone vs. ZDV+ maternal andinfant sdNVP vs.ZDV + maternalsdNVPZDV from 28 weeksOral IP: ZDV alone orZDV + sdNVPZDV for 1 weekwith or withoutsdNVP, infantonly• ZDV-alone arm was stoppedbecause of higher MTCT thanthe NVP-NVP arm (6.3% vs.1.1%). In arms in which themother received sdNVP, MTCTrate did not differ significantlybetween the infant receiving ornot receiving sdNVP (2.0% vs.2.8%).DITRAME Plus (ANRS1201.0) trialIvory Coast14Breastfeeding and formulafeedingOpen label, ZDV +sdNVPZDV from 36 weeksOral IP: ZDV plussdNVPsdNVP + ZDVfor 1 week,infant only• MTCT was 6.5% (95% CI,3.9%–9.1%) at 6 weeks;MTCT for historical controlgroup receiving short ZDV(98% breastfed) was 12.8%. DITRAME Plus (ANRS1201.1) trialIvory Coast14Breastfeeding and formulafeedingOpen label, ZDV +3TC + sdNVPZDV + 3TC from 32weeks (stopped at 3days PP)Oral IP: ZDV + 3TC +sdNVPsdNVP + ZDVfor 1 week,infant only• MTCT was 4.7% (95% CI,2.4%–7.0%) at 6 weeks;MTCT for historical controlgroup receiving short ZDV(98% breastfed) was 12.8%.NVAZ trialMalawi6BreastfeedingNeonatal sdNVPvs. sdNVP + ZDVNo AP or IP ARV(latecomers)sdNVP with orwithout ZDV for1 week, infantonly • MTCT was 15.3% in sdNVP +ZDV arm and 20.9% insdNVP-only arm at 6–8 weeks.MTCT rate at 6–8 weeksamong infants who were HIVuninfected at birth was 7.7%and 12.1%, respectively (36%efficacy).Postnatal NVP + ZDV trialMalawi7BreastfeedingNeonatal sdNVPvs. sdNVP + ZDV No AP ARVOral IP: sdNVPsdNVP with orwithout ZDV for1 week, infantonly• MTCT was 16.3% in NVP +ZDV arm and 14.1% in sdNVP-only arm at 6–8 weeks(difference not statisticallysignificant). MTCT rate at 6–8weeks among infants who wereHIV uninfected at birth was6.5% and 16.9%, respectively.Table 3. Results of Major Studies on Antiretroviral Prophylaxis to Prevent Mother-to-ChildTransmission of HIV (page 3 of 9)Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-10Study Location(s)Mode of Infant FeedingAntiretroviral(ARV) DrugsAntepartum andIntrapartumPostpartumMother-to-ChildTransmission (MTCT) Rateand EfficacyPost-exposure InfantProphylaxisSouth Africa8Breastfeeding and formulafeedingNeonatal sdNVP vs.ZDV for 6 weeksNo AP or IP ARV sdNVP vs. ZDVfor 6 weeks• For formula-fed infants only,MTCT was 14.3% in sdNVParm vs. 14.1% in ZDV arm at 6weeks (not significant, P =0.30). For breastfed infantsonly, MTCT was 12.2% insdNVP arm and 19.6% in ZDVarm (P = 0.03).MashiBotswana20, 36Breastfeeding and formulafeedingInitial: short-courseZDV with/withoutmaternal and infantsdNVP andwith/withoutbreastfeedingRevised: short-course ZDV + infantsdNVP with/withoutmaternal sdNVP andwith/withoutbreastfeeding;women with CD4 T-lymphocyte(CD4-cell) counts3receive combinationtherapy1st randomizationZDV from 34weeksOral IP: ZDV +either sdNVP vs.placebo2ndrandomizationBreastfeeding +ZDV (infant) 6months +sdNVP, infantonlyvs.Formula feeding+ ZDV (infant) 4weeks + sdNVP,infant only• Initial design: In formula-feeding arm, MTCT at 1 monthwas 2.4% in maternal andinfant sdNVP arm and 8.3% inplacebo arm (P = 0.05). Inbreastfeeding + infant ZDVarm, MTCT at 1 month was8.4% in sdNVP arm and 4.1%in placebo arm (difference notstatistically significant).• Revised design: MTCT at 1month was 4.3% in maternal +infant sdNVP arm and 3.7% inmaternal placebo + infantsdNVP arm (no significantdifference; no interaction withmode of infant feeding).• MTCT at 7 months was 9.1% inbreastfeeding + ZDV arm and5.6% in formula-feeding arm;mortality at 7 months was 4.9%in breastfeeding + ZDV arm vs.9.3% in formula-feeding arm;HIV-free survival at 18 monthswas 15.6% breastfeeding +ZDV arm vs. 14.2% formula-feeding arm.Table 3. Results of Major Studies on Antiretroviral Prophylaxis to Prevent Mother-to-ChildTransmission of HIV (page 4 of 9)Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-11Study Location(s)Mode of Infant FeedingAntiretroviral(ARV) DrugsAntepartum andIntrapartumPostpartumMother-to-ChildTransmission (MTCT) Rateand EfficacySWENUganda, Ethiopia, India23BreastfeedingsdNVP vs. NVP for 6weeksNo AP ARVOral IP: sdNVPInfant sdNVPvs. NVP for 6weeks• Postnatal infection in infantsuninfected at birth:- MTCT at 6 weeks was 5.3%in sdNVP arm vs. 2.5% inextended NVP arm (riskratio 0.54, P = 0.009).- MTCT at 6 months was9.0% in sdNVP arm vs.6.9% in extended NVP arm(risk ratio 0.80, P = 0.16).• HIV-free survival wassignificantly lower in extendedNVP arm at both 6 weeks and6 months of age.PEPI-Malawi Trial Malawi22BreastfeedingsdNVP + ZDV for 1week (control) vs.two extended infantregimens (NVP orNVP/ZDV) for 14weeksNo AP ARVOral IP: sdNVP (ifmother presents intime)Infant sdNVP +ZDV for 1 week(control) vs.control + NVPfor 14 weeksvs. control +NVP/ZDV for 14weeks• Postnatal infection in infantsuninfected at birth:- MTCT at age 6 weeks was5.1% in control vs. 1.7% inextended NVP (67%efficacy) and 1.6% inextended NVP/ZDV arms(69% efficacy).- MTCT at age 9 months was10.6% in control vs. 5.2% inextended NVP (51%efficacy) and 6.4% inextended NVP/ZDV arms(40% efficacy).• No significant difference inMTCT between the extendedprophylaxis arms; however,more hematologic toxicity withNVP/ZDV.MITRATanzania25BreastfeedingInfant 3TC for 6months(observational)ZDV/3TC from 36weeks throughlaborMaternalZDV/3TC for 1week; infant3TC for 6months• MTCT at age 6 months was4.9% (postnatal MTCTbetween ages 6 weeks and 6months was 1.2%).Table 3. Results of Major Studies on Antiretroviral Prophylaxis to Prevent Mother-to-ChildTransmission of HIV (page 5 of 9)Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-12Study Location(s)Mode of Infant FeedingAntiretroviral(ARV) DrugsAntepartum andIntrapartumPostpartumMother-to-ChildTransmission (MTCT) Rateand EfficacyKisumu BreastfeedingStudy (KiBS)Kenya27Breastfeeding Maternal triple-drugprophylaxis(observational) ZDV/3TC/NVP(NFV if CD4-cellcount >250cells/mm3) from34 weeks throughlaborMaternalZDV/3TC/NVP(NFV if CD4-cellcount >250cells/mm3) for6 months;infant sdNVP• MTCT at age 6 months was5.0% (postnatal MTCTbetween ages 7 days and 6months was 2.6%).MITRA-PLUSTanzania24BreastfeedingMaternal triple-drugprophylaxis(observational)ZDV/3TC/NVP(NFV if CD4-cellcount >200cells/mm3) from34 weeks throughlaborMaternalZDV/3TC/NVP(NFV if CD4-cellcount >200cells/mm3) for6 months;infant ZDV/3TCfor 1 week• MTCT at age 6 months was5.0% (postnatal MTCTbetween ages 6 weeks and 6months was 0.9%), notsignificantly different from 6months infant prophylaxis inMITRA.Kesho BoraMulti-African16Breastfeeding primarilyAntepartumZDV/sdNVP with nopostnatal prophylaxisvs. maternal triple-drug prophylaxis inwomen with CD4-cellcounts of 200–500cells/mm3Arm 1:ZDV/3TC/LPV/rArm 2:ZDV + sdNVPFrom 28 weeksthrough laborArm 1: MaternalZDV/3TC/LPV/rfor 6 months;infant sdNVP +ZDV for 1 weekArm 2: MaternalZDV/3TC for 1week (nofurtherpostnatalprophylaxis);infant sdNVP +ZDV for 1 week(no furtherpostnatalprophylaxis)• MTCT at birth was 1.8% withmaternal triple-drugprophylaxis Arm 1 and 2.5%with ZDV/sdNVP Arm 2, notsignificantly different. Inwomen with CD4-cell counts350–500 cells/mm3, MTCT atbirth was 1.7% in both arms.• MTCT at age 12 months was5.4% with maternal triple-drugprophylaxis Arm 1 and 9.5%with ZDV/sdNVP (with nofurther postnatal prophylaxisafter 1 week) Arm 2 (P =0.029).Mma BanaBotswana1BreastfeedingMaternal triple-drugprophylaxis(compares 2regimens) in womenwith CD4-cell counts>200 cells/mm3Arm 1:ZDV/3TC/ABCArm 2:ZDV/3TC/LPV/rFrom 26 weeksthrough laborArm 1: MaternalZDV/3TC/ABCfor 6 months;infant sdNVP +ZDV for 4weeksArm 2: MaternalZDV/3TC/LPV/rfor 6 months;infant sdNVP +ZDV for 4weeks• MTCT at age 6 months overallwas 1.3%: 2.1% inZDV/3TC/ABC Arm 1 and 0.4%in ZDV/3TC/LPV/r Arm 2 (P =0.53).Table 3. Results of Major Studies on Antiretroviral Prophylaxis to Prevent Mother-to-ChildTransmission of HIV (page 6 of 9)Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-13Study Location(s)Mode of Infant FeedingAntiretroviral(ARV) DrugsAntepartum andIntrapartumPostpartumMother-to-ChildTransmission (MTCT) Rateand EfficacyBANMalawi26, 37BreastfeedingPostpartummaternal triple-drug prophylaxisvs. infant NVP inwomen with CD4-cell counts ≥250cells/mm3No AP drugsIP regimens:Arm 1 (control):ZDV/3TC + sdNVPArm 2: ZDV/3TC +sdNVPArm 3: ZDV/3TC +sdNVPArm 1 (control):Maternal ZDV/3TCfor 1 week; infantsdNVP + ZDV/3TCfor 1 weekArm 2: Control asabove, thenmaternalZDV/3TC/LPV/rfor 6 monthsArm 3: Control asabove, then infantNVP for 6 months• Postnatal infection in infantsuninfected at age 2 weeks:- MTCT at age 28 weeks was5.7% in control Arm 1; 2.9%in maternal triple-drugprophylaxis Arm 2 (P = 0.009vs. control); 1.7% in infantNVP Arm 3 (P control).- MTCT at age 48 weeks was7.0% in control Arm 1; 4% inmaternal triple-drugprophylaxis Arm 2 (P = 0.0273vs. control); 4% in infant NVPArm 3 (P = 0.0027 vs.control).• No significant differencebetween maternal triple-drugprophylaxis Arm 2 and infantNVP Arm 3 (P = 0.12 at 28weeks and P = 0.426 at 48weeks).Table 3. Results of Major Studies on Antiretroviral Prophylaxis to Prevent Mother-to-ChildTransmission of HIV (page 7 of 9)Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-14Study Location(s)Mode of Infant FeedingAntiretroviral(ARV) DrugsAntepartum andIntrapartumPostpartumMother-to-ChildTransmission (MTCT) Rateand EfficacyHPTN 046South Africa, Tanzania,Uganda, Zimbabwe33BreastfeedingPostpartumprophylaxis ofbreast milktransmission ofHIV with 6 weeksvs. 6 months ofinfant NVPAP drugs allowedif required formaternal healthAll infantsreceived dailyNVP from birththrough age 6weeks.Arm 1: Dailyinfant NVP from 6weeks through 6months of ageArm 2: Dailyinfant placebofrom 6 weeksthrough age 6months of age• In infants uninfected at age 6weeks, the 6-month infant HIVinfection rate was 1.1% (0.3%–1.8%) in the extended NVP Arm1 and 2.4% (1.3%–3.6%) in theplacebo Arm 2 (P = 0.048).• At infant randomization at age 6weeks, 29% of mothers in eacharm were receiving a triple-drugARV regimen for treatment ofHIV.• For mothers receiving triple-drug ARV regimens at the timeof randomization, in infantsuninfected at age 6 weeks, the6-month infant HIV infectionrate was 0.2% and notstatistically different betweenextended NVP Arm 1 (0.5%)and placebo Arm 2 (0%).• For mothers with CD4-cellcounts >350 cells/mm3whowere not receiving triple-drugARV regimens, in infantsuninfected at age 6 weeks, the6-month infant HIV infectionrate was 0.7% (0%–1.5%) inthe extended NVP Arm 1 and2.8% (1.3%–4.4%) in theplacebo Arm 2 (P = 0.014).Table 3. Results of Major Studies on Antiretroviral Prophylaxis to Prevent Mother-to-ChildTransmission of HIV (page 8 of 9)Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-15Study Location(s)Mode of Infant FeedingAntiretroviral(ARV) DrugsAntepartum andIntrapartumPostpartumMother-to-ChildTransmission (MTCT) Rateand EfficacyNICHD-HPTN 040/PACTG1043 trial Argentina, Brazil, SouthAfrica, United States18Formula feedingInfant prophylaxiswith 6 weeks ZDVvs. 6 weeks infantZDV plus threedoses of NVP infirst week of life vs.6 weeks infant ZDVplus 2 weeks of3TC/NFVNo AP drugsIf motherpresented earlyenough, IV ZDVduring laborthrough deliveryArm 1 (control):Infant ZDV for 6weeksArm 2: Control asabove plus NVPwith first dosewithin 48 hours ofbirth, seconddose 48 hourslater, and thirddose 96 hoursafter the seconddoseArm 3: Control asabove, plus 3TCand NFV frombirth through 2weeks of age• IP HIV transmission amonginfants with negative HIV test atbirth: 4.8% (3.2%–7.1%) ZDV(Arm 1) vs. 2.2% (1.2%–3.9%)in ZDV plus NVP (Arm 2) (P =0.046 compared with Arm 1)vs. 2.4% (1.4%–4.3%) in ZDVplus 3TC/NFV (Arm 3) (P =0.046 compared with Arm 1).• Overall HIV transmission rates,including in utero infection:11.0% (8.7%–14.0%) ZDV(Arm 1) vs. 7.1% (5.2%–9.6%)in ZDV plus NVP (Arm 2) (P =0.035 compared with Arm 1)vs. 7.4% (5.4%–9.9%) in ZDVplus 3TC/NFV (Arm 3) (P =0.035 compared with Arm 1).• Grade 3 or 4 neutropenia morefrequent in ZDV/3TC/NFV Arm3, 70 infants, compared withZDV alone Arm 1, 33 infants, orZDV/NVP Arm 2, 32 infants (PTable 3. 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Available at http://www.ncbi.nlm.nih.gov/pubmed/27716975.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-16Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.19. Lallemant M, Jourdain G, Le Coeur S, et al. Single-dose perinatal nevirapine plus standard zidovudine to preventmother-to-child transmission of HIV-1 in Thailand. N Engl J Med. Jul 15 2004;351(3):217-228. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15247338.20. Shapiro RL, Thior I, Gilbert PB, et al. Maternal single-dose nevirapine versus placebo as part of an antiretroviralstrategy to prevent mother-to-child HIV transmission in Botswana. AIDS. Jun 12 2006;20(9):1281-1288. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16816557.21. Dorenbaum A, Cunningham CK, Gelber RD, et al. Two-dose intrapartum/newborn nevirapine and standardantiretroviral therapy to reduce perinatal HIV transmission: a randomized trial. JAMA. Jul 10 2002;288(2):189-198.Available at http://www.ncbi.nlm.nih.gov/pubmed/12095383.22. Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1transmission. N Engl J Med. Jul 10 2008;359(2):119-129. Available at http://www.ncbi.nlm.nih.gov/pubmed/18525035.23. Six Week Extended-Dose Nevirapine Study Team, Bedri A, Gudetta B, et al. Extended-dose nevirapine to 6 weeks ofage for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of threerandomised controlled trials. Lancet. Jul 26 2008;372(9635):300-313. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18657709.24. Kilewo C, Karlsson K, Ngarina M, et al. Prevention of mother-to-child transmission of HIV-1 through breastfeeding bytreating mothers with triple antiretroviral therapy in Dar es Salaam, Tanzania: the Mitra Plus study. J Acquir ImmuneDefic Syndr. Nov 1 2009;52(3):406-416. Available at http://www.ncbi.nlm.nih.gov/pubmed/19730269.25. Kilewo C, Karlsson K, Massawe A, et al. Prevention of mother-to-child transmission of HIV-1 through breast-feedingby treating infants prophylactically with lamivudine in Dar es Salaam, Tanzania: the Mitra Study. J Acquir ImmuneDefic Syndr. Jul 1 2008;48(3):315-323. Available at http://www.ncbi.nlm.nih.gov/pubmed/18344879.26. Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. NEngl J Med. Jun 17 2010;362(24):2271-2281. Available at http://www.ncbi.nlm.nih.gov/pubmed/20554982.27. Thomas TK, Masaba R, Borkowf CB, et al. Triple-antiretroviral prophylaxis to prevent mother-to-child HIVtransmission through breastfeeding—the Kisumu Breastfeeding Study, Kenya: a clinical trial. PLoS Med. Mar2011;8(3):e1001015. Available at http://www.ncbi.nlm.nih.gov/pubmed/21468300.28. Mofenson LM. Protecting the next generation—eliminating perinatal HIV-1 infection. N Engl J Med. Jun 172010;362(24):2316-2318. Available at http://www.ncbi.nlm.nih.gov/pubmed/20554987.29. Moorthy A, Gupta A, Bhosale R, et al. Nevirapine resistance and breast-milk HIV transmission: effects of single andextended-dose nevirapine prophylaxis in subtype C HIV-infected infants. PLoS One. 2009;4(1):e4096. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19119321.30. Lidstrom J, Guay L, Musoke P, et al. Multi-class drug resistance arises frequently in HIV-infected breastfeeding infantswhose mothers initiate HAART postpartum. Paper presented at: 17th Conference on Retroviruses and OpportunisticInfections (CROI); February 16-19, 2010; San Francisco, CA. Abstract 920.31. Zeh C, Weidle PJ, Nafisa L, et al. HIV-1 drug resistance emergence among breastfeeding infants born to HIV-infectedmothers during a single-arm trial of triple-antiretroviral prophylaxis for prevention of mother-to-child transmission: asecondary analysis. PLoS Med. Mar 2011;8(3):e1000430. Available at http://www.ncbi.nlm.nih.gov/pubmed/21468304.32. Fogel J, Li Q, Taha TE, et al. Initiation of antiretroviral treatment in women after delivery can induce multiclass drugresistance in breastfeeding HIV-infected infants. Clin Infect Dis. Apr 15 2011;52(8):1069-1076. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21460326.33. Coovadia HM, Brown ER, Fowler MG, et al. Efficacy and safety of an extended nevirapine regimen in infant childrenof breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): arandomised, double-blind, placebo-controlled trial. Lancet. Jan 21 2012;379(9812):221-228. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22196945.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-17Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.34. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virustype 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. Nov3 1994;331(18):1173-1180. Available at http://www.ncbi.nlm.nih.gov/pubmed/7935654.35. Dabis F, Msellati P, Meda N, et al. 6-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudineto reduce vertical transmission of HIV in breastfed children in Cote dIvoire and Burkina Faso: a double-blind placebo-controlled multicentre trial. DITRAME Study Group. DIminution de la Transmission Mere-Enfant. Lancet. Mar 61999;353(9155):786-792. Available at http://www.ncbi.nlm.nih.gov/pubmed/10459959.36. Thior I, Lockman S, Smeaton LM, et al. Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formulafeeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomizedtrial: the Mashi Study. JAMA. Aug 16 2006;296(7):794-805. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16905785.37. Jamieson DJ, Chasela CS, Hudgens MG, et al. Maternal and infant antiretroviral regimens to prevent postnatal HIV-1transmission: 48-week follow-up of the BAN randomised controlled trial. Lancet. Apr 25 2012. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22541418.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-18Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-19Perinatal Transmission of HIV and Maternal HIV RNA Copy Number(Last updated July 31, 2012; last reviewed July 31, 2012)Mother-to-child transmission has been observed across the entire range of plasma HIV RNA levels.1, 2HIVRNA levels correlate with risk of transmission even in women treated with antiretroviral (ARV) agents.3-5Although the risk of perinatal transmission in women with undetectable HIV RNA levels appears to beextremely low, transmission has been reported even in women with very low or undetectable levels ofmaternal HIV RNA on antiretroviral therapy (ART).3-5Additionally, although HIV RNA may be an importantrisk factor for transmission, other factors also appear to play a role.6-8Although there is a general correlation between viral loads in plasma and in the genital tract, discordancebetween blood and genital tract virus has also been reported; low level cervico-vaginal HIV RNA and DNAshedding has been detected even in women treated with ART who have undetectable plasma viral load,particularly in the presence of genital tract coinfections.9-11Penetration of ARV drugs into the female genitaltract has been shown to vary between drugs.12-14If exposure to HIV in the maternal genital tract duringdelivery is a risk factor for perinatal transmission, plasma HIV RNA levels may not always be an accurateindicator of risk. Long-term changes in one body compartment with ARV drugs may or may not beassociated with comparable changes in other compartments. Additional studies are needed to determine theeffect of ARV drugs on genital tract viral load and the association between such effects and the risk ofperinatal transmission of HIV. Because transmission can occur even when HIV RNA copy numbers are low or undetectable, all HIV-infected women should be counseled about and administered ARV drugs during pregnancy, regardless oftheir HIV RNA levels.References 1. Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the riskof perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med. Aug 5 1999;341(6):394-402.Available at http://www.ncbi.nlm.nih.gov/pubmed/10432324.2. Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of human immunodeficiency virustype 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med. Aug 51999;341(6):385-393. Available at http://www.ncbi.nlm.nih.gov/pubmed/10432323.3. Warszawski J, Tubiana R, Le Chenadec J, et al. Mother-to-child HIV transmission despite antiretroviral therapy in theANRS French Perinatal Cohort. AIDS. Jan 11 2008;22(2):289-299. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18097232.4. Tubiana R, Le Chenadec J, Rouzioux C, et al. Factors associated with mother-to-child transmission of HIV-1 despite amaternal viral load CO1). Clin Infect Dis. Feb 15 2010;50(4):585-596. Available at http://www.ncbi.nlm.nih.gov/pubmed/20070234.Panel’s Recommendation• All HIV-infected pregnant women should be counseled about and administered antiretroviral drugs during pregnancy forprevention of perinatal transmission, regardless of their HIV RNA levels (AI).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.5. European Collaborative Study. Mother-to-child transmission of HIV infection in the era of highly active antiretroviraltherapy. Clin Infect Dis. Feb 1 2005;40(3):458-465. Available at http://www.ncbi.nlm.nih.gov/pubmed/15668871.6. Maternal viral load and vertical transmission of HIV-1: an important factor but not the only one. The EuropeanCollaborative Study. AIDS. Jul 30 1999;13(11):1377-1385. Available athttp://www.ncbi.nlm.nih.gov/pubmed/10449292.7. Mock PA, Shaffer N, Bhadrakom C, et al. Maternal viral load and timing of mother-to-child HIV transmission,Bangkok, Thailand. Bangkok Collaborative Perinatal HIV Transmission Study Group. AIDS. Feb 25 1999;13(3):407-414. Available at http://www.ncbi.nlm.nih.gov/pubmed/10199232.8. Shaffer N, Roongpisuthipong A, Siriwasin W, et al. Maternal virus load and perinatal human immunodeficiency virustype 1 subtype E transmission, Thailand. Bangkok Collaborative Perinatal HIV Transmission Study Group. J Infect Dis.Mar 1999;179(3):590-599. Available at http://www.ncbi.nlm.nih.gov/pubmed/9952365.9. Launay O, Tod M, Tschope I, et al. Residual HIV-1 RNA and HIV-1 DNA production in the genital tract reservoir ofwomen treated with HAART: the prospective ANRS EP24 GYNODYN study. Antivir Ther. 2011;16(6):843-852.Available at http://www.ncbi.nlm.nih.gov/pubmed/21900716.10. Cu-Uvin S, DeLong AK, Venkatesh KK, et al. Genital tract HIV-1 RNA shedding among women with below detectableplasma viral load. AIDS. Oct 23 2010;24(16):2489-2497. Available at http://www.ncbi.nlm.nih.gov/pubmed/20736815.11. Henning TR, Kissinger P, Lacour N, Meyaski-Schluter M, Clark R, Amedee AM. Elevated cervical white blood cellinfiltrate is associated with genital HIV detection in a longitudinal cohort of antiretroviral therapy-adherent women. J Infect Dis. Nov 15 2010;202(10):1543-1552. Available at http://www.ncbi.nlm.nih.gov/pubmed/20925530.12. Yeh RF, Rezk NL, Kashuba AD, et al. Genital tract, cord blood, and amniotic fluid exposures of seven antiretroviraldrugs during and after pregnancy in human immunodeficiency virus type 1-infected women. Antimicrob AgentsChemother. Jun 2009;53(6):2367-2374. Available at http://www.ncbi.nlm.nih.gov/pubmed/19307360.13. Dumond JB, Yeh RF, Patterson KB, et al. Antiretroviral drug exposure in the female genital tract: implications for oralpre- and post-exposure prophylaxis. AIDS. Sep 12 2007;21(14):1899-1907. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17721097.14. Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the maleand female genital tract. Antivir Ther. 2011;16(8):1149-1167. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22155899.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States B-20Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States C-1Preconception Counseling and Care for HIV-Infected Women ofChildbearing AgeOverview (Last updated July 31, 2012; last reviewed July 31, 2012)The Centers for Disease Control and Prevention (CDC), the American College of Obstetricians andGynecologists, and other national organizations recommend offering all women of childbearing agecomprehensive family planning and the opportunity to receive preconception counseling and care as acomponent of routine primary medical care. The purpose of preconception care is to improve the health ofeach woman before conception by identifying risk factors for adverse maternal or fetal outcome, providingeducation and counseling targeted to patients’ individual needs, and treating or stabilizing medical conditionsto optimize maternal and fetal outcomes.1Preconception care is not a single clinical visit but, rather, aprocess of ongoing care and interventions integrated into primary care to address the needs of women duringthe different stages of reproductive life. Because more than half of all pregnancies in the United States areunintended2-5it is important that comprehensive family planning and preconception care be integrated intoroutine health visits. Providers should initiate and document a nonjudgmental conversation with all womenof reproductive age concerning their reproductive desires because women may be reluctant to bring this upthemselves.6, 7HIV care providers who routinely care for women of reproductive age play an important rolein promoting preconception health and informed reproductive decisions.The fundamental principles of preconception counseling and care are outlined in the CDC PreconceptionCare Work Group’s Recommendations to Improve Preconception Health and Health Care. In addition to thegeneral components of preconception counseling and care that are appropriate for all women of reproductiveage, HIV-infected women have specific needs that should be addressed.8, 9Because many women infectedwith HIV are aware of their HIV status before becoming pregnant, issues that impact pregnancy can beaddressed before conception during their routine medical care for HIV disease. In addition to the principlesoutlined by the CDC Preconception Care Work Group10, the following components of preconceptionPanel’s Recommendations• Discuss childbearing intentions with all women of childbearing age on an ongoing basis throughout the course of theircare (AIII).• Include information about effective and appropriate contraceptive methods to reduce the likelihood of unintendedpregnancy (AI).• During preconception counseling, include information on safer sexual practices and elimination of alcohol, illicit drugs,and smoking, which are important for the health of all women as well as for fetal/infant health, should pregnancy occur(AII).• When evaluating HIV-infected women, include assessment of HIV disease status and need for antiretroviral therapy (ART)for their own health (AII).• Choose an ART regimen for HIV-infected women of childbearing age based on consideration of effectiveness fortreatment of maternal disease, hepatitis B virus disease status, teratogenic potential of the drugs in the regimen shouldpregnancy occur, and possible adverse outcomes for mother and fetus (AII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.counseling and care are specifically recommended for HIV-infected women. Health care providers should:a. Discuss reproductive options; actively assess women’s pregnancy intentions on an ongoing basisthroughout the course of care; and, when appropriate, make referrals to experts in HIV and women’shealth, including experts in reproductive endocrinology and infertility when necessary.11, 12b. Offer all women effective and appropriate contraceptive methods to reduce the likelihood of unintendedpregnancy. Providers should be aware of potential interactions between antiretroviral (ARV) drugs andhormonal contraceptives that could lower contraceptive efficacy (see Table 4).c. Counsel on safe sexual practices that prevent HIV transmission to sexual partners, protect women fromacquiring sexually transmitted diseases, and reduce the potential to acquire more virulent or resistantstrains of HIV.d. Counsel on eliminating alcohol, illicit drug use, and cigarette smoking.e. Educate and counsel women about risk factors for perinatal transmission of HIV, strategies to reducethose risks, potential effects of HIV or of ARV drugs given either for treatment or solely for preventionof mother-to-child transmission (MTCT) on pregnancy course and outcomes, and the recommendationthat HIV-infected women in the United States not breastfeed because of the risk of transmission of HIVand the availability of safe and sustainable infant feeding alternatives.f. When prescribing antiretroviral therapy (ART) to women of childbearing age, consider the regimen’seffectiveness for treatment of HIV, an individual’s hepatitis B disease status, the drugs’ potential forteratogenicity should pregnancy occur, and possible adverse outcomes for mother and fetus.13-15g. Use the preconception period in women who are contemplating pregnancy to adjust ARV regimens toexclude efavirenz or other drugs with teratogenic potential.h. Make a primary treatment goal for women who are on ART for their own health and who want to getpregnant the attainment of a stable, maximally suppressed maternal viral load prior to conception todecrease the risk of MTCT.i. Evaluate and appropriately manage therapy-associated side effects such as hyperglycemia, anemia, andhepatotoxicity that may adversely impact maternal-fetal health outcomes.j. Evaluate the need for appropriate prophylaxis or treatment for opportunistic infections, including safety,tolerability, and potential toxicity of specific agents when used in pregnancy.k. Administer medical immunizations for influenza, pneumococcal or hepatitis A and B vaccines, and othervaccines as indicated (see http://www.cdc.gov/vaccines/recs/acip/rec-vac-preg.htmandhttp://www.cdc.gov/vaccines/recs/acip/downloads/preg-principles05-01-08.pdf).l. Encourage sexual partners to receive HIV testing and, if infected, to seek counseling and appropriateHIV care.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States C-2Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States C-3Antiretroviral Drug Effect on Drug LevelsDosing Recommendation/Clinical CommentNon-nucleoside Reverse Transcriptase Inhibitor (NNRTI)Efavirenz(EFV)Oral ethinyl estradiol/norgestimate:No effect on ethinyl estradiolconcentrations;↓active metabolites of norgestimate(levonorgestrel AUC ↓83%; norelgestrominAUC ↓64%)Implant: ↓etonogestrelLevonorgestrel AUC ↓58%A reliable method of barrier contraceptionmust be used in addition to hormonalcontraceptives. Efavirenz had no effect onethinyl estradiol concentrations, butprogestin levels (norelgestromin andlevonorgestrel) were markedly decreased. Noeffect of ethinyl estradiol/norgestimate onefavirenz plasma concentrations wasobserved.A reliable method of barrier contraceptionmust be used in addition to hormonalcontraceptives. The interaction betweenetonogestrel and efavirenz has not beenstudied. Decreased exposure of etonogestrelmay be expected. In postmarketing reports,contraceptive failure with etonogestrel hasbeen noted in efavirenz-exposed patients.Effectiveness of emergency postcoitalcontraception may be diminished.Etravirine(ETR)Ethinyl estradiol AUC ↑22%Norethindrone: no significant effectNo dosage adjustment needed.Nevirapine(NVP)Ethinyl estradiol AUC ↓20%Norethindrone AUC ↓19%DMPA: no significant changeAdditional methods recommended;alternative methods can be considered. No dosage adjustment needed.Rilpivirine(RPV)Ethinyl estradiol AUC ↑14%Norethindrone: no significant changeNo dose adjustment needed.Ritonavir (RTV)-boosted Protease Inhibitor (PI)Atazanavir/ritonavir (ATV/r)↓Ethinyl estradiol↑NorgestimateOral contraceptive should contain ≥35 mcgethinyl estradiol. Oral contraceptivescontaining progestins other thannorethindrone or norgestimate have not beenstudied.Table 4: Drug Interactions Between Antiretroviral Agents and Hormonal Contraceptives(page 1 of 2)Data on drug interactions between antiretroviral (ARV) agents and hormonal contraceptives primarily comefrom drug labels and the clinical implications have not been well studied. The magnitude of changes incontraceptive drug levels that may reduce contraceptive efficacy or increase contraceptive-associated adverseeffects is unknown. Hormonal contraceptives can be used with antiretroviral therapy (ART) in womenwithout other contraindications. Additional or alternative methods of contraception may be recommendedwhen drug interactions are known.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States C-4Antiretroviral Drug Effect on Drug LevelsDosing Recommendation/Clinical CommentDarunavir/ritonavir (DRV/r)Ethinyl estradiol AUC ↓44%Norethindrone AUC ↓14%Additional methods recommended; alternativemethods can be considered. Fosamprenavir/ritonavir (FPV/r)Ethinyl estradiol AUC ↓37%Norethindrone AUC ↓34%Alternative methods of nonhormonalcontraception are recommended. Lopinavir/ritonavir (LPV/r)Ethinyl estradiol AUC ↓42%Norethindrone AUC ↓17%Additional methods recommended; alternativemethods can be considered.Saquinavir/ritonavir (SQV/r)↓Ethinyl estradiol Additional methods recommended; alternativemethods can be considered. Tipranavir/ritonavir (TPV/r)Ethinyl estradiol AUC ↓48%Norethindrone: no significant changeAdditional methods recommended; alternativemethods can be considered. PI without RTVAtazanavir (ATV)Ethinyl estradiol AUC ↑48%Norethindrone AUC ↑110%Oral contraceptive should contain ≤30 mcg ofethinyl estradiol or use alternative method. Oralcontraceptives containing estradiol or progestins other than norethindroneor norgestimate have not been studied.Fosamprenavir(FPV)Amprenavir: ↑Ethinyl estradiol and ↑norethindroneFosamprenavir with ethinylestradiol/norethindrone: ↓Amprenavir (AUC 22%, Cmin20%)Use alternative method.Use of fosamprenavir alone with ethinylestradiol/norethindrone may lead to loss ofvirologic response.Indinavir(IDV)Ethinyl estradiol AUC ↑25%Norethindrone AUC ↑26%No dose adjustment needed.Nelfinavir(NFV)Ethinyl estradiol AUC ↓47%Norethindrone AUC ↓18%Additional methods recommended; alternativemethods may be considered. CCR5 AntagonistMaraviroc(MVC)No significant effect on ethinyl estradiolor levonorgestrelNo dose adjustment needed.Integrase InhibitorRaltegravir(RAL)No significant effect No dose adjustment needed.Key to Abbreviations:AUC = area under the curve, Cmin= minimum plasma concentration, DMPA = depot medroxyprogesterone acetateTable 4 derived from:Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Tables 15a, 15b, and 15d. Accessed June 7, 2012. Table 4: Drug Interactions Between Antiretroviral Agents and Hormonal Contraceptives(page 2 of 2)Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.References1. American College of Obstetricians and Gynecologists. ACOG Committee Opinion number 313, September 2005. Theimportance of preconception care in the continuum of womens health care. Obstet Gynecol. Sep 2005;106(3):665-666.Available at http://www.ncbi.nlm.nih.gov/pubmed/16135611.2. Johnson K, Posner SF, Biermann J, et al. Recommendations to improve preconception health and health care--UnitedStates. A report of the CDC/ATSDR Preconception Care Work Group and the Select Panel on Preconception Care.MMWR Recomm Rep. Apr 21 2006;55(RR-6):1-23. Available at http://www.ncbi.nlm.nih.gov/pubmed/16617292.3. Cohn SE, Umbleja T, Mrus J, Bardeguez AD, Andersen JW, Chesney MA. Prior illicit drug use and missed prenatalvitamins predict nonadherence to antiretroviral therapy in pregnancy: adherence analysis A5084. AIDS Patient CareSTDS. Jan 2008;22(1):29-40. Available at http://www.ncbi.nlm.nih.gov/pubmed/18442305.4. Finer LB, Zolna MR. Unintended pregnancy in the United States: incidence and disparities 2006, pub August 25, 2011.Contraception. 2011. Available at http://www.contraceptionjournal.org/article/S0010-7824(11)00472-0/abstract. 5. Elgalib A, Hegazi A, Samarawickrama A, et al. Pregnancy in HIV-infected teenagers in London. HIV Med. Feb2011;12(2):118-123. Available at http://www.ncbi.nlm.nih.gov/pubmed/20807252.6. Finocchario-Kessler S, Dariotis JK, Sweat MD, et al. Do HIV-infected women want to discuss reproductive plans withproviders, and are those conversations occurring? AIDS Patient Care STDS. May 2010;24(5):317-323. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20482467.7. Finocchario-Kessler S, Sweat MD, Dariotis JK, et al. Childbearing motivations, pregnancy desires, and perceivedpartner response to a pregnancy among urban female youth: does HIV-infection status make a difference? AIDS Care.2012;24(1):1-11. Available at http://www.ncbi.nlm.nih.gov/pubmed/21777077.8. Lampe MA. Human immunodeficiency virus-1 and preconception care. Matern Child Health J. Sep 2006;10(5Suppl):S193-195. Available at http://www.ncbi.nlm.nih.gov/pubmed/16832609.9. Aaron EZ, Criniti SM. Preconception health care for HIV-infected women. Top HIV Med. Aug-Sep 2007;15(4):137-141.Available at http://www.ncbi.nlm.nih.gov/pubmed/17721000.10. Centers for Disease Control and Prevention. Incorporating HIV prevention into the medical care of persons living withHIV. Recommendations of CDC, the Health Resources and Services Administration, the National Institutes of Health,and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. Jul 182003;52(RR-12):1-24. Available at http://www.ncbi.nlm.nih.gov/pubmed/12875251.11. Gosselin JT, Sauer MV. Life after HIV: examination of HIV serodiscordant couples desire to conceive through assistedreproduction. AIDS Behav. Feb 2011;15(2):469-478. Available at http://www.ncbi.nlm.nih.gov/pubmed/20960049.12. Finocchario-Kessler S, Sweat MD, Dariotis JK, et al. Understanding high fertility desires and intentions among asample of urban women living with HIV in the United States. AIDS Behav. Oct 2010;14(5):1106-1114. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19908135.13. Cotter AM, Garcia AG, Duthely ML, Luke B, OSullivan MJ. Is antiretroviral therapy during pregnancy associated withan increased risk of preterm delivery, low birth weight, or stillbirth? J Infect Dis. May 1 2006;193(9):1195-1201.Available at http://www.ncbi.nlm.nih.gov/pubmed/16586354.14. Tuomala RE, Shapiro DE, Mofenson LM, et al. Antiretroviral therapy during pregnancy and the risk of an adverseoutcome. N Engl J Med. Jun 13 2002;346(24):1863-1870. Available at http://www.ncbi.nlm.nih.gov/pubmed/12063370.15. Stek AM. Antiretroviral medications during pregnancy for therapy or prophylaxis. Curr HIV/AIDS Rep. May2009;6(2):68-76. Available at http://www.ncbi.nlm.nih.gov/pubmed/19358777.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States C-5Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States C-6Reproductive Options for HIV-Concordant and Serodiscordant Couples (Last updated July 31, 2012; last reviewed July 31, 2012)For serodiscordant couples who want to conceive, expert consultation is recommended so that approachescan be tailored to specific needs, which may vary from couple to couple.Before attempting to conceive, both partners should be screened for genital tract infections. If any suchinfections are identified, they should be treated because genital tract inflammation is associated with genitaltract shedding of HIV.1, 2Semen analysis is recommended for HIV-infected males before conception isattempted because HIV, and possibly antiretroviral therapy (ART), may be associated with a higherprevalence of semen abnormalities such as low sperm count, low motility, higher rate of abnormal forms, andlow semen volume. If such abnormalities are present, the uninfected female partner may be exposedunnecessarily and for prolonged periods to her partner’s infectious genital fluids when the likelihood ofgetting pregnant naturally is low or even nonexistent.3-6Observational studies have demonstrated a decreased rate of transmission of HIV in heterosexualserodiscordant couples among whom the index partners were on ART compared with those not on therapy.7-9HPTN 052 is a randomized clinical trial designed to evaluate whether immediate versus delayed initiation ofART by HIV-infected individuals with CD4 T-lymphocyte (CD4-cell) counts of 350 to 550 cells/mm3couldprevent sexual transmission of HIV among serodiscordant couples. Most of the participants were from Africa(54%), with 30% from Asia and 16% from North and South America. Data from this study showed thatearlier initiation of ART led to a significant reduction in transmission of HIV to the uninfected partner. Of 28cases of HIV infection documented to be genetically linked to the infected partner, 27 occurred in the 877couples in which the HIV-infected partner delayed initiation of ART until the CD4-cell count fell below 250cells/mm3, whereas only 1 case of HIV infection occurred in the 886 couples with an HIV-infected partnerPanel’s Recommendations• For serodiscordant couples who want to conceive, expert consultation is recommended so that approaches can betailored to specific needs, which may vary from couple to couple (AIII). It is important to recognize that treatment of theinfected partner may not be fully protective against sexual transmission of HIV.• Partners should be screened and treated for genital tract infections before attempting to conceive (AII).• For HIV-infected females with HIV-uninfected male partners, the safest conception option is artificial insemination,including the option of self-insemination with a partner’s sperm during the peri-ovulatory period (AIII).• For HIV-infected men with HIV-uninfected female partners, the use of sperm preparation techniques coupled with eitherintrauterine insemination or in vitrofertilization should be considered if using donor sperm from an HIV-uninfected maleis unacceptable (AII).• For serodiscordant couples who want to conceive, initiation of antiretroviral therapy (ART) for the HIV-infected partner isrecommended (AI for CD4 T-lymphocyte (CD4-cell) count ≤550 cells/mm3, BIII for CD4-cell count >550 cells/mm3). Iftherapy is initiated, maximal viral suppression is recommended before conception is attempted (AIII). • Periconception administration of antiretroviral pre-exposure prophylaxis (PrEP) for HIV-uninfected partners may offer anadditional tool to reduce the risk of sexual transmission (CIII). The utility of PrEP of the uninfected partner when theinfected partner is receiving ART has not been studied.Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.who began immediate ART; 17 of the 27 transmissions in the delayed therapy group occurred in individualswith CD4-cell counts >350 cells/mm3. The majority of transmissions (82%) were observed in participantsfrom Africa. These are the first data from a randomized trial to demonstrate that provision of treatment toinfected individuals can reduce the risk of transmission to their uninfected sexual partners.10Based on theresults from HPTN 052, initiation of ART would be recommended for the infected partner in aserodiscordant couple who has a CD4-cell count of ≤550 cells/mm3if the couple wishes to conceive.Initiation of ART is also recommended for HIV-infected individuals with CD4-cell counts >550 cells/mm3,although the benefit of ART in reducing sexual transmission from individuals with higher CD4-cell countshas not been determined. Before conception is attempted, maximal viral suppression is recommended forindividuals who are on ART for their own health and those who do not require therapy but opt to start ART toprevent sexual transmission.It is important to recognize that no single method (including treatment of the infected partner) is fullyprotective against transmission of HIV. Effective ART that decreases plasma viral load to undetectable levelsis also associated with decreased concentration of virus in genital secretions. In a prospective study of 2,521African HIV-infected serodiscordant couples, higher genital HIV RNA concentrations were associated withgreater risk of heterosexual HIV-1 transmission and this effect was independent of plasma HIVconcentrations. Each log10increase in genital HIV-1 RNA levels increased the risk of female-to-male ormale-to-female HIV transmission by 1.7-fold.11Discordance between plasma and genital viral loads has beenreported, and individuals with an undetectable plasma viral load may have detectable genital tract virus.12-14In addition, antiretroviral (ARV) drugs vary in their ability to penetrate the genital tract.15Thus, maximalplasma viral suppression may not completely eliminate risk of heterosexual transmission. Although use ofART may not eliminate all risk of sexual transmission, it may contribute to lowering risk in couples whohave decided to conceive through unprotected intercourse despite known risks.Reducing the risk of perinatal transmission is another potential rationale for starting ART before conceptionin HIV-infected women who do not yet need treatment for their own health. Data suggest that early andsustained control of HIV viral replication may be associated with decreasing residual risk of perinataltransmission,16, 17but that does not completely eliminate the risk of perinatal transmission.17In addition,reports are mixed on the possible effects of combination ARV drug regimens on prematurity and low birthweight, with some but not all data suggesting that such outcomes may be more frequent in women on ARVdrugs at conception18, 19(see Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-Infected Pregnant Women and Their Infants).The implications of initiating therapy before conception solely for prevention of sexual and/or perinataltransmission should be discussed with patients. These issues include willingness and ability to commit topotential lifelong therapy, the potential risks versus benefits of stopping or continuing the regimen afterconception in the male or postpartum in the female, and the need for strict adherence to achieve maximalviral suppression. Consultation with an expert in HIV care is strongly recommended. For HIV-discordant couples in which the female is the HIV-infected partner, the safest form of conception isartificial insemination, including the option to self-inseminate with the partner’s sperm during the peri-ovulatory period. Condom use should be advised at all times.For HIV-discordant couples in which the male is the HIV-infected partner, the use of sperm preparationtechniques coupled with either intrauterine insemination or in vitro fertilization has been reported to beeffective in avoiding seroconversion in uninfected women and offspring in several studies.20, 21The NationalPerinatal HIV Hotline (1-888-448-8765) is a resource for a list of institutions offering reproductive servicesfor HIV-serodiscordant couples. More data are needed to demonstrate the complete efficacy of thesetechniques, and couples should be cautioned about the potential risk of transmission of HIV to the uninfectedpartner and to their offspring.21Discordant couples who do not have access to assisted reproduction servicesRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States C-7Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.and who still want to try to conceive after comprehensive counseling should be advised that timed, peri-ovulatory unprotected intercourse after the infected partner has achieved maximal viral suppression (with useof condoms at all other times) may reduce but not completely eliminate the risk of sexual transmission.21Uninfected women who become pregnant should be regularly counseled regarding consistent condom use todecrease their risk of sexual transmission of HIV and the possible risk of perinatal transmission (seeMonitoring of HIV Uninfected Pregnant Women with a Partner Known to be HIV Infected).Periconception pre-exposure prophylaxis (PrEP) may offer an additional option in the future to minimize riskof transmission of HIV within discordant couples. PrEP is use of ARV medications by an HIV-uninfectedindividual to maintain blood and genital drug levels sufficient to prevent acquisition of HIV. An experimental1% tenofovir gel used intravaginally both before and after sex reduced the incidence of HIV infection inwomen by up to 54% in a randomized, placebo-controlled trial conducted in South Africa.22This product isnot available commercially, and additional trials are needed to confirm these findings. Five efficacy trials ofPrEP with oral ARV agents (primarily tenofovir alone) have been completed or are currently under way.23Inone study of daily tenofovir/emtricitabine in HIV-seronegative men who have sex with men, there was a 44%reduction in the risk of acquisition of HIV compared with placebo.24, 25The TDF2 study, a placebo-controlledtrial of PrEP to prevent sexual transmission in HIV-uninfected, heterosexual, sexually active, healthy adultsaged 18 to 39 years in Botswana, found that daily oral PrEP with tenofovir/emtricitabine taken by the HIV-uninfected partner reduced the risk of acquisition of HIV by 63% (95% confidence interval [CI], 21.5–83.4;P = .0133) and was effective in both men and women.26The Partners PrEP Study, a placebo-controlled,three-arm trial, also found that daily PrEP with tenofovir or tenofovir/emtricitabine significantly reducedHIV transmission in discordant heterosexual couples in Kenya and Uganda. Those who received tenofovirhad 62% fewer HIV infections (95% CI, 34–78; P = .0003) and those who received tenofovir/emtricitabinehad 73% fewer HIV infections (95% CI, 49–85; P = regimens were effective in both men and women.27However, the FEM-PrEP clinical trial, designed to studywhether HIV-uninfected women at high risk of being exposed to HIV can safely use a daily dose oftenofovir/emtricitabine to prevent infection, was stopped early by its Data and Safety Monitoring Board(DSMB) because it was highly unlikely the study would be able to demonstrate the effectiveness oftenofovir/emtricitabine in preventing HIV infection in the study population. The approximate rate of newHIV infections among trial participants was 5% per year. A total of 56 new HIV infections had occurred,with an equal number of infections in participants assigned to tenofovir/emtricitabine and those assigned to aplacebo.28The VOICE study is the first trial to evaluate both daily oral (tenofovir or tenofovir/emtricitabine)and topical (1% tenofovir microbicide gel) PrEP and has enrolled more than 5,000 HIV-uninfectedheterosexual women in South Africa, Uganda, and Zimbabwe. The oral tenofovir and tenofovir gel arms ofthe study were stopped by its DSMB because it concluded that the study would be unable to show anydifference between a daily dose of oral tenofovir or tenofovir gel and placebo in preventing HIV infection.The tenofovir/emtricitabine study arm is ongoing. Data on the FEM-PrEP, TDF2, Partners PrEP, and VOICEstudies are preliminary.Several studies evaluating the efficacy of PrEP in heterosexual discordant couples planning pregnancy areongoing but complete data are not yet available. One study evaluated timed intercourse with PrEP in 46heterosexual HIV-discordant couples with an HIV-uninfected female partner. The male HIV-infected partnerswere receiving ART and had undetectable plasma HIV RNA levels. One dose of oral tenofovir was taken bythe women at luteinizing hormone peak and a second oral dose was taken 24 hours later. None of the womenbecame HIV infected and pregnancy rates were high, reaching a plateau of 75% after 12 attempts.29The use of daily oral PrEP during pregnancy and lactation for HIV-uninfected women with HIV-infectedpartners has had limited study. PrEP may offer an additional strategy for safer conception. However, it willbe important to have outcome studies that examine adverse events, including risk of congenitalabnormalities. Additionally, the utility of daily oral PrEP when the HIV-infected partner is receiving ART hasRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States C-8Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.not been studied. If clinicians elect to use PrEP for HIV-uninfected women or men in serodiscordant couples,the couples should be educated about the potential risks and benefits and all available alternatives for saferconception. Only combination tenofovir/emtricitabine is being evaluated in current heterosexual PrEP trials.Laboratory testing for HIV infection, baseline renal function, and hepatitis B virus (HBV) infection shouldbe performed before initiating PrEP. Screening for sexually transmitted diseases also is recommended.Individuals receiving PrEP should be monitored for potential side effects such as renal dysfunction andclinical toxicities. They should be educated about symptoms associated with acute HIV infection and advisedto contact their providers immediately for further evaluation should symptoms occur. HIV-uninfectedpartners should undergo frequent HIV testing to detect HIV infection quickly. Should HIV infection bedocumented, the ARV agents should be discontinued to minimize selection of drug-resistant virus, andmeasures should be instituted to prevent perinatal transmission if pregnancy occurs. Individuals with chronicHBV should be monitored for possible hepatitis flares when PrEP is stopped.30Clinicians are stronglyencouraged to register uninfected women who become pregnant while receiving PrEP with the AntiretroviralPregnancy Registry.Monitoring of HIV-Uninfected Pregnant Women with Partners Known to Be HIVInfectedClinicians may increasingly be seeing HIV-uninfected women who present during pregnancy and indicatethat their partners are HIV infected. They, like all pregnant women, should be notified that HIV screening isrecommended and they will receive an HIV test as part of the routine panel of prenatal tests unless theydecline. These women also should receive a second HIV test during the third trimester, preferably before 36weeks of gestation, as is recommended for high-risk women. Furthermore, pregnant women who present inlabor without results of third-trimester testing should be screened with a rapid HIV test on the labor anddelivery unit. If at any time during pregnancy a clinician suspects that a pregnant woman may be in the“window” period of seroconversion (that is, she has signs or symptoms consistent with acute HIV infection),then a plasma HIV RNA test should be used in conjunction with an HIV antibody test. If the plasma HIVRNA is negative, it should be repeated in 2 weeks. All HIV-uninfected pregnant women with HIV-infectedpartners should always use condoms during sexual intercourse to prevent acquisition of HIV. Women shouldbe counseled regarding the symptoms of acute retroviral syndrome (that is, fever, pharyngitis, rash, myalgia,arthralgia, diarrhea, headache) and the importance of seeking medical care and testing if they experiencesuch symptoms.Women who test positive on either conventional or rapid HIV tests should receive appropriate evaluation andinterventions to reduce perinatal transmission of HIV, including immediate initiation of appropriate ARVprophylaxis and consideration of elective cesarean delivery according to established guidelines (seeTransmission and Mode of Delivery). In cases where confirmatory test results are not readily available, suchas with rapid testing during labor, it is still appropriate to initiate interventions to reduce perinataltransmission (see Infant Antiretroviral Prophylaxis).Women with HIV-infected partners who test HIV negative should continue to be regularly counseledregarding consistent condom use to decrease their risk of sexual transmission of HIV. Women with primaryHIV infection during pregnancy or lactation are at high risk of transmitting HIV to their infants.31, 32References1. Mitchell C, Hitti J, Paul K, et al. Cervicovaginal shedding of HIV type 1 is related to genital tract inflammationindependent of changes in vaginal microbiota. AIDS Res Hum Retroviruses. Jan 2011;27(1):35-39. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20929397.2. Johnson LF, Lewis DA. The effect of genital tract infections on HIV-1 shedding in the genital tract: a systematic reviewand meta-analysis. Sex Transm Dis. Nov 2008;35(11):946-959. Available atRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States C-9Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.http://www.ncbi.nlm.nih.gov/pubmed/18685546.3. Garrido N, Meseguer M, Remohi J, Simon C, Pellicer A. Semen characteristics in human immunodeficiency virus(HIV)- and hepatitis C (HCV)-seropositive males: predictors of the success of viral removal after sperm washing. HumReprod. Apr 2005;20(4):1028-1034. Available at http://www.ncbi.nlm.nih.gov/pubmed/15608027.4. Dulioust E, Du AL, Costagliola D, et al. Semen alterations in HIV-1 infected men. Hum Reprod. Aug 2002;17(8):2112-2118. Available at http://www.ncbi.nlm.nih.gov/pubmed/12151446.5. Cardona-Maya W, Velilla P, Montoya CJ, Cadavid A, Rugeles MT. Presence of HIV-1 DNA in spermatozoa from HIV-positive patients: changes in the semen parameters. Curr HIV Res. Jul 2009;7(4):418-424. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19601777.6. Bujan L, Sergerie M, Moinard N, et al. Decreased semen volume and spermatozoa motility in HIV-1-infected patientsunder antiretroviral treatment. J Androl. May-Jun 2007;28(3):444-452. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17215546.7. Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: aprospective cohort analysis. Lancet. Jun 12 2010;375(9731):2092-2098. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20537376.8. Del Romero J, Castilla J, Hernando V, Rodriguez C, Garcia S. Combined antiretroviral treatment and heterosexualtransmission of HIV-1: cross sectional and prospective cohort study. BMJ. 2010;340:c2205. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20472675.9. Lu W, Zeng G, Luo J, et al. HIV transmission risk among serodiscordant couples: a retrospective study of formerplasma donors in Henan, China. J Acquir Immune Defic Syndr. Oct 1 2010;55(2):232-238. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21423851.10. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl JMed. Aug 11 2011;365(6):493-505. Available at http://www.ncbi.nlm.nih.gov/pubmed/21767103.11. Baeten JM, Kahle E, Lingappa JR, et al. Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission. SciTransl Med. Apr 6 2011;3(77):77ra29. Available at http://www.ncbi.nlm.nih.gov/pubmed/21471433.12. Cu-Uvin S, DeLong AK, Venkatesh KK, et al. Genital tract HIV-1 RNA shedding among women with below detectableplasma viral load. AIDS. Oct 23 2010;24(16):2489-2497. Available at http://www.ncbi.nlm.nih.gov/pubmed/20736815.13. Sheth PM, Kovacs C, Kemal KS, et al. Persistent HIV RNA shedding in semen despite effective antiretroviral therapy.AIDS. Sep 24 2009;23(15):2050-2054. Available at http://www.ncbi.nlm.nih.gov/pubmed/19710596.14. Politch JA, Mayer KH, Welles SL, et al. Highly active antiretroviral therapy does not completely suppress HIV insemen of sexually active HIV-infected men who have sex with men. AIDS. Mar 23 2012. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22441253.15. Taylor S, Davies S. Antiretroviral drug concentrations in the male and female genital tract: implications for the sexualtransmission of HIV. Curr Opin HIV AIDS. Jul 2010;5(4):335-343. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20543610.16. Townsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-childtransmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS.May 11 2008;22(8):973-981. Available at http://www.ncbi.nlm.nih.gov/pubmed/18453857.17. Tubiana R, Le Chenadec J, Rouzioux C, et al. Factors associated with mother-to-child transmission of HIV-1 despite amaternal viral load CO1). Clin Infect Dis. Feb 15 2010;50(4):585-596. Available at http://www.ncbi.nlm.nih.gov/pubmed/20070234.18. Kourtis AP, Schmid CH, Jamieson DJ, Lau J. Use of antiretroviral therapy in pregnant HIV-infected women and the riskof premature delivery: a meta-analysis. AIDS. Mar 12 2007;21(5):607-615. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17314523.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States C-10Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.19. Rudin C, Spaenhauer A, Keiser O, et al. Antiretroviral therapy during pregnancy and premature birth: analysis of Swissdata. HIV Med. Apr 2011;12(4):228-235. Available at http://www.ncbi.nlm.nih.gov/pubmed/20726902.20. Aberg JA, Kaplan JE, Libman H, et al. Primary care guidelines for the management of persons infected with humanimmunodeficiency virus: 2009 update by the HIV medicine Association of the Infectious Diseases Society of America.Clin Infect Dis. Sep 1 2009;49(5):651-681. Available at http://www.ncbi.nlm.nih.gov/pubmed/19640227.21. Ethics Committee of the American Society for Reproductive M. Human immunodeficiency virus and infertilitytreatment. Fertil Steril. Jun 2010;94(1):11-15. Available at http://www.ncbi.nlm.nih.gov/pubmed/20236636.22. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviralmicrobicide, for the prevention of HIV infection in women. Science. Sep 3 2010;329(5996):1168-1174. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20643915.23. Okwundu CI, Okoromah CA. Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-riskindividuals. Cochrane Database Syst Rev. 2009(1):CD007189. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19160329.24. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex withmen. N Engl J Med. Dec 30 2010;363(27):2587-2599. Available at http://www.ncbi.nlm.nih.gov/pubmed/21091279.25. Michael NL. Oral preexposure prophylaxis for HIV--another arrow in the quiver? N Engl J Med. Dec 302010;363(27):2663-2665. Available at http://www.ncbi.nlm.nih.gov/pubmed/21091280.26. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral Preexposure Prophylaxis for Heterosexual HIVTransmission in Botswana. N Engl J Med. Jul 11 2012. Available at http://www.ncbi.nlm.nih.gov/pubmed/22784038.27. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women.N Engl J Med. Jul 11 2012. Available at http://www.ncbi.nlm.nih.gov/pubmed/22784037.28. Van Damme L, Corneli A, Ahmed K, et al. Preexposure Prophylaxis for HIV Infection among African Women. N Engl JMed. Jul 11 2012. Available at http://www.ncbi.nlm.nih.gov/pubmed/22784040.29. Vernazza PL, Graf I, Sonnenberg-Schwan U, Geit M, Meurer A. Preexposure prophylaxis and timed intercourse forHIV-discordant couples willing to conceive a child. AIDS. Oct 23 2011;25(16):2005-2008. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21716070.30. Lampe MA, Smith DK, Anderson GJ, Edwards AE, Nesheim SR. Achieving safe conception in HIV-discordant couples:the potential role of oral preexposure prophylaxis (PrEP) in the United States. Am J Obstet Gynecol. Jun2011;204(6):488 e481-488. Available at http://www.ncbi.nlm.nih.gov/pubmed/21457911.31. Marinda ET, Moulton LH, Humphrey JH, et al. In utero and intra-partum HIV-1 transmission and acute HIV-1 infectionduring pregnancy: using the BED capture enzyme-immunoassay as a surrogate marker for acute infection. Int JEpidemiol. Aug 2011;40(4):945-954. Available at http://www.ncbi.nlm.nih.gov/pubmed/21471020.32. Humphrey JH, Marinda E, Mutasa K, et al. Mother to child transmission of HIV among Zimbabwean women whoseroconverted postnatally: prospective cohort study. BMJ. 2010;341:c6580. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21177735.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States C-11Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-1Antepartum Care (Last updated August 7, 2012; last reviewed July 31, 2012)General Principles Regarding Use of Antiretroviral Drugs during PregnancyIn addition to the standard antenatal assessments for all pregnant women, the initial evaluation of those whoare HIV infected should include assessment of HIV disease status and recommendations for HIV-relatedmedical care. This initial assessment should include the following:a. review of prior HIV-related illnesses and past CD4 T-lymphocyte (CD4-cell) counts and plasma HIVviral loads;b. current CD4-cell count;c. current plasma HIV RNA copy number;d. assessment of the need for prophylaxis against opportunistic infections such as Pneumocystisjirovecii pneumonia and Mycobacterium avium complex (see Guidelines for Prevention andTreatment of Opportunistic Infections in HIV-Infected Adults and Adolescents)1;Panel’s Recommendations• Initial evaluation of infected pregnant women should include assessment of HIV disease status and recommendationsregarding initiation of antiretroviral (ARV) drugs or the need for any modification if currently receiving antiretroviraltherapy (ART) (AIII). The National Perinatal HIV Hotline (1-888-448-8765) provides free clinical consultation on allaspects of perinatal HIV care.• Regardless of plasma HIV RNA copy number or CD4 T-lymphocyte count, all pregnant HIV-infected women shouldreceive a combination ARV drug regimen antepartum to prevent perinatal transmission (AI). A combination regimen isrecommended both for women who require therapy for their own health (AI) and for prevention of perinatal transmissionin those who do not yet require therapy (AII).• The known benefits and potential risks of ARV use during pregnancy should be discussed with all women (AIII).• ARV drug-resistance studies should be performed before starting or modifying ARV drug regimens in women whose HIVRNA levels are above the threshold for resistance testing (that is, >500 to 1,000 copies/mL) (see Antiretroviral DrugResistance and Resistance Testing in Pregnancy) (AIII). When HIV is diagnosed later in pregnancy, ART or combinationARV prophylaxis should be initiated promptly without waiting for results of resistance testing (BIII).• In counseling patients, the importance of adherence to their ARV regimens should be emphasized (AII).• Considerations regarding continuing the ARV regimen for maternal treatment after delivery are the same as in non-pregnant individuals. The pros and cons of continuing versus discontinuing ARV drugs postpartum should be discussedwith women so they can make educated decisions about postpartum ARV use before delivery (AIII). Those decisionsshould be made in consultation with the provider who will assume responsibility for the women’s HIV care after delivery.• Coordination of services among prenatal care providers, primary care and HIV specialty care providers, mental health anddrug abuse treatment services, and public assistance programs is essential to ensure that infected women adhere to theirARV drug regimens (AIII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.e. screening for hepatitis C virus and tuberculosis in addition to standard screening for hepatitis B virus(HBV) infection;f. evaluation of immunization status per guidelines from the American College of Obstetricians andGynecologists, with particular attention to hepatitis A, HBV, influenza, pneumococcus, and Tdapimmunizations;2, 3g. baseline complete blood cell count and renal and liver function testing;h. HLA-B*5701 testing if abacavir use is anticipated (see Table 5);i history of prior and current antiretroviral (ARV) drug use, including prior ARV use for prevention ofperinatal transmission or treatment of HIV and history of adherence problems;j. results of prior and current HIV ARV drug-resistance studies; k. history of side effects or toxicities from prior ARV regimens; andl. assessment of supportive care needs.ARV drugs for prevention of perinatal transmission of HIV are recommended for all pregnant women,regardless of CD4-cell counts and HIV RNA levels. In general, guidelines for the use of antiretroviraltherapy (ART) for the benefit of maternal health during pregnancy are the same as for women who are notpregnant, with some modifications based on concerns about specific drugs and limited experience duringpregnancy with newer drugs. Decisions regarding initiation or modification of ARV drug regimens during pregnancy includeconsiderations regarding the benefits and risks of ARV drugs that are common to all HIV-infected adults plusthose unique to pregnancy. In general, the ARV drug combinations now available are more convenient andbetter tolerated than regimens used previously, resulting in greater efficacy and improved adherence. Duringpregnancy, maternal ARV toxicities must be considered, along with the potential impact of the ARV regimenon pregnancy outcome and on fetuses and infants. Decisions about ARV drug regimens are furthercomplicated because only limited data exist on the long-term maternal consequences of use of agents duringpregnancy solely for preventing transmission. Similarly, only limited data are available on the long-termconsequences to infants of in utero exposure to ARVs.The known benefits and known and unknown risks of ARV drug use during pregnancy should be consideredand discussed with women (see Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-Infected Pregnant Women and Their Infants). Results from preclinical and animal studies and available clinicalinformation about use of the various agents during pregnancy also should be discussed (see Supplement: Safetyand Toxicity of Individual Antiretroviral Agents in Pregnancy). Potential risks of these drugs should be placedinto perspective by reviewing the substantial benefits of ARV drugs for maternal health and in reducing the riskof transmission of HIV to infants. Counseling of pregnant women about ARV use should be noncoercive, andproviders should help them make informed decisions regarding use of ARV drugs. Discussions with women about initiation of ARV drug regimens should include information about:a. maternal risk of disease progression and the benefits and risks of initiation of therapy for maternalhealth;b. benefit of combination ARV regimens for preventing perinatal transmission of HIV;4c. benefits of therapy for reducing sexual transmission to discordant partners when viral suppression ismaintained;5d. potential adverse effects of ARV drugs for mothers, fetuses, and infants, including potentialinteractions with other medications the women may already be receiving;e. the limited long-term outcome data for both women who temporarily use ARV drugs duringRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-2Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.pregnancy for prophylaxis of transmission and infants with in utero drug exposure; andf. the need for strict adherence to the prescribed drug regimen to avoid resistance.Studies of zidovudine in prevention of perinatal transmission suggest that an important mechanism of infantpre-exposure prophylaxis is transplacental drug passage. Thus, when selecting an ARV regimen for apregnant woman, at least one nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) agent with highplacental transfer should be included as a component of the dual-NRTI backbone (see Table 5).6-9In women with plasma HIV RNA levels above the threshold for resistance testing (that is, >500–1,000copies/mL), ARV drug-resistance studies should be performed before starting ARV drugs for maternal healthor prophylaxis. When HIV is diagnosed later in pregnancy, however, ARV drugs should be initiated promptlywithout waiting for results of resistance testing (see Antiretroviral Drug Resistance and Resistance Testing inPregnancy).Counseling should emphasize the importance of adherence to the ARV drug regimen. Support services,mental health services, and drug abuse treatment may be required, depending on women’s individualcircumstances. Coordination of services among prenatal care providers, primary care and HIV specialty careproviders, mental health and drug abuse treatment services, and public assistance programs is essential toensure that infected women adhere to their ARV drug regimens.Providers should work with women to develop long-range plans regarding continuity of medical care anddecisions about continuing ARV drugs postpartum. Considerations regarding postpartum continuation ofARV drugs for maternal therapeutic indications are the same as for non-pregnant individuals. The impact onshort- and long-term maternal health is unknown for postpartum discontinuation of combination ARV drugregimens used solely to prevent perinatal transmission. This is particularly important because women mayhave multiple pregnancies resulting in episodic receipt of ARV drugs. No increase in disease progression hasbeen seen so far, however, in studies of pregnant women with relatively high CD4-cell counts who stopcombination ARV drug regimens after delivery.10-12The risks versus benefits of stopping ARV drug regimenspostpartum in women with high CD4-cell counts are being evaluated in the ongoing PROMISE study(clinical trial number NCT00955968).Current adult treatment guidelines strongly recommend ART for all individuals with CD4-cell counts cells/mm3based on randomized, controlled clinical trial data demonstrating a clear benefit in reduction ofmortality and morbidity. Pregnant women with CD4-cell counts 3should begin ART as soonas possible during pregnancy and be counseled about the need to continue therapy after delivery and theimportance of adherence to the regimen.Based on observational cohort data and recent results from a randomized trial, the adult treatment guidelinesalso recommend initiating lifelong ART in individuals with CD4-cell counts between 350 and 500 cells/mm3.Observational studies suggest a relative decrease in mortality (although the overall number of events wassmall) and possibly a decrease in complications such as cardiovascular events with initiation of ART in thissetting compared with waiting until CD4-cell counts drop below 350 cells/mm3. 13, 14The HPTN 052 studywas a large, multinational randomized trial evaluating whether treatment of HIV-infected individuals reducestransmission to their uninfected sexual partners.5An additional objective was to examine if ART reducedclinical events in the HIV-infected participants. This trial enrolled 1,763 HIV-infected participants with CD4-cell counts between 350 and 550 cells/mm3and their HIV-uninfected partners. The infected participants wererandomized to immediate initiation of ART or delay of initiation until they had 2 consecutive CD4-cellcounts 3. At median follow-up of 1.7 years, there were 40 events/deaths in participantsassigned to immediate ART versus 65 in participants assigned to delayed initiation (hazard ratio [HR]: 0.59;95% confidence interval [CI]: 0.40–0.88). The observed difference was driven mainly by the incidence ofextrapulmonary tuberculosis (3 vs. 17 events). There was no significant difference in mortality ratesRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-3Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.observed in the immediate versus deferred therapy arms (10 vs. 13 deaths, respectively; HR: 0.77; 95% CI:0.34–1.76). The trial was stopped early because of a significantly reduced rate of transmission to sexualpartners in the group who started therapy immediately compared with those who delayed. Of 28transmissions that were virologically linked to the infected partner, only 1 occurred in the immediate-therapyarm (HR, 0.04; 95% CI, 0.01–0.27; P 5Pregnant women with CD4-cell counts between 350 and 500 cells/mm3should be started on a combinationARV regimen during pregnancy to prevent perinatal transmission of HIV and counseled about the currenttreatment recommendations, the potential risks versus benefits of stopping versus continuing the regimen afterdelivery (including reduction in transmission to discordant partners with continuing therapy when viralsuppression is maintained), and the need for sustained strict adherence if the regimen is continued postpartum.For individuals with CD4-cell counts >500 cells/mm3, the adult guidelines recommend initiating lifelongtherapy as a moderate recommendation, given that data are incomplete on the clinical benefit of startingtreatment at higher CD4-cell counts (>500 cells/mm3). So far, no increased risk of disease progression hasbeen shown in studies of pregnant women with relatively high CD4-cell counts who stop ARV drugs afterdelivery.10-12The potential benefits of early therapy must be weighed against possible drug toxicity, cost, andthe risk of development of viral resistance with suboptimal adherence, which may be more likelypostpartum.15Pregnant women with CD4-cell counts >500 cells/mm3should be started on a combinationARV regimen during pregnancy to prevent perinatal transmission. They should be assessed for theirwillingness and ability to commit to ongoing continuous therapy and counseled about the current treatmentguidelines, the benefits and risks of therapy, the inconclusive nature of data on the clinical benefit of startinglifelong treatment at CD4-cell counts >500 cells/mm3, and the importance of adherence if the regimen iscontinued postpartum.In general, when drugs are discontinued postnatally, all drugs should be stopped simultaneously. However, asdiscussed later (see Stopping Antiretroviral Therapy during Pregnancy), in women receiving non-nucleosidereverse transcriptase inhibitor (NNRTI)-based regimens, continuing the dual-NRTI backbone for a period oftime after stopping the NNRTI is recommended to reduce the development of NNRTI resistance. Analternative strategy is to replace the NNRTI with a protease inhibitor (PI) while continuing the NRTI andthen discontinue all the drugs at the same time.16The optimal interval between stopping an NNRTI andstopping the other ARV drugs is unknown, but a minimum of 7 days is recommended. Drug concentrationsmay be detectable for more than 3 weeks after efavirenz is stopped in patients receiving an efavirenz-basedNNRTI regimen. Therefore, for patients receiving the drug, some experts recommend continuing the otherARV agents or substituting a PI plus two other agents for up to 30 days.Medical care of HIV-infected pregnant women requires coordination and communication between HIVspecialists and obstetrical providers. General counseling should include current knowledge about risk factorsfor perinatal transmission. Risk of perinatal transmission of HIV has been associated with potentiallymodifiable factors, including cigarette smoking, illicit drug use, genital tract infections, and unprotectedsexual intercourse with multiple partners during pregnancy.17-21Besides improving maternal health, cessationof cigarette smoking and drug use, treatment of genital tract infections, and use of condoms with sexualintercourse during pregnancy may reduce risk of perinatal transmission. In addition, the Centers for DiseaseControl and Prevention recommends that HIV-infected women in the United States (including thosereceiving ART) refrain from breastfeeding to avoid postnatal transmission of HIV to their infants throughbreast milk22and avoid premastication of food for their infants, a potential risk factor for transmission.23The National Perinatal HIV Hotline (1-888-448-8765)The National Perinatal HIV Hotline is a federally funded service providing free clinical consultation toproviders caring for HIV-infected women and their infants.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-4Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-5Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 1 of 16)(See also Safety and Toxicity of Individual Antiretroviral Drugs in Pregnancysupplement for additional toxicity data and Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescentsfor detailed guidelines regarding treatment options.)ARV DrugGeneric Name(Abbreviation)Trade NameFormulationDosingRecommendationsaRecommendations for Use inPregnancyPKs inPregnancybConcerns in PregnancyNRTIsNRTIs are recommended for use as part ofcombination regimens, usually including twoNRTIs with either an NNRTI or one or morePIs. Use of single or dual NRTIs alone is notrecommended for treatment of HIV infection. See text for discussion of potentialmaternal and infant mitochondrialtoxicity.Preferred AgentsLamivudine(3TC)EpivirEpivir150-, 300-mgtablets or 10-mg/mL oralsolutionEpivir150 mg BID or 300 mg once dailyTake without regard tomeals.Because of extensive experience with 3TC inpregnancy in combination with ZDV, 3TC plusZDV is a recommended dual-NRTI backbonefor pregnant women.PK not significantlyaltered inpregnancy; nochange in doseindicated.24Highplacental transferto fetus.No evidence of humanteratogenicity (can rule out 1.5-foldincrease in overall birth defects).25Well tolerated; short-term safetydemonstrated for mothers andinfants. If hepatitis B coinfected,possible hepatitis B flare if drugstopped postpartum; see SpecialSituations: Hepatitis B VirusCoinfection.Combivir3TC 150 mg +ZDV 300 mgCombivir1 tablet BIDEpzicom3TC 300 mg +ABC 600 mgEpzicom1 tablet once dailyTrizivirc3TC 150 mg +ZDV 300 mg +ABC 300 mgTrizivir1 tablet BIDDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-6Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 2 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulationDosingRecommendationsaRecommendations for Use inPregnancyPKs inPregnancybConcerns in PregnancyZidovudine(AZT, ZDV)RetrovirRetrovir100-mg capsules,300-mg tablets,10-mg/mL IV solution,10-mg/mL oral solutionRetrovir300 mg BID or200 mg TIDTake without regard tomeals.Because of extensive experience withZDV in pregnancy in combination with3TC, ZDV plus 3TC is a recommendeddual-NRTI backbone for pregnantwomen.PK not significantlyaltered in pregnancy;no change in doseindicated.26Highplacental transfer tofetus.No evidence of humanteratogenicity (can rule out 1.5-foldincrease in overall birth defects).25Well tolerated; short-term safetydemonstrated for mothers andinfants.CombivirZDV 300 mg +3TC 150 mgCombivir1 tablet BIDTrizivircZDV 300 mg + 3TC 150 mg + ABC 300 mgTrizivir1 tablet BIDAlternative AgentsAbacavir(ABC)ZiagenZiagen300-mg tablets or 20-mg/mLoral solutionZiagen300 mg BID or600 mg once dailyTake without regard tomeals.Alternative NRTI for dual-NRTIbackbone of combination regimens.See footnote regarding use in triple-NRTI regimen.cPK not significantlyaltered in pregnancy;no change in doseindicated.27Highplacental transfer tofetus.No evidence of humanteratogenicity (can rule out 2-foldincrease in overall birth defects).25Hypersensitivity reactions occur in~5%–8% of non-pregnantindividuals; a much smallerpercentage are fatal and are usuallyassociated with re-challenge. Ratein pregnancy unknown. Testing forHLA-B*5701 identifies patients atrisk of reactions 28, 29and shouldbe done and documented asnegative before starting ABC.Patients should be educatedregarding symptoms ofhypersensitivity reaction.EpzicomABC 600 mg + 3TC 300 mg Epzicom1 tablet once dailyTrizivircABC 300 mg + ZDV 300 mg + 3TC 150 mg Trizivir1 tablet BIDDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-7Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 3 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulationDosingRecommendationsaRecommendations for Usein PregnancyPKs inPregnancybConcerns in PregnancyAlternative Agents, continuedEmtricitabine(FTC)EmtrivaEmtriva200-mg capsuleor 10-mg/mL oral solutionEmtriva200-mg capsule once daily or240-mg (24-mL) oralsolution once dailyTake without regard to meals.Alternative NRTI for dual-NRTIbackbone of combinationregimens.PK study showsslightly lower levelsin third trimester,compared withpostpartum.30Noclear need toincrease dose. Highplacental transfer tofetus.No evidence of human teratogenicity(can rule out 2-fold increase inoverall birth defects).25If hepatitis Bcoinfected, possible hepatitis B flareif drug stopped postpartum; seeSpecial Situations: Hepatitis B VirusCoinfection.TruvadaFTC 200 mg + TDF 300 mg Truvada1 tablet once dailyAtriplaFTC 200 mg + EFVd600 mg + TDF 300 mgAtripla1 tablet at or before bedtimeTake on an empty stomach toreduce side effects.TenofovirDisoproxilFumarate(TDF)VireadViread300-mg tabletViread1 tablet once dailyTake without regard to meals.Alternative NRTI for dual-NRTIbackbone of combinationregimens. TDF would be apreferred NRTI in combinationwith 3TC or FTC in women withchronic HBV infection. Because ofpotential for renal toxicity, renalfunction should be monitored.AUC lower in thirdtrimester thanpostpartum buttrough levelsadequate.31Highplacental transfer tofetus.7, 32-35No evidence of human teratogenicity(can rule out 2-fold increase inoverall birth defects).25Studies inmonkeys at doses approximately 2-fold higher than that for humantherapeutic use show decreased fetalgrowth and reduction in fetal boneporosity within 2 months of startingmaternal therapy.36Clinical studies inhumans (particularly children) showbone demineralization with chronicuse; clinical significance unknown.37,38If hepatitis B coinfected, possiblehepatitis B flare if drug stoppedpostpartum; see Special Situations:Hepatitis B Virus Coinfection.TruvadaTDF 300 mg + FTC 200 mg Truvada1 tablet once dailyAtriplaTDF 300 mg + EFVd600 mg + FTC 200 mg Atripla1 tablet at or before bedtimeTake on an empty stomach toreduce side effects.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-8Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 4 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulationDosingRecommendationsaRecommendations for Usein PregnancyPKs inPregnancybConcerns in PregnancyUse in Special CircumstancesDidanosine(ddI)Videx EC,generic didanosine(dose same asVidex EC)Videx EC125-, 200-, 250-, 400-mgcapsulesBuffered tablets (non-EC)no longer availableVidex10-mg/mL oral solutionBody weight ≥60kg: 400 mgonce daily; with TDF, 250 mgonce dailyBody weight once daily; with TDF, 200 mgonce dailyTake 1/2 hour before or 2hours after a meal.Preferred dosing with oralsolution is BID (total dailydose divided into 2 doses).Because of the need to administeron empty stomach and potentialtoxicity, ddI should be used onlyin special circumstances wherepreferred or alternative NRTIscannot be used. ddI should notbe used with d4T.PK not significantlyaltered in pregnancy;no change in doseindicated.39Moderateplacental transfer tofetus.In the APR, an increased rate of birthdefects with ddI compared to generalpopulation was noted after both firsttrimester (19/409, 4.6%, 95% CI,2.8–7.2) and later exposure (20/460,4.3%, 95% CI 2.7–6.6). Thisdifference may have been due tomaternal characteristics such asolder age or more advanced diseaseamong women using ddI. No specificpattern of defects was noted andclinical relevance is uncertain. Lacticacidosis, sometimes fatal, has beenreported in pregnant womenreceiving ddI and d4T together.40, 41Stavudine(d4T)ZeritZerit15-, 20-, 30-, 40-mgcapsules or 1-mg/mL oralsolutionBody weight ≥60 kg:40 mg BIDBody weight 30 mg BIDTake without regard to meals.WHO recommends 30-mgBID dosing regardless ofbody weight.Because of potential toxicities,d4T should be used only inspecial circumstances wherepreferred or alternative NRTIscannot be used. d4T should notbe used with ddI or ZDV. PKs not significantlyaltered in pregnancy;no change in doseindicated.9Highplacental transfer.No evidence of human teratogenicity(can rule out 2-fold increase inoverall birth defects).25Lacticacidosis, sometimes fatal, has beenreported in pregnant womenreceiving ddI and d4T together.40, 41Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-9Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 5 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulationDosingRecommendationsaRecommendations for Usein PregnancyPKs inPregnancybConcerns in PregnancyNNRTIsNNRTIs are recommended foruse in combination regimens with2 NRTI drugs.Hypersensitivity reactions, includinghepatic toxicity, and rash morecommon in women; unclear ifincreased in pregnancy.Preferred AgentsNevirapine(NVP)Viramune200-mg tablets or50-mg/5-mL oralsuspension200 mg once daily for 14days (lead-in period);thereafter, 200 mg BIDTake without regard to meals.Repeat lead-in period iftherapy is discontinued for>7 days.In patients who develop mild-to-moderate rash withoutconstitutional symptomsduring lead-in, continue lead-in dosing until rash resolves,but ≤28 days total.NVP should be initiated inpregnant women with CD4 T-lymphocyte (CD4-cell) counts>250 cells/mm3only if benefitclearly outweighs risk because ofthe increased risk of potentiallylife-threatening hepatotoxicity inwomen with high CD4-cellcounts. Elevated transaminaselevels at baseline also mayincrease the risk of NVP toxicity.Women who become pregnantwhile taking NVP-containingregimens and are tolerating themwell can continue therapy,regardless of CD4-cell count.PK not significantlyaltered in pregnancy;no change in doseindicated.42-44Highplacental transfer tofetus.No evidence of human teratogenicity(can rule out 2-fold increase inoverall birth defects).25Increasedrisk of symptomatic, often rash-associated, and potentially fatal livertoxicity among women with CD4-cellcounts >250/mm3when firstinitiating therapy; 45, 46unclear ifpregnancy increases risk.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-10Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 6 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulationDosingRecommendationsaRecommendations for Use inPregnancyPKs inPregnancybConcerns in PregnancyUse in Special CircumstancesEfavirenzd(EFV)Sustiva50-, 200-mg capsulesor 600-mg tablets600 mg once daily at orbefore bedtimeTake on an empty stomachto reduce side effects.Non-pregnant women of childbearingpotential should undergo pregnancytesting before initiation of EFV andcounseling about the potential risk tothe fetus and desirability of avoidingpregnancy while on EFV-containingregimens. Alternate ARV regimens thatdo not include EFV should be stronglyconsidered in women who 1) areplanning to become pregnant or 2) aresexually active and not using effectivecontraception, assuming thesealternative regimens are acceptable tothe provider and are not thought tocompromise the health of the woman.Because the risk of neural tube defectsis restricted to the first 5–6 weeks ofpregnancy and pregnancy is rarelyrecognized before 4–6 weeks ofpregnancy, and unnecessary ARV drugchanges during pregnancy may beassociated with loss of viral control andincreased risk of perinataltransmission, EFV may be continued inpregnant women receiving an EFV-based regimen who present forantenatal care in the first trimester,provided there is virologic suppressionon the regimen (see HIV-InfectedPregnant Women Who are CurrentlyReceiving Antiretroviral Treatment).AUC decreasedduring thirdtrimester, comparedwith postpartum, butnearly all third-trimester subjectsexceeded targetexposure and nochange in dose isindicated.47Moderateplacental transfer tofetus.FDA Pregnancy Class D; significantmalformations (anencephaly,anophthalmia, cleft palate) wereobserved in 3 of 20 infants (15%)born to cynomolgus monkeysreceiving EFV during the firsttrimester at a dose resulting inplasma levels comparable tosystemic human therapeuticexposure. There are 4 retrospectivecase reports and 1 prospective casereport of neural tube defects inhumans with first-trimester exposureand 1 prospective case ofanophthalmia with facial clefts; 25, 48,49relative risk unclear.AtriplaEFVd600 mg + FTC 200 mg + TDF 300 mgAtripla1 tablet once daily at orbefore bedtimeDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-11Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 7 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulationDosingRecommendationsaRecommendations forUse in PregnancyPKs in PregnancybConcerns in PregnancyInsufficient Data to Recommend UseEtravirine(ETR)Intelence100-, 200-mg tablets 200 mg BIDTake following a meal.Safety and PK data inpregnancy are insufficient torecommend use duringpregnancy.Limited PK data in pregnancy;in 4 pregnant women, druglevels and AUC similar tothose in non-pregnant adults,suggesting no dosemodification needed.50Limited experience in humanpregnancy. Only 23 first-trimesterexposures have been reported toAPR. No evidence of teratogenicity inrats and rabbits.Rilpivirine(RPV)Endurant25-mg tablets 25 mg once daily with ameal.Safety and PK data inpregnancy are insufficient torecommend use duringpregnancy.No PK studies in humanpregnancy, placental transferrate unknown.No published experience in humanpregnancy. No evidence ofteratogenicity in rats or rabbits.CompleraRPV 25 mg +TDF 300 mg +FTC 200 mgComplera1 tablet once dailyPIsPIs are recommended for usein combination regimens with2 NRTI drugs.Hyperglycemia, new onset orexacerbation of diabetes mellitus,and diabetic ketoacidosis reportedwith PI use; unclear if pregnancyincreases risk. Conflicting dataregarding preterm delivery in womenreceiving PIs (see text).Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-12Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 8 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulation Dosing RecommendationsaRecommendations for Usein PregnancyPKs in PregnancybConcerns in PregnancyPreferred AgentsAtazanavir(ATV)Reyataz (combinedwith low-dose RTVboosting)100-, 150-, 200-,300-mg capsulesATV 300 mg + RTV 100 mg oncedailySecond and third trimester:Some experts recommendincreased dose (ATV 400 mg +RTV 100 mg once daily) in allpregnant women in the secondand third trimestersATV package insert recommendsincreased dose (ATV 400 mg +RTV 100 mg once daily) in thefollowing situations:- With TDF or H2-receptorantagonist (not both; use ofboth with ATV notrecommended) in ARV-experienced pregnant patients- With EFVdin ARV-naive patients(Concurrent use of ATV with EFVin ARV-experienced patients isnot recommended because ofdecreased ATV levels.)Take with food.Preferred PI for use incombination regimens inpregnancy. Should give as low-dose RTV-boosted regimen, mayuse once-daily dosing. Severalstudies have shown decreasedATV plasma concentrations withstandard dosing duringpregnancy.32, 51, 52Use of anincreased dose during the secondand third trimesters resulted inplasma concentrations equivalentto those in non-pregnant adults onstandard dosing.53Although someexperts recommend increasedATV dosing in all women duringthe second and third trimesters,the package insert recommendsincreased ATV dosing only forARV-experienced pregnant womenin the second and third trimestersalso receiving either TDF or an H2-receptor antagonist or ARV-naivepregnant women receiving EFV.ATV should not be used in patientsreceiving both TDF and H2receptor antagonists or in ARV-experienced patients also takingEFV.Two of three intensive PKstudies of ATV with RTVboosting during pregnancyand the PK study described inthe recently approved productlabel suggest that standarddosing in pregnancy results indecreased plasmaconcentrations, comparedwith non-pregnant adults.32, 35,51, 52ATV concentrationsfurther reduced ~25% withconcomitant TDF use.32, 35Low placental transfer tofetus.32, 51No evidence of humanteratogenicity (can rule out 2-fold increase in overall birthdefects).25Theoretical concernregarding increased indirectbilirubin levels causingsignificant exacerbation inphysiologic hyperbilirubinemiain neonates has not beenobserved in clinical trials todate.32, 35, 51, 52, 54Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-13Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 9 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulation Dosing RecommendationsaRecommendations for Usein PregnancyPKs in PregnancybConcerns inPregnancyPreferred Agents, continuedLopinavir +Ritonavir (LPV/r)KaletraTablets: (LPV 200 mg +RTV 50 mg) or(LPV 100 mg + RTV 25 mg)Oral solution: Each 5 mLcontains LPV 400 mg +RTV 100 mgOral solution contains42% alcohol andtherefore may not beoptimal for use inpregnancy.LPV/r 400 mg/100 mg BIDSecond and third trimester:Some experts recommendincreased dose (LPV/r 600mg/150 mg BID) in second andthird trimesters.With EFVd or NVP (PI-naive or PI-experienced patients):LPV/r 500 mg/125 mg tablets BID(Use a combination of two LPV/r200 mg/50 mg tablets + oneLPV/r 100 mg/25 mg tablet tomake a total dose of LPV/r 500mg/125 mg)orLPV/r 533 mg/133 mg oralsolution (6.5mL) BID.Tablets: Take without regard to meals.Oral solution: Take with food.Not used in pregnancy: Adultdosage of LPV/r 800 mg/200 mgonce daily is not recommendedfor use in pregnancy.PK studies suggest dose shouldbe increased to 600 mg/150 mgBID in second and thirdtrimesters, especially in PI-experienced patients. If standarddosing is used, monitor virologicresponse and LPV drug levels, ifavailable. Once-daily LPV/r dosingis not recommended duringpregnancy because there are nodata to address whether druglevels are adequate with suchadministration.AUC decreased in secondand third trimesters withstandard dosing.55-57AUCwith dose of LPV/r 600mg/150 mg twice daily inthird trimester in U.S.women resulted in AUCsimilar to that in non-pregnant adults taking LPV/r400 mg/100 mg dose twicedaily.30Low placentaltransfer to fetus.No evidence of humanteratogenicity (can rule out2-fold increase in overallbirth defects).25Welltolerated; short-termsafety demonstrated inPhase I/II studies.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-14Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 10 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulation Dosing RecommendationsaRecommendations for Usein PregnancyPKs in PregnancybConcerns in PregnancyPreferred Agents, continuedRitonavir(RTV)NorvirWhen used as low-dose booster withother PIs100-mg capsules100-mg tablets80-mg/mL oralsolutionOral solutioncontains 43%alcohol andtherefore may notbe optimal for usein pregnancy.As PK booster for other PIs: 100–400 mg per day in 1–2divided doses (Refer to other PIsfor specific dosingrecommendations.)Tablets: Take with food.Capsule and oral solution: Takewith food if possible, which mayimprove tolerability.Should only be used incombination with second PI aslow-dose RTV “boost” to increaselevels of second PI because of lowdrug levels in pregnant womenwhen used as a sole PI and poortolerance when given as full dose.Phase I/II study in pregnancyshowed lower levels duringpregnancy compared withpostpartum.58Minimalplacental transfer to fetus.No evidence of humanteratogenicity (can rule out 2-fold increase in overall birthdefects).25Limited experienceat full dose in humanpregnancy; should be used aslow-dose RTV boosting withother PIs.Alternative AgentsDarunavir(DRV)Prezista (must becombined withlow-dose RTVboosting)75-, 150-, 400-,600-mg tabletsARV-naive patients:(DRV 800 mg + RTV 100 mg)once dailyARV-experienced patients:(DRV 800 mg + RTV 100 mg)once daily if no DRV resistancemutations(DRV 600 mg + RTV 100 mg) BIDif any DRV resistance mutationsSome experts recommend use ofonly twice-daily dosing (DRV 600mg + RTV 100 mg BID) duringpregnancy.Unboosted DRV is notrecommended.Take with food.Safety and PK data in pregnancyare limited. DRV may beconsidered when preferred andalternative agents cannot be used.Must give as low-dose RTV-boosted regimen.In PK study of women in thethird trimester andpostpartum, third-trimesterDRV average plasmaconcentrations weredecreased by 23%–28% withonce- and twice-daily dosingand third-trimester DRVtrough concentrations werelow, especially with once-dailydosing.59Some expertsrecommend use of only twice-daily dosing during pregnancyand investigation of use of anincreased twice-daily dose isunder way. Low placentaltransfer to fetus.59Insufficient data to assess forteratogenicity in humans. Noevidence of teratogenicity inmice, rats, or rabbits but lowbioavailability limited exposure.Limited experience in humanpregnancy.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-15Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 11 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulation Dosing RecommendationsaRecommendations forUse in PregnancyPKs in PregnancybConcerns in PregnancyAlternative Agents, continuedSaquinavir(SQV)Invirase(available ascapsules andtablets. SQV mustbe combined withlow-dose RTVboosting.)500-mg tablets or200-mg capsules(SQV 1000 mg + RTV 100 mg)BIDUnboosted SQV is notrecommended.Take with meals or within 2 hoursafter a meal.PK data on SQV capsules andthe tablet formulation inpregnancy are limited. RTV-boosted SQV capsules or SQVtablets are alternative PIs forcombination regimens inpregnancy and are alternativeinitial ARV recommendationsfor non-pregnant adults. Mustgive as low-dose RTV-boostedregimen.Limited PK data oncapsules and the 500-mgtablet formulation suggestthat 1000-mg SQV capsules/100 mg RTV given twicedaily achieves adequateSQV drug levels in pregnantwomen.60Minimal placentaltransfer to fetus.Insufficient data to assess forteratogenicity in humans. No evidenceof teratogenicity in rats or rabbits butlow bioavailability limited exposure.Well tolerated; short-term safetydemonstrated for mothers and infantsfor SQV in combination with low-doseRTV. Baseline ECG recommendedbefore starting because PR and/or QTinterval prolongations have beenobserved and drug is contraindicatedin patients with pre-existing cardiacconduction system disease. Use in Special CircumstancesIndinavir(IDV)Crixivan(combined withlow-dose RTVboosting)100-, 200-, 400-mg capsulesWith RTV:(IDV 800 mg + RTV 100–200 mg)BIDTake without regard to meals.Not used in pregnancy: Adultdosage of IDV (without RTV) 800mg every 8 hours is notrecommended for use inpregnancy.Because of twice-daily dosing,pill burden, and potential forrenal stones, IDV should onlybe used when preferred andalternative agents cannot beused. Must give as low-doseRTV-boosted regimen.Two studies including 18women receiving IDV 800mg TID showed markedlylower levels duringpregnancy compared withpostpartum, althoughsuppression of HIV RNAlevels was seen.61, 62In astudy of RTV-boosted IDV(400 mg IDV/100 mg RTVtwice daily), 82% of womenmet the target troughlevel.63Minimal placentaltransfer to fetus.No evidence of human teratogenicity(can rule out 2-fold increase inoverall birth defects).25Theoreticalconcern regarding increased indirectbilirubin levels, which mayexacerbate physiologichyperbilirubinemia in neonates, butminimal placental passage. Use ofunboosted IDV during pregnancy isnot recommended. Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-16Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 12 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulation Dosing RecommendationsaRecommendations forUse in PregnancyPKs in PregnancybConcerns in PregnancyUse in Special Circumstances, continuedNelfinavir(NFV)Viracept250-, 625-mgtablets50-mg/g oralpowder1250 mg BIDTake with food.Not used in pregnancy: Adultdosage of NFV 750 mg TID is notrecommended for use inpregnancy.Given PK data and extensiveexperience with use inpregnancy, NFV might beconsidered in specialcircumstances for prophylaxisof transmission in women inwhom therapy would nototherwise be indicated whenalternative agents are nottolerated. In clinical trials ofinitial therapy in non-pregnantadults, NFV-based regimenshad a lower rate of viralresponse compared with LPV/r-or EFV-based regimens butsimilar viral response to ATV-or NVP-based regimens.Adequate drug levels areachieved in pregnant womenwith NFV 1250 mg given twicedaily, although levels arevariable in late pregnancy.43, 64,65In a study of women in theirsecond and third trimestersdosed at 1250 mg twice daily,women in the third trimesterhad lower concentration of NFVthan those in the secondtrimester.65In a study of thenew 625-mg tablet formulationdosed at 1250 mg twice daily,lower AUC and peak levelswere observed during the thirdtrimester than postpartum.66Minimal to low placentaltransfer to fetus.No evidence of human teratogenicity(can rule out 2-fold increase inoverall birth defects).25Welltolerated; short-term safetydemonstrated for mothers andinfants.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-17Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 13 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulation Dosing RecommendationsaRecommendations forUse in PregnancyPKs in PregnancybConcerns in PregnancyInsufficient Data to Recommend UseFosamprenavir(FPV)Lexiva (a prodrugof amprenavir)(recommended tobe combined withlow-dose RTVboosting)700-mg tabletor 50-mg/mLoralsuspensionARV-naive patients:• FPV 1400 mg BID or• (FPV 1400 mg + RTV 100–200mg) once daily or• (FPV 700 mg + RTV 100 mg)BIDPI-experienced patients (once-daily dosing not recommended):• (FPV 700 mg + RTV 100 mg)BIDWith EFV:• (FPV 700 mg + RTV 100 mg)BID or• (FPV 1400 mg + RTV 300 mg)once dailyTablet: Take without regard to meals (ifnot boosted with RTV tablet).Suspension: Take without food.FPV with RTV tablet: Take with meals.Safety and PK data inpregnancy are insufficient torecommend routine use duringpregnancy in ARV-naivepatients. Recommended to begiven as low-dose RTV-boostedregimen.With RTV boosting, AUC isreduced during the thirdtrimester. However, exposure isgreater during the thirdtrimester with boosting than innon-pregnant adults withoutboosting and troughconcentrations achieved duringthe third trimester wereadequate for patients withoutPI resistance mutations.67Lowplacental transfer to fetus.Insufficient data to assess forteratogenicity in humans. Increasedfetal loss in rabbits but no increase indefects in rats and rabbits. Limitedexperience in human pregnancy.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-18Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 14 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulation Dosing RecommendationsaRecommendations forUse in PregnancyPKs in PregnancybConcerns in PregnancyInsufficient Data to Recommend Use, continuedTipranavir(TPV)Aptivus (must becombined withlow-dose RTVboosting)250-mg capsulesor 100-mg/mL oralsolution(TPV 500 mg + RTV 200 mg) BIDUnboosted TPV is notrecommended.TPV taken with RTV tablets:Take with meals.TPV taken with RTV capsules orsolution:Take without regard to meals.Safety and PK data inpregnancy are insufficient torecommend routine use duringpregnancy in ARV-naivepatients. Must give as low-dose RTV-boosted regimen.Limited PK studies in humanpregnancy. Moderate placentaltransfer to fetus reported inone patient.68Insufficient data to assess forteratogenicity in humans. Noteratogenicity in rats or rabbits.Limited experience in humanpregnancy.Entry InhibitorsInsufficient Data to Recommend UseEnfuvirtide(T20)Fuzeon• Injectable—supplied aslyophilizedpowder• Each vialcontains 108mg of T20;reconstitutewith 1.1 mL ofsterile water forinjection fordelivery ofapproximately90 mg/1 mL.90 mg (1mL) SQ BID Safety and PK data inpregnancy are insufficient torecommend use duringpregnancy in ARV-naivepatients.Limited PK studies in humanpregnancy. No placentaltransfer to fetus, based on verylimited data.68 ,69Insufficient data to assess forteratogenicity in humans. Noevidence of teratogenicity in rats orrabbits. Minimal data in humanpregnancy.68, 70Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-19Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 15 of 16)ARV DrugGeneric Name(Abbreviation)Trade NameFormulation Dosing RecommendationsaRecommendations forUse in PregnancyPKs inPregnancybConcerns in PregnancyEntry Inhibitors, continuedInsufficient Data to Recommend Use, continuedMaraviroc(MVC)Selzentry150-, 300-mgtablets• 150 mg BID when given with strongCYP3A inhibitors (with or without CYP3Ainducers) including PIs (except TPV/r)• 300 mg BID when given with NRTIs,NVP, RAL, T-20, TPV/r, and other drugsthat are not strong CYP3A inhibitors orinducers• 600 mg BID when given with CYP3Ainducers, including EFV, ETR (without aCYP3A inhibitor)Take without regard to meals.Safety and PK data inpregnancy are insufficient torecommend use duringpregnancy in ARV-naivepatients.No PK studies inhuman pregnancy.Unknown placentaltransfer rate to fetus.Insufficient data to assess forteratogenicity in humans. Noevidence of teratogenicity in rats orrabbits. Limited experience inhuman pregnancy.Integrase InhibitorsUse in Special CircumstancesRaltegravir(RAL)Isentress400-mg tablets 400 mg BIDWith rifampin:800 mg BIDTake without regard to meals.Safety and PK data inpregnancy are limited; can beconsidered for use in specialcircumstances when preferredand alternative agents cannotbe used.During third trimester,RAL PK showedextensive variabilitybut RAL exposurewas not consistentlyaltered comparedwith postpartum andhistorical data. Thestandard doseappears appropriateduring pregnancy.71Variable but highplacental transfer tofetus.71, 72Insufficient data to assess forteratogenicity in humans. Increasedskeletal variants in rats, no increasein defects in rabbits. Limitedexperience in human pregnancy.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-20Key to Abbreviations: APR = Antiretroviral Pregnancy Registry, ARV = antiretroviral, AUC = area under the curve, BID = twice daily, CI = confidence interval, CYP = cytochrome P, EC =enteric coated, ECG = electrocardiogram, FDA = Food and Drug Administration, HBV = hepatitis B virus, IV = intravenous, NNRTI = non-nucleoside reverse transcriptase inhibitor, NRTI= nucleoside/nucleotide reverse transcriptase inhibitor, PI = protease inhibitor, PK = pharmacokinetic, PPI = proton pump inhibitor, SQ = subcutaneous injection, TID = three timesdaily, WHO = World Health OrganizationaDosage should be adjusted in renal or hepatic insufficiency (see Adult Guidelines, Appendix B, Table 7).bPlacental transfer categories—Mean or median cord blood/maternal delivery plasma drug ratio:High: >0.6Moderate: 0.3–0.6Low: 0.1–0.3Minimal: cTriple-NRTI regimens including abacavir have been less potent virologically compared with PI-based combination ARV drug regimens. Triple-NRTI regimens should be used onlywhen an NNRTI- or PI-based combination regimen cannot be used, such as because of significant drug interactions.dSee Teratogenicityfor discussion of efavirenz and risks in pregnancy.Table 5. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy andRecommendations for Use in Pregnancy (page 16 of 16)Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-21Recommendations for Use of Antiretroviral Drugs during PregnancyThe Panel recommends that choice of ARV drug regimens for HIV-infected pregnant women be based on thesame principles used to choose regimens for non-pregnant individuals, unless there are compellingpregnancy-specific maternal or fetal safety issues associated with specific drugs. The Panel reviews clinicaltrial data published in peer-reviewed journals and data prepared by manufacturers for Food and DrugAdministration review related to treatment of HIV-infected adult women, both pregnant and non-pregnant.The durability, tolerability, and simplicity of a medication regimen is particularly important for preservingfuture options for women who decide to stop medications after delivery and those who meet standard criteriafor initiation of ART per adult guidelines and will continue their regimens after pregnancy. Regimenselection should be individualized and the following factors should be considered:• comorbidities,• patient adherence potential,• convenience,• potential adverse maternal drug effects,• potential drug interactions with other medications,• results of genotypic resistance testing,• pharmacokinetic (PK) changes in pregnancy, • potential teratogenic effects and other adverse effects on fetuses or newborns, and• experience with use in pregnancy.Information used by the Panel for recommendations on specific drugs or regimens for pregnant womeninclude:• Data from randomized, prospective clinical trials that demonstrate durable viral suppression as wellas immunologic and clinical improvement;• Incidence rates and descriptions of short- and long-term drug toxicity of ARV regimens, with specialattention to maternal toxicity and potential teratogenicity and fetal safety;• Specific knowledge about drug tolerability and simplified dosing regimens;• Known efficacy of ARV drug regimens in reducing mother-to-child transmission of HIV;• PK data during the prenatal period. (The physiologic changes of pregnancy have the potential to alterdrug PK. ARV dosing during pregnancy should be based on PK data from studies in pregnant women.Physiologic changes are not fixed throughout pregnancy but, rather, reflect a continuum of change aspregnancy progresses, with return to baseline at various rates in the postpartum period.); and• Data from animal teratogenicity studies.Categories of ARV regimens include:• Preferred:Drugs or drug combinations are designated as preferred for use in pregnant women whenclinical trial data in adults have demonstrated optimal efficacy and durability with acceptable toxicityand ease of use; pregnancy-specific PK data are available to guide dosing; and no evidence ofteratogenic effects or established association with teratogenic or clinically significant adverseoutcomes for mothers, fetuses, or newborn are present.• Alternative:Drugs or drug combinations are designated as alternatives for initial therapy in pregnantwomen when clinical trial data in adults show efficacy but any one or more of the followingconditions apply: Experience in pregnancy is limited; data are lacking on teratogenic effects on theDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-22fetus; or the drug or regimen is associated with dosing, formulation, administration, or interactionissues.• Use in Special Circumstances:Drug or drug combinations in this category can be considered foruse when intolerance or resistance prohibits use of other drugs with fewer toxicity concerns or inwomen who have comorbidities or require concomitant medications that may limit drug choice, suchas active tuberculosis requiring rifampin therapy.• Not Recommended:Drugs and drug combinations listed in this category are not recommended fortherapy in pregnant women because of inferior virologic response, potentially serious maternal orfetal safety concerns, or pharmacologic antagonism.• Insufficient Data to Recommend:The drugs and drug combinations in this category are approvedfor use in adults but lack pregnancy-specific PK or safety data or such data are too limited to make arecommendation for use in pregnancy.In pregnancy, a combination ARV regimen with at least three agents is recommended for either treatment orprophylaxis. Recommendations for choice of ARV drug regimen during pregnancy must be individualizedaccording to a pregnant woman’s specific ARV history and the presence of comorbidities. Some women maybecome pregnant and present for obstetrical care while receiving ART for their own health. In these cases,the choice of active drugs with known safety data in pregnancy may be more limited. In general, women whoare already on a fully suppressive regimen should continue their regimens (see HIV-Infected PregnantWomen Who Are Currently Receiving Antiretroviral Therapy).Other HIV-infected women may not be receiving ART at the time they present for obstetrical care. Somewomen have never received ARV drugs, and others may have taken ARV drugs for treatment that wasstopped, for prophylaxis to prevent perinatal transmission of HIV in prior pregnancies, or for pre- or post-exposure prophylaxis. The following sections provide detailed discussions of recommendations based onmaternal ARV history and whether there are maternal indications for therapy.For ARV-naive women, a combination regimen including two NRTIs and either an NNRTI or a PI (generallywith low-dose ritonavir) would be preferred.The preferred NRTI combination for ARV-naive pregnant women is zidovudine/lamivudine, based onefficacy studies in preventing perinatal transmission (see Lessons from Clinical Trials of AntiretroviralInterventions to Reduce Perinatal HIV Transmission) and extensive experience with safe use in pregnancy.Alternate regimens can be used in women who are intolerant of zidovudine because of toxicity such assevere anemia or who have known resistance to the drug. Tenofovir is a preferred NRTI for non-pregnant women. Data from the Antiretroviral Pregnancy Registry on1,219 pregnancies with first-trimester exposure to the drug have shown no increase in overall birth defectscompared with the general population.25Animal studies, however, have shown decreased fetal growth andreduction in fetal bone porosity, and some studies in infected children on chronic tenofovir-based therapyhave shown bone demineralization in some children. Therefore, tenofovir would be considered an alternativeNRTI during pregnancy for ARV-naive women. For pregnant women with chronic HBV infection, however,tenofovir in combination with emtricitabine or lamivudine would be the preferred NRTI backbone in acombination ARV regimen. The combination of stavudine/didanosine should not be used in pregnant womenbecause fatal cases of lactic acidosis and hepatic failure have been reported in women who received thiscombination throughout pregnancy.In addition to the two NRTIs, either an NNRTI or a PI would be preferred for combination regimens in ARV-naive pregnant women. Efavirenz, the preferred NNRTI for non-pregnant adults, is not recommended forinitiation in ARV-naive women in the first trimester because of concerns related to teratogenicity (seeDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-23Teratogenicity). Non-pregnant women of childbearing potential should undergo pregnancy testing beforeinitiation of EFV and counseling about the potential risk to the fetus and desirability of avoiding pregnancywhile on EFV-containing regimens. Alternate ARV regimens that do not include EFV should be stronglyconsidered in women who 1) are planning to become pregnant or 2) are sexually active and not usingeffective contraception, assuming these alternative regimens are acceptable to the provider and are notthought to compromise the health of the woman. Because the risk of neural tube defects is restricted to thefirst 5–6 weeks of pregnancy and pregnancy is rarely recognized before 4–6 weeks of pregnancy, andunnecessary ARV drug changes during pregnancy may be associated with loss of viral control and increasedrisk of perinatal transmission, EFV may be continued in pregnant women receiving an EFV-based regimenwho present for antenatal care in the first trimester, provided there is virologic suppression on the regimen(see HIV-Infected Pregnant Women Who are Currently Receiving Antiretroviral Treatment). Initiation ofefavirenz can be considered after the first trimester, based on clinical indication, but current data are limitedin defining the safety of this use. Nevirapine would be the preferred NNRTI for ARV-naive pregnant womenwith CD4-cell counts 3, and it can be continued in ARV-experienced women already receivinga nevirapine-based regimen, regardless of CD4-cell count. In general, nevirapine should not be initiated intreatment-naive women with CD4-cell counts >250 cells/mm3because of an increased risk of symptomaticand potentially fatal rash and hepatic toxicity (see Special Considerations Regarding the Use of AntiretroviralDrugs by HIV-Infected Pregnant Women and their Infants). Elevated transaminase levels at baseline alsomay increase the risk of nevirapine toxicity.73Safety and PK data on etravirine and rilpivirine in pregnancyare insufficient to recommend use of these NNRTI drugs in ARV-naive women.Lopinavir/ritonavir and atazanavir with low-dose ritonavir boosting are the preferred PI drugs for use inARV-naive pregnant women, based on efficacy studies in adults and experience with use in pregnancy (seeTable 5for dosing considerations). Alternative PIs include ritonavir-boosted saquinavir or darunavir,although experience is more limited with these regimens in pregnancy.59, 74, 75Nelfinavir can be considered inspecial circumstances when used solely for prophylaxis of perinatal transmission in ARV-naive women forwhom therapy would not otherwise be indicated and who cannot tolerate alternative agents. PK data andextensive clinical experience do exist for nelfinavir in pregnancy, but the rate of viral response to nelfinavir-based regimens was lower than lopinavir/ritonavir or efavirenz-based regimens in clinical trials of initialtherapy in non-pregnant adults. Indinavir also can be considered in special circumstances for women inwhom preferred or alternative drugs cannot be used. Indinavir may be associated with renal stones and has ahigher pill burden than many other PI drugs. Data on use in pregnancy are too limited to recommend routineuse of fosamprenavir and tipranavir in pregnant women, although they can be considered for women who areintolerant of other agents.Safety and PK data in pregnancy are insufficient to recommend use of the entry inhibitors enfuvirtide andmaraviroc in ARV-naive women during pregnancy. Use of these agents can be considered for women whohave failed therapy with several other classes of ARV drugs after consultation with HIV and obstetricspecialists.Data on the integrase inhibitor raltegravir during pregnancy are limited but increasing; ART regimensincluding raltegravir can be considered for use in pregnancy in special circumstances when preferred andalternative agents cannot be used.71, 72, 74, 76, 77Although data are insufficient to support or refute the teratogenic risk of ARV drugs when administeredduring the first trimester, information to date does not support major teratogenic effects for the majority ofsuch agents. (For further data, see www.APRegistry.com.) However, certain drugs are of more concern thanothers—for example, efavirenz should be avoided during the first trimester when possible (see Supplement:Safety and Toxicity of Individual Antiretroviral Drugs in Pregnancy).Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Table 5provides recommendations for use of specific ARV drugs in pregnancy and data on PK and toxicityin pregnancy. Table 6summarizes management recommendations for the mothers and infants in a variety ofclinical scenarios.Table 6. Clinical Scenario Summary Recommendations for Antiretroviral Drug Use by Pregnant HIV-Infected Women and Prevention of Perinatal Transmission of HIV-1 in the United States (page 1 of 4)Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-24Clinical Scenario RecommendationsNon-pregnant HIV-infected women ofchildbearing potential (sexually activeand not using contraception) who haveindications for initiating antiretroviraltherapy (ART)Initiate combination antiretroviral (ARV) drug therapy as per adult treatmentguidelines. When feasible, include one or more nucleoside reverse transcriptaseinhibitors (NRTIs) with good placental passage as a component of the ARVregimen.• Exclude pregnancy and ensure access to effective contraception for sexuallyactive women before starting treatment with efavirenz; alternative ART regimensthat do not include efavirenz should be strongly considered in women who areplanning to become pregnant. Emphasize need for women on efavirenz to reviewtheir regimens with their providers before discontinuing contraception.HIV-infected women on ART whobecome pregnantWomen:• In general, in women who require treatment, ARV drugs should not be stoppedduring the first trimester or during pregnancy.• Continue current combination ARV regimen, assuming the regimen is toleratedand effective in successfully suppressing viremia.• Perform HIV ARV drug-resistance testing in women on therapy who havedetectable viremia (that is, >500–1,000 copies/mL).• Continue the ART regimen during the intrapartum period (if oral zidovudine ispart of the antepartum regimen, and a woman’s viral load is >400 copies/mL, theoral zidovudine component of her regimen should be stopped while she receiveszidovudine as an intravenous continuous infusionaduring labor and other ARVagents are continued orally) and postpartum.• Schedule cesarean delivery at 38 weeks if plasma HIV RNA remains >1,000copies/mL near the time of delivery.Infants:• Start zidovudine as soon as possible after birth and administer for 6 weeks.bDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-25Clinical Scenario RecommendationsHIV-infected pregnant women who areARV naiveWomen: Perform HIV ARV drug-resistance testing before initiating combinationARV drug therapy and repeat after initiating therapy if viral suppression issuboptimal (pregnancy, the ARV regimen should be initiated promptly without waiting for theresults of resistance testing.• Initiate combination ARV regimen.- Delayed initiation of ARVs until after the first trimester can be considered inwomen with high CD4 T-lymphocyte (CD4-cell) counts and low HIV RNAlevels, but earlier initiation may be more effective in reducing perinataltransmission of HIV. Benefits of first trimester use must be weighed againstpotential fetal effects of first-trimester exposure.- Avoid initiation of efavirenz or other potentially teratogenic drugs in the firsttrimester and drugs with known adverse potential for mother throughout thepregnancy.- When feasible, include one or more NRTIs with good placental passage(zidovudine, lamivudine, emtricitabine, tenofovir, or abacavir) in the ARVregimen.- Use nevirapine as a component of the ARV regimen only in women who haveCD4-cell counts ≤250 cells/mm3. Because of the increased risk of severehepatic toxicity, use nevirapine in women with CD4-cell counts >250cells/mm3only if the benefit clearly outweighs the risk.• Continue the combination regimen intrapartum. Continuous infusion zidovudineashould be administered to HIV-infected women with HIV RNA >400 copies/mL(or unknown HIV RNA) near delivery, regardless of antepartum regimen or modeof delivery. If oral zidovudine is part of the antepartum regimen, and a woman’sviral load is >400 copies/mL, the oral zidovudine component of her regimenshould be stopped while she receives zidovudine as an intravenous continuousinfusionaduring labor while other ARV agents are continued orally andpostpartum. • Schedule cesarean delivery at 38 weeks if plasma HIV RNA remains >1,000copies/mL near the time of delivery.• Evaluate need for continuing the combination regimen postpartum. Followingdelivery, considerations for continuation of the mother’s ARV regimen are thesame as in other non-pregnant individuals (see General Principles RegardingUse of Antiretroviral Drugs in Pregnancy). If treatment is to be stopped and theregimen includes a drug with a long half-life, such as a non-nucleoside reversetranscriptase inhibitor [NNRTI]), continue NRTIs for at least 7 days afterstopping NNRTI (see Stopping Antiretroviral Therapyand Prevention ofAntiretroviral Drug Resistance).Infants:• Start zidovudine as soon as possible after birth and administer for 6 weeks.bTable 6. Clinical Scenario Summary Recommendations for Antiretroviral Drug Use by Pregnant HIV-Infected Women and Prevention of Perinatal Transmission of HIV-1 in the United States (page 2 of 4)Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-26Clinical Scenario RecommendationsHIV-infected pregnant women who areARV experienced but not currentlyreceiving ARV drugsWomen:• Obtain full ARV drug history, including prior resistance testing, and evaluateneed for ART for maternal health.• Test for HIV ARV drug resistance before reinitiating ARV prophylaxis or therapyand retest after initiating combination ARV regimen if viral suppression issuboptimal (pregnancy, the ARV regimen should be initiated promptly without waiting for theresults of resistance testing.• Initiate a combination ARV regimen (that is, at least three drugs), with theregimen chosen based on results of resistance testing and history of priortherapy.- Delayed initiation of ARVs until after the first trimester can be considered inwomen with high CD4-cell counts and low HIV RNA levels, but earlierinitiation of prophylaxis may be more effective in reducing perinataltransmission of HIV. Benefits of first trimester use must be weighed againstpotential fetal effects of first-trimester exposure.- Avoid initiation of efavirenz or other potentially teratogenic drugs in the firsttrimester and drugs with known adverse potential for the mother throughoutthe pregnancy.- When feasible, include one or more NRTIs with good transplacental passage(zidovudine, lamivudine, emtricitabine, tenofovir, or abacavir) as acomponent of the ARV regimen.- Use nevirapine as a component of therapy in women who have CD4-cellcounts >250 cells/mm3only if the benefit clearly outweighs the risk becauseof the drug’s association with an increased risk of severe hepatic toxicity.• Continue the combination regimen intrapartum. Continuous infusion zidovudineashould be administered to HIV-infected women with HIV RNA >400 copies/mL(or unknown HIV RNA) near delivery, regardless of antepartum regimen or modeof delivery. If oral zidovudine is part of the antepartum regimen, and a woman’sviral load is >400 copies/mL, the oral zidovudine component of her regimenshould be stopped while she receives zidovudine as an intravenous continuousinfusionaduring labor while other ARV agents are continued orally.• Evaluate need for continuing the combination regimen postpartum. Followingdelivery, considerations for continuation of the mother’s ARV regimen are thesame as in other non-pregnant adults (see General Principles Regarding Use ofAntiretroviral Drugs in Pregnancy). If treatment is to be stopped and the regimenincludes a drug with a long half-life, such as NNRTIs, continue NRTIs for at least7 days after stopping NNRTIs (see Stopping Antiretroviral TherapyandPrevention of Antiretroviral Drug Resistance).• Schedule cesarean delivery at 38 weeks if plasma HIV RNA remains >1,000copies/mL near the time of delivery.Infant:• Start zidovudine as soon as possible after birth and administer for 6 weeks.bTable 6. Clinical Scenario Summary Recommendations for Antiretroviral Drug Use by Pregnant HIV-Infected Women and Prevention of Perinatal Transmission of HIV-1 in the United States (page 3 of 4)Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-27Clinical Scenario RecommendationsHIV-infected women who have receivedno ARV before laborWomen:Give zidovudine as continuous infusionaduring labor.Infants:Infants born to HIV-infected women who have not received antepartumARV drugs should receive prophylaxis with a combination ARV drug regimenstarted as close to the time of birth as possible. Zidovudinebgiven for 6 weekscombined with three doses of nevirapine in the first week of life (at birth, 48 hourslater, and 96 hours after the second dose) has been shown to be effective in arandomized controlled trial and less toxic than a three-drug regimen withnelfinavir and lamivudine for 2 weeks and 6 weeks of zidovudine. The two-drugregimen is preferred because of lower toxicity and because nelfinavir powder is nolonger available in the United States (see Infant Antiretroviral ProphylaxisandTable 9). • Evaluate need for initiation of maternal therapy postpartum.Infants born to HIV-infected womenwho have received no ARV before orduring labor• Infants born to HIV-infected women who have not received antepartum ARVdrugs should receive prophylaxis with a combination ARV drug regimen startedas close to the time of birth as possible. Zidovudinebgiven for 6 weekscombined with three doses of nevirapine in the first week of life (at birth, 48hours later, and 96 hours after the second dose) has been shown to be effectivein a randomized controlled trial and less toxic than a three-drug regimen withnelfinavir and lamivudine for 2 weeks and 6 weeks of zidovudine. The two-drugregimen is preferred because of lower toxicity and because nelfinavir powder isno longer available in the United States (see Infant Antiretroviral ProphylaxisandTable 9).• Evaluate need for initiation of maternal therapy postpartum.Table 6. 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AIDS. Sep 24 2010;24(15):2416-2418. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20827058.73. Peters PJ, Stringer J, McConnell MS, et al. Nevirapine-associated hepatotoxicity was not predicted by CD4 count ≥250cells/muL among women in Zambia, Thailand and Kenya. HIV Med. Nov 2010;11(10):650-660. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20659176.74. Jaworsky D, Thompson C, Yudin MH, et al. Use of newer antiretroviral agents, darunavir and etravirine with or withoutraltegravir, in pregnancy: a report of two cases. Antivir Ther. 2010;15(4):677-680. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20587860.75. Ivanovic J, Bellagamba R, Nicastri E, et al. Use of darunavir/ritonavir once daily in treatment-naive pregnant woman:pharmacokinetics, compartmental exposure, efficacy and safety. AIDS. Apr 24 2010;24(7):1083-1084. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20386380.76. Taylor N, Touzeau V, Geit M, et al. Raltegravir in pregnancy: a case series presentation. Int J STD AIDS. Jun2011;22(6):358-360. Available at http://www.ncbi.nlm.nih.gov/pubmed/21680678.77. Pinnetti C, Baroncelli S, Villani P, et al. Rapid HIV-RNA decline following addition of raltegravir and tenofovir toongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 ofpregnancy. J Antimicrob Chemother. Sep 2010;65(9):2050-2052. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20630894.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-32Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-33HIV-Infected Pregnant Women Who Have Never Received Antiretroviral Drugs (Antiretroviral Naive) (Last updated July 31, 2012; last reviewed July 31, 2012)Pregnant women with HIV infection should receive standard clinical, immunologic, and virologic evaluation. They should be counseled about and offered combination antiretroviral (ARV) regimens containing at least 3drugs for prevention of perinatal transmission of HIV. Use of an ARV regimen that successfully reducesplasma HIV RNA to undetectable levels substantially lowers the risk of perinatal transmission of HIV,lessens the need for consideration of elective cesarean delivery as an intervention to reduce risk oftransmission, and reduces risk of ARV drug resistance in the mother. In an analysis of perinatal transmissionin 5,151 HIV-infected women between 2000 and 2006 in the United Kingdom and Ireland, the overallmother-to-child transmission rate was 1.2%. A transmission rate of 0.8% was seen in women on ARV drugsfor at least the last 14 days of pregnancy, regardless of the type of ARV regimen or mode of delivery.1Afteradjustment for viral load, mode of delivery, and sex of the infant, longer duration of use of ARV drugs wasassociated with reduced transmission rates.The ARV regimen used in pregnancy generally should consist of two nucleoside reverse transcriptaseinhibitors (NRTIs) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI),consistent with the principles of treatment for non-pregnant adults but taking into account what is knownabout use of the drugs in pregnancy and risks of teratogenicity (see General Principles Regarding Use ofAntiretroviral Drugs during Pregnancy).2The regimen initiated during pregnancy can be modified afterdelivery to include simplified regimens that were not used in pregnancy because there were insufficientpregnancy safety data or drugs may be stopped in women who do not feel prepared to continue lifelongPanel’s Recommendations• All HIV-infected pregnant women should receive a potent combination antiretroviral (ARV) regimen to reduce the risk ofperinatal transmission of HIV (AI). The choice of regimen should take into account current adult treatment guidelines,what is known about the use of specific drugs in pregnancy, and the risk of teratogenicity (Table 5).• The decision as to whether to start the regimen in the first trimester or delay until 12 weeks’ gestation will depend on CD4T-lymphocyte (CD4-cell) count, HIV RNA levels, and maternal conditions such as nausea and vomiting (AIII). Earlierinitiation of a combination ARV regimen may be more effective in reducing transmission, but benefits must be weighedagainst potential fetal effects of first-trimester drug exposure.• Combination ARV regimens should include a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone thatincludes one or more NRTIs with high levels of transplacental passage (zidovudine, lamivudine, emtricitabine, tenofovir,or abacavir) (AIII).• ARV drug-resistance studies should be performed before starting the ARV regimen if HIV RNA is above the threshold forresistance testing (that is, >500–1,000 copies/mL) (see Antiretroviral Drug Resistance and Resistance Testing inPregnancy) (AI). If HIV is diagnosed later in pregnancy the ARV regimen should be initiated promptly without waiting forthe results of resistance testing (BIII).• Nevirapine can be used as a component of the ARV regimen in pregnant women with CD4 cell counts ≤250 cells/mm3. Inpregnant women with CD4 cell counts >250 cells/mm3, however, nevirapine should be used only if the benefit clearlyoutweighs the risk because the drug is associated with an increased risk of hepatic toxicity (AII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.therapy at that point. Decisions regarding ARV use after pregnancy should be made by women inconsultation with their HIV care providers, taking into account current recommendations and lifecircumstances (see General Principles Regarding Use of Antiretroviral Drugs during Pregnancy).Fetuses are most susceptible to the potential teratogenic effects of drugs during the first trimester and therisks of ARV drug exposure during that period are not fully known. Therefore, women in the first trimesterwho do not require immediate initiation of therapy for symptomatic HIV disease can consider delayinginitiation of ARV drugs until after 12 weeks’ gestation. This decision should be carefully considered byhealth care providers and the women. The discussion should include an assessment of a woman’s healthstatus and the benefits and risks to her health of delaying initiation of ARV drugs for several weeks. Although most perinatal transmission of HIV events occur late in pregnancy or during delivery, recentanalyses suggest that early control of viral replication may be important in preventing transmission. In arecent French study, lack of early and sustained control of maternal viral load appeared strongly associatedwith residual perinatal transmission of HIV.3That study evaluated risk factors for perinatal transmission inwomen with HIV RNA who transmitted were less likely to have received ARV drugs at the time of conception than werenontransmitters and were less likely to have HIV RNA By multivariate analysis, plasma viral load at 30 weeks’ gestation was significantly associated withtransmission. Among women starting ARV drugs during pregnancy, the gestational age at initiation oftherapy did not differ between groups (30 weeks), but viral load decreased earlier in the nontransmitters. Thenumber of patients initiating therapy during pregnancy was too small to assess whether initiation of ARVdrugs in the first trimester was associated with lower rates of transmission; although not statisticallysignificant, viral load in naive women appeared to also decrease earlier in the nontransmitters. These datasuggest that early and sustained control of HIV viral replication is associated with decreasing residual risk oftransmission and favor initiating ARV drugs sufficiently early in naive women to suppress viral replicationby the third trimester; however, this potential benefit must be balanced against the unknown long-termoutcome of first-trimester drug exposure.ARV drug-resistance testing should be performed before starting an ARV regimen if HIV RNA is above thethreshold for resistance testing (that is, >500–1,000 copies/mL). For details regarding genotypic andphenotypic resistance testing, see Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adultsand Adolescents. Given the association of earlier viral suppression with lower risk of transmission asdiscussed above, if HIV is diagnosed in the second half of pregnancy the ARV regimen should be initiatedpromptly without waiting for the results of resistance testing. Because clinically significant resistance to PIsis less common than resistance to NNRTIs in ARV-naive individuals, a PI-based ARV drug regimengenerally should be considered in this situation.ARV prophylaxis is recommended for all pregnant women with HIV infection, regardless of viral load.Although rates of perinatal transmission are low in women with undetectable or low HIV RNA levels, thereis no threshold below which lack of transmission can be ensured.4-6The mechanism by which ARV drugsreduce perinatal transmission of HIV is multifactorial. Although lowering maternal antenatal viral load is animportant component of prevention in women with higher viral load, ARV prophylaxis is effective even inwomen with low viral load.7-11Additional mechanisms of protection include pre-exposure prophylaxis (PrEP)and post-exposure prophylaxis of the infant. With PrEP, passage of the ARV drug across the placenta resultsin presence of drug levels sufficient for inhibition of viral replication in the fetus, particularly during the birthprocess when there is intensive viral exposure. Therefore, whenever possible, combination ARV drugregimens initiated during pregnancy should include zidovudine or another NRTI with high transplacentalpassage, such as lamivudine, emtricitabine, tenofovir, or abacavir (see Table 5).12-15With post-exposureprophylaxis, ARV drugs are administered to the infant after birth.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-34Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Use of nevirapine in pregnancy requires special consideration. A review of a large database of nevirapinestudies indicated that women with CD4 cell counts >250 cells/mm3have an increased risk of developingsymptomatic, often rash-associated, nevirapine-related hepatotoxicity that can be severe, life threatening, andin some cases fatal.16, 17A more recent study involving 820 women in Kenya, Zambia, and Thailand,however, did not find an association between CD4 cell count and development of hepatotoxicity.18Increasedrisk of rash and liver toxicity were associated with elevated baseline liver transaminases but not with CD4cell count; all deaths from hepatic toxicity occurred in women with CD4 cell counts 3atbaseline on concomitant anti-tuberculosis therapy. In women with CD4 cell counts >250 cells/mm3,nevirapine should be used as a component of a combination ARV regimen only when the benefit clearlyoutweighs the risk. If nevirapine is used, baseline and frequent monitoring of transaminase levels is required,particularly during the first 18 weeks of treatment (see Nevirapine and Hepatic/Rash Toxicity). Transaminaselevels should be checked before starting nevirapine and again in women who develop a rash. Nevirapineshould be stopped immediately in women who develop signs or symptoms of hepatitis.The use of raltegravir in late pregnancy for women who have high viral loads has been suggested because ofits ability to rapidly suppress viral load (approximately 2-log copies/mL decrease by Week 2 of therapy).19-22However, the efficacy and safety of this approach have not been evaluated and only anecdotal reports areavailable. Until more data become available on the safety of raltegravir use in pregnancy, this approachcannot be recommended for therapy-naive women.Some women may wish to restrict fetal exposure to ARV drugs while reducing the risk of HIV transmissionto their infants. Use of zidovudine alone during pregnancy for prophylaxis of perinatal transmission is notoptimal, but it could be an option for women with low viral loads (that is, drugs. In the U.K. study discussed above, transmission rates were 0.7% for women receiving a triple-ARVdrug regimen combined with planned cesarean delivery or with planned vaginal delivery and 0.5% in 464women with HIV RNA levels below 10,000 copies/mL who received single-drug prophylaxis withzidovudine combined with planned cesarean delivery, not significantly different between groups. Zidovudinesingle-drug prophylaxis is recommended in the British HIV Association guidelines for women with HIVRNA levels 23Time-limited administration of zidovudine during the second and third trimesters is less likely to inducedevelopment of resistance in women with low viral loads than in those with higher viral loads. This lowerrate of resistance is likely because of the low level of viral replication and the short duration of exposure.24, 25Women’s choices after counseling to use or not use ARV drugs during pregnancy should be respected.After delivery, considerations regarding continuation of the ARV regimen for treatment in mothers are thesame as in other non-pregnant adults (see General Principles Regarding Use of Antiretroviral Drugs duringPregnancy).References1. Townsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-childtransmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS.May 11 2008;22(8):973-981. Available at http://www.ncbi.nlm.nih.gov/pubmed/18453857.2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed June 7, 2012. 3. Tubiana R, Le Chenadec J, Rouzioux C, et al. Factors associated with mother-to-child transmission of HIV-1 despite amaternal viral load CO1). Clin Infect Dis. Feb 15 2010;50(4):585-596. Available at http://www.ncbi.nlm.nih.gov/pubmed/20070234.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-35Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.4. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. Apr 152002;29(5):484-494. Available at http://www.ncbi.nlm.nih.gov/pubmed/11981365.5. Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of human immunodeficiency virustype 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med. Aug 51999;341(6):385-393. Available at http://www.ncbi.nlm.nih.gov/pubmed/10432323.6. Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the riskof perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med. Aug 5 1999;341(6):394-402.Available at http://www.ncbi.nlm.nih.gov/pubmed/10432324.7. Ioannidis JP, Abrams EJ, Ammann A, et al. Perinatal transmission of human immunodeficiency virus type 1 by pregnantwomen with RNA virus loads http://www.ncbi.nlm.nih.gov/pubmed/11170978.8. Wade NA, Birkhead GS, Warren BL, et al. Abbreviated regimens of zidovudine prophylaxis and perinatal transmissionof the human immunodeficiency virus. N Engl J Med. Nov 12 1998;339(20):1409-1414. Available athttp://www.ncbi.nlm.nih.gov/pubmed/9811915.9. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine forprevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012randomised trial. Lancet. Sep 13 2003;362(9387):859-868. Available athttp://www.ncbi.nlm.nih.gov/pubmed/13678973.10. Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and latetransmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial. Lancet. Apr 6 2002;359(9313):1178-1186. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11955535.11. Moodley D, Moodley J, Coovadia H, et al. A multicenter randomized controlled trial of nevirapine versus a combinationof zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of humanimmunodeficiency virus type 1. J Infect Dis. Mar 1 2003;187(5):725-735. Available athttp://www.ncbi.nlm.nih.gov/pubmed/12599045.12. Hirt D, Urien S, Rey E, et al. Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Antimicrob Agents Chemother. Mar 2009;53(3):1067-1073. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19104016.13. Hirt D, Urien S, Ekouevi DK, et al. Population pharmacokinetics of tenofovir in HIV-1-infected pregnant women andtheir neonates (ANRS 12109). Clin Pharmacol Ther. Feb 2009;85(2):182-189. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18987623.14. Moodley D, Pillay K, Naidoo K, et al. Pharmacokinetics of zidovudine and lamivudine in neonates followingcoadministration of oral doses every 12 hours. J Clin Pharmacol. Jul 2001;41(7):732-741. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11452705.15. Wade NA, Unadkat JD, Huang S, et al. Pharmacokinetics and safety of stavudine in HIV-infected pregnant women andtheir infants: Pediatric AIDS Clinical Trials Group protocol 332. J Infect Dis. Dec 15 2004;190(12):2167-2174.Available at http://www.ncbi.nlm.nih.gov/pubmed/15551216.16. Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL. A comprehensive hepatic safety analysis ofnevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr. Sep 2003;34(Suppl 1):S21-33. Available at http://www.ncbi.nlm.nih.gov/pubmed/14562855.17. Boehringer-Ingelheim Pharmaceuticals Inc. Viramune drug label. March 25, 2011. Available athttp://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020933s028,020636s037lbl.pdf.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-36Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.18. Peters PJ, Stringer J, McConnell MS, et al. Nevirapine-associated hepatotoxicity was not predicted by CD4 count ≥250cells/muL among women in Zambia, Thailand and Kenya. HIV Med. Nov 2010;11(10):650-660. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20659176.19. Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518)in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. Apr 142007;369(9569):1261-1269. Available at http://www.ncbi.nlm.nih.gov/pubmed/17434401.20. Papendorp SG, van den Berk GE. Preoperative use of raltegravir-containing regimen as induction therapy: very rapiddecline of HIV-1 viral load. AIDS. Mar 27 2009;23(6):739. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19279447.21. Pinnetti C, Baroncelli S, Villani P, et al. Rapid HIV-RNA decline following addition of raltegravir and tenofovir toongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 ofpregnancy. J Antimicrob Chemother. Sep 2010;65(9):2050-2052. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20630894.22. McKeown DA, Rosenvinge M, Donaghy S, et al. High neonatal concentrations of raltegravir following transplacentaltransfer in HIV-1 positive pregnant women. AIDS. Sep 24 2010;24(15):2416-2418. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20827058.23. de Ruiter A, Taylor GP, Clayden P, et al for the British HIV Association. Guidelines for the management of HIVinfection in pregnant women 2012. Available athttp://www.bhiva.org/documents/Guidelines/treatment/2012/120430pregnancyguidelines.pdf. Accessed on July 5, 2012.24. Read P, Costelloe S, Mullen J, et al. New mutations associated with resistance not detected following zidovudinemonotherapy in pregnancy when used in accordance with British HIV Association guidelines. HIV Med. Aug2008;9(7):448-451. Available at http://www.ncbi.nlm.nih.gov/pubmed/18840150.25. Larbalestier N, Mullen J, OShea S, et al. Drug resistance is uncommon in pregnant women with low viral loads takingzidovudine monotherapy to prevent perinatal HIV transmission. AIDS. Dec 5 2003;17(18):2665-2667. Available athttp://www.ncbi.nlm.nih.gov/pubmed/14685064.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-37Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-38HIV-Infected Pregnant Women Who Are Currently Receiving Antiretroviral Therapy (Last updated July 31, 2012; last reviewed July 31, 2012)In general, women who have been receiving antiretroviral therapy (ART) for their HIV infection shouldcontinue that treatment during pregnancy, assuming it is tolerated and effective in suppressing viralreplication. Discontinuation of therapy could lead to an increase in viral load with possible decline inimmune status and disease progression as well as adverse consequences for the fetus, including increasedrisk of HIV transmission. Continuation of therapy, therefore, is recommended when pregnancy is identifiedin HIV-infected women receiving ART.HIV-infected women receiving ART who present for care during the first trimester should be counseledregarding the benefits and potential risks of administration of antiretroviral (ARV) drugs during this periodand that continuation of ART is recommended. There are concerns regarding efavirenz use in the firsttrimester of pregnancy and potential for neural tube defects, based on preclinical primate data andretrospective case reports (for more details see Special Considerations Regarding the Use of AntiretroviralDrugs by HIV-Infected Pregnant Women and their Infants: Teratogenicity). A recent meta-analysis includingdata on 1,437 women with first-trimester efavirenz exposure from 19 prospective studies did not find anincreased relative risk (RR) of overall birth defects in infants born to women receiving efavirenz-basedversus non-efavirenz–based regimens (RR 0.85, 95% confidence interval [CI], 0.6–1.2) and identified 1neural tube defect, resulting in an incidence of 0.07% (95% CI, 0.002–0.39%).1Although a 2- to 3-foldincreased incidence of a rare outcome (such as neural tube defects [0.02%–0.2% incidence in the UnitedStates]) cannot be ruled out given the limited data on first-trimester efavirenz exposure, the available datasuggest that first-trimester exposure is not associated with a large (that is, 10-fold or more) increase in risk ofneural tube defects. Analyses from the Italian Group on Surveillance on Antiretroviral Treatment inPregnancy found that treatment changes during pregnancy significantly increased the risk of incomplete viralsuppression at the end of pregnancy.2The risk of neural tube defects is restricted to the first 5 to 6 weeks ofpregnancy (the neural tube closes at 36–39 days after last menstrual period), pregnancy is rarely recognizedbefore 4 to 6 weeks of pregnancy, and unnecessary changes of ARV drugs in pregnancy may be associatedwith loss of viral control and, thus, increase risk of transmission to the infant. Therefore, the Panelrecommends that efavirenz be continued in pregnant women receiving efavirenz-based ART who present forantenatal care in the first trimester, provided that the regimen is resulting in virologic suppression. In suchPanel’s Recommendations• In general, HIV-infected women receiving antiretroviral therapy (ART) who present for care during the first trimester shouldcontinue treatment during pregnancy, assuming the regimen is tolerated and effective in suppressing viral replication (AII).The Panel recommends that efavirenz be continued in pregnant women receiving efavirenz-based ART who present forantenatal care in the first trimester provided the regimen is resulting in virologic suppression (see text) (CIII).• Pregnant women receiving and tolerating nevirapine-containing regimens who are virologically suppressed shouldcontinue the regimen, regardless of CD4 count (AIII).• HIV antiretroviral drug-resistance testing is recommended for pregnant women who have detectable viremia (that is,>500–1,000 copies/mL) on therapy (see Failure of Viral Suppression) (AI).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.situations, additional fetal monitoring (such as with second-trimester ultrasound) should be considered toevaluate fetal anatomy.Resistance testing should be performed in women who are on therapy but in whom viral replication is notfully suppressed. The results can be used to select a new regimen with a greater likelihood of suppressingviral replication to undetectable levels. Drug resistance testing is generally done in individuals with HIVRNA levels >1,000 copies/mL; however, in persons with HIV RNA levels >500 but testing may be unsuccessful but should still be considered.Pregnant women for whom nevirapine-containing regimens are achieving virologic suppression and who aretolerating therapy may be continued on that regimen, regardless of current CD4 T-lymphocyte (CD4-cell)count. Although hepatic toxicity is a concern in women starting a nevirapine-containing regimen who haveCD4-cell counts >250 cells/mm3, an increased risk of hepatic toxicity has not been seen in women receivingnevirapine-based therapy in whom the therapy has produced immune reconstitution.References1. Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review andmeta-analysis. AIDS. Nov 28 2011;25(18):2301-2304. Available at http://www.ncbi.nlm.nih.gov/pubmed/21918421.2. Floridia M, Ravizza M, Pinnetti C, et al. Treatment change in pregnancy is a significant risk factor for detectable HIV-1RNA in plasma at end of pregnancy. HIV Clin Trials. Nov-Dec 2010;11(6):303-311. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21239358.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-39Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-40HIV-Infected Pregnant Women Who Have Previously Received Antiretroviral Treatmentor Prophylaxis but Are Not Currently Receiving Any Antiretroviral Medications (Last updated July 31, 2012; last reviewed July 31, 2012)During a previous pregnancy, HIV-infected women may have received antiretroviral (ARV) drugs solely forprevention of perinatal transmission. At any time in the past, they also may have discontinued ARV drugsgiven to them for treatment of their own disease. A small number of clinical trials or observational studieshave generated information about how effective antiretroviral therapy (ART) is in individuals who previouslyreceived ARV prophylaxis. The data are limited to outcomes with therapy containing nevirapine initiatedafter the use of peripartum single-dose nevirapine.1-5Initial reports suggested a diminished virologic and clinical response to nevirapine-based ART if therapy wasinitiated within 6 months of intrapartum single-dose nevirapine exposure.1-3Subsequent reports haveconfirmed that a shorter interval between intrapartum single-dose nevirapine exposure and initiation oftherapy with ART regimens containing nevirapine is associated with decreased efficacy of therapy andsuggested that the diminished response may persist 12 to 24 months after exposure.4, 5In addition, thesubsequent failure of non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART after single-dosenevirapine has been associated with lower CD4 T-lymphocyte (CD4-cell) count and higher HIV-RNA plasmaconcentration at the time of single-dose nevirapine exposure and genotypic resistance to nevirapine.However, in a retrospective analysis of virologic suppression rates after initiation of an efavirenz-based ARTregimen within 24 months of receipt of intrapartum single-dose nevirapine for prevention of perinataltransmission, no difference was seen between cases and controls who had never received single-dosenevirapine. Efficacy was similar when therapy was initiatied within and after 6 months of single-dosenevirapine.6Adding other ARV drugs to single-dose nevirapine (such as use of an ARV “tail”) decreases ratesof nevirapine resistance7, 8(see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy), but thePanel’s Recommendations• Obtain an accurate history of all prior antiretroviral (ARV) regimens used for treatment of HIV disease or prevention oftransmission, including virologic efficacy, tolerance to the medications, results of prior resistance testing, and anyadherence issues (AIII).• If HIV RNA is above the threshold for resistance testing (that is, >500–1,000 copies/mL), ARV drug-resistance studiesshould be performed before starting an ARV drug regimen (see Antiretroviral Drug Resistance and Resistance Testing inPregnancy) (AIII). In women who present late in pregnancy, therapy or prophylaxis should be initiated promptly withoutwaiting for the results of resistance testing (BIII).• Choose and initiate a combination ARV drug regimen based on results of resistance testing and prior history ofantiretroviral therapy while avoiding drugs with teratogenic potential or with known adverse potential for the mother (AII).• Consult specialists in treatment of HIV infection about the choice of a combination ARV regimen in women whopreviously received ARV drugs for their own health (AIII).• Perform repeat ARV drug-resistance testing (AI), assess adherence, and consult with an HIV treatment specialist to guidechanges in ARV drugs in women who do not achieve virologic suppression on their ARV regimens (see Monitoring of theWoman and Fetus During Pregnancy).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.effect on clinical response of subsequent initiation of NNRTI-based ART is unknown.There is concern that time-limited use of ARV drugs during pregnancy for prophylaxis of perinataltransmission may lead to genotypic resistance and, thus, reduced efficacy of these ARV drugs when usedeither for indicated HIV therapy in a woman or during a subsequent pregnancy for prevention of perinataltransmission. Rates of resistance appear to be low, based on standard genotyping, after prophylaxis forprevention of perinatal transmission with combination ARVs consisting of zidovudine, lamivudine, andnevirapine.9, 10However, minority populations of virus with resistance to nevirapine or lamivudine have beendetected using sensitive allele-specific polymerase chain reaction (PCR) techniques, particularly in womenwhose virus was inadequately suppressed during prophylaxis.10-12Only limited data are available on theimpact of these resistance-conferring minority variants on prediction of virologic or clinical failure ofsubsequent ART, and the PCR-based assays are not widely available. Both standard and sensitive genotypingtechniques appear to show a low rate of resistance to protease inhibitors (PIs) after pregnancy-limited use ofPI-based combination ARV regimens for prophylaxis, but these results reflect assessments in only smallnumbers of women.12, 13To date, treatment failure has not been demonstrated with reinitiation of combination ARV regimensfollowing prophylactic use in pregnancy for prevention of transmission. In ACTG 5227, 52 women who hadpreviously received combination ARV regimens for prevention of perinatal transmission, had no evidence ofHIV drug resistance, and had an indication for restarting ART were prescribed a fixed-dose combination ofefavirenz plus tenofovir/emtricitabine once daily. After 6 months of therapy, 81% achieved plasma viralloads below the limit of detection; the virologic suppression rate was similar regardless of the drug class ofthe prior combination ARV regimen and whether women had received such ARV regimens in 1 or more than1 previous pregnancy.14Data from the French Perinatal Cohort assessed virologic suppression with a PI-based combination ARV regimen administered for prevention of perinatal transmission to women who hadreceived ARV prophylaxis during a previous pregnancy. No differences in rates of undetectable viral load atdelivery were noted among ARV-naive women when compared with those with previous prophylaxis oraccording to type of previous prophylaxis regimens received.15In addition, the United Kingdom and Ireland-based National Study of HIV in Pregnancy and Childhood found no increased risk of perinatal transmissionin sequential pregnancies compared with 1 pregnancy at a time when most women received interventions forprevention of perinatal HIV transmission.16However, sufficiently large, prospective, observational studiesand clinical trials are lacking to show that pregnancy-limited ARV prophylaxis has no effect on virologicoutcome of subsequent ART.Given the lack of substantive data, it is reasonable to use results of initial resistance testing, if available, tomake preliminary decisions about ARV regimens in women whose only previous exposure to ARV drugs wasduring pregnancy for prophylaxis of perinatal transmission. However, interpretation of resistance testingafter discontinuation of ARV drugs can be complex because drug-resistance testing is most accurate ifperformed while an individual is taking the ARV regimen or within 4 weeks of treatment discontinuation. Inthe absence of selective drug pressure, resistant virus may revert to wild-type virus, and although detection ofdrug-resistance mutations is informative for choosing a regimen, a negative finding does not rule out thepresence of archived drug-resistant virus that could re-emerge once drugs are reinitiated. Therefore, whenselecting a new regimen for use during the current pregnancy, all information from the previous pregnancy—including regimens received, viral response, laboratory testing (including HLA-B*5701 results), and anytolerance or adherence issues—and the results of resistance testing should be taken into consideration. Inwomen who present late in pregnancy, therapy or prophylaxis should be initiated pending results ofresistance testing. Careful monitoring of virologic response to the chosen ARV regimen is important.If the chosen regimen produces an insufficient viral response, decisions about switching regimens should beguided by repeat resistance testing and assessment of medication adherence. These measures should beundertaken in consultation with an HIV treatment specialist.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-41Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Some women who receive ART for their own health choose to discontinue the drugs for a variety of reasons,and the length of time between treatment termination and pregnancy may vary. In these cases, careful clinicaland laboratory assessments are necessary before therapy is reinitiated during pregnancy. The evaluationsshould include a review of a woman’s prior history of virologic response and medication toxicity and heradherence to therapy. The appropriate choice of ARV regimen to be initiated during pregnancy will varyaccording to a woman’s history of ART; the indication for stopping therapy; the effect of prior therapy onclinical, virologic, and immunologic status; and the results of past and current testing for resistance and forHLA-B*5701. It may be possible, for example, to restart the same regimen in women with a history of priorART associated with successful suppression of viral load who then stopped all drugs simultaneously (orstaggered discontinuation, if therapy was NNRTI based) and who have no evidence of resistance. On theother hand, the selection of an appropriate ARV regimen may be challenging even for health care providersexperienced in HIV care in women with advanced HIV disease, a history of extensive prior ART, or previoussignificant toxicity or nonadherence to ARV drugs. In such cases, restarting the prior regimen for a week ortwo before performing a resistance assay may yield more accurate results. In addition to obtaining genotypicresistance testing, it is strongly recommended that specialists in the treatment of HIV infection be consultedearly during the pregnancy about the choice of a suitable combination ARV regimen.References1. Lockman S, Shapiro RL, Smeaton LM, et al. Response to antiretroviral therapy after a single, peripartum dose ofnevirapine. N Engl J Med. Jan 11 2007;356(2):135-147. Available at http://www.ncbi.nlm.nih.gov/pubmed/17215531.2. Coovadia A, Hunt G, Abrams E, et al. Peristent minority K103N mutations among women exposed to single-dosenevirapine and virologic response to nonnucleotide reverse-transcriptase inhibitor-based therapy. Clin Infect Dis. 2009Feb 15;48(4)462-72. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19133804.3. Chi BH, Sinkala M, Stringer EM, et al. Early clinical and immune response to NNRTI-based antiretroviral therapyamong women with prior exposure to single-dose nevirapine. AIDS. May 11 2007;21(8):957-964. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17457089.4. Lockman S, Hughes MD, McIntyre J, et al. Antiretroviral therapies in women after single-dose nevirapine exposure. NEngl J Med. Oct 14 2010;363(16):1499-1509. Available at http://www.ncbi.nlm.nih.gov/pubmed/20942666.5. Stringer JS, McConnell MS, Kiarie J, et al. Effectiveness of non-nucleoside reverse-transcriptase inhibitor-basedantiretroviral therapy in women previously exposed to a single intrapartum dose of nevirapine: a multi-country,prospective cohort study. PLoS Med. Feb 2010;7(2):e1000233. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20169113.6. Bolhaar MG, Karstaedt AS. Efavirenz-based combination antiretroviral therapy after peripartum single-dose nevirapine.Int J STD AIDS. Jan 2011;22(1):38-42. Available at http://www.ncbi.nlm.nih.gov/pubmed/21364065.7. Chi BH, Sinkala M, Mbewe F, et al. Single-dose tenofovir and emtricitabine for reduction of viral resistance to non-nucleoside reverse transcriptase inhibitor drugs in women given intrapartum nevirapine for perinatal HIV prevention: anopen-label randomised trial. Lancet. Nov 17 2007;370(9600):1698-1705. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17997151.8. McIntyre JA, Hopley M, Moodley D, et al. Efficacy of short-course AZT plus 3TC to reduce nevirapine resistance inthe prevention of mother-to-child HIV transmission: a randomized clinical trial. PLoS Med. 2009 Oct;6(10):e1000172.Available at: http://www.ncbi.nlm.nih.gov/pubmed/19859531.9. Perez H, Vignoles M, Laufer N, et al. Low rate of emergence of nevirapine and lamivudine resistance after post-partuminterruption of a triple-drug regimen. Antivir Ther. 2008;13(1):135-139. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18389908.10. Lehman DA, Chung MH, Mabuka JM, et al. Lower risk of resistance after short-course HAART compared withzidovudine/single-dose nevirapine used for prevention of HIV-1 mother-to-child transmission. J Acquir Immune DeficRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-42Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Syndr. Aug 15 2009;51(5):522-529. Available at http://www.ncbi.nlm.nih.gov/pubmed/19502990.11. Rowley CF, Boutwell CL, Lee EJ, et al. Ultrasensitive detection of minor drug-resistant variants for HIV afternevirapine exposure using allele-specific PCR: clinical significance. AIDS Res Hum Retroviruses. Mar 2010;26(3):293-300. Available at http://www.ncbi.nlm.nih.gov/pubmed/20334564.12. Paredes R, Cheng I, Kuritzkes DR, Tuomala RE, Women, Infants Transmission Study Group. Postpartum antiretroviraldrug resistance in HIV-1-infected women receiving pregnancy-limited antiretroviral therapy. AIDS. Jan 22010;24(1):45-53. Available at http://www.ncbi.nlm.nih.gov/pubmed/19915448.13. Gingelmaier A, Eberle J, Kost BP, et al. Protease inhibitor-based antiretroviral prophylaxis during pregnancy and thedevelopment of drug resistance. Clin Infect Dis. Mar 15 2010;50(6):890-894. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20166821.14. Vogler MA, Smeaton L, et al. Effect of prior cART used only to prevent MTCT of HIV-1 on subsequent cART efficacyin HIV+ women restarting HIV therapy with a standard first-line regimen: ACTG A5227 study. Paper presented at: 18thConference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Abstract752.15. Briand N, Mandelbrot L, Blanche S, et al. Previous antiretroviral therapy for prevention of mother-to-child transmissionof HIV does not hamper the initial response to PI-based multitherapy during subsequent pregnancy. J Acquir ImmuneDefic Syndr. Jun 1 2011;57(2):126-135. Available at http://www.ncbi.nlm.nih.gov/pubmed/21436712.16. French C, Thorne C, et al.Are sequential pregnancies in HIV+ women associated with an increased risk of MTCT.Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI) February 27-March 2, 2011;Boston, MA. Abstract 736.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-43Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-44Special Situations — HIV/Hepatitis B Virus Coinfection (Last updated July 31, 2012; lastreviewed July 31, 2012)For additional information on hepatitis B and HIV, see HIV/Hepatitis B (HBV) Coinfectionin Guidelines forthe Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents(http://AIDSinfo.nih.gov)1andHepatitis B Virus Infectionin the Guidelines for Prevention and Treatment of Opportunistic Infections inHIV-Infected Adults and Adolescents, Recommendations from the Centers for Disease Control andPrevention (CDC), the National Institutes of Health (NIH), and the HIV Medicine Association of theInfectious Diseases Society of America.2All HIV-infected pregnant women should be screened for hepatitis A, B, and C. The management ofHIV/hepatitis B virus (HBV) coinfection in pregnancy is complex and consultation with an expert in HIVand HBV infection is strongly recommended. HIV-infected women who are found to have chronic HBVinfection on the basis of persistent hepatitis B surface antigenemia for at least 6 months and who are hepatitisA immunoglobulin G negative should receive the hepatitis A virus (HAV) vaccine series because of thePanel’s Recommendations• Screening for hepatitis B virus (HBV) infection with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), and hepatitis B surface antibody (anti-HBs) is recommended for all pregnant women who have not been screenedduring the current pregnancy (AII).• The HBV vaccine series should be administered to pregnant women who screen negative for hepatitis B (that is, HBsAgnegative, anti-HBc negative, and anti-HBs negative) (AII).• Pregnant women with chronic HBV infection should be screened for antibodies to hepatitis A virus (HAV), and those whoscreen negative should receive the HAV vaccine series (AII).• Interferon alfa and pegylated interferon alfa are not recommended during pregnancy (AIII).• The management of HIV/HBV coinfection in pregnancy is complex and consultation with an expert in HIV and HBV isstrongly recommended (AIII).• All pregnant women with HIV/HBV coinfection should receive antiretroviral therapy (ART), including a dual nucleosidereverse transcriptase inhibitor (NRTI)/nucleotide analogue reverse transcriptase inhibitor (NtRTI) backbone with twodrugs active against both HIV and HBV (AII). Tenofovir plus lamivudine or emtricitabine is the preferred dual NRTI/NtRTIbackbone of antepartum ART in HIV/HBV-coinfected pregnant women (AI).• If antiretroviral (ARV) drugs are discontinued postpartum in women with HIV/HBV coinfection, frequent monitoring ofliver function tests for potential exacerbation of HBV infection is recommended, with prompt reinitiation of treatment forboth HIV and HBV if a flare is suspected (BIII).• Pregnant women with HIV/HBV coinfection receiving ARV drugs should be counseled about the signs and symptoms ofliver toxicity, and liver transaminases should be assessed 1 month following initiation of ARV drugs and at least every 3months thereafter (BIII).• Within 12 hours of birth, infants born to women with HBV infection should receive hepatitis B immune globulin and thefirst dose of the HBV vaccine series. The second and third doses of vaccine should be administered at ages 1 and 6months, respectively (AI).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.added risk of acute hepatitis A in persons with chronic viral hepatitis. Although the safety of HAVvaccination during pregnancy has not been determined, HAV vaccine is produced from inactivated HAV andthe theoretical risk to the developing fetus is expected to be low.3HIV-infected pregnant women who test negative for hepatitis B surface antibody (anti-HBs) and hepatitis Bsurface antigen (HBsAg) should receive the HBV vaccine series. Limited data indicate no apparent risk todeveloping fetuses of adverse events from hepatitis B vaccine, and current vaccines contain noninfectiousHBsAg and should cause no risk to fetuses.3A positive test for hepatitis B core antibody (anti-HBc) alonecan be a false-positive result, or it may signify past exposure with subsequent loss of anti-HBs or “occult”HBV infection, which can be confirmed by detection of HBV DNA.4, 5The clinical significance of isolatedanti-HBc is unknown.6, 7Some experts recommend that HIV-infected individuals with anti-HBc alone betested for HBV DNA before vaccination for HBV or before treatment or prophylaxis with antiretroviral(ARV) drugs is initiated because of the risk of a paradoxical exacerbation of HBV and the occurrence ofimmune reconstitution inflammatory syndrome (IRIS).2An ARV regimen that includes drugs active against both HIV and HBV is recommended for all individualswith HIV/HBV coinfection who require HBV treatment or who are starting ARV drugs, including pregnantwomen. Initiation of an ARV regimen that does not include anti-HBV drugs may be associated withreactivation of HBV and development of IRIS; IRIS-related flare of HBV activity during pregnancy canoccur even in women with relatively high CD4 T-lymphocyte (CD4-cell) counts at the time of ARVinitiation. In addition, use of ARV drugs with anti-HBV activity during pregnancy lowers HBV viremia,potentially increasing the efficacy of neonatal hepatitis B immune globulin (HBIG) and hepatitis B vaccinein prevention of perinatal transmission of HBV. High maternal HBV DNA levels are strongly correlated withperinatal HBV transmission and with failures of HBV passive-active immunoprophylaxis.8-10Several smallstudies suggest that lamivudine or telbivudine may reduce the risk of perinatal transmission of HBV if givenduring the third trimester to HBV-infected, HIV-seronegative women with high HBV DNA viremia.11-14Although a high HBV viral load clearly is important, it is not the only factor predisposing to failure ofprophylaxis.15Because lamivudine, tenofovir, and emtricitabine have activity against both HIV and HBV, the recommendeddual-nucleoside reverse transcriptase (NRTI)/nucleotide analogue reverse transcriptase inhibitor (NtRTI)backbone for HIV/HBV-coinfected individuals, including pregnant women, is tenofovir/emtricitabine ortenofovir/lamivudine. Lamivudine has been extensively studied and is recommended for use in pregnancy(Table 5). The Antiretroviral Pregnancy Registry includes reports on the outcomes of 4,088 pregnancies thatinvolved administration of lamivudine in the first trimester and there is no indication that the exposure wasassociated with an increased risk of birth defects.16Similarly, no increase in birth defects has been noted in899 cases of first-trimester exposure to emtricitabine, which is an alternative NRTI for use in pregnancy(Table 5). Tenofovir is not teratogenic in animals, but reversible bone changes at high doses have been seenin multiple animal species. A total of 1,370 cases of first-trimester exposure have been reported to theAntiretroviral Pregnancy Registry, with no increase in birth defects noted.16Although tenofovir isrecommended as an alternative NtRTI during pregnancy for ARV-naive women, it is a preferred NtRTI inwomen with HIV/HBV coinfection (Table 5).Several other antivirals with activity against HBV, including entecavir, adefovir, and telbivudine, have hadminimal evaluation in pregnancy. Entecavir is associated with skeletal anomalies in rats and rabbits but only atdoses high enough to cause toxicity to the mother. Fewer than 70 cases of exposure to each of these drugsduring pregnancy have been reported to the Antiretroviral Pregnancy Registry.16Telbivudine was given to 135HBV-positive, HIV-negative women during the third trimester and was well tolerated, and perinataltransmission of HBV was lower in telbivudine-treated mothers (0% vs. 8%; P = 0.002).14, 17Each of these anti-HBV drugs should be administered only in addition to a fully suppressive regimen for HIV. Because theseother anti-HBV drugs also have weak activity against HIV, they may select for anti-HIV drug resistance in theRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-45Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.absence of a fully suppressive ARV regimen as well as potential cross resistance to other ARV drugs.(Entecavir, for example, can select for the M184V mutation, which confers HIV resistance to lamivudine andemtricitabine.) These drugs should be used during pregnancy only if the preferred drugs are not appropriate inspecific cases. Cases of exposure during pregnancy to any of the ARV drugs and HBV drugs listed should bereported to the Antiretroviral Pregnancy Registry (800-258-4263; http://www.apregistry.com). Interferon alfa and pegylated interferon alfa are not recommended for use in pregnancy and should be usedonly if the potential benefits outweigh the potential risks. Although interferons are not teratogenic, they areabortifacient at high doses in monkeys and should not be used in pregnant women because of the directantigrowth and antiproliferative effects of these agents.18Following initiation of ARV drugs, an elevation in hepatic enzymes can occur in HIV/HBV-coinfectedwomen—particularly those with low CD-cell counts at the time of treatment initiation—as a result of animmune-mediated flare in HBV disease triggered by immune reconstitution with effective HIV therapy. HBVinfection also can increase hepatotoxic risk of certain ARV drugs, specifically protease inhibitors andnevirapine. Pregnant women with HIV/HBV coinfection should be counseled about signs and symptoms ofliver toxicity, and transaminases should be assessed 1 month following initiation of ARV drugs and at leastevery 3 months thereafter. If hepatic toxicity occurs, it may be necessary to consider substituting a lesshepatotoxic regimen or, if clinical symptoms or significant elevations of transaminases occur, drugs may needto be temporarily discontinued. Differentiating between a flare in HBV disease due to immune reconstitutionand drug toxicity often can be difficult, and consultation with an expert in HIV and HBV coinfection isstrongly recommended. Because tenofovir has potential to cause renal toxicity, kidney function also should bemonitored regularly in women receiving this drug, based on toxicity seen in non-pregnant adults.Following delivery, considerations regarding continuation of the ARV drug regimen are the same as for othernon-pregnant individuals (see General Principles Regarding Use of Antiretroviral Drugs During Pregnancy).Discontinuation of agents with anti-HBV activity may be associated with hepatocellular damage resultingfrom reactivation of HBV. Frequent monitoring of liver function tests for potential HBV flare isrecommended in women with HIV/HBV coinfection whose ARV drugs are discontinued postpartum, withprompt reinitiation of treatment for both HIV and HBV if a flare is suspected.Within 12 hours of birth, all infants who weigh >2,000 g born to mothers with chronic HBV infection shouldreceive HBIG and the first dose of the HBV vaccination series. The second and third doses of vaccine shouldbe administered at ages 1 and 6 months, respectively. This regimen is >95% effective in preventing HBVinfection in these infants. Consult the CDC MMWR recommendations for similar infants with birth weights19References1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed June 19, 2012. 2. Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV MedicineAssociation of the Infectious Diseases Society of America. MMWR Recomm Rep. Apr 10 2009;58(RR-4):1-207; quizCE201-204. Available at http://www.ncbi.nlm.nih.gov/pubmed/19357635.3. Centers for Disease Control and Prevention. Guidelines for Vaccinating Pregnant Women, Hepatitis A. UpdatedDecember 20, 2011. Available at (http://www.cdc.gov/vaccines/pubs/preg-guide.htm#hepa) 4. Grob P, Jilg W, Bornhak H, et al. Serological pattern "anti-HBc alone": report on a workshop. J Med Virol. Dec2000;62(4):450-455. Available at http://www.ncbi.nlm.nih.gov/pubmed/11074473.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-46Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-475. Hofer M, Joller-Jemelka HI, Grob PJ, Luthy R, Opravil M. Frequent chronic hepatitis B virus infection in HIV-infectedpatients positive for antibody to hepatitis B core antigen only. Swiss HIV Cohort Study. Eur J Clin Microbiol Infect Dis.Jan 1998;17(1):6-13. Available at http://www.ncbi.nlm.nih.gov/pubmed/9512175.6. Silva AE, McMahon BJ, Parkinson AJ, Sjogren MH, Hoofnagle JH, Di Bisceglie AM. Hepatitis B virus DNA in personswith isolated antibody to hepatitis B core antigen who subsequently received hepatitis B vaccine. Clin Infect Dis. Apr1998;26(4):895-897. Available at http://www.ncbi.nlm.nih.gov/pubmed/9564471.7. Lok AS, Lai CL, Wu PC. Prevalence of isolated antibody to hepatitis B core antigen in an area endemic for hepatitis Bvirus infection: implications in hepatitis B vaccination programs. Hepatology. Jul-Aug 1988;8(4):766-770. Available athttp://www.ncbi.nlm.nih.gov/pubmed/2968945.8. del Canho R, Grosheide PM, Schalm SW, de Vries RR, Heijtink RA. Failure of neonatal hepatitis B vaccination: therole of HBV-DNA levels in hepatitis B carrier mothers and HLA antigens in neonates. J Hepatol. Apr 1994;20(4):483-486. Available at http://www.ncbi.nlm.nih.gov/pubmed/8051386.9. Ngui SL, Andrews NJ, Underhill GS, Heptonstall J, Teo CG. Failed postnatal immunoprophylaxis for hepatitis B:characteristics of maternal hepatitis B virus as risk factors. Clin Infect Dis. Jul 1998;27(1):100-106. Available athttp://www.ncbi.nlm.nih.gov/pubmed/9675462.10. Wiseman E, Fraser MA, Holden S, et al. Perinatal transmission of hepatitis B virus: an Australian experience. Med JAust. May 4 2009;190(9):489-492. Available at http://www.ncbi.nlm.nih.gov/pubmed/19413519.11. van Nunen AB, de Man RA, Heijtink RA, Niesters HG, Schalm SW. Lamivudine in the last 4 weeks of pregnancy toprevent perinatal transmission in highly viremic chronic hepatitis B patients. J Hepatol. Jun 2000;32(6):1040-1041.Available at http://www.ncbi.nlm.nih.gov/pubmed/10898328.12. van Zonneveld M, van Nunen AB, Niesters HG, de Man RA, Schalm SW, Janssen HL. Lamivudine treatment duringpregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat. Jul 2003;10(4):294-297.Available at http://www.ncbi.nlm.nih.gov/pubmed/12823596.13. Shi Z, Yang Y, Ma L, Li X, Schreiber A. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis Bvirus: a systematic review and meta-analysis. Obstet Gynecol. Jul 2010;116(1):147-159. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20567182.14. Pan CQ, Han GR, Jiang HX, et al. Telbivudine prevents vertical transmission from HBeAg-positive women withchronic hepatitis B. Clin Gastroenterol Hepatol. 2012 May;10(5):520-6. Available at:http://www.ncbi.nlm.nih.gov/pubmed/22343511. 15. Kazim SN, Wakil SM, Khan LA, Hasnain SE, Sarin SK. Vertical transmission of hepatitis B virus despite maternallamivudine therapy. Lancet. Apr 27 2002;359(9316):1488-1489. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11988251.16. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.17. Han GR, Cao MK, Zhao W, et al. A prospective and open-label study for the efficacy and safety of telbivudine inpregnancy for the prevention of perinatal transmission of hepatitis B virus infection. J Hepatol. Dec 2011;55(6):1215-1221. Available at http://www.ncbi.nlm.nih.gov/pubmed/21703206.18. Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G. The reproductive effects of beta interferon therapy in pregnancy: alongitudinal cohort. Neurology. Sep 27 2005;65(6):807-811. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16186517.19. Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis Bvirus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP)part 1: immunization of infants, children, and adolescents. MMWR Recomm Rep. Dec 23 2005;54(RR-16):1-31.Available at http://www.ncbi.nlm.nih.gov/pubmed/16371945.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-48Special Situations — HIV/Hepatitis C Virus Coinfection (Last updated July 31, 2012; lastreviewed July 31, 2012)For additional information on hepatitis C and HIV, see Hepatitis C Virus Infectionof the Guidelines forPrevention and Treatment of Opportunistic Infections in HIV-infected Adults and Adolescents,Recommendations from the Centers for Disease Control and Prevention (CDC), the National Institutes ofHealth (NIH), and the HIV Medicine Association of the Infectious Diseases Society of Americaathttp://www.cdc.gov/mmwr/pdf/rr/rr5804.pdf.1Coinfection with hepatitis C virus (HCV) is not uncommon in HIV-infected women, particularly those infectedvia parenteral use of drugs; among HIV-infected pregnant women, the HCV seroprevalence rate ranges from17% to 54%.2Screening for chronic HCV infection using a sensitive immunoassay for HCV antibody isrecommended for all HIV-infected individuals, including pregnant women. False-negative anti-HCVimmunoassay results can occur in HIV-infected individuals, particularly those with very low CD4 T-lymphocyte (CD4-cell) counts, but it is uncommon with the most sensitive immunoassays. Individuals whohave a positive HCV antibody test should undergo confirmatory testing for plasma HCV RNA using acommercially available quantitative diagnostic assay. Testing for HCV RNA also should be performed onindividuals whose serologic test results are indeterminate or negative but in whom HCV infection is suspectedbecause of elevated aminotransaminase levels or risk factors such as a history of intravenous drug use.Panel’s Recommendations• Screening for hepatitis C virus (HCV) infection is recommended for all HIV-infected pregnant women who have not beenscreened during the current pregnancy (AIII).• Interferon alfa and pegylated interferon alfa are not recommended and ribavirin is contraindicated during pregnancy(AIII).• Recommendations for antiretroviral (ARV) drug use during pregnancy are the same for women who have chronic HCV asfor those without HCV coinfection (BIII).• Pregnant women with HIV/HCV coinfection receiving ARV drugs should be counseled about signs and symptoms of livertoxicity, and transaminases should be assessed 1 month following initiation of ARV drugs and then every 3 monthsthereafter (BIII).• Decisions concerning mode of delivery in HIV/HCV-coinfected pregnant women should be based on standard obstetricand HIV-related indications alone (see Intrapartum Care) (BIII).• Infants born to women with HIV/HCV coinfection should be evaluated for HCV infection with anti-HCV antibody testingafter age 18 months (AII). Infants who test positive for anti-HCV antibodies should undergo confirmatory HCV RNAtesting. If earlier diagnosis is indicated or desired, HCV RNA virologic testing can be performed between ages 3 and 6months (AIII).• Women who are found to have chronic HCV infection should also be screened for hepatitis A virus (HAV) and hepatitis Bvirus (HBV) because they are at increased risk of complications from those two infections. Women with chronic HCV whoare negative for hepatitis A immunoglobulin G should receive the HAV vaccine series (AIII). If they are not infected withHBV (that is, hepatitis B surface antigen negative, hepatitis B core antibody negative, and hepatitis B surface antibodynegative), they should receive the HBV vaccine series (AIII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Few data exist on the optimal management of HIV-infected pregnant women with HCV coinfection.Recommendations for antiretroviral (ARV) drug use during pregnancy for treatment of HIV and/orprevention of mother-to-child transmission (MTCT) are the same for women who have HCV coinfection asfor those with HIV alone (see HIV/Hepatitis C [HCV] Coinfectionin Guidelines for the Use of AntiretroviralAgents in HIV-1-Infected Adults and Adolescents, http://AIDSinfo.nih.gov). However, currently availableanti-HCV treatments are not recommended during pregnancy. Interferons are not recommended for use inpregnancy because they are abortifacient at high doses in monkeys and have direct antigrowth andantiproliferative effects,3and ribavirin is contraindicated (Food and Drug Administration [FDA] PregnancyCategory X) because of teratogenicity at low doses in multiple animal species. Ribavirin-associated defectsin animals include limb abnormalities, craniofacial defects, anencephaly, and anophthalmia. Concerns havebeen raised about potential mutagenic effects of ribavirin in the offspring of men taking ribavirin beforeconception because of possible accumulation of ribavirin in spermatozoa. However, in a small number ofinadvertent pregnancies occurring in partners of men receiving ribavirin therapy, no adverse outcomes werereported.4Pregnancies that occur in women taking ribavirin should be reported to the Ribavirin PregnancyRegistry (800-593-2214 or http://www.ribavirinpregnancyregistry.com). There are no data in pregnancy ontelaprevir or boceprevir, both recently approved by the FDA for treatment of HCV. Telaprevir and boceprevirare Pregnancy Category B agents; however, these agents must be used in combination with pegylatedinteferon and ribavirin, which should not be used in pregnancy. In addition, recent data demonstratedpotential drug interactions between boceprevir and certain ritonavir-boosted protease inhibitor (PI) regimensthat may reduce the effectiveness of these medications if used together (for more detailed information seeGuidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents).5Pregnancy doesnot appear to influence the course of HCV infection and women with chronic HCV generally do quite wellduring pregnancy, provided that their infections have not progressed to decompensated cirrhosis.6Because of the added risk of acute infection with hepatitis A virus (HAV) and hepatitis B virus (HBV) inindividuals with chronic HCV, women who are found to have chronic HCV infection should also be screenedfor HAV and HBV. Women with chronic HCV infection who are hepatitis A immunoglobulin G negativeshould receive the HAV vaccine series, and if they are not infected with HBV (that is, hepatitis B surfaceantigen negative, hepatitis B core antibody negative, and hepatitis B surface antibody negative), they shouldreceive the HBV vaccine series.In a majority of studies, the incidence of HCV transmission from mother to infant increases if the mother iscoinfected with HIV, with transmission rates between 10% and 20%.7-10These higher transmission rates arelikely related to an increase in HCV viremia and/or other HIV-related impact on HCV disease activity.11AEuropean study of perinatal transmission of HCV found that use of effective combination therapy for HIVwas associated with a strong trend toward reduction in HCV transmission (odds ratio 0.26, 95% confidenceinterval, 0.07–1.01).12Maternal HIV/HCV coinfection also may increase the risk of perinatal transmission ofHIV.13Therefore, potent antiretroviral therapy (ART) with at least three drugs is recommended for allHIV/HCV-coinfected pregnant women, regardless of CD4-cell count or HIV viral load.As with chronic HBV infection, an elevation in hepatic enzymes following initiation of ART can occur inHIV/HCV-coinfected women—particularly in those with low CD4-cell counts at treatment initiation—as aresult of an immune-mediated flare in HCV disease triggered by immune reconstitution with effective ART.Like HBV, HCV infection may increase the hepatotoxic risk of certain ARV agents, specifically PIs andnevirapine. Pregnant women with HIV/HCV coinfection should be counseled about signs and symptoms ofliver toxicity, and transaminase levels should be assessed 1 month after initiation of ARV drugs and thenevery 3 months thereafter. If hepatic toxicity occurs, consideration may need to be given to substituting a lesshepatotoxic drug regimen, and if clinical symptoms or significant elevations of transaminases occur, drugsmay need to be temporarily discontinued. Differentiating between a flare in HCV disease associated withRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-49Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.immune reconstitution and drug toxicity often can be difficult; therefore, consultation with an expert in HIVand HCV coinfection is strongly recommended. As with transmission of HIV, risk of MTCT of HCV may be increased by use of internal fetal monitoring,amniocentesis, and rupture of membranes for more than 6 hours.9, 14The majority of studies of electivecesarean delivery that have included HIV-infected women have found that the procedure does not reduce therisk of perinatal transmission of HCV.12, 15-17The general recommendations for intrapartum management arethe same in women with HIV/HCV coinfection as in those with HIV infection alone (see Intrapartum Care). Infants born to women with HIV/HCV coinfection should be assessed for HCV infection with anti-HCVantibody testing after age 18 months. Infants who screen positive should undergo confirmatory HCV RNAtesting. HCV RNA virologic testing can be done between ages 3 and 6 months, if earlier diagnosis isindicated or desirable.18, 19Because HCV viremia can be intermittent, at least two negative tests are needed toexclude HCV infection. Children are considered to be HCV infected if they have two or more positive HCVRNA polymerase chain reaction results or are HCV antibody positive beyond age 18 months.References1. Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV MedicineAssociation of the Infectious Diseases Society of America. MMWR Recomm Rep. Apr 10 2009;58(RR-4):1-207; quizCE201-204. Available at http://www.ncbi.nlm.nih.gov/pubmed/19357635.2. Thomas SL, Newell ML, Peckham CS, Ades AE, Hall AJ. A review of hepatitis C virus (HCV) vertical transmission:risks of transmission to infants born to mothers with and without HCV viraemia or human immunodeficiency virusinfection. Int J Epidemiol. Feb 1998;27(1):108-117. Available at http://www.ncbi.nlm.nih.gov/pubmed/9563703.3. Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G. The reproductive effects of beta interferon therapy in pregnancy: alongitudinal cohort. Neurology. Sep 27 2005;65(6):807-811. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16186517.4. Hegenbarth K, Maurer U, Kroisel PM, Fickert P, Trauner M, Stauber RE. No evidence for mutagenic effects ofribavirin: report of two normal pregnancies. The American journal of gastroenterology. Jul 2001;96(7):2286-2287.Available at http://www.ncbi.nlm.nih.gov/pubmed/11467687. 5. U.S. Food and Drug Administration. Victrelis (boceprevir) and Ritonavir-Boosted HIV Protease Inhibitor Drugs - DrugInteractions. Available at http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm291389.htm. Posted2/10/2012, accessed March 12, 2012. 6. Sookoian S. Effect of pregnancy on pre-existing liver disease: chronic viral hepatitis. Ann Hepatol. Jul-Sep2006;5(3):190-197. Available at http://www.ncbi.nlm.nih.gov/pubmed/17060881.7. Tovo PA, Palomba E, Ferraris G, et al. Increased risk of maternal-infant hepatitis C virus transmission for womencoinfected with human immunodeficiency virus type 1. Italian Study Group for HCV Infection in Children. Clin InfectDis. Nov 1997;25(5):1121-1124. Available at http://www.ncbi.nlm.nih.gov/pubmed/9402369.8. Gibb DM, Goodall RL, Dunn DT, et al. Mother-to-child transmission of hepatitis C virus: evidence for preventableperipartum transmission. Lancet. Sep 9 2000;356(9233):904-907. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11036896.9. Mast EE, Hwang LY, Seto DS, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the naturalhistory of HCV infection acquired in infancy. J Infect Dis. Dec 1 2005;192(11):1880-1889. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16267758.10. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol. 2006;44(1 Suppl):S6-9. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16352363. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-50Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.11. Polis CB, Shah SN, Johnson KE, Gupta A. Impact of maternal HIV coinfection on the vertical transmission of hepatitisC virus: a meta-analysis. Clin Infect Dis. Apr 15 2007;44(8):1123-1131. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17366462.12. European Paediatric Hepatitis C Virus Network. A significant sex--but not elective cesarean section--effect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis. Dec 1 2005;192(11):1872-1879. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16267757.13. Hershow RC, Riester KA, Lew J, et al. Increased vertical transmission of human immunodeficiency virus from hepatitisC virus-coinfected mothers. Women and Infants Transmission Study. J Infect Dis. Aug 1997;176(2):414-420. Availableat http://www.ncbi.nlm.nih.gov/pubmed/9237706.14. Valladares G, Chacaltana A, Sjogren MH. The management of HCV-infected pregnant women. Ann Hepatol.2010;9(Suppl):92-97. Available at http://www.ncbi.nlm.nih.gov/pubmed/20714003.15. Ghamar Chehreh ME, Tabatabaei SV, Khazanehdari S, Alavian SM. Effect of cesarean section on the risk of perinataltransmission of hepatitis C virus from HCV-RNA+/HIV- mothers: a meta-analysis. Arch Gynecol Obstet. Feb2011;283(2):255-260. Available at http://www.ncbi.nlm.nih.gov/pubmed/20652289.16. Marine-Barjoan E, Berrebi A, Giordanengo V, et al. HCV/HIV co-infection, HCV viral load and mode of delivery: riskfactors for mother-to-child transmission of hepatitis C virus? AIDS. Aug 20 2007;21(13):1811-1815. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17690581.17. McMenamin MB, Jackson AD, Lambert J, et al. Obstetric management of hepatitis C-positive mothers: analysis ofvertical transmission in 559 mother-infant pairs. Am J Obstet Gynecol. Sep 2008;199(3):315 e311-315. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18771997.18. Indolfi G, Resti M. Perinatal transmission of hepatitis C virus infection. J Med Virol. May 2009;81(5):836-843.Available at http://www.ncbi.nlm.nih.gov/pubmed/19319981.19. Polywka S, Pembrey L, Tovo PA, Newell ML. Accuracy of HCV-RNA PCR tests for diagnosis or exclusion ofvertically acquired HCV infection. J Med Virol. Feb 2006;78(2):305-310. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16372293.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-51Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-52Special Situations — HIV-2 Infection and Pregnancy (Last updated July 31, 2012; lastreviewed July 31, 2012)HIV-2 infection is endemic in West African countries including Ivory Coast, Ghana, Cape Verde, Gambia,Mali, Senegal, Liberia, Guinea, Burkina Faso, Nigeria, Mauritania, Sierra Leone, Guinea Bissau, Niger, SaoTome, and Togo; Angola; Mozambique; and in parts of India.1-3It also occurs in countries such as France andPortugal, which have large numbers of immigrants from these regions.3, 4HIV-2 is rare in the United States.Between 1998 and 2010, a total of 242 HIV-2 cases were reported to the Centers for Disease Control andPrevention (CDC), with 166 cases meeting criteria for HIV-2 diagnosis. These 166 cases constituted only0.01% of the more than 1.4 million U.S. cases of HIV infection.5Of the 50 women aged 15 to 44 years atdiagnosis, 24 (48%) were pregnant at or after HIV-2 diagnosis.5HIV-2 infection should be suspected inpregnant women who are from—or who have partners from—countries in which the disease is endemic, whoare HIV-1 antibody positive on an initial enzyme-linked immunoassay screening test, and who have repeatedlyindeterminate results on HIV-1 Western blot along with HIV-1 RNA viral loads at or below the limit ofdetection.6, 7This pattern of HIV testing can also be seen in patients who have a false-positive HIV-1 test.Although most commercially available HIV screening tests can detect both HIV-1 and HIV-2, they do notdistinguish between the two viruses. The Bio-Rad Laboratories Multispot HIV-1/HIV-2 test is the onlyantibody test that can distinguish between HIV-1 and HIV-2 that is approved by the Food and DrugPanel’s Recommendations• HIV-2 infection should be suspected in pregnant women who are from—or have partners from—countries in which thedisease is endemic, who are HIV antibody positive on an initial enzyme-linked immunoassay screening test, and who haverepeatedly indeterminate results on HIV-1 Western blot along with HIV-1 RNA viral loads at or below the limit of detection(BII).• A regimen with two nucleoside reverse transcriptase inhibitors (NRTIs) and a boosted protease inhibitor (PI) currently isrecommended for HIV-2-infected pregnant women who require treatment for their own health because they havesignificant clinical disease or CD4 T-lymphocyte (CD4-cell) counts 3(AIII).ºBased on available data on safety in pregnancy, zidovudine/lamivudine plus lopinavir/ritonavir would be preferred(AIII). Tenofovir plus lamivudine or emtricitabine plus lopinavir/ritonavir can be considered as an alternative (BIII).• Optimal prophylactic regimens have not been defined for HIV-2-infected pregnant women who do not require treatmentfor their own health (that is, CD4-cell counts >500 cells/mm3and no significant clinical disease). Experts haverecommended the following approaches:ºA boosted PI-based regimen (two NRTIs plus lopinavir/ritonavir) for prophylaxis, with the drugs stopped postpartum(BIII); orºZidovudine prophylaxis alone during pregnancy and intrapartum (BIII).• Non-nucleoside reverse transcriptase inhibitors and enfuvirtide are not active against HIV-2 and should not be used fortreatment or prophylaxis (AIII).• All infants born to HIV-2-infected mothers should receive the standard 6-week zidovudine prophylactic regimen (BIII).• In the United States, breastfeeding is not recommended for infants of HIV-2-infected mothers (AIII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Administration (FDA) and should be used if HIV-2 is suspected. In some commercial and public healthlaboratories, HIV-2 supplemental tests, such as HIV-2 immunoblot or HIV-2-specific Western blot, areavailable. However, none of these tests has been FDA approved for diagnosis or clinical management of HIV-2.HIV-2 viral load assays available in the United States are not FDA approved and hence cannot berecommended for clinical use. All HIV-2 cases should be reported to the HIV surveillance program of the stateor local health department, which can arrange for additional confirmatory testing for HIV-2 by the CDC.HIV-2 has a longer asymptomatic phase than HIV-1, with a slower progression to AIDS. The most commonmode of HIV-2 transmission is through heterosexual sex. HIV-2 is less infectious than HIV-1, with a 5-foldlower rate of sexual transmission and 20- to 30-fold lower rate of vertical transmission.3, 8, 9Several studiesconfirm that rates of mother-to-child transmission (MTCT) of HIV-2 are low with and without interventions(0%–4%), which may be a result of reduced plasma viral loads and less cervical viral shedding, comparedwith that seen in HIV-1-infected women.10-13HIV-2 also can be transmitted through breastfeeding. HIV-2infection does not protect against HIV-1 and dual infection, which carries the same prognosis as HIV-1monoinfection, can occur.Few data exist on which to base treatment decisions or strategies for prevention of mother-to-childtransmission (PMTCT) in patients infected with HIV-2. Non-nucleoside reverse transcriptase inhibitors(NNRTIs) and enfuvirtide are not active against HIV-2 and should not be used for treatment or prophylaxis.14,15HIV-2 has variable sensitivity to protease inhibitors (PIs), with lopinavir, saquinavir, and darunavir havingthe most activity against the virus.16The integrase inhibitors raltegravir and elvitegravir also appear to beeffective against HIV-2.3, 17, 18The care of HIV-2-infected pregnant women has been based on expert opinion. A regimen with twonucleoside reverse transcriptase inhibitors and a boosted PI currently is recommended for HIV-2-infectedpregnant women who require treatment for their own health because they have significant clinical disease orCD4-cell counts 3.19Based on available data on safety in pregnancy, zidovudine/lamivudineplus lopinavir/ritonavir would be preferred. Tenofovir plus lamivudine or emtricitabine pluslopinavir/ritonavir can be considered as an alternative.20, 21NNRTIs should not be used because they are notactive against HIV-2. All infants born to mothers infected with HIV-2 should receive the standard 6-weekzidovudine prophylactic regimen.For HIV-2-infected pregnant women with CD4-cell counts >500 cells/mm3and no significant clinical disease,who do not require treatment for their own health, some experts would use a boosted PI-based regimen forprophylaxis and stop the drugs postpartum. Other experts would consider zidovudine prophylaxis alone duringpregnancy and intrapartum.11Because HIV-2 has a significantly lower risk of MTCT than does HIV-1, single-drug prophylaxis with zidovudine alone can be considered for PMTCT. All infants born to mothers infectedwith HIV-2 should receive the standard 6-week zidovudine prophylactic regimen.21The possible risks andbenefits of antiretroviral (ARV) prophylaxis should be discussed with the mothers.Pregnant women who have HIV-1/HIV-2 coinfection should be treated according to the guidelines for HIV-1-monoinfected patients, making sure that the ARV regimen chosen is also appropriate for HIV-2.Other than the standard obstetrical indications, no data exist regarding the role of elective cesarean deliveryin women who are infected with HIV-2. The risk to infants from breastfeeding is lower for HIV-2 than forHIV-1, but breastfeeding should be avoided in the United States and other resource-rich countries where safeinfant formula is readily available.11Infants born to HIV-2-infected mothers should be tested for HIV-2 infection with HIV-2-specific virologicassays at time points similar to those used for HIV-1 testing.22HIV-2 virologic assays are not commerciallyavailable, but the National Perinatal HIV Hotline (1-888-448-8765) can provide a list of sites that performthis testing.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-53Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Testing of infants at age 18 months (for example, with the Bio-Rad Laboratories Multispot HIV-1/HIV-2 test)also is recommended to confirm clearance of HIV-2 antibodies.21References1. De Cock KM, Brun-Vezinet F. Epidemiology of HIV-2 infection. AIDS. 1989;3(Suppl 1):S89-95. Available athttp://www.ncbi.nlm.nih.gov/pubmed/2514761.2. De Cock KM, Adjorlolo G, Ekpini E, et al. Epidemiology and transmission of HIV-2. Why there is no HIV-2 pandemic.JAMA. Nov 3 1993;270(17):2083-2086. Available at http://www.ncbi.nlm.nih.gov/pubmed/8147962.3. Campbell-Yesufu OT, Gandhi RT. Update on human immunodeficiency virus (HIV)-2 infection. Clin Infect Dis. Mar 152011;52(6):780-787. Available at http://www.ncbi.nlm.nih.gov/pubmed/21367732.4. Barin F, Cazein F, Lot F, et al. Prevalence of HIV-2 and HIV-1 Group O infections among new HIV diagnoses inFrance: 2003-2006. AIDS 2007 Nov 12;21 (17):2351-53. Available at http://www.ncbi.nlm.nih.gov/pubmed/18090288.5. Centers for Disease Control and Prevention. HIV-2 Infection Surveillance--United States, 1987-2009. MMWR MorbMortal Wkly Rep. Jul 29 2011;60(29):985-988. Available at http://www.ncbi.nlm.nih.gov/pubmed/21796096.6. OBrien TR, George JR, Epstein JS, Holmberg SD, Schochetman G. Testing for antibodies to human immunodeficiencyvirus type 2 in the United States. MMWR Recomm Rep. Jul 17 1992;41(RR-12):1-9. Available athttp://www.ncbi.nlm.nih.gov/pubmed/1324395.7. Torian LV, Eavey JJ, Punsalang AP, et al. HIV type 2 in New York City, 2000-2008. Clin Infect Dis. Dec 12010;51(11):1334-1342. Available at http://www.ncbi.nlm.nih.gov/pubmed/21039219.8. Kanki PJ, Travers KU, S MB, et al. Slower heterosexual spread of HIV-2 than HIV-1. Lancet. Apr 161994;343(8903):943-946. Available at http://www.ncbi.nlm.nih.gov/pubmed/7909009.9. Matheron S, Courpotin C, Simon F, et al. Vertical transmission of HIV-2. Lancet. May 5 1990;335(8697):1103-1104.Available at http://www.ncbi.nlm.nih.gov/pubmed/1970407.10. ODonovan D, Ariyoshi K, Milligan P, et al. Maternal plasma viral RNA levels determine marked differences in mother-to-child transmission rates of HIV-1 and HIV-2 in The Gambia. MRC/Gambia Government/University College LondonMedical School working group on mother-child transmission of HIV. AIDS. Mar 10 2000;14(4):441-448. Available athttp://www.ncbi.nlm.nih.gov/pubmed/10770548.11. Burgard M, Jasseron C, Matheron S, et al. Mother-to-child transmission of HIV-2 infection from 1986 to 2007 in theANRS French Perinatal Cohort EPF-CO1. Clin Infect Dis. Oct 1 2010;51(7):833-843. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20804413.12. Adjorlolo-Johnson G, De Cock KM, Ekpini E, et al. Prospective comparison of mother-to-child transmission of HIV-1and HIV-2 in Abidjan, Ivory Coast. JAMA. Aug 10 1994;272(6):462-466. Available athttp://www.ncbi.nlm.nih.gov/pubmed/8040982.13. Andreasson PA, Dias F, Naucler A, Andersson S, Biberfeld G. A prospective study of vertical transmission of HIV-2 inBissau, Guinea-Bissau. AIDS. Jul 1993;7(7):989-993. Available at http://www.ncbi.nlm.nih.gov/pubmed/8357558.14. Tuaillon E, Gueudin M, Lemee V, et al. Phenotypic susceptibility to nonnucleoside inhibitors of virion-associatedreverse transcriptase from different HIV types and groups. J Acquir Immune Defic Syndr. Dec 15 2004;37(5):1543-1549. Available at http://www.ncbi.nlm.nih.gov/pubmed/15577405.15. Poveda E, Rodes B, Toro C, Soriano V. Are fusion inhibitors active against all HIV variants? AIDS Res HumRetroviruses. Mar 2004;20(3):347-348. Available at http://www.ncbi.nlm.nih.gov/pubmed/15117459.16. Desbois D, Roquebert B, Peytavin G, et al. In vitro phenotypic susceptibility of human immunodeficiency virus type 2clinical isolates to protease inhibitors. Antimicrob Agents Chemother. Apr 2008;52(4):1545-1548. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18227188.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-54Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.17. Roquebert B, Damond F, Collin G, et al. HIV-2 integrase gene polymorphism and phenotypic susceptibility of HIV-2clinical isolates to the integrase inhibitors raltegravir and elvitegravir in vitro. J Antimicrob Chemother. Nov2008;62(5):914-920. Available at http://www.ncbi.nlm.nih.gov/pubmed/18718922.18. Bercoff DP, Triqueneaux P, Lambert C, et al. Polymorphisms of HIV-2 integrase and selection of resistance toraltegravir. Retrovirology. 2010;7:98. Available at http://www.ncbi.nlm.nih.gov/pubmed/21114823.19. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed June 19, 2012. 20. Gilleece Y, Chadwick DR, Breuer J, et al. British HIV Association guidelines for antiretroviral treatment of HIV-2-positive individuals 2010. HIV Med. Nov 2010;11(10):611-619. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20961377.21. de Ruiter A, Mercey D, Anderson J, et al. British HIV Association and Childrens HIV Association guidelines for themanagement of HIV infection in pregnant women 2008. HIV Med. Aug 2008;9(7):452-502. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18840151.22. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use ofAntiretroviral Agents in Pediatric HIV Infection. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/PediatricGuidelines.pdf. Accessed June 19, 2012. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-55Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-56Special Situations —Acute HIV Infection (Last updated July 31, 2012; last reviewedJuly 31, 2012)Primary or acute HIV infection in pregnancy or during breastfeeding is associated with an increased risk ofperinatal transmission of HIV and may represent a significant proportion of residual mother-to-childtransmission (MTCT) in the United States.In North Carolina from 2002 to 2005, 5 of 15 women found to have acute HIV infection on nucleic acidamplification testing of pooled HIV antibody-negative specimens were pregnant at the time of testing.1All 5women received antiretroviral (ARV) drugs and delivered HIV-uninfected infants.From 2002 to 2006, 3,396 HIV-exposed neonates were born in New York State; 22% (9 of 41) of infants born tomothers who acquired HIV during pregnancy became infected with HIV, compared with 1.8% of those born tomothers who did not acquire HIV during pregnancy (odds ratio 15.19; 95% confidence interval, 3.98–56.30).Maternal acquisition of HIV during pregnancy was documented in only 1.3% of perinatal HIV exposures, but itwas associated with 9 (13.8%) of the 65 MTCT cases.2A case series from China reported a perinataltransmission rate of 35.8% in 106 breastfeeding infants of mothers who acquired HIV postnatally through bloodtransfusion.3The high rate of transmission associated with acute infection likely is related to the combination ofthe high viral load in plasma, breast milk, and the genital tract associated with acute infection4, 5and the fact thatthe diagnosis is easy to miss, which results in lost opportunities for implementation of prevention interventions.Health care providers should maintain a high level of suspicion of acute HIV infection in women who arepregnant or breastfeeding and have a compatible clinical syndrome, even when they do not report high-riskbehaviors, because it is possible that their sexual partners are practicing high-risk behaviors of which thewomen are unaware.Panel’s Recommendations• When acute retroviral syndrome is suspected in pregnancy or during breastfeeding, a plasma HIV RNA test should beobtained in conjunction with an HIV antibody test (see Identifying, Diagnosing, and Managing Acute HIV-1 Infection in theGuidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents) (AII).• Repeat HIV antibody testing in the third trimester is recommended for pregnant women with initial negative HIV antibodytests who are known to be at risk of HIV, are receiving care in facilities that have an HIV incidence in pregnant women ofat least 1 per 1,000 per year, are incarcerated, or who reside in jurisdictions with elevated HIV incidence (see RevisedRecommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-Care Settings) (AII).• All pregnant women with acute or recent HIV infection should start a combination antiretroviral (ARV) drug regimen assoon as possible to prevent mother-to-child transmission, with the goal of suppressing plasma HIV RNA to belowdetectable levels (AI).• In women with acute HIV infection, baseline genotypic resistance testing should be performed simultaneously withinitiation of the combination ARV regimen, and the ARV regimen should be adjusted, if necessary, to optimize virologicresponse (AIII).• Because clinically significant resistance to protease inhibitors (PIs) is less common than resistance to non-nucleosidereverse transcriptase inhibitors in ARV-naive individuals in general, a ritonavir-boosted PI-based regimen should beinitiated (AIII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.An estimated 40%–90% of patients with acute HIV infection will experience symptoms of acute retroviralsyndrome, characterized by fever, lymphadenopathy, pharyngitis, skin rash, myalgias/arthralgias, and othersymptoms.4, 6-11Providers often do not recognize acute HIV infection, however, because the symptoms aresimilar to those of other common illnesses and individuals with the condition also can be asymptomatic.When acute retroviral syndrome is suspected, a plasma HIV RNA test typically is used in conjunction withan HIV antibody test to diagnose acute infection. A low-positive HIV RNA level (represent a false-positive test because values in acute infection generally are very high (>100,000copies/mL).4, 10In individuals infected with non-B HIV-1 subtypes, however, HIV RNA levels may be lower,even with acute infection, because those subtypes may not amplify as well as subtype B. In that situation,consultation with an HIV treatment specialist is recommended. Confirmatory serologic testing should beperformed within 3 months on patients whose acute HIV infection is diagnosed with virologic testing butwho are antibody negative or whose antibody levels cannot be determined.Recent HIV infection also can be detected by repeat HIV antibody testing later in pregnancy in womenwhose initial HIV antibody testing earlier in pregnancy was negative. A report from the Mother-Infant RapidIntervention at Delivery study found that 6 (11%) of 54 women whose HIV was identified with rapid HIVtesting during labor had primary infection.12Repeat HIV testing in the third trimester is recommended forpregnant women known to be at risk of HIV who receive care in facilities with an HIV incidence of at least 1case per 1,000 pregnant women per year, who are incarcerated, or who reside in jurisdictions with elevatedHIV incidence (see Revised Recommendations for HIV Testing of Adults, Adolescents, and Pregnant Womenin Health-Care Settings).13Whether treatment of acute or recent HIV infection results in long-term virologic, immunologic, or clinicalbenefit is unknown, and in non-pregnant adults, therapy currently is considered optional.14In pregnant orbreastfeeding women, however, acute or recent HIV infection is associated with a high risk of perinataltransmission of HIV. All HIV-infected pregnant women with acute or recent infection should start acombination ARV regimen as soon as possible, with the goal of preventing perinatal transmission by optimalsuppression of plasma HIV RNA below detectable levels. Data from the United States and Europedemonstrate that in 6%–16% of patients, transmitted virus may be resistant to at least one ARV drug.15-17Therefore, baseline genotypic resistance testing should be performed to guide selection or adjustment of anoptimal ARV drug regimen. If results of resistance testing or the source virus’s resistance pattern are known,that information should be used to guide selection of the drug regimen, but initiation of the combination ARVregimen should not be delayed. Because clinically significant resistance to protease inhibitors (PIs) is lesscommon than resistance to non-nucleoside reverse transcriptase inhibitors in ARV-naive persons, a PI-basedARV drug regimen generally should be initiated. Choice of regimen should be based on recommendationsfor use of ARV drugs in pregnancy (see Table 5). Following delivery, considerations regarding continuationof the ARV regimen for treatment are the same for mothers as for other non-pregnant individuals.When acute HIV infection is diagnosed during pregnancy, and particularly if it is documented in latepregnancy, cesarean delivery is likely to be necessary because there may be insufficient time to fullysuppress a patient’s viral load. In nursing mothers in whom seroconversion is suspected, breastfeeding shouldbe interrupted and it should not resume if infection is definitively confirmed (see Breastfeeding Infants ofMothers Diagnosed with HIV Infectionin Infant Antiretroviral Prophylaxis). In such a situation, consultationwith a pediatric HIV specialist regarding appropriate infant management is recommended. All women who are pregnant or breastfeeding should be counseled about prevention of acquisition of HIV(Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV andRecommendations for Postexposure Prophylaxisand Antiretroviral Postexposure Prophylaxis After Sexual,Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States). Several studiessuggest that pregnancy may be a time of increased risk of transmission of HIV18-21, even when controlling forsexual risk behaviors.18It is hypothesized that the heightened risk may be attributable to hormonal changesRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-57Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.that affect the genital tract mucosa or immune responses.18Although no reliable data on HIV serodiscordancerates in the United States exist, data on women from sub-Saharan Africa show that women in serodiscordantrelationships may be particularly vulnerable to acquisition of HIV.22, 23HIV testing of the sexual partners ofpregnant women should be encouraged. The importance of using condoms should be reinforced in pregnantand breastfeeding women who may be at risk of acquisition of HIV, including those whose partners are HIVinfected. References1. Patterson KB, Leone PA, Fiscus SA, et al. Frequent detection of acute HIV infection in pregnant women. AIDS. Nov 122007;21(17):2303-2308. Available at http://www.ncbi.nlm.nih.gov/pubmed/18090278.2. Birkhead GS, Pulver WP, Warren BL, Hackel S, Rodriguez D, Smith L. Acquiring human immunodeficiency virusduring pregnancy and mother-to-child transmission in New York: 2002-2006. Obstet Gynecol. Jun 2010;115(6):1247-1255. Available at http://www.ncbi.nlm.nih.gov/pubmed/20502297.3. Liang K, Gui X, Zhang YZ, Zhuang K, Meyers K, Ho DD. A case series of 104 women infected with HIV-1 via bloodtransfusion postnatally: high rate of HIV-1 transmission to infants through breast-feeding. J Infect Dis. Sep 12009;200(5):682-686. Available at http://www.ncbi.nlm.nih.gov/pubmed/19627245.4. Hecht FM, Busch MP, Rawal B, et al. Use of laboratory tests and clinical symptoms for identification of primary HIVinfection. AIDS. May 24 2002;16(8):1119-1129. Available at http://www.ncbi.nlm.nih.gov/pubmed/12004270.5. Morrison CS, Demers K, Kwok C, et al. Plasma and cervical viral loads among Ugandan and Zimbabwean womenduring acute and early HIV-1 infection. AIDS. Feb 20 2010;24(4):573-582. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20154581.6. Tindall B, Cooper DA. Primary HIV infection: host responses and intervention strategies. AIDS. Jan 1991;5(1):1-14.Available at http://www.ncbi.nlm.nih.gov/pubmed/1812848.7. Niu MT, Stein DS, Schnittman SM. Primary human immunodeficiency virus type 1 infection: review of pathogenesisand early treatment intervention in humans and animal retrovirus infections. J Infect Dis. Dec 1993;168(6):1490-1501.Available at http://www.ncbi.nlm.nih.gov/pubmed/8245534.8. Kinloch-de Loes S, de Saussure P, Saurat JH, Stalder H, Hirschel B, Perrin LH. Symptomatic primary infection due tohuman immunodeficiency virus type 1: review of 31 cases. Clin Infect Dis. Jul 1993;17(1):59-65. Available athttp://www.ncbi.nlm.nih.gov/pubmed/8353247.9. Schacker T, Collier AC, Hughes J, Shea T, Corey L. Clinical and epidemiologic features of primary HIV infection. AnnIntern Med. Aug 15 1996;125(4):257-264. Available at http://www.ncbi.nlm.nih.gov/pubmed/8678387.10. Daar ES, Little S, Pitt J, et al. Diagnosis of primary HIV-1 infection. Los Angeles County Primary HIV InfectionRecruitment Network. Ann Intern Med. Jan 2 2001;134(1):25-29. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11187417.11. Yerly S, Hirschel B. Diagnosing acute HIV infection. Expert Rev Anti Infect Ther. Jan 2012;10(1):31-41. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22149612.12. Nesheim S, Jamieson DJ, Danner SP, et al. Primary human immunodeficiency virus infection during pregnancy detectedby repeat testing. Am J Obstet Gynecol. Aug 2007;197(2):149 e141-145. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17689629.13. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, andpregnant women in health-care settings. MMWR Recomm Rep. Sep 22 2006;55(RR-14):1-17; quiz CE11-14. Availableat http://www.ncbi.nlm.nih.gov/pubmed/16988643.14. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed June 7, 2012Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-58Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.15. Wheeler WH, Ziebell RA, Zabina H, et al. Prevalence of transmitted drug resistance associated mutations and HIV-1subtypes in new HIV-1 diagnoses, U.S.-2006. AIDS. May 15 2010;24(8):1203-1212. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20395786.16. Wheeler WH, Ziebell RA, et al. Prevalence of transmitted drug resistance associated mutations and HIV-1 subtypes innew HIV-1 diagnoses, U.S.-2006. AIDS. 2010 May 15;24(8):1203-12. Available at:http://www.ncbi.nlm.nih.gov/pubmed/20395786.17. Wensing AM, van de Vijver DA, Angarano G, et al. Prevalence of drug-resistant HIV-1 variants in untreated individualsin Europe: implications for clinical management. J Infect Dis. Sep 15 2005;192(6):958-966. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16107947.18. Gray RH, Li X, Kigozi G, et al. Increased risk of incident HIV during pregnancy in Rakai, Uganda: a prospective study.Lancet. Oct 1 2005;366(9492):1182-1188. Available at http://www.ncbi.nlm.nih.gov/pubmed/16198767.19. Bernasconi D, Tavoschi L, Regine V, et al. Identification of recent HIV infections and of factors associated with virusacquisition among pregnant women in 2004 and 2006 in Swaziland. J Clin Virol. Jul 2010;48(3):180-183. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20537582.20. Moodley D, Esterhuizen TM, Pather T, Chetty V, Ngaleka L. High HIV incidence during pregnancy: compelling reasonfor repeat HIV testing. AIDS. Jun 19 2009;23(10):1255-1259. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19455017.21. Mugo NR, Heffron R, Donnell D, et al. Increased risk of HIV-1 transmission in pregnancy: a prospective study amongAfrican HIV-1-serodiscordant couples. AIDS. Sep 24 2011;25(15):1887-1895. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21785321.22. Carpenter LM, Kamali A, Ruberantwari A, Malamba SS, Whitworth JA. Rates of HIV-1 transmission within marriagein rural Uganda in relation to the HIV sero-status of the partners. AIDS. Jun 18 1999;13(9):1083-1089. Available athttp://www.ncbi.nlm.nih.gov/pubmed/10397539.23. Brubaker SG, Bukusi EA, Odoyo J, Achando J, Okumu A, Cohen CR. Pregnancy and HIV transmission among HIV-discordant couples in a clinical trial in Kisumu, Kenya. HIV Med. May 2011;12(5):316-321. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21205129.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-59Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-60Special Situations —Stopping Antiretroviral Drugs During Pregnancy (Last updatedJuly 31, 2012; last reviewed July 31, 2012)Discontinuation of antiretroviral (ARV) drug regimens during pregnancy may be indicated in somesituations, including serious drug-related toxicity, pregnancy-induced hyperemesis unresponsive toantiemetics, acute illnesses or planned surgeries that preclude oral intake, lack of available medication, or atpatients’ request.HIV-infected women receiving antiretroviral therapy (ART) who present for care during the first trimestershould continue treatment during pregnancy. Discontinuation of therapy could lead to an increase in viralload with possible decline in immune status and disease progression as well as adverse consequences for thefetus, including increased risk of in uterotransmission of HIV. A recent analysis from a prospective cohort of937 HIV-infected mother-child pairs found that interruption of ART during pregnancy, including interruptionin the first and third trimesters, was independently associated with perinatal transmission. In the firsttrimester, the median time at interruption was 6 weeks’ gestation and length of time without therapy was 8weeks (interquartile range [IQR], 7–11 weeks); in the third trimester, the median time at interruption was 32weeks and length of time without therapy was 6 weeks (IQR, 2–9 weeks). Although the perinataltransmission rate for the entire cohort was only 1.3%, transmission occurred in 4.9% (95% confidenceinterval [CI], 1.9%–13.2%; adjusted odds ratio [AOR] 10.33; P= .005) with first-trimester interruption and18.2% (95% CI, 4.5%–72.7%; AOR 46.96; P= .002) with third-trimester interruption.1Although the use ofefavirenz should be avoided during the first trimester when possible, therapy should not be interrupted inwomen taking the drug who present in the first trimester (see HIV-Infected Pregnant Women Who AreCurrently Receiving Antiretroviral Treatment).Continuation of all drugs during the intrapartum period generally is recommended. Women who are havingelective cesarean delivery can take oral medications before the procedure and restart drugs following surgery.Because most drugs are given once or twice daily, it is likely that no doses would be missed or that at mostthe postpartum dose would be given a few hours late.Panel’s Recommendations• HIV-infected women receiving antiretroviral therapy (ART) who present for care during the first trimester should continuetreatment during pregnancy (AII). If an antiretroviral (ARV) drug regimen is stopped acutely for severe or life-threateningtoxicity, severe pregnancy-induced hyperemesis unresponsive to antiemetics, or other acute illnesses that preclude oralintake, all ARV drugs should be stopped and reinitiated at the same time (AIII).• If an ARV drug regimen is being stopped electively and the patient is receiving a non-nucleoside reverse transcriptaseinhibitor (NNRTI) drug, consideration should be given to either: (1) stopping the NNRTI first and continuing the otherARV drugs for a period of time or (2) switching from an NNRTI to a protease inhibitor (PI) before interruption andcontinuing the PI with the other ARV drugs for a period of time before electively stopping. The optimal interval betweenstopping an NNRTI and the other ARV drugs is unknown; at least 7 days is recommended. Given the potential forprolonged detectable efavirenz concentrations for >3 weeks in patients receiving efavirenz-based therapy, some expertsrecommend continuing the other ARV agents or substituting a PI plus two other agents for up to 30 days (CIII).• If nevirapine is stopped and more than 2 weeks have passed before restarting therapy, nevirapine should be restarted withthe 2-week half-dose escalation period (AII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.When short-term drug interruption is indicated, in most cases, all ARV drugs should be stopped andreintroduced at the same time. This can be problematic with drugs that have a long half-life. However, inconditions such as serious or life-threatening toxicity, severe pregnancy-induced hyperemesis unresponsive toantiemetics, or other acute illnesses precluding oral intake, the clinician has no choice but to stop all therapy atthe same time. In the rare case in which a woman has limited oral intake that does not meet food requirementsfor certain ARV agents, decisions about the ARV regimen administered during the antepartum or intrapartumperiod should be made on an individual basis and in consultation with an HIV treatment expert.Non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs such as nevirapine and efavirenz have verylong half-lives and can be detected for 21 days or longer after discontinuation; efavirenz has a longer half-life than nevirapine.2-6Because other drugs in the ARV regimen have shorter half-lives and are cleared morerapidly, only detectable NNRTI drug levels persist, resulting in subtherapeutic drug levels that can increasethe risk of selection of NNRTI-resistant mutations. In addition, certain genetic polymorphisms, which maybe more common among ethnic groups such as African Americans and Hispanics, may have the potential toresult in a slower rate of clearance.4, 6To prevent prolonged exposure to a single drug, some expertsrecommend stopping the NNRTI first and continuing the other ARV drugs for a period of time.3However,the optimal interval between stopping an NNRTI and the other ARV drugs is unknown; detectable levels ofNNRTIs may be present from 3 weeks after discontinuation, with the longer duration primarilyobserved with efavirenz.6An alternative strategy is to substitute a protease inhibitor (PI) for the NNRTI andto continue the PI with dual nucleoside reverse transcriptase inhibitors (NRTIs) for a period of time. In apost-study analysis of the patients who interrupted therapy in the SMART trial, patients who were switchedfrom an NNRTI- to a PI-based regimen before interruption had a lower rate of NNRTI-resistant mutationafter interruption and a greater chance of HIV RNA resuppression after restarting therapy than those whostopped all the drugs simultaneously or stopped the NNRTI before the dual NRTIs.7The optimal duration for continuing either dual nucleosides or the substituted PI-based regimen afterstopping the NNRTI is unknown, but a minimum of 7 days is recommended based on studies to reduceresistance following single-dose nevirapine.8, 9A pharmacokinetic study of nevirapine elimination in African adults following cessation of steady-statenevirapine-containing regimens found that nevirapine concentrations were estimated to have fallen below 20ng/mL in 3 of 19 (16%) and 14 of 19 (74%) subjects by 7 and 14 days, respectively, after the cessation ofdosing.10Elimination half-life was 39 hours in these subjects, considerably shorter than that observed afterperipartum exposure to single doses of nevirapine (average 55–60 hours), likely related to induction ofnevirapine metabolism with chronic nevirapine exposure.2, 11, 12Because efavirenz concentrations have thepotential to be detectable for more than 3 weeks, some experts suggest that if efavirenz-based therapy isstopped, the dual NRTIs or PI may need to be continued for up to 30 days. Further research is needed toassess appropriate strategies for stopping NNRTI-containing combination regimens.Another consideration is reintroduction of nevirapine if it is temporarily stopped and subsequently restarted.A 2-week, half-dose escalation currently is recommended in patients who are started on nevirapine. Doseescalation is necessary because nevirapine induces its own metabolism by inducing cytochrome P450 3A4liver metabolic enzymes; thus, initial administration of the full therapeutic dose will result in elevated druglevels until metabolic enzyme induction has occurred. In cases where nevirapine has been discontinued formore than 2 weeks, another 2-week dose escalation is recommended when it is reintroduced.References1. Galli L, Puliti D, Chiappini E, et al. Is the interruption of antiretroviral treatment during pregnancy an additional majorrisk factor for mother-to-child transmission of HIV type 1? Clin Infect Dis.May 1 2009;48(9):1310-1317. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19309307.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-61Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.2. Cressey TR, Jourdain G, Lallemant MJ, et al. Persistence of nevirapine exposure during the postpartum period afterintrapartum single-dose nevirapine in addition to zidovudine prophylaxis for the prevention of mother-to-childtransmission of HIV-1. J Acquir Immune Defic Syndr. Mar 1 2005;38(3):283-288. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15735445.3. Mackie NE, Fidler S, Tamm N, et al. Clinical implications of stopping nevirapine-based antiretroviral therapy: relativepharmacokinetics and avoidance of drug resistance. HIV Med. May 2004;5(3):180-184. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15139985.4. Nolan M, Fowler MG, Mofenson LM. Antiretroviral prophylaxis of perinatal HIV-1 transmission and the potentialimpact of antiretroviral resistance. J Acquir Immune Defic Syndr. Jun 1 2002;30(2):216-229. Available athttp://www.ncbi.nlm.nih.gov/pubmed/12045685.5. Sadiq ST, Fredericks S, Khoo SH, Rice P, Holt DW. Efavirenz detectable in plasma 8 weeks after stopping therapy andsubsequent development of non-nucleoside reverse transcriptase inhibitor-associated resistance. AIDS. Oct 142005;19(15):1716-1717. Available at http://www.ncbi.nlm.nih.gov/pubmed/16184054.6. Ribaudo HJ, Haas DW, Tierney C, et al. Pharmacogenetics of plasma efavirenz exposure after treatmentdiscontinuation: an Adult AIDS Clinical Trials Group Study. Clin Infect Dis. Feb 1 2006;42(3):401-407. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16392089.7. Fox Z, Phillips A, Cohen C, et al. Viral resuppression and detection of drug resistance following interruption of asuppressive non-nucleoside reverse transcriptase inhibitor-based regimen. AIDS. Nov 12 2008;22(17):2279-2289.Available at http://www.ncbi.nlm.nih.gov/pubmed/18981767.8. McIntyre JA, Hopley M, Moodley D, et al. Efficacy of short-course AZT plus 3TC to reduce nevirapine resistance inthe prevention of mother-to-child HIV transmission: a randomized clinical trial. PLoS Med. Oct 2009;6(10):e1000172.Available at http://www.ncbi.nlm.nih.gov/pubmed/19859531.9. Farr SL, Nelson JA, Ngombe TJ, et al. Addition of 7 days of zidovudine plus lamivudine to peripartum single-dosenevirapine effectively reduces nevirapine resistance postpartum in HIV-infected mothers in Malawi. J Acquir ImmuneDefic Syndr. Aug 2010;54(5):515-523. Available at http://www.ncbi.nlm.nih.gov/pubmed/20672451.10. Kikaire B, Khoo S, Walker AS, et al. Nevirapine clearance from plasma in African adults stopping therapy: apharmacokinetic substudy. AIDS. Mar 30 2007;21(6):733-737. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17413694.11. Muro E, Droste JA, Hofstede HT, Bosch M, Dolmans W, Burger DM. Nevirapine plasma concentrations are stilldetectable after more than 2 weeks in the majority of women receiving single-dose nevirapine: implications forintervention studies. J Acquir Immune Defic Syndr. Aug 1 2005;39(4):419-421. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16010163.12. Musoke P, Guay LA, Bagenda D, et al. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS. Mar 11 1999;13(4):479-486. Available athttp://www.ncbi.nlm.nih.gov/pubmed/10197376.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-62Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-63Special Situations —Failure of Viral Suppression (Last updated July 31, 2012; lastreviewed July 31, 2012)A three-pronged approach is indicated for management of women on antiretroviral (ARV) regimens whohave suboptimal suppression of HIV RNA (that is, detectable virus at any time during pregnancy usingultrasensitive assays). They should a) be evaluated for resistant virus (if plasma HIV RNA is >500–1,000copies/mL); b) assessed for adherence, tolerability, incorrect dosing, or potential problems with absorption(such as with nausea/vomiting or lack of attention to food requirements); and, c) consideration should begiven to modifying the ARV regimen. Experts in the care of ARV-experienced adults should be consulted,particularly if a change in drug regimen is necessary. Hospitalization may be considered for directly observeddrug administration, adherence education, and treatment of comorbidities such as nausea and vomiting.Among 662 pregnancies followed in Italy between 2001 and 2008, treatment modification during pregnancywas independently associated with an HIV-1 RNA level >400 copies/mL in late pregnancy (adjusted odds ratio,1.66; 95% confidence interval, 1.07–2.57; P = 0.024), highlighting the importance of using potent and well-tolerated regimens during pregnancy to maximize effectiveness and minimize need to modify treatment.1HIV RNA levels should be assessed 2–4 weeks after an ARV drug regimen is initiated or changed to providean initial assessment of effectiveness.2Baseline HIV RNA levels have been shown to affect the time toresponse in both pregnant and non-pregnant individuals.3Most patients with an adequate viral response at 24weeks have had at least a 1-log copies/mL HIV RNA decrease within 1–4 weeks after starting therapy.2Treatment-naive individuals should have HIV RNA copies/mL after 48 weeks of treatment. The role of therapeutic drug monitoring in reducing the risk ofvirologic failure is still undefined.4Because maternal antenatal viral load correlates with risk of perinatal transmission of HIV, suppression ofHIV RNA to undetectable levels should be achieved as rapidly as possible. The addition of raltegravir in latepregnancy has been suggested for women who have high viral loads and/or in whom multiple drug-resistantmutations have resulted in incomplete suppression of viremia because of the ability of raltegravir to rapidlysuppress viral load (approximately 2-log copies/mL decrease by Week 2 of therapy).5-8However, the efficacyand safety of this approach have not been evaluated and only anecdotal reports are available. In the setting ofa failing regimen related to nonadherence and/or resistance, there are concerns that the addition of a singleagent may further increase risk of resistance and potential loss of future effectiveness with raltegravir.Therefore, at the current time, this approach cannot be recommended. Scheduled cesarean delivery isPanel’s Recommendations• If an ultrasensitive HIV RNA assay indicates failure of viral suppression (that is, detectable virus) after an adequate periodof treatment:ºAssess resistance and adherence (AII).ºConsult an HIV treatment expert (AIII).• Scheduled cesarean delivery is recommended for HIV-infected pregnant women who have HIV RNA levels >1,000copies/mL near the time of delivery (AII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.recommended for HIV-infected pregnant women who have HIV RNA levels >1,000 copies/mL near the timeof delivery (see Transmission and Mode of Delivery).References1. Floridia M, Ravizza M, Pinnetti C, et al. Treatment change in pregnancy is a significant risk factor for detectable HIV-1RNA in plasma at end of pregnancy. HIV Clin Trials. Nov-Dec 2010;11(6):303-311. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21239358.2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed June 7, 2012.3. European Collaborative Study, Patel D, Cortina-Borja M, Thorne C, Newell ML. Time to undetectable viral load afterhighly active antiretroviral therapy initiation among HIV-infected pregnant women. Clin Infect Dis. Jun 152007;44(12):1647-1656. Available at http://www.ncbi.nlm.nih.gov/pubmed/17516411.4. Liu X, Ma Q, Zhang F. Therapeutic drug monitoring in highly active antiretroviral therapy. Expert Opin Drug Saf. Sep2010;9(5):743-758. Available at http://www.ncbi.nlm.nih.gov/pubmed/20350281.5. Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518)in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. Apr 142007;369(9569):1261-1269. Available at http://www.ncbi.nlm.nih.gov/pubmed/17434401.6. Papendorp SG, van den Berk GE. Preoperative use of raltegravir-containing regimen as induction therapy: very rapiddecline of HIV-1 viral load. AIDS. Mar 27 2009;23(6):739. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19279447.7. Pinnetti C, Baroncelli S, Villani P, et al. Rapid HIV-RNA decline following addition of raltegravir and tenofovir toongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 ofpregnancy. J Antimicrob Chemother. Sep 2010;65(9):2050-2052. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20630894.8. McKeown DA, Rosenvinge M, Donaghy S, et al. High neonatal concentrations of raltegravir following transplacentaltransfer in HIV-1 positive pregnant women. AIDS. Sep 24 2010;24(15):2416-2418. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20827058.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-64Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-65Monitoring of the Woman and Fetus During Pregnancy (Last updated July 31, 2012; lastreviewed July 31, 2012)Viral load should be monitored in HIV-infected pregnant women at the initial visit, 2 to 4 weeks after initiatingor changing antiretroviral (ARV) regimens, monthly until undetectable, and at least every 3 months thereafter.If adherence is a concern, more frequent monitoring is recommended because of the potential increased risk ofperinatal HIV infection associated with detectable HIV viremia during pregnancy. More frequent viral loadmonitoring is recommended in pregnant versus non-pregnant individuals because of the urgency to lower viralload as rapidly as possible to reduce the risk of perinatal transmission. Therefore, there is a need to identifypregnant women in whom the decline in viral load is slower than expected. Adult ARV guidelines note thatpatients should have a decrease in plasma HIV RNA level by at least one log10copies/mL within 1 month afterinitiation of potent therapy.1Viral suppression generally is achieved in 16 to 24 weeks in ARV-naive treatment-adherent individuals who do not harbor resistance mutations to the drugs they are receiving but, in rare cases, itmay take longer. Viral load also should be assessed at approximately 34 to 36 weeks’ gestation to informdecisions about mode of delivery (see Transmission and Mode of Delivery).In HIV-infected pregnant women, CD4 T-lymphocyte (CD4-cell) count should be monitored at the initialvisit and at least every 3 months during pregnancy. CD4-cell counts can be performed every 6 months inPanel’s Recommendations• Plasma HIV RNA levels should be monitored at the initial visit (AI); 2 to 4 weeks after initiating (or changing) antiretroviral(ARV) drug regimens (BI); monthly until RNA levels are undetectable (BIII); and then at least every 3 months duringpregnancy (BIII). HIV RNA levels also should be assessed at approximately 34 to 36 weeks’ gestation to inform decisionsabout mode of delivery (see Transmission and Mode of Delivery) (AIII).• CD4 T-lymphocyte (CD4-cell) count should be monitored at the initial antenatal visit (AI)and at least every 3 monthsduring pregnancy (BIII). Monitoring of CD4-cell count can be performed every 6 months in patients on antiretroviraltherapy (ART) for more than 2 to 3 years who are adherent to therapy, clinically stable, and have sustained viralsuppression (CIII).• Genotypic ARV drug-resistance testing should be performed at baseline in all HIV-infected pregnant women with HIVRNA levels >500 to 1,000 copies/mL, whether they are ARV naive or currently on therapy (AIII). Repeat testing isindicated following initiation of an ARV regimen in women who have suboptimal viral suppression or who have persistantviral rebound to detectable levels after prior viral suppression on an ARV regimen (AII).• Monitoring for complications of ARV drugs during pregnancy should be based on what is known about the adverseeffects of the drugs a woman is receiving (AIII).• First-trimester ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery is necessary, toguide timing of the procedure (see Transmission and Mode of Delivery) (AII).• In women on effective ART, no perinatal transmissions have been reported after amniocentesis, but a small risk oftransmission cannot be ruled out. If amniocentesis is indicated in HIV-infected women, it should be done only afterinitiation of an effective ART regimen and, if possible, when HIV RNA levels are undetectable (BIII). In women withdetectable HIV RNA levels in whom amniocentesis is deemed necessary, consultation with an expert should beconsidered. Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.patients on antiretroviral therapy (ART) for more than 2 to 3 years who are adherent to therapy, clinicallystable, and have sustained viral suppression. Because of physiologic changes such as hemodilution that areassociated with pregnancy, CD4 percentage may be more stable than absolute CD4 count during pregnancy.2-5Nevertheless, most clinicians still rely on absolute CD4 count to evaluate immune status during pregnancybecause parameters for initiating therapy are based on those values.Whenever feasible, ARV drug-resistance testing should be performed in HIV-infected pregnant womenbefore initiation of ARV drugs if HIV RNA levels are above the threshold for resistance testing (that is,>500–1,000 copies/mL) unless delay in getting results back would lead to delay in starting ARV forprevention of mother-to-child transmission. Testing also should be performed on women taking an ARVregimen who have suboptimal viral suppression or who have persistant viral rebound to detectable levelsafter prior viral suppression on an ARV regimen (see Antiretroviral Drug Resistance and Resistance Testingin Pregnancy). Drug-resistance testing in the setting of virologic failure should be performed while patientsare receiving ARV drugs or within 4 weeks after discontinuation of drugs. Genotypic testing is preferable tophenotypic testing because it costs less, has a faster turnaround time, and is more sensitive for detection ofmixtures of wild-type and resistant virus.Monitoring for potential complications of ARV drugs during pregnancy should be based on what is knownabout the adverse effects of the drugs a woman is receiving. For example, routine hematologic monitoring isrecommended for women receiving zidovudine-containing regimens and routine renal monitoring should berecommended for women on tenofovir. Liver function should be monitored in all women receiving ARVdrugs. Hepatic dysfunction has been observed in pregnant women on protease inhibitors, and hepaticsteatosis and lactic acidosis in pregnancy have been related to nucleoside reverse transcriptase inhibitor use.Women with CD4-cell counts >250 cells/mm3are thought to be at particular risk of developing symptomatic,rash-associated, nevirapine-associated hepatotoxicity within the first 18 weeks after initiation of therapy.However, recent data from an international study did not show the same association between nevirapinetoxicity and CD4-cell counts among pregnant women.6Additional data from a 2010 study suggest thatabnormal liver transaminase levels at baseline may be more predictive of risk than CD4-cell count.7Transaminase levels should be monitored more frequently and carefully in pregnant women initiating therapywith nevirapine, and they should also be watched for clinical symptoms of potential hepatotoxicity (seeNevirapine and Hepatic/Rash Toxicity). The drug can be used cautiously with careful monitoring in womenwith mildly abnormal liver function tests at the time of ARV drug initiation. First-trimester ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery isnecessary, to guide potential timing because such deliveries for prevention of perinatal transmission of HIVshould be performed at 38 weeks’ gestation (see Transmission and Mode of Delivery).8, 9In patients who arenot seen until later in gestation, second-trimester ultrasound can be used for both anatomical scanning anddetermination of gestational age.Although data are still somewhat limited, the risk of transmission does not appear to be increased withamniocentesis or other invasive diagnostic procedures in women receiving effective ART resulting in viralsuppression. This is in contrast to the pre-ART era, during which invasive procedures such as amniocentesisand chorionic villus sampling (CVS) were associated with a two- to fourfold increased risk of perinataltransmission of HIV.10-13Although no transmissions have occurred among 159 cases reported to date ofamniocentesis or other invasive diagnostic procedures among women on effective ART regimens, a smallincrease in risk of transmission cannot be ruled out.14-17HIV-infected women who have indications forinvasive testing in pregnancy, such as abnormal ultrasound or aneuploidy screening, should be counseledabout the potential risk of transmission of HIV along with other risks of the procedure and allowed to makean informed decision about testing. Some experts consider CVS and cordocentesis too risky to offer to HIV-infected women and they recommend limiting invasive procedures to amniocentesis,15but existing data onRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-66Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.transmission risk associated with these procedures are limited. At a minimum, HIV-infected pregnant womenshould receive effective ART before undergoing any invasive prenatal testing and, ideally, have anundetectable HIV RNA level at the time of the procedure. In women with detectable HIV RNA levels forwhom amniocentesis is deemed necessary, consultation with an expert should be considered. Theseprocedures should be done under continuous ultrasound guidance and, if possible, the placenta should beavoided.References1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed June 19, 2012. 2. Miotti PG, Liomba G, Dallabetta GA, Hoover DR, Chiphangwi JD, Saah AJ. T lymphocyte subsets during and afterpregnancy: analysis in human immunodeficiency virus type 1-infected and -uninfected Malawian mothers. J Infect Dis.Jun 1992;165(6):1116-1119. Available at http://www.ncbi.nlm.nih.gov/pubmed/1583330.3. Tuomala RE, Kalish LA, Zorilla C, et al. Changes in total, CD4+, and CD8+ lymphocytes during pregnancy and 1 yearpostpartum in human immunodeficiency virus-infected women. The Women and Infants Transmission Study. ObstetGynecol. Jun 1997;89(6):967-974. Available at http://www.ncbi.nlm.nih.gov/pubmed/9170476.4. Ekouevi DK, Inwoley A, Tonwe-Gold B, et al. Variation of CD4 count and percentage during pregnancy and afterdelivery: implications for HAART initiation in resource-limited settings. AIDS Res Hum Retroviruses. Dec2007;23(12):1469-1474. Available at http://www.ncbi.nlm.nih.gov/pubmed/18160003.5. Towers CV, Rumney PJ, Ghamsary MG. Longitudinal study of CD4+ cell counts in HIV-negative pregnant patients. JMatern Fetal Neonatal Med. Oct 2010;23(10):1091-1096. Available at http://www.ncbi.nlm.nih.gov/pubmed/20121393.6. Peters PJ, Polle N, Zeh C, et al. Nevirapine-Associated Hepatotoxicity and Rash among HIV-Infected Pregnant Womenin Kenya. J Int Assoc Physicians AIDS Care (Chic). Mar-Apr 2012;11(2):142-149. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22020069.7. Peters PJ, Stringer J, McConnell MS, et al. Nevirapine-associated hepatotoxicity was not predicted by CD4 count ≥250cells/muL among women in Zambia, Thailand and Kenya. HIV Med. Nov 2010;11(10):650-660. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20659176.8. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 58. Ultrasonography in pregnancy. ObstetGynecol. Dec 2004;104(6):1449-1458. Available at http://www.ncbi.nlm.nih.gov/pubmed/15572512.9. Bennett KA, Crane JM, OShea P, Lacelle J, Hutchens D, Copel JA. First trimester ultrasound screening is effective inreducing postterm labor induction rates: a randomized controlled trial. Am J Obstet Gynecol. Apr 2004;190(4):1077-1081. Available at http://www.ncbi.nlm.nih.gov/pubmed/15118645.10. Mandelbrot L, Mayaux MJ, Bongain A, et al. Obstetric factors and mother-to-child transmission of humanimmunodeficiency virus type 1: the French perinatal cohorts. SEROGEST French Pediatric HIV Infection Study Group.Am J Obstet Gynecol. Sep 1996;175(3 Pt 1):661-667. Available at http://www.ncbi.nlm.nih.gov/pubmed/8828431.11. Tess BH, Rodrigues LC, Newell ML, Dunn DT, Lago TD. Breastfeeding, genetic, obstetric and other risk factorsassociated with mother-to-child transmission of HIV-1 in Sao Paulo State, Brazil. Sao Paulo Collaborative Study forVertical Transmission of HIV-1. AIDS. Mar 26 1998;12(5):513-520. Available athttp://www.ncbi.nlm.nih.gov/pubmed/9543450.12. Shapiro DE, Sperling RS, Mandelbrot L, Britto P, Cunningham BE. Risk factors for perinatal human immunodeficiencyvirus transmission in patients receiving zidovudine prophylaxis. Pediatric AIDS Clinical Trials Group protocol 076Study Group. Obstet Gynecol. Dec 1999;94(6):897-908. Available at http://www.ncbi.nlm.nih.gov/pubmed/10576173.13. Maiques V, Garcia-Tejedor A, Perales A, Cordoba J, Esteban RJ. HIV detection in amniotic fluid samples.Amniocentesis can be performed in HIV pregnant women? Eur J Obstet Gynecol Reprod Biol. Jun 10 2003;108(2):137-Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-67Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.141. Available at http://www.ncbi.nlm.nih.gov/pubmed/12781400.14. Somigliana E, Bucceri AM, Tibaldi C, et al. Early invasive diagnostic techniques in pregnant women who are infectedwith the HIV: a multicenter case series. Am J Obstet Gynecol. Aug 2005;193(2):437-442. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16098867.15. Coll O, Suy A, Hernandez S, et al. Prenatal diagnosis in human immunodeficiency virus-infected women: a newscreening program for chromosomal anomalies. Am J Obstet Gynecol. Jan 2006;194(1):192-198. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16389031.16. Ekoukou D, Khuong-Josses MA, Ghibaudo N, Mechali D, Rotten D. Amniocentesis in pregnant HIV-infected patients.Absence of mother-to-child viral transmission in a series of selected patients. Eur J Obstet Gynecol Reprod Biol. Oct2008;140(2):212-217. Available at http://www.ncbi.nlm.nih.gov/pubmed/18584937.17. Mandelbrot L, Jasseron C, Ekoukou D, et al. Amniocentesis and mother-to-child human immunodeficiency virustransmission in the Agence Nationale de Recherches sur le SIDA et les Hepatites Virales French Perinatal Cohort. Am JObstet Gynecol. Feb 2009;200(2):160 e161-169. Available at http://www.ncbi.nlm.nih.gov/pubmed/18986640.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States D-68Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-1Special Considerations Regarding the Use of Antiretroviral Drugsby HIV-Infected Pregnant Women and Their Infants Overview (Last updated July 31, 2012; last reviewed July 31, 2012)Recommendations regarding the choice of antiretroviral (ARV) drugs for HIV-infected pregnant women aresubject to unique considerations. These include:a. possible changes in dosing requirements resulting from physiologic changes associated with pregnancy;b. potential toxicities of ARV drugs that may be exacerbated in pregnant women;c. the pharmacokinetics (PKs) and toxicity of transplacentally transferred drugs; andd. the potential short- and long-term effects of the ARV drug on fetuses and newborns, including thepotential for preterm birth, teratogenicity, mutagenicity, or carcinogenicity.ARV drug recommendations for HIV-infected pregnant women have been based on the concept that drugs ofknown benefit to women should not be withheld during pregnancy unless there are known adverse effects onthe mother, fetus, or infant and unless these adverse effects outweigh the benefits to the woman.1Pregnancyshould not preclude the use of optimal drug regimens. The decision to use any ARV drug during pregnancyshould be made by a woman after discussing with her health care provider the known and potential benefitsand risks to her and her fetus. Although clinical data are more limited on ARV drugs in pregnant women than in non-pregnant individuals,sufficient data exist on which to base recommendations related to drug choice for many of the available ARVdrugs. Table 5 provides information on PKs in pregnancy and pregnancy-related concerns for each of theavailable ARV drugs; drugs are classified for use in pregnancy as preferred, alternative, use in specialcircumstances, insufficient data to recommend use, and not recommended (see General Principles RegardingUse of Antiretroviral Drugs during Pregnancy). This table should be used in conjunction with the Guidelinesfor the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents when developing treatmentregimens for pregnant women.Reference1. Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol. Feb 1997;176(2):478-489. Available at http://www.ncbi.nlm.nih.gov/pubmed/9065202.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-2Pharmacokinetic Changes (Last updated July 31, 2012; last reviewed July 31, 2012)Physiologic changes that occur during pregnancy can affect drug absorption, distribution, biotransformation,and elimination, thereby also affecting requirements for drug dosing and potentially altering thesusceptibility of pregnant women to drug toxicity.1, 2During pregnancy, gastrointestinal transit time becomesprolonged; body water and fat increase throughout gestation and are accompanied by increases in cardiacoutput, ventilation, and liver and renal blood flow; plasma protein concentrations decrease; renal sodiumreabsorption increases; and changes occur in cellular transporters and drug metabolizing enzymes in the liverand intestine. Placental transport of drugs, compartmentalization of drugs in the embryo/fetus and placenta,biotransformation of drugs by the fetus and placenta, and elimination of drugs by the fetus also can affectdrug pharmacokinetics (PKs) in the pregnant woman.Currently available data on the PKs of antiretroviral agents in pregnancy are summarized in Table 5. Ingeneral, the PKs of nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptaseinhibitors are similar in pregnant and non-pregnant women, whereas protease inhibitor (PI) PKs are morevariable, particularly in later pregnancy. Current data suggest that with standard adult dosing, plasmaconcentrations of lopinavir/ritonavir, atazanavir, darunavir, and nelfinavir are reduced during the secondand/or third trimesters (see Table 5). The need for a dose adjustment depends on the PI, an individualpatient’s treatment experience, and use (if any) of concomitant medications with potential for druginteractions.3-10References1. Mirochnick M, Capparelli E. Pharmacokinetics of antiretrovirals in pregnant women. Clin Pharmacokinet.2004;43(15):1071-1087. Available at http://www.ncbi.nlm.nih.gov/pubmed/15568888.2. Roustit M, Jlaiel M, Leclercq P, Stanke-Labesque F. Pharmacokinetics and therapeutic drug monitoring ofantiretrovirals in pregnant women. Br J Clin Pharmacol. Aug 2008;66(2):179-195. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18537960.3. Bristol-Myers Squibb. Reyataz drug label, 2/4/2011. Available athttp://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021567s025lbl.pdf. Accessed on June 26, 2012.4. Stek AM, Mirochnick M, Capparelli E, et al. Reduced lopinavir exposure during pregnancy. AIDS. Oct 32006;20(15):1931-1939. Available at http://www.ncbi.nlm.nih.gov/pubmed/16988514.5. Villani P, Floridia M, Pirillo MF, et al. Pharmacokinetics of nelfinavir in HIV-1-infected pregnant and nonpregnantwomen. Br J Clin Pharmacol. Sep 2006;62(3):309-315. Available at http://www.ncbi.nlm.nih.gov/pubmed/16934047.6. Bryson YJ, Mirochnick M, Stek A, et al. Pharmacokinetics and safety of nelfinavir when used in combination withzidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol353. HIV Clin Trials. Mar-Apr 2008;9(2):115-125. Available at http://www.ncbi.nlm.nih.gov/pubmed/18474496.Panel’s Recommendation• Altered dosing during pregnancy may be required for some protease inhibitors, such as lopinavir/ritonavir (see Table 5)(AII)Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.7. Mirochnick M, Best BM, Stek AM, et al. Lopinavir exposure with an increased dose during pregnancy. J AcquirImmune Defic Syndr. Dec 15 2008;49(5):485-491. Available at http://www.ncbi.nlm.nih.gov/pubmed/18989231.8. Read JS, Best BM, Stek AM, et al. Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy andpostpartum. HIV Med. Nov 2008;9(10):875-882. Available at http://www.ncbi.nlm.nih.gov/pubmed/18795962.9. Bouillon-Pichault M, Jullien V, Azria E, et al. Population analysis of the pregnancy-related modifications in lopinavirpharmacokinetics and their possible consequences for dose adjustment. J Antimicrob Chemother. Jun 2009;63(6):1223-1232. Available at http://www.ncbi.nlm.nih.gov/pubmed/19389715.10. Best BM, Stek AM, Mirochnick M, et al. Lopinavir tablet pharmacokinetics with an increased dose during pregnancy. JAcquir Immune Defic Syndr. Aug 2010;54(4):381-388. Available at http://www.ncbi.nlm.nih.gov/pubmed/20632458.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-3Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-4Teratogenicity (Last updated July 31, 2012; last reviewed July 31, 2012)The potential harm to the fetus from maternal ingestion of a specific drug depends not only on the drug itselfbut also on the dose ingested; the gestational age of the fetus at exposure; the duration of exposure; theinteraction with other agents to which the fetus is exposed; and, to an unknown extent, the genetic makeup ofmother and fetus.Information regarding the safety of drugs in pregnancy is derived from animal toxicity data, anecdotalexperience, registry data, and clinical trials. Data are limited for antiretroviral (ARV) drugs, particularly whenused in combination therapy. Drug choice should be individualized and must be based on discussion with awoman and available data from preclinical and clinical testing of the individual drugs. Preclinical data includeresults of in vitroand animal in vivoscreening tests for carcinogenicity, clastogenicity/mutagenicity, andreproductive and teratogenic effects. However, the predictive value of such tests for adverse effects in humansis unknown. For example, of approximately 1,200 known animal teratogens, only about 30 are known to beteratogenic in humans.1Limited data exist regarding placental passage, pharmacokinetics and safety inpregnancy, and long-term safety for exposed infants for the Food and Drug Administration (FDA)-approvedARV drugs (see Supplement: Safety and Toxicity of Individual Antiretroviral Agents in Pregnancy). In general,reports of birth defects in fetuses/infants of women enrolled in observational studies who receive ARVregimens during pregnancy are reassuring and find no difference in rates of birth defects for first-trimestercompared with later exposures.2-4However, concerns have been raised about the risk of several ARV agents.Significant malformations were observed in 3 of 20 infant cynomolgus monkeys receiving efavirenz fromgestational Days 20 to 150 at a dose resulting in plasma concentrations comparable to systemic humanexposure at therapeutic dosage.5The malformations included anencephaly and unilateral anophthalmia inone, microphthalmia in another, and cleft palate in the third. Among pregnancies prospectively reported tothe Antiretroviral Pregnancy Registry through January 2012 that had exposure to efavirenz-based regimens, aPanel’s Recommendations• All cases of antiretroviral (ARV) drug exposure during pregnancy should be reported to the Antiretroviral PregnancyRegistry (see details at http://www.APRegistry.com) (AIII).• Non-pregnant women of childbearing potential should undergo pregnancy testing before initiation of efavirenz and receivecounseling about the potential risk to the fetus and desirability of avoiding pregnancy while on efavirenz-containingregimens (AIII).ºAlternate ARV regimens that do not include efavirenz should be strongly considered in women who are (1) planning tobecome pregnant or (2) sexually active and not using effective contraception, assuming these alternative regimens areacceptable to the provider and are not thought to compromise the woman’s health (BIII).• Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy and pregnancy is rarelyrecognized before 4 to 6 weeks of pregnancy, and unnecessary changes in ARV drugs during pregnancy may beassociated with loss of viral control and increased risk of perinatal transmission, efavirenz can be continued in pregnantwomen receiving an efavirenz-based regimen who present for antenatal care in the first trimester, provided the regimenproduces virologic suppression (see HIV-Infected Pregnant Women Who are Currently Receiving Antiretroviral Treatment)(CIII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.2.7% incidence of overall birth defects was seen with first-trimester exposure, a proportion not significantlydifferent from that observed among U.S. births in the general population.6Defects reported prospectivelyincluded 1 report of myelomeningocele and a separate report of anophthalmia. The case of anophthalmiaincluded severe oblique facial clefts and amniotic banding that is known to be associated with anophthalmia.6In addition, 6 cases of central nervous system defects, including myelomeningocele, have beenretrospectively reported in infants born to mothers receiving efavirenz during the first trimester.5However,retrospective reports can be biased toward reporting of more unusual and severe cases and are less likely tobe representative of the general population experience.A meta-analysis including data from 9 cohorts with prospective reporting on 1,132 first-trimester exposuresdid not find an increased risk of overall birth defects in infants born to women on efavirenz during the firsttrimester compared with those on other ARV drugs during the first trimester (relative risk [RR] 0.87; 95%confidence interval [CI], 0.61–1.24).7One neural tube defect occurred among 1,256 live births. An update tothe meta-analysis included 181 additional live births with first-trimester efavirenz exposure and had similarresults; the RR of overall birth defects on efavirenz versus non-efavirenz regimens was 0.85 (95% CI, 0.61–1.20), and 1 neural tube defect (the same as previous) was observed, giving an incidence of 0.07% (95% CI,0.002–0.39).8However, the number of reported first-trimester efavirenz exposures still remains insufficientto rule out a significant 2- to 3-fold increase in low-incidence birth defects (incidence of neural tube defectsin the general U.S. population is 0.02–0.2%).In contrast to the meta-analysis, the Pediatric AIDS Clinical Trials Protocols (PACTG) 219 and 219C studiesreported a higher defect rate in infants with first-trimester exposure to efavirenz compared with those withoutfirst-trimester efavirenz exposure (adjusted odds ratio 4.31; 95% CI, 1.56–11.86). However, only 32 infantshad efavirenz exposure. PACTG protocol P1025 is a companion study of PACTG 219 with considerableoverlap in cases enrolled. Although P1025 reports a significant increased risk of congenital anomalies ininfants born between 2002 and 2007 with first-trimester exposure to efavirenz, there is overlap in the defectcases between the 2 studies and only 42 infants are included in this analysis. Thus, additional data are neededon first-trimester efavirenz exposures to be able to more conclusively determine if risk of neural tube defectsor other malformations is elevated.Although a causal relationship has not been established between these events and the use of efavirenz, inlight of similar findings in primates, efavirenz has been classified as FDA Pregnancy Category D. Because ofthe potential for teratogenicity, pregnancy should be avoided in women receiving efavirenz, and treatmentwith efavirenz should be avoided during the first trimester (the primary period of fetal organogenesis)whenever possible. Women of childbearing potential should undergo pregnancy testing before initiation ofefavirenz and should be counseled about the potential risk to the fetus and desirability of avoiding pregnancywhile on efavirenz-containing regimens. Alternate ARV regimens that do not include efavirenz should bestrongly considered in women who are planning to become pregnant or who are sexually active and not usingeffective contraception if such alternative regimens are acceptable to provider and patient and will notcompromise the woman’s health. However, the Panel now recommends that efavirenz can be continued inwomen who present for care in the first trimester and are receiving efavirenz-based ARV therapy that iseffective in suppressing viral replication. This is because the neural tube closes at 36 to 39 days after the lastmenstrual period; hence the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy (andpregnancy is rarely recognized before 5–6 weeks of pregnancy), and unnecessary changes in ARV drugsduring pregnancy may be associated with a loss of virologic control and, thus, increased risk of transmissionto the infant.9For more details, see HIV-Infected Pregnant Women Who are Currently ReceivingAntiretroviral Treatment.Tenofovir has not demonstrated teratogenicity in rodents or monkeys. In infant monkeys with in uteroexposure to tenofovir at maternal doses resulting in levels approximately 25 times those used in humans, lowRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-5Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.birth weights and reductions in fetal bone porosity were seen. Chronic administration of tenofovir toimmature animals of multiple species has resulted in reversible bone abnormalities; these effects were dose,exposure, age, and species specific. Data from the Antiretroviral Pregnancy Registry show a birth defectincidence of 2.3% in 1,370 women with first-trimester tenofovir exposure, similar to that in the generalpopulation.6An Italian study assessed growth patterns, bone health, and markers of bone metabolism in 33infants with in uteroexposure to tenofovir and found no difference compared with infants born to HIV-infected women who had not been exposed to tenofovir.10A larger study from the United States included2,029 HIV-exposed but uninfected infants, 449 (21%) of whom had in uteroexposure to tenofovir.11Although there were no differences in anthropomorphic parameters at birth, at age 1 year, infants exposed totenofovir-based regimens had slight but significantly lower adjusted mean length and head circumference forage z-score than those without exposure to tenofovir. Because of the limited data on use in human pregnancyand concern regarding potential fetal bone effects and potential nephrotoxicity, tenofovir is recommended asan alternative rather than a preferred drug for use in pregnancy unless a pregnant woman is HIV/hepatitis Bcoinfected (see Table 5).A modest but statistically significant increase in overall birth defect rates for didanosine and nelfinavir isobserved when compared with the U.S. population-based Metropolitan Atlanta Congenital Defects Program(MACDP).6The lower bound of the CI for didanosine and nelfinavir (2.8%) is slightly above the higherbound (2.76%) for the MACDP rate. No specific pattern of defects has been detected with either didanosineor nelfinavir, and the clinical relevance of this statistical finding is unclear. The Registry will continue tomonitor didanosine and nelfinavir for any signal or pattern of birth defects.See Supplement: Safety and Toxicity of Individual Antiretroviral Drugs in Pregnancyto obtain detailedinformation on individual drugs.Health care providers who are caring for HIV-infected pregnant women and their newborns are stronglyadvised to report instances of prenatal exposure to ARV drugs (either alone or in combination) to theAntiretroviral Pregnancy Registry. This registry is an epidemiologic project to collect observational,nonexperimental data regarding ARV exposure during pregnancy for the purpose of assessing the potentialteratogenicity of these drugs. Registry data will be used to supplement animal toxicology studies and assistclinicians in weighing the potential risks and benefits of treatment for individual patients. The AntiretroviralPregnancy Registry is a collaborative project of pharmaceutical manufacturers with an advisory committeeof obstetric and pediatric practitioners. The registry does not use patient names, and registry staff obtain birthoutcome follow-up information from the reporting physician.Referrals should be directed to: Antiretroviral Pregnancy RegistryResearch Park1011 Ashes DriveWilmington, NC 28405Telephone: 1–800–258–4263Fax: 1–800–800–1052http://www.APRegistry.comReferences1. Mills JL. Protecting the embryo from X-rated drugs. N Engl J Med. Jul 13 1995;333(2):124-125. Available athttp://www.ncbi.nlm.nih.gov/pubmed/7777019.2. Watts DH, Huang S, Culnane M, et al. Birth defects among a cohort of infants born to HIV-infected women onantiretroviral medication. J Perinat Med. Mar 2011;39(2):163-170. Available atRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-6Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.http://www.ncbi.nlm.nih.gov/pubmed/21142844.3. Knapp KM, Brogly SB, Muenz DG, et al. Prevalence of congenital anomalies in infants with in uteroexposure toantiretrovirals. Pediatr Infect Dis J. Feb 2012;31(2):164-170. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21983213.4. Joao EC, Calvet GA, Krauss MR, et al. Maternal antiretroviral use during pregnancy and infant congenital anomalies:the NISDI perinatal study. J Acquir Immune Defic Syndr.Feb 2010;53(2):176-185. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20104119.5. Bristol-Myers Squibb. Sustiva drug label, 11/30/2010.http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021360s024lbl.pdf. Accessed July 6, 2012.6. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.7. Ford N, Mofenson L, Kranzer K, et al. Safety of efavirenz in first-trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts. AIDS. Jun 19 2010;24(10):1461-1470. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20479637.8. Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review andmeta-analysis. AIDS. Nov 28 2011;25(18):2301-2304. Available at http://www.ncbi.nlm.nih.gov/pubmed/21918421.9. Floridia M, Ravizza M, Pinnetti C, et al. Treatment change in pregnancy is a significant risk factor for detectable HIV-1RNA in plasma at end of pregnancy. HIV Clin Trials. Nov-Dec 2010;11(6):303-311. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21239358.10. Vigano A, Mora S, Giacomet V, et al. In uteroexposure to tenofovir disoproxil fumarate does not impair growth andbone health in HIV-uninfected children born to HIV-infected mothers. Antivir Ther. 2011;16(8):1259-1266. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22155907.11. Siberry GK, Williams PL, Mendez H, et al. Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS. Jun 1 2012;26(9):1151-1159. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22382151.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-7Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-8Combination Antiretroviral Drug Regimens and Pregnancy Outcome (Last updated July 31, 2012; last reviewed July 31, 2012)Early data were conflicting as to whether receipt of combination antiretroviral (ARV) regimens duringpregnancy is associated with adverse pregnancy outcomes and, in particular, preterm delivery. The EuropeanCollaborative Study and the Swiss Mother + Child HIV Cohort Study investigated the effects of combinationARV regimens in a population of 3,920 mother-child pairs. Adjusting for CD4 T-lymphocyte (CD4-cell)count and intravenous drug use, they found a roughly twofold increase in the odds of preterm delivery forinfants exposed to combination regimens with or without protease inhibitors (PIs) compared with no drugs;women receiving combination regimens that had been initiated before pregnancy were twice as likely todeliver prematurely as those who started drugs during the third trimester.1However, PI-based combinationregimens were received by only 108 (3%) of the women studied; confounding by severity or indication mayhave biased the results (that is, sicker women may have received PIs more often, but their advanced HIVinfection may have actually caused the preterm births). Exposure to nucleoside reverse transcriptase inhibitor(NRTI) single-drug prophylaxis (primarily zidovudine) was not associated with prematurity.An updated report from the European Collaborative Study, based on an adjusted analysis that included 2,279mother-child pairs, found a 1.9-fold increased risk of delivery at less than 37 weeks with combination ARVregimens started during pregnancy and a 2.1-fold increased risk with combination ARV regimens started pre-pregnancy compared with mono- or dual-NRTI prophylaxis.2In this report, 767 women receivedcombination ARV regimens during pregnancy, although the proportion receiving PIs was not specified. Therisk of delivery before 34 weeks’ gestation was increased by 2.5-fold for those starting combination ARVregimens during pregnancy and 4.4-fold for those entering pregnancy on combination ARV regimens.In contrast, in an analysis of 7 prospective clinical studies that included 2,123 HIV-infected pregnant womenwho delivered infants between 1990 and 1998 and had received antenatal ARV regimens and 1,143 womenwho did not receive antenatal ARV drugs, the use of multiple ARV drugs compared with no drugs ortreatment with 1 drug was not associated with increased rates of preterm birth, low birth weight, low Apgarscores, or stillbirth.3Nor were any significant associations between adverse pregnancy outcome and use ofARV drugs by class or by category (including combination ARV regimens) found in an analysis from theWomen and Infants Transmission Study, including 2,543 HIV-infected women (some of whom were includedin the previous meta-analysis).4More recent data have continued to be conflicting as to whether preterm delivery is increased with combinationARV regimens. Table 7 reviews results from studies that have evaluated the association of ARV drug useduring pregnancy and preterm delivery. Multiple studies have detected small but significant increases (oddsratio [OR] 1.2–1.8 in the largest studies) in preterm birth with PI- or non-PI-based combination ARV regimensPanel’s Recommendation• Clinicians should be aware of a possible small increased risk of preterm birth in pregnant women receiving proteaseinhibitor (PI)-based combination antiretroviral regimens; however, given the clear benefits of such regimens for both awoman’s health and prevention of mother-to-child transmission, PIs should not be withheld for fear of altering pregnancyoutcome (AII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.as well.5-8However, other recent studies that have controlled for maternal and pregnancy characteristics as wellas factors related to HIV infection have shown no increase in adverse outcomes including preterm delivery andlow birth weight in association with PI-containing drug regimens.9-11A meta-analysis of 14 European andAmerican clinical studies found no increase in risk of preterm birth with either any ARV drug receipt comparedwith no drugs or combination ARV regimens including PIs compared with no drugs.12However, a significantbut modest increased risk of preterm birth (OR 1.35; 95% confidence interval [CI], 1.08–1.70) was found inwomen who received combination regimens with PIs compared with combination regimens without PIs. Otherreports have found increased rates of preterm birth when combination ARV regimens are compared with dualregimens13and when combination ARV regimens containing non-nucleoside reverse transcriptase inhibitorswere compared with other combination ARV regimens.14Other variables may confound these observational studies. Some studies have found increased rates ofpreterm birth if a combination ARV regimen is begun before conception or earlier in pregnancy comparedwith later during pregnancy, which itself may reflect confounding by severity or indication.14, 15Recentstudies have assessed spontaneous preterm birth only, excluding delivery that was initiated at a pretermgestation because of medical or obstetrical reasons, and found no association between ARV and pretermbirth.16, 17In an analysis of HIV-infected women enrolled in the ANRS French Perinatal Cohort from 1990 to2009, preterm delivery rates were seen to increase over time, and preterm delivery was associated withcombination ARV regimens versus either mono- or dual-ARV regimens and were highest in those who hadinitiated ARV before pregnancy.18A restricted analysis within this cohort of PI-based combination ARVregimens comparing boosted to unboosted PIs showed an association with induced preterm delivery forboosted PI regimens (adjusted odds ratio [AOR] 2.03; 95% CI, 2.06–3.89) that was not seen withspontaneous preterm birth. Boosted PI regimens were also associated with both medical and obstetricalcomplications, raising the possibility that the association with induced preterm delivery was mediatedthrough these complications.A secondary analyses of data collected during a randomized, controlled clinical trial conducted in Botswanain women with CD4 T-lymphocyte counts >200 cells/mm3—267 randomized to receive lopinavir/ritonavir/zidovudine/lamivudine (PI group) and 263 randomized to receive abacavir/zidovudine/lamivudine (NRTIgroup) begun between 26 and 34 weeks’ gestation for prevention of mother-to-child transmission and not formaternal health indications—did show an association between PI-containing ARV regimens and pretermdelivery. In logistic regression analysis, use of combination PI-based ARV regimens was the most significantrisk factor for preterm delivery (OR 2.03; 95% CI, 1.26–3.27).19Those receiving the latest initiation of ARVdrugs had the highest preterm delivery rates. However the 20% background rate for preterm delivery in thispopulation was not different from that seen in the PI group, and there was no difference between the 2 groupsin neonatal morbidity and mortality. An observational study also from Botswana found that use ofcombination ARV regimens from before conception was not associated with very preterm delivery (AOR0.78), which could not be assessed in the controlled clinical trial.20Clinicians should be aware of a possible increased risk of preterm birth with use of combination ARV drugregimens; however, given the clear benefits for maternal health and reduction in perinatal transmission, theseagents should not be withheld because of the possibility of increased risk of preterm delivery. Until moreinformation is known, HIV-infected pregnant women who are receiving combination regimens for treatmentof their HIV infection should continue their provider-recommended regimens. They should receive careful,regular monitoring for pregnancy complications and for potential toxicities.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-9Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Table 7. Results of Studies Assessing Association Between Antiretroviral Regimens and PretermDelivery (page 1 of 3)Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-10StudyLocation(s)/Dates of Study/ReferenceTotal Number ofPregnancies/Total onARV DrugsTypes of ARVRegimens Compared(Numbers)Association NotedBetween PI-Containingor Other Multi-ARVRegimens and PTD Special NotesEuropean Collaborative+ Swiss Mother andChild HIV Cohort Study1986–200013,920/896 Mono (573)Multi, no PI (215)PI-multi (108)YES (compared with noARV)Multi: 1.82 (1.13–2.92)PI-multi: 2.60 (1.43–4.7)• Increase in PTD ifARV begun beforepregnancy versus inthird trimesterUnited States1990–199833,266/2,123 Mono (1,590)Multi (396)PI-multi (137)NO (compared with mono)Multi: 0.95 (0.60–1.48)PI-multi: 1.45 (0.81–2.50)• 7 prospective clinicalstudiesEuropean CollaborativeStudy1986–200424,372/2,033 Mono (704)Dual (254)Multi (1,075)YES (compared withmono/dual)Multi in pregnancy: 1.88(1.34–2.65)Multi prepregnancy: 2.05(1.43–2.95)United States1990–200242,543/not given Early (Mono (621)Multi (≥2 without PI orNNRTI) (198)Multi (with PI orNNRTI) (357)Late (≥32 weeks):Mono (932)Multi (≥2 without PI orNNRTI) (258)Multi (with PI orNNRTI) (588)NO (compared with mono)No association between anyARV and PTD• PTD decreased withARV compared withno ARVUnited States1990–2002211,337/999 Mono (492)Multi (373)PI-multi (134)YES (compared with othermulti)PI-multi: 1.8 (1.1–3.03)• PI-multi reserved foradvanced disease,those who failedother multi-ARVregimensBrazil, Argentina,Mexico, Bahamas2002–200522681/681 Mono/dual NRTI (94)Multi-NNRTI (257)Multi-PI (330)NO (compared withmono/dual NRTI)No association between anyARV regimen and PTD• All on ARV for at least28 days duringpregnancy• Preeclampsia/eclampsia, cesareandelivery, diabetes, lowBMI associated withPTDDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-11Table 7. Results of Studies Assessing Association Between Antiretroviral Regimens and PretermDelivery (page 2 of 3)StudyLocation(s)/Dates of Study/ReferenceTotal Number ofPregnancies/Total onARV DrugsTypes of ARVRegimens Compared(Numbers)Association NotedBetween PI-Containingor Other Multi-ARVRegimens and PTD Special NotesMeta-analysis, Europeand United States1986–20041211,224/not given Multi-no PI [includingdual] or multi-PI (2,556)YES (only comparing PIwith multi)PI versus multi no PI: 1.35(1.08–1.70)• 14 studies, 5 in PTD-ARV comparison• No overall increase inPTD with antepartumARV• PTD increased inthose on ARV pre-pregnancy and in firsttrimester comparedwith later useItaly2001–20067419/366 Multi-PI second trimester(97)Multi-PI third trimester(146)YESMulti-PI second trimester:2.24 (1.22–4.12)Multi-PI third trimester:2.81 (1.46–5.39)• Multivariateassociation also withhepatitis CUnited States1989–200468,793/6,228 Mono (2,621)Dual (1,044)Multi-no PI (1,781)Multi-PI (782)YES (compared with dual)Multi-PI associated withPTD 1.21 (1.04–1.40)• Lack of antepartumARV also associatedwith PTD• PTD and low birthweight decreasedover timeUnited Kingdom,Ireland1990–200555,009/4,445 Mono/dual (1,061)Multi-NNRTI or Multi-PI(3,384) YES (compared with mono/dual)Multi: 1.51 (1.19–1.93)• Similar increased riskwith PI or no-PI multi• No association withduration of useGermany, Austria1995–20018183/183 Mono (77)Dual (31)Multi-PI (21)Multi-NNRTI (54)YES (compared with mono)Multi-PI: 3.40 (1.13–10.2)United States2002–200716777/777 Mono (6)Dual (11)Multi, no PI (202) Multi-PI (558)NO (compared PI with allnon-PI)Multi-PI: 1.22 (0.70–2.12)• All started ARVduring pregnancy• Analyzed onlyspontaneous PTD7Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-12Table 7. Results of Studies Assessing Association Between Antiretroviral Regimens and PretermDelivery (page 3 of 3)StudyLocation(s)/Dates of Study/ReferenceTotal Number ofPregnancies/Total onARV DrugsTypes of ARVRegimens Compared(Numbers)Association NotedBetween PI-Containingor Other Multi-ARVRegimens and PTD Special NotesSwiss Mother andChild HIV CohortStudy1985–2007131,180/941 Mono (94)Dual (53)Multi (PI or no PI)(409)Multi-PI (385)YES (compared with noARV)Multi: 2.5 (1.4–4.3)• No associationmono/dual with PTDcompared with no ARV• No confounding byduration of ARV ormaternal risk factorsBotswana2006–200819530/530 Lopinavir/ritonavir+zidovudine+lamivudine (267)Abacavir+zidovudine+lamivudine (263)YESMulti-PI versus multi-NRTI:2.03 (1.26–3.27)• Secondary analysis ofdata from randomized,controlled clinical trial ofARV begun 26–34weeks for MTCTprevention• All CD4-cell counts>200 cells/mm3Botswana2007–2010204,347/3,659 ARV, regimenunspecified (70) Mono (2,473)Multi, 91% NNRTI(1,116)NONo association betweenmulti-ART and very PTD(• Observational multi-ARTbefore conceptionassociated with verysmall for gestational ageand maternalhypertension duringpregnancy Spain2000–200810803/739 Mono/dual (32)Multi-no PI (281)Multi-PI (426)NONo association betweenARV and PTD• Greatest PTD risk if noantepartum ARVreceivedSpain1986–201017519/371 Mono/dual NRTI (73)All multi (298)Multi-PI (178)NO (compared with no ARV+ mono/dual)• Spontaneous PTD notassociated with multi-ARVor multi-PI before orduring pregnancy• Iatrogenic PTDassociated with multi-ARV given in secondhalf of pregnancy andprior PTDKey to Abbreviations: ARV = antiretroviral, BMI = body mass index, dual = two ARV drugs, mono = single ARV drug, MTCT = mother-to-child transmission, multi = three or more ARV drugs, multi-PI = combination ARV with PI, NNRTI = non-nucleoside analogue reverse transcriptase inhibitor, NRTI = nucleoside analogue reverse transcriptase inhibitor, PI = protease inhibitor, PTD = preterm deliveryReferences1. European Collaborative Study, Swiss Mother andChild HIV Cohort Study. Combination antiretroviral therapy andduration of pregnancy. AIDS. Dec 22 2000;14(18):2913-2920. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11398741.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.2. Thorne C, Patel D, Newell ML. Increased risk of adverse pregnancy outcomes in HIV-infected women treated withhighly active antiretroviral therapy in Europe. AIDS. Nov 19 2004;18(17):2337-2339. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15577551.3. Tuomala RE, Shapiro DE, Mofenson LM, et al. Antiretroviral therapy during pregnancy and the risk of an adverseoutcome. N Engl J Med. Jun 13 2002;346(24):1863-1870. Available at http://www.ncbi.nlm.nih.gov/pubmed/12063370.4. Tuomala RE, Watts DH, Li D, et al. Improved obstetric outcomes and few maternal toxicities are associated withantiretroviral therapy, including highly active antiretroviral therapy during pregnancy. J Acquir Immune Defic Syndr.Apr 1 2005;38(4):449-473. Available at http://www.ncbi.nlm.nih.gov/pubmed/15764963.5. Townsend CL, Cortina-Borja M, Peckham CS, Tookey PA. Antiretroviral therapy and premature delivery in diagnosedHIV-infected women in the United Kingdom and Ireland. AIDS. May 11 2007;21(8):1019-1026. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17457096.6. Schulte J, Dominguez K, Sukalac T, Bohannon B, Fowler MG, Pediatric Spectrum of HIV Disease Consortium.Declines in low birth weight and preterm birth among infants who were born to HIV-infected women during an era ofincreased use of maternal antiretroviral drugs: Pediatric Spectrum of HIV Disease, 1989-2004. Pediatrics. Apr2007;119(4):e900-906. Available at http://www.ncbi.nlm.nih.gov/pubmed/17353299.7. Ravizza M, Martinelli P, Bucceri A, et al. Treatment with protease inhibitors and coinfection with hepatitis C virus areindependent predictors of preterm delivery in HIV-infected pregnant women. J Infect Dis. Mar 15 2007;195(6):913-914;author reply 916-917. Available at http://www.ncbi.nlm.nih.gov/pubmed/17299723.8. Grosch-Woerner I, Puch K, Maier RF, et al. Increased rate of prematurity associated with antenatal antiretroviraltherapy in a German/Austrian cohort of HIV-1-infected women. HIV Med. Jan 2008;9(1):6-13. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18199167.9. Dola CP, Khan R, Denicola N, et al. Combination antiretroviral therapy with protease inhibitors in HIV-infectedpregnancy. J Perinat Med. Nov 2 2011. Available at http://www.ncbi.nlm.nih.gov/pubmed/22044007.10. Gonzalez-Tome MI, Cuadrado I, et al. Risk factors of preterm delivery and low birth weight in a multicenter cohort ofHIV-infected pregnant women. Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections(CROI); February 27-March 2, 2011; Boston, MA. Abstract 744.11. Beckerman K, Albano J, et al. Exposure to combination antritretoviral (cARV) regimens containing protease inhibitors(PI) during pregnancy and revalence of low birth weight/preterm delivery (LBS/PTD) among women with low pre-existing risk for LBW/PTD: a astratified analysis of 10,082 pregnancies. Paper presented at: 6th IAS Conference onHIV Pathogenesis and Treatment and Prevention; July 17-20, 2011; Rome, Italy.12. Kourtis AP, Schmid CH, Jamieson DJ, Lau J. Use of antiretroviral therapy in pregnant HIV-infected women and the riskof premature delivery: a meta-analysis. AIDS. Mar 12 2007;21(5):607-615. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17314523.13. Rudin C, Spaenhauer A, Keiser O, et al. Antiretroviral therapy during pregnancy and premature birth: analysis of Swissdata. HIV Med. Apr 2011;12(4):228-235. Available at http://www.ncbi.nlm.nih.gov/pubmed/20726902.14. van der Merwe K, Hoffman R, Black V, Chersich M, Coovadia A, Rees H. Birth outcomes in South African womenreceiving highly active antiretroviral therapy: a retrospective observational study. J Int AIDS Soc. 2011;14:42. Availableat http://www.ncbi.nlm.nih.gov/pubmed/21843356.15. Machado ES, Hofer CB, Costa TT, et al. Pregnancy outcome in women infected with HIV-1 receiving combinationantiretroviral therapy before versus after conception. Sex Transm Infect. Apr 2009;85(2):82-87. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18987014.16. Patel K, Shapiro DE, Brogly SB, et al. Prenatal protease inhibitor use and risk of preterm birth among HIV-infectedwomen initiating antiretroviral drugs during pregnancy. J Infect Dis. Apr 1 2010;201(7):1035-1044. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20196654.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-13Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.17. Lopez M, Figueras F, Hernandez S, et al. Association of HIV infection with spontaneous and iatrogenic pretermdelivery: effect of HAART. AIDS. Jan 2 2012;26(1):37-43. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22008651.18. Sibiude J, Warszawski J, Tubiana R, et al. Premature delivery in HIV-infected women starting protease inhibitor therapyduring pregnancy: role of the ritonavir boost? Clin Infect Dis. May 2012;54(9):1348-1360. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22460969.19. Powis KM, Kitch D, Ogwu A, et al. Increased risk of preterm delivery among HIV-infected women randomized toprotease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis. Aug 152011;204(4):506-514. Available at http://www.ncbi.nlm.nih.gov/pubmed/21791651.20. Parekh N, Ribaudo H, Souda S, et al. Risk factors for very preterm delivery and delivery of very-small-for-gestational-age infants among HIV-exposed and HIV-unexposed infants in Botswana. Int J Gynaecol Obstet. Oct2011;115(1):20-25. Available at http://www.ncbi.nlm.nih.gov/pubmed/21767835.21. Cotter AM, Garcia AG, Duthely ML, Luke B, OSullivan MJ. Is antiretroviral therapy during pregnancy associated withan increased risk of preterm delivery, low birth weight, or stillbirth? J Infect Dis. May 1 2006;193(9):1195-1201.Available at http://www.ncbi.nlm.nih.gov/pubmed/16586354.22. Szyld EG, Warley EM, Freimanis L, et al. Maternal antiretroviral drugs during pregnancy and infant low birth weightand preterm birth. AIDS. Nov 28 2006;20(18):2345-2353. Available at http://www.ncbi.nlm.nih.gov/pubmed/17117021.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-14Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-15Nevirapine and Hepatic/Rash Toxicity (Last updated September 14, 2011; last reviewedJuly 31, 2012)Increases in hepatic transaminase levels (alanine aminotransferase [ALT] and aspartate aminotransferase[AST]) associated with rash or systemic symptoms may be observed during the first 18 weeks of treatmentwith nevirapine. Signs and symptoms of systemic toxicity may be nonspecific and can include fatigue,malaise, anorexia, nausea, jaundice, liver tenderness, or hepatomegaly with or without initially abnormalhepatic transaminases.1Development of severe nevirapine-associated skin rash has been reported to be 5.5 to7.3 times more common in women than men and has been reported in pregnant women.2, 3Other studies havefound that hepatic adverse events with systemic symptoms (predominantly rash) were 3.2-fold more commonin women than in men.4, 5The degree of risk of rash and hepatic toxicity also appears to vary with CD4 T-lymphocyte (CD4-cell) count. In a summary analysis of data from 17 clinical trials of nevirapine therapy,women with CD4-cell counts >250 cells/mm3were 9.8 times more likely than women with lower CD4-cellcounts to experience symptomatic, rash-associated, nevirapine-related hepatotoxicity;4a single-center studyalso found higher CD4-cell counts to be associated with increased risk of severe nevirapine-associated skinrash.2CD4-cell counts >250 cells/mm3predicted rash illness, but not liver enzyme elevation, amongpregnant and non-pregnant women initiating nevirapine-based combination antiretroviral (ARV) regimens inthree U.S. university clinics.6Other international cohorts of non-pregnant women have experiencedhepatotoxicity and rash at similar rates as in U.S. studies, but not in association with CD4-cell counts >250cells/mm3.7In general, in controlled clinical trials, hepatic events, regardless of severity, have occurred in4.0% (range 0%–11.0%) of patients who received nevirapine; severe or life-threatening rash has occurred inapproximately 2% of patients receiving nevirapine.8Several early reports of death due to hepatic failure in HIV-infected pregnant women receiving nevirapine aspart of a combination ARV regimen raised concerns that pregnant women might be at increased risk ofhepatotoxicity from nevirapine compared with other ARV drugs.9, 10Recent data challenge the notion thatnevirapine is uniquely associated with increased hepatotoxicity during pregnancy.11In an analysis of twomulticenter, prospective cohorts, pregnancy itself was a risk factor for liver enzyme elevations (relative risk4.7; 5% confidence interval, 3.4–6.5), but nevirapine use was not, regardless of pregnancy status.11Additional data from the same cohorts did not show any increased risk of hepatotoxicity in HIV-infectedpregnant women receiving nevirapine-based combination ARV regimens versus non-nevirapine-basedcombination ARV regimens.12These data suggest that nevirapine is no more toxic in pregnant women than innon-pregnant women. Nevertheless, if nevirapine is used in pregnancy, health care providers should be awareof potential hepatotoxicity with or without rash and should conduct frequent and careful monitoring ofclinical symptoms and hepatic transaminases (that is, ALT and AST), particularly during the first 18 weeks ofnevirapine use. Some clinicians measure serum transaminases at baseline, every 2 weeks for the first month,Panel’s Recommendations• Nevirapine-based regimens should be initiated in women with CD4 T-lymphocyte (CD4-cell) counts >250 cells/mm3onlyif the benefits clearly outweigh the risks because of the drug’s potential for causing hepatic toxicity/hypersensitivityreaction (AII).• Women who become pregnant while receiving nevirapine-containing regimens and who are tolerating the regimen wellcan continue on the therapy regardless of CD4-cell count (AII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.monthly through Month 4, and every 1 to 3 months thereafter (see the Hepatotoxicity section of the table onAntiretroviral Therapy-Associated Common and/or Severe Adverse Effects in the Guidelines for the Use ofAntiretroviral Agents in HIV-1-Infected Adults and Adolescents). In patients with pre-existing liver disease,monitoring should be performed more frequently when initiating nevirapine and monthly thereafter.1Transaminase levels should be checked in all women who develop a rash while receiving nevirapine. Patientswho develop suggestive clinical symptoms accompanied by elevation in serum transaminase levels (ALTand/or AST) or who have asymptomatic but severe transaminase elevations (that is, more than 5 times theupper limit of normal) should stop nevirapine and not receive nevirapine again in the future.Hepatic toxicity has not been seen in women receiving single-dose nevirapine during labor for prevention ofperinatal transmission of HIV.13Women who enter pregnancy on nevirapine-containing regimens and aretolerating them well can continue therapy, regardless of CD4-cell count.References1. Kontorinis N, Dieterich DT. Toxicity of non-nucleoside analogue reverse transcriptase inhibitors. Semin Liver Dis. May2003;23(2):173-182. Available at http://www.ncbi.nlm.nih.gov/pubmed/12800070.2. Bersoff-Matcha SJ, Miller WC, Aberg JA, et al. Sex differences in nevirapine rash. Clin Infect Dis. Jan 2001;32(1):124-129. Available at http://www.ncbi.nlm.nih.gov/pubmed/11118391.3. Mazhude C, Jones S, Murad S, Taylor C, Easterbrook P. Female sex but not ethnicity is a strong predictor of non-nucleoside reverse transcriptase inhibitor-induced rash. AIDS. Jul 26 2002;16(11):1566-1568. Available athttp://www.ncbi.nlm.nih.gov/pubmed/12131201.4. Baylor MS, Johann-Liang R. Hepatotoxicity associated with nevirapine use. J Acquir Immune Defic Syndr.2004;35(5):538-539. Available athttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15021321.5. Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL. A comprehensive hepatic safety analysis ofnevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr. Sep 2003;34(Suppl 1):S21-33. Available at http://www.ncbi.nlm.nih.gov/pubmed/14562855.6. Aaron E, Kempf MC, Criniti S, et al. Adverse events in a cohort of HIV infected pregnant and non-pregnant womentreated with nevirapine versus non-nevirapine antiretroviral medication. PLoS One. 2010;5(9):e12617. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20838641.7. Peters PJ, Stringer J, McConnell MS, et al. Nevirapine-associated hepatotoxicity was not predicted by CD4 count ≥250cells/muL among women in Zambia, Thailand and Kenya. HIV Med. Nov 2010;11(10):650-660. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20659176.8. Boehringer-Ingelheim Pharmaceuticals Inc. Viramune drug label. March 25, 2011. Available athttp://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020933s028,020636s037lbl.pdf.9. Lyons F, Hopkins S, Kelleher B, et al. Maternal hepatotoxicity with nevirapine as part of combination antiretroviraltherapy in pregnancy. HIV Med. May 2006;7(4):255-260. Available at http://www.ncbi.nlm.nih.gov/pubmed/16630038.10. Hitti J, Frenkel LM, Stek AM, et al. Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG1022. J Acquir Immune Defic Syndr. Jul 1 2004;36(3):772-776. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15213559.11. Ouyang DW, Shapiro DE, Lu M, et al. Increased risk of hepatotoxicity in HIV-infected pregnant women receivingantiretroviral therapy independent of nevirapine exposure. AIDS. Nov 27 2009;23(18):2425-2430. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19617813.12. Ouyang DW, Brogly SB, Lu M, et al. Lack of increased hepatotoxicity in HIV-infected pregnant women receivingnevirapine compared with other antiretrovirals. AIDS. Jan 2 2010;24(1):109-114. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19926957.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-16Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.13. McKoy JM, Bennett CL, Scheetz MH, et al. Hepatotoxicity associated with long- versus short-course HIV-prophylacticnevirapine use: a systematic review and meta-analysis from the Research on Adverse Drug events And Reports(RADAR) project. Drug Saf. 2009;32(2):147-158. Available at http://www.ncbi.nlm.nih.gov/pubmed/19236121.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-17Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-18Nucleoside Reverse Transcriptase Inhibitor Drugs and Mitochondrial Toxicity (Last updated July 31, 2012; last reviewed July 31, 2012)Nucleoside reverse transcriptase inhibitor (NRTI) drugs are known to induce mitochondrial dysfunctionbecause the drugs have varying affinity for mitochondrial gamma DNA polymerase. This affinity caninterfere with mitochondrial replication, resulting in mitochondrial DNA (mtDNA) depletion anddysfunction.1The relative potency of the NRTI drugs in inhibiting mitochondrial gamma DNA polymerase invitro is highest for zalcitabine, followed by didanosine, stavudine, zidovudine, lamivudine, abacavir, andtenofovir.2In one study, didanosine and didanosine-containing regimens were associated with the greatestdegree of mitochondrial suppression.3Toxicity related to mitochondrial dysfunction has been reported tooccur in infected patients receiving long-term treatment with NRTI drugs and generally has resolved withdiscontinuation of the drug or drugs; a possible genetic susceptibility to these toxicities has been suggested.1These toxicities may be of particular concern for pregnant women and infants with in utero exposure toNRTI drugs.Lactic acidosis with microvacuolar hepatic steatosis is a toxicity related to NRTI drugs that is thought to berelated to mitochondrial toxicity; it has been reported to occur in infected individuals treated with NRTIdrugs for longer than 6 months. In a report from the Food and Drug Administration Spontaneous AdverseEvent Program, typical initial symptoms included 1 to 6 weeks of nausea, vomiting, abdominal pain,dyspnea, and weakness.4Metabolic acidosis with elevated serum lactate levels and elevated hepatic enzymeswas common. Patients described in that report were predominantly female and overweight.During PregnancyClinical disorders linked to mitochondrial toxicity include neuropathy, myopathy, cardiomyopathy,pancreatitis, hepatic steatosis, and lactic acidosis. Among these disorders, symptomatic lactic acidosis andhepatic steatosis may have a female preponderance.5, 6These syndromes have similarities to rare but life-threatening syndromes that occur during pregnancy, most often during the third trimester: acute fatty liverand hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Data suggest that a disorder ofmitochondrial fatty acid oxidation in the mother or her fetus during late pregnancy may play a role indevelopment of acute fatty liver of pregnancy and HELLP syndrome 7-10and possibly contribute tosusceptibility to antiretroviral (ARV)-associated mitochondrial toxicity. HELLP syndrome also can occurpostpartum in women with severe preeclampsia.11The frequency of this syndrome in pregnant HIV-infected women receiving NRTI drugs is unknown but anumber of case reports of severe (1) or fatal (3) outcomes have been reported including several cases withPanel’s Recommendations• The combination of stavudine and didanosine should not be prescribed during pregnancy because of reports of lacticacidosis and maternal/neonatal mortality with prolonged use in pregnancy (AII).• Mitochondrial dysfunction should be considered in uninfected children with perinatal exposure to antiretroviral (ARV)drugs who present with severe clinical findings of unknown etiology, particularly neurologic findings (AII).• Long-term clinical follow-up is recommended for any child with in uteroexposure to ARV drugs (AIII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.didanosine/stavudine used in combination during pregnancy. Nonfatal cases of lactic acidosis also have beenreported in pregnant women receiving combination stavudine/didanosine.12Because of these reports ofmaternal mortality secondary to lactic acidosis with prolonged use of the combination of stavudine anddidanosine by HIV-infected pregnant women, clinicians should not prescribe this ARV combination duringpregnancy. Likewise, combination stavudine/didanosine also is not recommended for non-pregnant adults.It is unclear if pregnancy augments the incidence of the lactic acidosis/hepatic steatosis syndrome that hasbeen reported for non-pregnant individuals receiving NRTI drugs. However, because pregnancy itself canmimic some of the early symptoms of the lactic acidosis/hepatic steatosis syndrome or be associated withother disorders of liver metabolism, these cases emphasize the need for physicians caring for HIV-infectedpregnant women receiving NRTI drugs to be alert for early signs of this syndrome.In addition to low platelets and elevated liver enzymes, other laboratory findings reported in HIV-infectedpregnant women on ARV drugs include depletion of mtDNA in the placenta but without evidence ofultrastructural damage to placental cells. The clinical significance of reduced mtDNA in placentas exposed toARV drugs remains unknown.13A recent report by Hernandez et al. assessed mitochondrial and apoptoticparameters in mononuclear cells from maternal peripheral blood and infant cord blood from 27 HIV-infectedand ARV-treated pregnant women and their infants and 35 uninfected controls and their infants.14Reducednewborn mtDNA levels, decreased maternal and fetal mitochondrial protein synthesis, and reduced maternalglycerol-3-phosphate and complex III function were observed in HIV- and ARV-exposed mothers and infantscompared with uninfected controls. Maternal mtDNA depletion was particularly seen in HIV-infectedpregnant women who had cumulative exposure to NRTIs of more than 100 months, suggesting NRTI-mediated injury. Also, Jitratkosol et al. reported increased prevalence of AG/TG mtDNA mutations amongHIV-infected pregnant women receiving antiretroviral therapy.15However, no clinical adverse outcomeswere linked to these findings in either pregnant women or their infants.In Utero ExposureIt has been suggested that mitochondrial dysfunction may develop in infants with in utero exposure to NRTIdrugs. Data from a French cohort of 1,754 uninfected infants born to HIV-infected women who receivedARV drugs during pregnancy identified 8 infants with in utero or neonatal exposure to eitherzidovudine/lamivudine (4) or zidovudine alone (4) who developed indications of mitochondrial dysfunctionafter the first few months of life.16Two of these infants (both exposed to zidovudine/lamivudine) contractedsevere neurologic disease and died; 3 had mild-to-moderate symptoms; and 3 had no symptoms but hadtransient laboratory abnormalities.In a larger cohort of 4,392 uninfected children (including the children in the previous study) followed withinthe French Pediatric Cohort or identified within a French National Register, the 18-month incidence ofclinical symptoms of mitochondrial dysfunction was 0.26% and 0.07% for mortality.17All children hadperinatal exposure to ARV drugs; risk was higher among infants exposed to combination ARV drugs(primarily zidovudine/lamivudine) than to zidovudine alone. The children presented with neurologicsymptoms, often with abnormal magnetic resonance imaging and/or episodes of significant hyperlactatemia,and deficits in mitochondrial respiratory chain complex enzyme function on biopsy of muscle. The samegroup also has reported an increased risk of simple febrile seizures in the first 18 months of life andpersistently lower (but clinically insignificant) neutrophil, lymphocyte, and platelet counts in infants with inutero exposure to NRTIs.18, 19More recently, in continued follow-up of the French Perinatal Cohort,researchers reported severe neurologic symptoms in the first 2 years of life as a rare event (0.3%–0.5%).20Other clinical studies from the United States and Europe generally have not duplicated the French reports.21-27The Perinatal Safety Review Working Group performed a retrospective review of deaths occurring inchildren born to HIV-infected women and followed from 1986 to 1999 in 5 large, prospective U.S. perinatalRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-19Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.cohorts. No deaths similar to those reported from France or with clinical findings attributable tomitochondrial dysfunction were identified in a database of more than 16,000 uninfected children born toHIV-infected women with and without exposure to ARV drugs.22However, most of the infants with exposureto ARVs had been exposed to zidovudine alone and only a relatively small proportion (approximately 6%)had been exposed to zidovudine/lamivudine.The European Collaborative Study reviewed clinical symptoms in 2,414 uninfected children in their cohortwith median follow-up of 2.2 years (maximum, 16 years); 1,008 had perinatal exposure to ARV drugs.24Noassociation was found between clinical manifestations suggestive of mitochondrial abnormalities and perinatalexposure to ARV drugs. Of the 4 children with seizures in this cohort, none had perinatal exposure to ARVdrugs. In a report from a long-term follow-up study in the United States (PACTG 219/219C), 20 children withpossible symptoms of mitochondrial dysfunction were identified in a cohort of 1,037 uninfected infants born toHIV-infected mothers.26Definitive diagnosis was not available because none of the children had biopsies formitochondrial function. Three of the 20 children had no exposure to ARV drugs. In the 17 remaining children,although overall exposure to NRTIs was not associated with symptoms, there was an association betweensymptoms and first exposure to zidovudine/lamivudine limited to the third trimester. Some small alterations inmtDNA and oxidative phosphorylation enzyme activities were found in stored specimens from these children,but the clinical significance of these observations remains unknown.28, 29Laboratory abnormalities without clinical symptoms have been reported in infants with perinatal exposure toARV drugs compared with unexposed infants in a number of studies, most of which are limited by smallnumbers of subjects. In one study, mtDNA quantity was lower in cord and peripheral blood white cells at ages1 and 2 years in 20 infants born to HIV-infected women compared with 30 infants born to uninfected womenand was lowest in 10 HIV-exposed infants with zidovudine exposure compared with 10 without zidovudineexposure.30In a subsequent study, mitochondrial changes were evaluated in umbilical cord endothelial cells andcord blood from human infants and monkeys with in utero exposure to various NRTI-containing regimens.31Similar morphologic changes and mtDNA depletion were seen in the human and monkey infants. In themonkey study, mitochondrial damage demonstrated a gradient, with greatest damage with stavudine/lamivudine > zidovudine/didanosine > zidovudine/lamivudine > lamivudine. In a Canadian study of 73 ARV-exposed infants and 81 controls with blood samples during the first 8 months of life, investigators found that inthe first weeks of life, blood mtDNA levels were higher and blood mitochondrial RNA levels were lower in theHIV- and ARV-exposed infants compared with infants without HIV and ARV exposure.32Aldrovandi et al. reported that peripheral blood mononuclear cell mtDNA levels were lower at birth in HIV-exposed, ARV-exposed infants compared with non-HIV, non-ARV-exposed infants.33However, among theHIV-exposed infants, those with combination ARV drug exposure in utero had higher mtDNA levels thanthose exposed only to zidovudine in utero. Umbilical cord mtDNA sequence variants were 3-fold higheramong HIV- and zidovudine-exposed infants compared with infants born to HIV-uninfected mothers.34Mostrecently, Jitratkosol reported blood mtDNA mutations in HIV-exposed infants and Hernandez et al. reportedsubclinical mitochondrial dysfunction with decreased mtDNA levels and mtDNA protein synthesis.14, 15Other laboratory findings among HIV-exposed infants:Transient hyperlactatemia during the first few weeks of life was reported in 17 HIV-exposed infants withperinatal exposure to ARV drugs; lactate levels returned to normal in all children and none developedsymptoms of mitochondrial dysfunction during follow-up.35Similarly, the French Perinatal Cohort Study hasreported asymptomatic hyperlactatemia in one-third of zidovudine-exposed newborns, which resolvedfollowing perinatal exposure to the drug.20Clinically asymptomatic hematologic findings have been reportedby several investigators in uninfected infants with in utero exposure to ARV regimens in the United Statesand Europe,36-38and infants with exposure to triple-combination ARV regimens were found to be at increasedrisk of lowered hemoglobin compared with those with perinatal exposure to zidovudine orRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-20Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.zidovudine/lamivudine.39Similar hematologic findings of anemia have also been reported in a Botswanastudy. Dryden-Peterson et al. reported that 12.5% of breastfed infants of mothers on ARV drugs duringpregnancy and during breastfeeding in Botswana experienced at least 1 episode of Grade 3 or Grade 4reduced hemoglobin by age 6 months compared with 5.3% of breastfed infants exposed to zidovudine inutero followed by daily infant zidovudine for 6 months and 2.5% of infants who were exposed to the drug inutero and for 1 month post-birth and were formula fed.40The Botswana study group has also reporteddecreased birth weight and decreased weight for age and length for age in the first several months of life ininfants exposed to ARV drugs.Echocardiographic abnormalities have been reported among 136 ARV drug- and HIV-exposed uninfectedinfants compared with 216 HIV-exposed, uninfected infants without ARV drug exposure in the NHLBICHAART-1 study.41In infants up to age 2 years, prenatal ARV exposure was associated with reduced leftventricular mass, dimension, and septal wall thickness z-scores and increased left ventricular fractionalshortening and contractility compared with lack of ARV drug exposure. These findings were more prominentin female than in male infants.The clinical significance of these differences in mtDNA, lactate levels, and hematologic and cardiaclaboratory findings remains unclear. Further long-term studies are needed to validate the findings and assesswhether they affect long-term growth and development of infants exposed to ARV drugs. Even if anassociation is more clearly demonstrated, the development of severe or fatal mitochondrial disease appears tobe extremely rare and must be balanced against the proven benefit of ARV prophylaxis in significantlyreducing transmission of HIV from mothers to their infants.24, 42, 43Development of new diagnostic techniques, including use of flow cytometry assays to screen formitochondrial function, may lead to more accurate assessment of mitochondrial toxicity.44Mitochondrialdysfunction should be considered in uninfected children with perinatal exposure to ARV drugs who presentwith severe clinical findings of unknown etiology, particularly neurologic findings. Currentrecommendations emphasize the need for long-term clinical follow-up for any child with in utero,peripartum, or postnatal exposure to ARV drugs used for prevention of mother-to-child transmission.References1. Brinkman K, Ter Hofstede HJM, Burger DM, et al. Adverse effects of reverse transcriptase inhibitors: mitochondrialtoxicity as common pathway. AIDS. 1998;12(14):1735-1744. Available athttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9792373&dopt=Abstract.2. Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir:comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. Mar 2002;46(3):716-723. Available at http://www.ncbi.nlm.nih.gov/pubmed/11850253.3. Saitoh A, Haas RH, Naviaux RK, Salva NG, Wong JK, Spector SA. Impact of nucleoside reverse transcriptaseinhibitors on mitochondrial DNA and RNA in human skeletal muscle cells. Antimicrob Agents Chemother. Aug2008;52(8):2825-2830. Available at http://www.ncbi.nlm.nih.gov/pubmed/18541728.4. Fleischer R, Boxwell D, Sherman KE. Nucleoside analogues and mitochondrial toxicity. Clin Infect Dis. Apr 152004;38(8):e79-80. Available at http://www.ncbi.nlm.nih.gov/pubmed/15095236.5. Currier JS. Sex differences in antiretroviral therapy toxicity: lactic acidosis, stavudine, and women. Clin Infect Dis. Jul15 2007;45(2):261-262. Available at http://www.ncbi.nlm.nih.gov/pubmed/17578789.6. Bolhaar MG, Karstaedt AS. A high incidence of lactic acidosis and symptomatic hyperlactatemia in women receivinghighly active antiretroviral therapy in Soweto, South Africa. Clin Infect Dis. Jul 15 2007;45(2):254-260. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17578788.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-21Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.7. Ibdah JA, Bennett MJ, Rinaldo P, et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnantwomen. N Engl J Med. Jun 3 1999;340(22):1723-1731. Available at http://www.ncbi.nlm.nih.gov/pubmed/10352164.8. Strauss AW, Bennett MJ, Rinaldo P, et al. Inherited long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and afetal-maternal interaction cause maternal liver disease and other pregnancy complications. Semin Perinatol. Apr1999;23(2):100-112. Available at http://www.ncbi.nlm.nih.gov/pubmed/10331463.9. Sims HF, Brackett JC, Powell CK, et al. The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenasedeficiency associated with maternal acute fatty liver of pregnancy. Proc Natl Acad Sci U S A. Jan 31 1995;92(3):841-845. Available at http://www.ncbi.nlm.nih.gov/pubmed/7846063.10. Ibdah JA, Yang Z, Bennett MJ. Liver disease in pregnancy and fetal fatty acid oxidation defects. Mol Genet Metab. Sep-Oct 2000;71(1-2):182-189. Available at http://www.ncbi.nlm.nih.gov/pubmed/11001809.11. Gasem T, Al Jama FE, Burshaid S, Rahman J, Al Suleiman SA, Rahman MS. Maternal and fetal outcome of pregnancycomplicated by HELLP syndrome. J Matern Fetal Neonatal Med. Dec 2009;22(12):1140-1143. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19916711.12. Mandelbrot L, Kermarrec N, Marcollet A, et al. Case report: nucleoside analogue-induced lactic acidosis in the thirdtrimester of pregnancy. AIDS. Jan 24 2003;17(2):272-273. Available at http://www.ncbi.nlm.nih.gov/pubmed/12545093.13. Gingelmaier A, Grubert TA, Kost BP, et al. Mitochondrial toxicity in HIV type-1-exposed pregnancies in the era ofhighly active antiretroviral therapy. Antivir Ther. 2009;14(3):331-338. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19474467.14. Hernandez S, Moren C, Lopez M, et al. Perinatal outcomes, mitochondrial toxicity and apoptosis in HIV-treatedpregnant women and in-utero-exposed newborn. AIDS. Feb 20 2012;26(4):419-428. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22156962.15. Jitratkosol MH, Sattha B, Maan EJ, et al. Blood mitochondrial DNA mutations in HIV-infected women and their infantsexposed to HAART during pregnancy. AIDS. Mar 27 2012;26(6):675-683. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22436539.16. Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviralnucleoside analogues. Lancet. Sep 25 1999;354(9184):1084-1089. Available athttp://www.ncbi.nlm.nih.gov/pubmed/10509500.17. Barret B, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants:clinical screening in a large prospective cohort. AIDS. Aug 15 2003;17(12):1769-1785. Available athttp://www.ncbi.nlm.nih.gov/pubmed/12891063.18. Landreau-Mascaro A, Barret B, Mayaux MJ, Tardieu M, Blanche S, French Perinatal Cohort Study Group. Risk of earlyfebrile seizure with perinatal exposure to nucleoside analogues. Lancet. Feb 16 2002;359(9306):583-584. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11867117.19. Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C, Blanche S, Enquete Perinatale Francaise Study Group. Perinatalantiretroviral treatment and hematopoiesis in HIV-uninfected infants. AIDS. Sep 26 2003;17(14):2053-2061. Availableat http://www.ncbi.nlm.nih.gov/pubmed/14502008.20. Benhammou V, Tardieu M, Warszawski J, Rustin P, Blanche S. Clinical mitochondrial dysfunction in uninfectedchildren born to HIV-infected mothers following perinatal exposure to nucleoside analogues. Environ Mol Mutagen.Apr-May 2007;48(3-4):173-178. Available at http://www.ncbi.nlm.nih.gov/pubmed/17358031.21. Sperling RS, Shapiro DE, McSherry GD, et al. Safety of the maternal-infant zidovudine regimen utilized in thePediatric AIDS Clinical Trial Group 076 Study. AIDS. Oct 1 1998;12(14):1805-1813. Available athttp://www.ncbi.nlm.nih.gov/pubmed/9792381.22. The Perinatal Safety Review Working Group. Nucleoside exposure in the children of HIV-infected women receivingantiretroviral drugs: absence of clear evidence for mitochondrial disease in children who died before 5 years of age infive United States cohorts. J Acquir Immune Defic Syndr. Nov 1 2000;25(3):261-268. Available atRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-22Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.http://www.ncbi.nlm.nih.gov/pubmed/11115957.23. Lipshultz SE, Easley KA, Orav EJ, et al. Absence of cardiac toxicity of zidovudine in infants. Pediatric Pulmonary andCardiac Complications of Vertically Transmitted HIV Infection Study Group. N Engl J Med. Sep 14 2000;343(11):759-766. Available at http://www.ncbi.nlm.nih.gov/pubmed/10984563.24. European Collaborative Study. Exposure to antiretroviral therapy in utero or early life: the health of uninfected childrenborn to HIV-infected women. J Acquir Immune Defic Syndr. 2003;32(4):380-387. Available athttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12640195&dopt=Abstract.25. Alimenti A, Forbes JC, Oberlander TF, et al. A prospective controlled study of neurodevelopment in HIV-uninfectedchildren exposed to combination antiretroviral drugs in pregnancy. Pediatrics. Oct 2006;118(4):e1139-1145. Availableat http://www.ncbi.nlm.nih.gov/pubmed/16940166.26. Brogly SB, Ylitalo N, Mofenson LM, et al. In utero nucleoside reverse transcriptase inhibitor exposure and signs ofpossible mitochondrial dysfunction in HIV-uninfected children. AIDS. May 11 2007;21(8):929-938. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17457086.27. Hankin C, Lyall H, Peckham C, Tookey P. Monitoring death and cancer in children born to HIV-infected women inEngland and Wales: use of HIV surveillance and national routine data. AIDS. Apr 23 2007;21(7):867-869. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17415042.28. Brogly SB, DiMauro S, Van Dyke RB, et al. Short communication: transplacental nucleoside analogue exposure andmitochondrial parameters in HIV-uninfected children. AIDS Res Hum Retroviruses. Jul 2011;27(7):777-783. Availableat http://www.ncbi.nlm.nih.gov/pubmed/21142587.29. Brogly SB, Foca M, Deville JG, et al. Potential confounding of the association between exposure to nucleosideanalogues and mitochondrial dysfunction in HIV-uninfected and indeterminate infants. J Acquir Immune Defic Syndr.Jan 2010;53(1):154-157. Available at http://www.ncbi.nlm.nih.gov/pubmed/20035168.30. Poirier MC, Divi RL, Al-Harthi L, et al. Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers. J Acquir Immune Defic Syndr. Jun 1 2003;33(2):175-183. Available athttp://www.ncbi.nlm.nih.gov/pubmed/12794551.31. Divi RL, Leonard SL, Kuo MM, et al. Transplacentally exposed human and monkey newborn infants show similarevidence of nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity. Environ Mol Mutagen. Apr-May2007;48(3-4):201-209. Available at http://www.ncbi.nlm.nih.gov/pubmed/16538687.32. Cote HC, Raboud J, Bitnun A, et al. Perinatal exposure to antiretroviral therapy is associated with increased bloodmitochondrial DNA levels and decreased mitochondrial gene expression in infants. J Infect Dis. Sep 152008;198(6):851-859. Available at http://www.ncbi.nlm.nih.gov/pubmed/18684095.33. Aldrovandi GM, Chu C, Shearer WT, et al. Antiretroviral exposure and lymphocyte mtDNA content among uninfectedinfants of HIV-1-infected women. Pediatrics. Dec 2009;124(6):e1189-1197. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19933732.34. Torres SM, Walker DM, McCash CL, et al. Mutational analysis of the mitochondrial tRNA genes and flanking regionsin umbilical cord tissue from uninfected infants receiving AZT-based therapies for prophylaxis of HIV-1. Environ MolMutagen. Jan 2009;50(1):10-26. Available at http://www.ncbi.nlm.nih.gov/pubmed/19031409.35. Giaquinto C, De Romeo A, Giacomet V, et al. Lactic acid levels in children perinatally treated with antiretroviral agentsto prevent HIV transmission. AIDS. May 25 2001;15(8):1074-1075. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11399997.36. Pacheco SE, McIntosh K, Lu M, et al. Effect of perinatal antiretroviral drug exposure on hematologic values in HIV-uninfected children: An analysis of the women and infants transmission study. J Infect Dis. Oct 152006;194(8):1089-1097. Available at http://www.ncbi.nlm.nih.gov/pubmed/16991083.37. European Collaborative Study. Levels and patterns of neutrophil cell counts over the first 8 years of life in children ofHIV-1-infected mothers. AIDS. Oct 21 2004;18(15):2009-2017. Available atRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-23Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.http://www.ncbi.nlm.nih.gov/pubmed/15577622.38. Bunders M, Thorne C, Newell ML, European Collaborative Study. Maternal and infant factors and lymphocyte, CD4and CD8 cell counts in uninfected children of HIV-1-infected mothers. AIDS. Jul 1 2005;19(10):1071-1079. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15958839.39. Feiterna-Sperling C, Weizsaecker K, Buhrer C, et al. Hematologic effects of maternal antiretroviral therapy andtransmission prophylaxis in HIV-1-exposed uninfected newborn infants. J Acquir Immune Defic Syndr. May 12007;45(1):43-51. Available at http://www.ncbi.nlm.nih.gov/pubmed/17356471.40. Dryden-Peterson S, Shapiro RL, Hughes MD, et al. Increased risk of severe infant anemia after exposure to maternalHAART, Botswana. J Acquir Immune Defic Syndr. Apr 15 2011;56(5):428-436. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21266910.41. Lipshultz SE, Shearer WT, Thompson B, et al. Cardiac effects of antiretroviral therapy in HIV-negative infants born toHIV-positive mothers: NHLBI CHAART-1 (National Heart, Lung, and Blood Institute Cardiovascular Status ofHAART Therapy in HIV-Exposed Infants and Children cohort study). J Am Coll Cardiol. Jan 4 2011;57(1):76-85.Available at http://www.ncbi.nlm.nih.gov/pubmed/21185505.42. Morris AA, Carr A. HIV nucleoside analogues: new adverse effects on mitochondria? Lancet. Sep 251999;354(9184):1046-1047. Available at http://www.ncbi.nlm.nih.gov/pubmed/10509488.43. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. Apr 152002;29(5):484-494. Available at http://www.ncbi.nlm.nih.gov/pubmed/11981365.44. Lin CH, Sloan DD, Dang CH, et al. Assessment of mitochondrial toxicity by analysis of mitochondrial proteinexpression in mononuclear cells. Cytometry B Clin Cytom. May 2009;76(3):181-190. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18823003.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-24Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-25Protease Inhibitor Therapy and Hyperglycemia (Last updated July 31, 2012; lastreviewed July 31, 2012)Hyperglycemia, new-onset diabetes mellitus, exacerbation of existing diabetes mellitus, and diabeticketoacidosis have been reported in HIV-infected patients taking protease inhibitors (PIs).1-4In addition,pregnancy is itself a risk factor for hyperglycemia. To date, however, the majority of studies have not shownan increased risk of glucose intolerance with PI-based regimens during pregnancy. One small retrospectivestudy that included 41 women receiving PI-based combination antiretroviral (ARV) regimens found anincreased risk of glucose intolerance, but not gestational diabetes, among women on combination ARVregimens compared with zidovudine alone,5although 2 other retrospective studies did not find an increasedrisk of glucose intolerance with PIs.6, 7Secondary analyses of 2 large cohorts did not find an associationbetween the type of ARV regimen and gestational diabetes, except for an association between initiation ofPIs before pregnancy or during the first trimester and gestational diabetes in the PACTG 316 cohort.8, 9Finally, a prospective study including detailed evaluations for glucose intolerance and insulin resistanceamong HIV-infected pregnant women did not find differences between women on PI-containing and non-PI-containing regimens.10In both groups, however, the rate of impaired glucose tolerance was high (38%),likely related to high body mass index and race/ethnicity among trial subjects.HIV-infected women receiving ARV regimens during pregnancy should receive standard glucose screeningat 24 to 28 weeks’ gestation. Some experts would perform earlier glucose screening in women with ongoingPI-based ARV regimens initiated before pregnancy (particularly those of minority race/ethnicity), similar torecommendations for women with high risk factors for glucose intolerance, such as maternal obesity,advanced maternal age, and family history of type II diabetes mellitus.References1. Food and Drug Administration. FDA Public Health Advisory: reports of diabetes and hyperglycemia in patientsreceiving protease inhibitors for treatment of human immunodeficiency virus (HIV). Food and Drug Administration,Public Health Service, Department of Health and Human Services. Rockville, MD: June 11, 1997. Available athttp://www.fda.gov/cder/news/proteaseletter.htm.2. Visnegarwala F, Krause KL, Musher DM. Severe diabetes associated with protease inhibitor therapy. Ann Intern Med.Nov 15 1997;127(10):947. Available at http://www.ncbi.nlm.nih.gov/pubmed/9382374.3. Eastone JA, Decker CF. New-onset diabetes mellitus associated with use of protease inhibitor. Ann Intern Med. Nov 151997;127(10):948. Available at http://www.ncbi.nlm.nih.gov/pubmed/9382376.4. Dube MP, Sattler FR. Metabolic complications of antiretroviral therapies. AIDS Clin Care. Jun 1998;10(6):41-44.Panel’s Recommendation• HIV-infected women taking antiretroviral drug regimens during pregnancy should undergo standard glucose screening at24 to 28 weeks’ gestation (AIII). Some experts would perform earlier glucose screening in women receiving ongoingprotease inhibitor-based regimens initiated before pregnancy, similar to recommendations for women with high riskfactors for glucose intolerance (BIII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Available at http://www.ncbi.nlm.nih.gov/pubmed/11365497.5. Chmait R, Franklin P, Spector SA, Hull AD. Protease inhibitors and decreased birth weight in HIV-infected pregnantwomen with impaired glucose tolerance. J Perinatol. Jul-Aug 2002;22(5):370-373. Available athttp://www.ncbi.nlm.nih.gov/pubmed/12082471.6. Dinsmoor MJ, Forrest ST. Lack of an effect of protease inhibitor use on glucose tolerance during pregnancy. Infect DisObstet Gynecol. 2002;10(4):187-191. Available at http://www.ncbi.nlm.nih.gov/pubmed/12648312.7. Tang JH, Sheffield JS, Grimes J, et al. Effect of protease inhibitor therapy on glucose intolerance in pregnancy. ObstetGynecol. May 2006;107(5):1115-1119. Available at http://www.ncbi.nlm.nih.gov/pubmed/16648418.8. Tuomala RE, Watts DH, Li D, et al. Improved obstetric outcomes and few maternal toxicities are associated withantiretroviral therapy, including highly active antiretroviral therapy during pregnancy. J Acquir Immune Defic Syndr.Apr 1 2005;38(4):449-473. Available at http://www.ncbi.nlm.nih.gov/pubmed/15764963.9. Watts DH, Balasubramanian R, Maupin RT, Jr., et al. Maternal toxicity and pregnancy complications in humanimmunodeficiency virus-infected women receiving antiretroviral therapy: PACTG 316. Am J Obstet Gynecol. Feb2004;190(2):506-516. Available at http://www.ncbi.nlm.nih.gov/pubmed/14981398.10. Hitti J, Andersen J, McComsey G, et al. Protease inhibitor-based antiretroviral therapy and glucose tolerance inpregnancy: AIDS Clinical Trials Group A5084. Am J Obstet Gynecol. Apr 2007;196(4):331 e331-337. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17403409.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States E-26Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States F-1Antiretroviral Drug Resistance and Resistance Testing inPregnancy (Last updated July 31, 2012; last reviewed July 31, 2012)Indications for Antiretroviral Drug-Resistance Testing in HIV-Infected Pregnant WomenIn addition to a comprehensive history of antiretroviral (ARV) drug use, genotypic resistance testing isrecommended for all ARV-naive pregnant women with HIV RNA levels above the threshold for resistancetesting (e.g., >500–1,000 copies/mL) before initiating antiretroviral treatment (ART) or prophylaxis. Fordetails regarding genotypic and phenotypic resistance testing see Guidelines for the Use of AntiretroviralAgents in HIV-1-Infected Adults and Adolescents.Resistance testing should also be performed before initiation of ARV drugs in pregnant women with HIVRNA levels above the threshold for resistance testing (meaning >500–1,000 copies/mL) who receivedprophylaxis in previous pregnancies and are now restarting ARV drugs for prevention of perinatalPanel’s Recommendations• HIV drug-resistance studies should be performed before starting or modifying antiretroviral (ARV) regimens in allpregnant women whose HIV RNA levels are above the threshold for resistance testing (that is >500–1,000 copies/mL)before initiation of ARVs (AIII) and for those entering pregnancy with detectable HIV RNA levels while receivingantiretroviral therapy or who have suboptimal viral suppression after starting ARVs during pregnancy (AII).• In women who present late in pregnancy, an empiric ARV regimen should be initiated promptly without waiting for theresults of resistance testing, with adjustment as needed after test results are available, for optimal prevention of perinataltransmission and maternal health (BIII).• Women who have documented zidovudine resistance and are on regimens that do not include zidovudine for their ownhealth should still receive intravenous zidovudine during labor along with their established ARV regimens if they have HIVRNA levels >400 copies/mL near delivery (see Intrapartum Antiretroviral Prophylaxis/Therapy), unless a history ofhypersensitivity is documented (AII).• The optimal prophylactic regimen for newborns of women with ARV resistance is unknown (see Infant AntiretroviralProphylaxis). Therefore, ARV prophylaxis for an infant born to a woman with known or suspected drug resistance shouldbe determined in consultation with a pediatric HIV specialist, preferably before delivery (see Infant AntiretroviralProphylaxis) (AIII).• HIV-infected pregnant women should be given combination ARV drug regimens to maximally suppress viral replication,which is the most effective strategy for preventing development of resistance and minimizing risk of perinataltransmission (AII).• All pregnant and postpartum women should be counseled about the importance of adherence to prescribed ARVmedications to reduce the potential for development of resistance (AII).• To minimize development of resistance, pregnant women who receive a non-nucleoside reverse transcriptase inhibitor(NNRTI)-based combination ARV regimen that is discontinued after delivery should receive either dual nucleosideanalogue reverse transcriptase agents alone (AI) or with a protease inhibitor (BII) for 7 to 30 days (AII) after stopping theNNRTI drug. The optimal interval between stopping an NNRTI and the other ARV drugs is unknown (see StoppingAntiretroviral Therapy during Pregnancy and Postpartum Follow-Up of HIV-Infected Women).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.transmission. The identification of baseline resistance mutations may allow selection of more effective anddurable ARV regimens. Resistance testing also should be performed following initiation of an ARV regimen during pregnancy or inHIV-infected pregnant women who are receiving ART when they present for obstetrical care if there issuboptimal viral suppression or persistent viral load rebound to detectable levels after prior viral suppressionon the ARV regimen.In most settings, the results of resistance testing guide selection of the initial ARV regimen. In somesituations in pregnant women, however, the clinician may choose to initiate an empiric ARV drug regimenbefore resistance-testing results are available to optimize prevention of perinatal transmission of HIV. Mostexperts believe that for women in the third trimester, the benefits of immediate initiation of ARV drugs forprevention of mother-to-child transmission (PMTCT), pending results of resistance testing, outweigh thepossible risks of short-term use of a regimen that could be suboptimal because of pre-existing resistance.Once resistance-test results are obtained, the ARV drug regimen can be modified as needed. Incidence and Significance of Antiretroviral Drug Resistance in PregnancyThe development of ARV drug resistance is one of the major factors leading to therapeutic failure in HIV-infected individuals. Additionally, pre-existing resistance to a drug in an ARV prophylaxis regimen maydiminish the regimen’s efficacy in preventing perinatal transmission. The development of resistance to drugsused during pregnancy for prophylaxis of perinatal transmission may limit future maternal treatment optionsor decrease the effectiveness of prophylactic regimens in the current pregnancy or during future pregnancies.Infant treatment options also may be limited if maternal resistance is present or develops and resistant virusis transmitted to the fetus.Several factors unique to pregnancy may increase the risk of development of resistance. If drugs withsignificant differences in half-life (such as nevirapine or efavirenz combined with two nucleoside analoguedrugs) are included in the ARV regimen, simultaneous postpartum discontinuation of all regimencomponents may result in persistent subtherapeutic drug levels and increase the risk of development of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance (see Stopping Antiretroviral Therapy duringPregnancy). Problems such as nausea and vomiting in early pregnancy may compromise adherence andincrease the risk of resistance in women receiving ARV drugs. Pharmacokinetic changes during pregnancy,such as increased plasma volume and renal clearance, may lead to subtherapeutic drug levels, increasing therisk that resistance will develop.ARV drug-resistance mutations have been observed in HIV-infected women receiving combination ARVdrug regimens that are stopped postpartum and appear to be most common when drugs with different half-lives or with a low genetic barrier to resistance (such as NNRTI drugs or lamivudine and emtricitabine) areused during pregnancy and subsequently stopped.1, 2Thus, as noted above, resistance testing before initiationof ARV drugs is recommended in pregnant women with detectable HIV RNA levels who receivedprophylaxis in previous pregnancies and are restarting ARV drugs for prevention of perinatal transmission.Issues relating to discontinuation of NNRTI-based combination therapy are discussed in Prevention ofAntiretroviral Drug Resistance. The Impact of Resistance on the Risk of Perinatal Transmission of HIV and MaternalResponse to Subsequent TherapyPerinatal TransmissionPerinatal transmission of resistant virus has been reported, but appears to be unusual. There is little evidencethat presence of resistance mutations increases risk of transmission when current recommendations for ARVRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States F-2Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.management in pregnancy are followed. A substudy of the Women and Infants Transmission Study followedpregnant women receiving zidovudine alone for treatment of HIV infection in the early 1990s. In this study,detection of zidovudine resistance conferred an increased risk of transmission when analysis was adjusted forduration of membrane rupture and total lymphocyte count;3however, women in this cohort hadcharacteristics that would indicate a need for ART under the current Department of Health and HumanServices recommendations for maternal health and for prevention of perinatal transmission. Whentransmitting mothers had mixed viral populations of wild-type and virus with low-level zidovudineresistance, only wild-type virus was detected in their infants,4and other studies have suggested that drug-resistance mutations may diminish viral fitness,5possibly leading to a decrease in transmissibility. In anotherstudy, prevalence of ARV drug resistance among HIV-infected newborns in New York State was examined.Eleven (12.1%) of 91 infants born between 1989 and 1999 and 8 (19%) of 42 infants born between 2001 and2002 had mutations associated with decreased drug susceptibility. However, perinatal exposure to ARVs wasnot found to be a significant risk factor for the presence of resistance during either time period.6, 7Neitherresistance to NNRTI drugs that develops as a result of exposure to single-dose nevirapine nor exposure tosingle-dose nevirapine in a prior pregnancy has been shown to affect perinatal transmission rates.8, 9Maternal Response to Subsequent Treatment RegimensFew studies have evaluated response to subsequent therapy in women who receive current combination ARVregimens for prophylaxis and discontinue the drugs postpartum. In theory, however, resistance should not occurif the regimen that was discontinued had fully suppressed viral replication. The French Perinatal Cohortevaluated the association between exposure to ARV drugs for PMTCT during a previous pregnancy andpresence of a detectable viral load with exposure to ARV drugs during the current pregnancy in women followedbetween 2005 and 2009.10In 1,166 women not receiving ARVs at the time of conception, 869 were ARV naiveand 247 had received ARV drugs for PMTCT during a previous pregnancy. Previous ARV prophylaxis wasprotease inhibitor (PI) based in 48%, non-PI based in 4%, nucleoside reverse transcriptase inhibitor (NRTI) dualARVs in 19%, and zidovudine as a single ARV in 29%. A PI-based ARV regimen was initiated in 90% of thewomen during the current pregnancy; in multivariate analysis, previous ARV exposure in a prior pregnancy wasnot associated with detectable viral load in the current pregnancy. A separate study reported in abstract form—ACTG A5227—evaluated viral suppression in 52 women with prior combination ARV exposure for PMTCTwho had stopped ARV at least 24 weeks before study entry and were now initiating ART (efavirenz, tenofovir,and emtricitabine) for treatment.11None of the women had prior or recent resistance detected on standard bulkgenotyping. Viral suppression was observed in 81% of women after 24 weeks of follow-up, with no differencein response by number of prior ARV exposures for PMTCT or the drug class of prior exposure.Management of Antiretroviral Drug Resistance during Pregnancy For women who have documented zidovudine resistance and whose antepartum regimen does not includezidovudine, the drug still should be given intravenously during labor when indicated (meaning HIV RNA>400 copies/mL near delivery; see Intrapartum Antiretroviral Drug Treatment/Prophylaxis). Other ARVsshould be continued orally during labor to the extent possible. The rationale for including zidovudineintrapartum when a woman is known to harbor virus with zidovudine resistance is based on several factors.Data thus far have suggested that only wild-type virus appears to be transmitted to infants by mothers whohave mixed populations of wild-type virus and virus with low-level zidovudine resistance.4Other studieshave suggested that drug-resistance mutations may diminish viral fitness and possibly decreasetransmissibility.5The efficacy of the zidovudine prophylaxis appears to be based not only on a reduction inmaternal HIV viral load but also on pre- and post-exposure prophylaxis in the infant.12-14Zidovudine crossesthe placenta readily and has a high maternal-to-cord blood ratio. In addition, zidovudine is metabolized to theactive triphosphate within the placenta,15, 16which may provide additional protection against transmission.Metabolism to the active triphosphate, which is required for activity of all nucleoside analogue agents, hasRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States F-3Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.not been observed within the placenta with other nucleoside analogues that have been evaluated (didanosineand zalcitabine). Zidovudine penetrates the central nervous system (CNS) better than do other nucleosideanalogues except stavudine, which has similar CNS penetration; this may help to eliminate a potentialreservoir for transmitted HIV in the infant.17, 18Thus, intrapartum intravenous administration of zidovudinewhen indicated currently is recommended even in the presence of known resistance because of the drug’sunique characteristics and its proven record in reducing perinatal transmission.The optimal prophylactic regimen for newborns of women with ARV drug-resistant virus is unknown.Therefore, ARV prophylaxis for infants born to women with known or suspected drug-resistant virus shouldbe determined with a pediatric HIV specialist, preferably before delivery (see Infant AntiretroviralProphylaxis).Prevention of Antiretroviral Drug Resistance The most effective way to prevent development of ARV drug resistance in pregnancy is to use and adhere toan effective combination of ARV drugs to achieve maximal viral suppression. More frequent monitoring ofviral load in pregnant women than in non-pregnant individuals is recommended because of the potentialincreased risk of perinatal HIV infection associated with detectable HIV viremia during pregnancy (seeMonitoring of the Woman and Fetus During Pregnancy).Several studies have demonstrated that women’s adherence to ART may worsen in the postpartum period.19-22Clinicians caring for postpartum women receiving ART should specifically address adherence, includingevaluating specific factors that facilitate or impede adherence.Because of the prolonged half-life of NNRTI drugs, if an NNRTI-based ARV regimen is stopped postpartumthere is a risk of development of NNRTI-resistance mutations if all drugs in the regimen are stoppedsimultaneously. This has been demonstrated for nevirapine and efavirenz but may also be a problem withnewer NNRTI drugs with long half-lives, such as etravirine and rilpivirine. Several studies have shown thatdevelopment of NNRTI resistance is significantly decreased (but not eliminated) when zidovudine/lamivudine is given intrapartum and administered for 3 to 7 days postpartum in women who have receivedsingle-dose intrapartum nevirapine.23-25A variety of other regimens (such as tenofovir/emtricitabine,zidovudine/didanosine, zidovudine/didanosine/lopinavir/ritonavir) given for 7 to 30 days postpartumfollowing maternal single-dose nevirapine have also been shown to be very effective in reducing thedevelopment of NNRTI resistance.25-28These data suggest that the NRTI components of an NNRTI-basedregimen should be continued for 7 to 30 days after discontinuation of the NNRTI to minimize the risk ofresistance. An alternative strategy is to substitute a PI for the NNRTI and to continue the PI with dual NRTIsfor a period of time.29The optimal duration for continuation of either dual nucleosides or the substituted PI-based regimen after stopping the NNRTI is unknown. NNRTI drugs have long half-lives, and drug levels canpersist for up to 1 to 3 weeks after stopping the drugs; efavirenz levels persist longer than nevirapinelevels.30, 31More research is needed on the optimal duration of time and regimen to “cover” this period ofprolonged NNRTI exposure to prevent the emergence of resistance after discontinuation of an NNRTI-basedARV regimen.References1. Ellis GM, Huang S, Hitti J, Frenkel LM, P1022 Study Team. Selection of HIV resistance associated with antiretroviraltherapy initiated due to pregnancy and suspended postpartum. J Acquir Immune Defic Syndr. Nov 1 2011;58(3):241-247. Available at http://www.ncbi.nlm.nih.gov/pubmed/21765365.2. Paredes R, Cheng I, Kuritzkes DR, Tuomala RE, Women and Infants Transmission Study (WITS) Group. Postpartumantiretroviral drug resistance in HIV-1-infected women receiving pregnancy-limited antiretroviral therapy. AIDS. Jan 2Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States F-4Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.2010;24(1):45-53. Available at http://www.ncbi.nlm.nih.gov/pubmed/19915448.3. Welles SL, Pitt J, Colgrove R, et al. HIV-1 genotypic zidovudine drug resistance and the risk of maternal—infanttransmission in the women and infants transmission study. The Women and Infants Transmission Study Group. AIDS.Feb 18 2000;14(3):263-271. Available at http://www.ncbi.nlm.nih.gov/pubmed/10716502.4. Colgrove RC, Pitt J, Chung PH, Welles SL, Japour AJ. Selective vertical transmission of HIV-1 antiretroviral resistancemutations. AIDS. Dec 3 1998;12(17):2281-2288. Available at http://www.ncbi.nlm.nih.gov/pubmed/9863870.5. Sheth PM, Kovacs C, Kemal KS, et al. Persistent HIV RNA shedding in semen despite effective antiretroviral therapy.AIDS. Sep 24 2009;23(15):2050-2054. Available at http://www.ncbi.nlm.nih.gov/pubmed/19710596.6. Taylor S, Davies S. Antiretroviral drug concentrations in the male and female genital tract: implications for the sexualtransmission of HIV. Curr Opin HIV AIDS. Jul 2010;5(4):335-343. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20543610.7. Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: aprospective cohort analysis. Lancet. Jun 12 2010;375(9731):2092-2098. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20537376.8. Del Romero J, Castilla J, Hernando V, Rodriguez C, Garcia S. Combined antiretroviral treatment and heterosexualtransmission of HIV-1: cross sectional and prospective cohort study. BMJ. 2010;340:c2205. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20472675.9. Martinson NA, Ekouevi DK, Dabis F, et al. Transmission rates in consecutive pregnancies exposed to single-dosenevirapine in Soweto, South Africa and Abidjan, Cote dIvoire. J Acquir Immune Defic Syndr. Jun 1 2007;45(2):206-209. Available at http://www.ncbi.nlm.nih.gov/pubmed/17438480.10. Briand N, Mandelbrot L, Blanche S, et al. Previous antiretroviral therapy for prevention of mother-to-child transmissionof HIV does not hamper the initial response to PI-based multitherapy during subsequent pregnancy.J Acquir ImmuneDefic Syndr. Jun 1 2011;57(2):126-135. Available at http://www.ncbi.nlm.nih.gov/pubmed/21436712.11. Vogler MA, Smeaton L, et al. Effect of prior cART used only to prevent MTCT of HIV-1 on subsequent cART efficacy inHIV+ women restarting HIV therapy with a standard first-line regimen: ACTG A5227 Study. Paper presented at: 18thConference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Abstract 752.12. Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment, and the risk of transmission ofhuman immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 StudyGroup. N Engl J Med. Nov 28 1996;335(22):1621-1629. Available at http://www.ncbi.nlm.nih.gov/pubmed/8965861.13. Wade NA, Birkhead GS, Warren BL, et al. Abbreviated regimens of zidovudine prophylaxis and perinatal transmissionof the human immunodeficiency virus. N Engl J Med. Nov 12 1998;339(20):1409-1414. Available athttp://www.ncbi.nlm.nih.gov/pubmed/9811915.14. Melvin AJ, Burchett SK, Watts DH, et al. Effect of pregnancy and zidovudine therapy on viral load in HIV-1-infectedwomen. J Acquir Immune Defic Syndr Hum Retrovirol. Mar 1 1997;14(3):232-236. Available athttp://www.ncbi.nlm.nih.gov/pubmed/9117455.15. Qian M, Bui T, Ho RJ, Unadkat JD. Metabolism of 3-azido-3-deoxythymidine (AZT) in human placental trophoblastsand Hofbauer cells. Biochemical pharmacology. Jul 19 1994;48(2):383-389. Available athttp://www.ncbi.nlm.nih.gov/pubmed/8053935.16. Sandberg JA, Binienda Z, Lipe G, et al. Placental transfer and fetal disposition of 2,3-dideoxycytidine and 2,3-dideoxyinosine in the rhesus monkey. Drug metabolism and disposition: the biological fate of chemicals. Aug1995;23(8):881-884. Available at http://www.ncbi.nlm.nih.gov/pubmed/7493557.17. Peters PJ, Stringer J, McConnell MS, et al. Nevirapine-associated hepatotoxicity was not predicted by CD4 count ≥250cells/muL among women in Zambia, Thailand and Kenya. HIV Med. Nov 2010;11(10):650-660. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20659176.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States F-5Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.18. Thomas SA. Anti-HIV drug distribution to the central nervous system. Curr Pharm Des. 2004;10(12):1313-1324.Available athttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15134483.19. Bardeguez AD, Lindsey JC, Shannon M, et al. Adherence to antiretrovirals among US women during and afterpregnancy. J Acquir Immune Defic Syndr. Aug 1 2008;48(4):408-417. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18614923.20. Mellins CA, Chu C, Malee K, et al. Adherence to antiretroviral treatment among pregnant and postpartum HIV-infectedwomen. AIDS Care. Sep 2008;20(8):958-968. Available at http://www.ncbi.nlm.nih.gov/pubmed/18608073.21. Rana AI, Gillani FS, Flanigan TP, Nash BT, Beckwith CG. Follow-up care among HIV-infected pregnant women inMississippi. J Womens Health (Larchmt). Oct 2010;19(10):1863-1867. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20831428.22. Anderson J. Women and HIV: motherhood and more. Curr Opin Infect Dis. Feb 2012;25(1):58-65. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22156896.23. McIntyre JA, Hopley M, Moodley D, et al. Efficacy of short-course AZT plus 3TC to reduce nevirapine resistance inthe prevention of mother-to-child HIV transmission: a randomized clinical trial. PLoS Med. Oct 2009;6(10):e1000172.Available at http://www.ncbi.nlm.nih.gov/pubmed/19859531.24. Chaix ML, Ekouevi DK, Rouet F, et al. Low risk of nevirapine resistance mutations in the prevention of mother-to-childtransmission of HIV-1: Agence Nationale de Recherches sur le SIDA Ditrame Plus, Abidjan, Cote dIvoire. J Infect Dis.Feb 15 2006;193(4):482-487. Available at http://www.ncbi.nlm.nih.gov/pubmed/16425126.25. Farr SL, Nelson JA, Ngombe TJ, et al. Addition of 7 days of zidovudine plus lamivudine to peripartum single-dosenevirapine effectively reduces nevirapine resistance postpartum in HIV-infected mothers in Malawi. J Acquir ImmuneDefic Syndr. Aug 2010;54(5):515-523. Available at http://www.ncbi.nlm.nih.gov/pubmed/20672451.26. TEmAA ANRS 12109 Study Group, Arrive E, Chaix ML, et al. Maternal and nenonatal tenofovir and emtricitabine toprevent vertical transmission of HIV-1: tolerance and resistance. AIDS. Oct 23 2010;24(16):2481-2488. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20827166.27. Lallemant M, Ngo-Giang-Huong N, Jourdain G, et al. Efficacy and safety of 1-month postpartum zidovudine-didanosine to prevent HIV-resistance mutations after intrapartum single-dose nevirapine. Clin Infect Dis. Mar 152010;50(6):898-908. Available at http://www.ncbi.nlm.nih.gov/pubmed/20158398.28. Van Dyke RB, Ngo-Giang-Huong N, Shapiro DE, et al. A comparison of 3 regimens to prevent nevirapine resistancemutations in HIV-infected pregnant women receiving a singly intrapartum dose of nevirapine. Clin Infect Dis. Jan 152012;54(2):285-93. Available at http://www.ncbi.nlm.nih.gov/pubmed/22144539.29. Fox Z, Phillips A, Cohen C, et al. Viral resuppression and detection of drug resistance following interruption of asuppressive non-nucleoside reverse transcriptase inhibitor-based regimen. AIDS. Nov 12 2008;22(17):2279-2289.Available at http://www.ncbi.nlm.nih.gov/pubmed/18981767.30. Cressey TR, Jourdain G, Lallemant MJ, et al. Persistence of nevirapine exposure during the postpartum period afterintrapartum single-dose nevirapine in addition to zidovudine prophylaxis for the prevention of mother-to-childtransmission of HIV-1. J Acquir Immune Defic Syndr. Mar 1 2005;38(3):283-288. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15735445.31. Sadiq ST, Fredericks S, Khoo SH, Rice P, Holt DW. Efavirenz detectable in plasma 8 weeks after stopping therapy andsubsequent development of non-nucleoside reverse transcriptase inhibitor-associated resistance. AIDS. Oct 142005;19(15):1716-1717. Available at http://www.ncbi.nlm.nih.gov/pubmed/16184054.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States F-6Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-1Intrapartum CareIntrapartum Antiretroviral Therapy/Prophylaxis (Last updated July 31, 2012; lastreviewed July 31, 2012Women Who Have Received Antepartum Antiretroviral DrugsUse of Intravenous Zidovudine during LaborThe PACTG 076 zidovudine regimen included a continuous intravenous (IV) infusion of zidovudine duringlabor (initial loading dose of 2 mg/kg IV over 1 hour, followed by continuous infusion of 1 mg/kg/hour untildelivery) for all women. This regimen along with maternal antepartum and infant zidovudine reducedperinatal transmission by 66% overall. Combination antiretroviral (ARV) regimens are now recommendedfor treatment and prevention of perinatal transmission of HIV; the additional benefit of IV zidovudine inwomen receiving combination regimens has not been evaluated in randomized clinical trials. The FrenchPerinatal Cohort evaluated transmission in >5,000 HIV-infected pregnant women receiving ARV (19%zidovudine alone, 33% dual ARV, and 48% triple ARV) who delivered between 1997 and 2004, stratified byviral load at delivery; 96% received IV intrapartum zidovudine.1Overall, intrapartum IV zidovudineprophylaxis was associated with lower risk of transmission (1.2% [59/5,006] transmission with intrapartumprophylaxis vs. 3.1% [7/230] without intrapartum prophylaxis, P =.025) but this association was related toHIV RNA level at delivery. In 364 women who had HIV RNA >10,000 copies/mL at delivery, intrapartumprophylaxis was strongly associated with a lower risk of transmission: 5.3% (18/339) with intrapartumprophylaxis versus 22.7% (5/22) without intrapartum prophylaxis (P =.009). However, intrapartumprophylaxis was not associated with transmission in 2,845 women with HIV RNA delivery: 0.6% (17/2,750) with intrapartum prophylaxis versus 0% (0/95) without intrapartum prophylaxis.Data were not provided for women with viral load 400 to 9,999 copies/mL. Based on this study, IVPanel’s Recommendations• Women who are receiving an antepartum combination antiretroviral (ARV) drug regimen should continue this regimen onschedule as much as possible during labor and before scheduled cesarean delivery (AIII).• Intravenous (IV) zidovudine should be administered to HIV-infected women with HIV RNA ≥400 copies/mL (or unknownHIV RNA) near delivery, regardless of antepartum regimen or mode of delivery (AI).• IV zidovudine is not required for HIV-infected women receiving combination ARV regimens who have HIV RNA copies/mL near delivery (BII).• For women who have received antepartum ARV drugs but have suboptimal viral suppression near delivery (that is, HIVRNA >1,000 copies/mL), scheduled cesarean delivery is recommended (see Mode of Delivery) (AI).• Women whose HIV status is unknown who present in labor should undergo rapid HIV antibody testing (AII). If the resultsare positive, a confirmatory HIV test should be done as soon as possible and maternal (IV zidovudine)/infant(combination ARV prophylaxis) ARV drugs should be initiated pending results of the confirmatory test (AII). If theconfirmatory HIV test is positive, infant ARV drugs should be continued for 6 weeks (see Infant Antiretroviral Prophylaxis)(AI); if the test is negative, the infant ARV drugs should be stopped.Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-2zidovudine is not required for HIV-infected women receiving combination ARV regimens with HIV RNA≥400 copies/mL near delivery (or unknown HIV RNA levels), regardless of antepartum regimen.In women with HIV RNA >400 copies/mL receiving a scheduled cesarean delivery for prevention oftransmission, IV zidovudine administration should begin 3 hours before the scheduled operative delivery.This recommendation is based on a pharmacokinetic (PK) study of zidovudine given orally during pregnancyand as a continuous infusion during labor. Maternal zidovudine levels were measured at baseline, after theinitial IV loading dose and then every 3 to 4 hours until delivery, and in cord blood.2Systemic andintracellular zidovudine levels increased from baseline but appeared to stabilize after 3 hours of infusion;cord blood zidovudine levels were assocated with maternal levels and maternal infusion duration. If cesareansection is being performed for other indications and maternal viral load is delivery, administration of IV zidovudine is not required.If antenatal use of zidovudine was precluded by known or suspected zidovudine resistance, intrapartum useof the drug still should be recommended in women with HIV RNA >400 copies/mL near delivery, except inwomen with documented histories of hypersensitivity. This intrapartum use of the drug is recommendedbecause of the unique characteristics of zidovudine and its proven record in reducing perinatal transmission,even in the presence of maternal resistance to the drug (see Management of Antiretroviral Drug Resistanceduring Pregnancy).In some international studies, oral, rather than IV zidovudine has been administered during labor (seeLessons from Clinical Trials of Antiretroviral Interventions to Reduce Perinatal Transmission of HIV). Dataare limited on the PKs of oral compared with IV zidovudine during labor. Additionally, the drug levelsneeded for prophylaxis are unknown, although extrapolations have been made using therapeutic drug leveltargets. In a study of oral intrapartum zidovudine 300 mg every 3 hours in Thailand, most cord bloodzidovudine levels were at therapeutic levels but were lower than those reported after continuous IVadministration; 17% of infants had subtherapeutic levels at birth.3In another study, the PKs of two dosingregimens of oral zidovudine during labor were evaluated in 10 HIV-infected pregnant women.4The oralregimen was well tolerated; plasma zidovudine concentrations were substantially lower with 300 mg every 3hours given orally during labor than previously reported with continuous IV therapy. A revised regimen witha 600-mg oral loading dose, followed by 400 mg every 3 hours, resulted in increased zidovudineconcentrations but inter-patient variance was significant. In both cohorts, PK parameters suggested erraticabsorption during labor. Therefore, in women with HIV RNA >400 copies/mL near delivery for whomzidovudine is recommended, IV would be preferred to oral administration in the United States; in situationswhere IV administration is not possible, oral administration can be considered.Continuation of Antenatal Antiretroviral Drugs during LaborWomen who are receiving an antepartum combination ARV drug regimen should continue that regimen onschedule as much as possible during the intrapartum period to provide maximal virologic effect and tominimize the chance of development of drug resistance. If oral zidovudine is part of the antepartum regimenand a woman’s HIV-1 RNA viral load is >400 copies/mL, the oral zidovudine component of her regimenshould be stopped while she receives IV zidovudine. When cesarean delivery is planned, oral medicationscan be continued preoperatively with sips of water. Medications requiring food ingestion for absorption canbe taken with liquid dietary supplements, contingent on consultation with the attending anesthesiologist inthe preoperative period. If the maternal ARV regimen must be interrupted temporarily (meaning for less than24 hours) during the peripartum period, all drugs should be stopped and reinstituted simultaneously tominimize the chance that resistance will develop.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Women Who Have Received Antepartum Antiretroviral Drugs But Have SuboptimalViral Suppression Near DeliveryWomen who have received combination ARV drug regimens may not achieve complete viral suppression bythe time of delivery because of factors such as poor adherence, viral resistance, or late entry into care.Regardless of the reason, all women who have HIV RNA levels >1,000 copies/mL near the time of deliveryshould be offered a scheduled cesarean delivery at 38 weeks, which may significantly reduce risk oftransmission (see Transmission and Mode of Delivery).Women with incomplete viral suppression at the time of delivery should receive IV zidovudine along withtheir other ARVs orally, as described above. In certain high-risk situations, additional medications forprophylaxis in infants may be warranted, such as in cases where maternal HIV RNA levels are high at or nearthe time of delivery, especially if delivery is not a scheduled cesarean delivery (see Infant AntiretroviralProphylaxis and Table 9).Women Who Have Not Received Antepartum Antiretroviral DrugsWomen Who Present in Labor Without Documentation of HIV StatusAll women without documentation of HIV status at the time of labor should be screened with rapid HIVtesting unless they decline (opt-out screening). Rapid HIV testing is also recommended for womenpresenting in labor who tested negative for HIV in early pregnancy but are at increased risk of HIV infectionand were not retested in the third trimester.5Factors that may increase risk of infection include diagnosis of asexually transmitted disease, illicit drug use or exchange of sex for money or drugs, multiple sexual partnersduring pregnancy, a sexual partner at risk of HIV infection, signs/symptoms of acute HIV infection, or livingin a region with an elevated incidence of HIV in women of childbearing age and not undergoing repeat HIVtesting in the third trimester.5Rapid HIV antibody testing should be available on a 24-hour basis at all facilities with a maternity serviceand/or neonatal intensive care unit. Statutes and regulations regarding rapid testing vary from state to state;see http://www.nccc.ucsf.edu/consultation_library/state_hiv_testing_laws for a review of state HIV testinglaws. Current information on rapid testing also should be available at all facilities with a maternity serviceand/or neonatal intensive care unit.Women with positive rapid HIV antibody tests should be presumed to be infected until standard HIV antibodyconfirmatory testing clarifies their infection status. IV zidovudine should be started immediately in all womenwith positive rapid HIV tests in labor to prevent perinatal transmission of HIV, as discussed below.In the postpartum period, along with confirmatory HIV antibody testing, these women should receiveappropriate assessments as soon as possible to determine their health status, including CD4 T-lymphocytecount and HIV-1 RNA viral load. Arrangements also should be made for establishing HIV care and providingongoing psychosocial support after discharge.Choice of Intrapartum/Postpartum Antiretroviral Regimen for Women without AntepartumAntiretroviral TherapyAll HIV-infected women who have not received antepartum ARV drugs should have IV zidovudine startedimmediately to prevent perinatal transmission of HIV. Although intrapartum/neonatal ARV medications willnot prevent perinatal transmission that occurs before labor, most transmission occurs near to or during laborand delivery. Pre-exposure prophylaxis for the fetus can be provided by giving mothers a drug that rapidlycrosses the placenta, producing fetal systemic ARV drug levels during intensive exposure to HIV in maternalgenital secretions and in blood during birth. In general, zidovudine and other nucleoside reverse transcriptaseinhibitor drugs and non-nucleoside reverse transcriptase inhibitor drugs cross the placenta well, whereasRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-3Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.protease inhibitors do not (see Table 5). A large international trial (NICHD-HPTN 040/PACTG 1043) demonstrated that adding ARV agents to theneonatal portion of the intrapartum/neonatal zidovudine regimen can further reduce mother-to-childtransmission of HIV for mothers who have received no antepartum ARV drugs (see Infant AntiretroviralProphylaxis). In this study, women who had not received antepartum ARV drugs received IV zidovudine ifthey were identified in labor or no zidovudine when diagnosed immediately postpartum, and their infantsreceived either 6 weeks of zidovudine alone or zidovudine in combination with other agents; the combinationinfant regimens resulted in a 50% reduction in transmission compared with zidovudine alone. Therefore, noadditional intrapartum drugs, including intrapartum maternal single-dose nevirapine, are indicated for awoman in this situation.6References:1. Warszawski J, Tubiana R, Le Chenadec J, et al. Mother-to-child HIV transmission despite antiretroviral therapy in theANRS French Perinatal Cohort. AIDS. Jan 11 2008;22(2):289-299. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18097232.2. Rodman JH, Flynn PM, Robbins B, et al. Systemic pharmacokinetics and cellular pharmacology of zidovudine inhuman immunodeficiency virus type 1-infected women and newborn infants. J Infect Dis. Dec 1999;180(6):1844-1850.Available at http://www.ncbi.nlm.nih.gov/pubmed/10558940.3. Bhadrakom C, Simonds RJ, Mei JV, et al. Oral zidovudine during labor to prevent perinatal HIV transmission,Bangkok: tolerance and zidovudine concentration in cord blood. Bangkok Collaborative Perinatal HIV TransmissionStudy Group. AIDS. Mar 31 2000;14(5):509-516. Available at http://www.ncbi.nlm.nih.gov/pubmed/10780713.4. Mirochnick M, Rodman JH, Robbins BL, et al. Pharmacokinetics of oral zidovudine administered during labour: apreliminary study. HIV Med. Oct 2007;8(7):451-456. Available at http://www.ncbi.nlm.nih.gov/pubmed/17760737.5. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, andpregnant women in health-care settings. MMWR Recomm Rep. Sep 22 2006;55(RR-14):1-17; quiz CE11-14. Availableat http://www.ncbi.nlm.nih.gov/pubmed/16988643.6. Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIVinfection. N Engl J Med. Jun 21 2012;366(25):2368-2379. Available at http://www.ncbi.nlm.nih.gov/pubmed/22716975.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-4Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-5Transmission and Mode of Delivery (Last updated July 31, 2012; last reviewed July 31, 2012)Basis for Current RecommendationsScheduled cesarean delivery, defined as cesarean delivery performed before the onset of labor and beforerupture of membranes, is recommended for prevention of perinatal transmission of HIV in women with HIVRNA levels >1,000 copies/mL near the time of delivery and for women with unknown HIV RNA levels.1This recommendation is based on findings from a multicenter, randomized clinical trial2and from a largeindividual patient data meta-analysis.3These two studies were conducted at a time when the majority of HIV-infected women received no antiretroviral (ARV) medications or zidovudine as a single drug and before theavailability of viral load information. Study results have since been extrapolated to make currentrecommendations about the mode of delivery in an era when combination ARV regimens during pregnancyare recommended and viral load information is readily available.In the randomized clinical trial, 1.8% of infants born to women randomized to undergo cesarean delivery wereHIV infected compared with 10.5% of infants born to women randomized to vaginal delivery (P When adjusted for ARV use in pregnancy (zidovudine alone), scheduled cesarean delivery lowered risk ofHIV transmission by 80%, although the results were no longer statistically significant (odds ratio [OR] 0.2;95% confidence interval [CI], 0–1.7). The protective effect still remained for scheduled delivery (adjusted OR[AOR] 0.3; 95% CI, 0.1–0.8) but not for emergency cesarean delivery (AOR 1.0; 95% CI, 0.3–3.7) when thedata were analyzed by actual mode of delivery rather than by the group to which women were allocated.2Results from a large meta-analysis of individual patient data from 15 prospective cohort studies alsodemonstrated the benefit of scheduled cesarean delivery with a 50% reduction in risk.3Primarily based onthese data, the American College of Obstetricians and Gynecologists (ACOG) has recommendedconsideration of scheduled cesarean delivery for HIV-infected pregnant women since 1999.4Panel’s Recommendations• Scheduled cesarean delivery at 38 weeks’ gestation to minimize perinatal transmission of HIV is recommended forwomen with HIV RNA levels >1,000 copies/mL or unknown HIV levels near the time of delivery, irrespective ofadministration of antepartum antiretroviral (ARV) drugs (AII). Scheduled cesarean delivery is not recommended forprevention of perinatal transmission in pregnant women receiving combination ARV drugs with plasma HIV RNA levelsdelivery used solely for prevention of perinatal transmission in women with HIV RNA levels the low rate of transmission in these patients, it is unclear whether scheduled cesarean delivery would confer additionalbenefit in reducing transmission. In women with HIV RNA levels standard obstetrical indications should be scheduled for 39 weeks’ gestation.• It is not clear whether cesarean delivery after rupture of membranes or onset of labor provides benefit in preventingperinatal transmission. Management of women originally scheduled for cesarean delivery who present with rupturedmembranes or in labor must be individualized at the time of presentation based on duration of rupture and/or labor,plasma HIV RNA level, and current ARV regimen (BII).• Women should be informed of the risks associated with cesarean delivery. If the indication for cesarean delivery isprevention of perinatal transmission of HIV, the risks to a woman should be balanced with potential benefits expected forthe neonate (AII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.HIV RNA Level of 1,000 copies/mL as a Threshold for Recommendation of ScheduledCesarean DeliveryThe original ACOG committee opinion was updated in 2000 to include further refinements based on HIVRNA levels.1Currently, ACOG1recommends that women with HIV RNA >1,000 copies/mL be counseledregarding the potential benefits of scheduled cesarean delivery. Initially, the threshold of 1,000 copies/mLwas based largely on data from the Women and Infants Transmission Study, a large prospective cohort studythat reported no HIV transmission among 57 women with HIV RNA levels less than 1,000 copies/mL.5Studies reported since then have demonstrated that HIV transmission can occur in infants born to womenwith low viral loads.In an analysis of 957 women with plasma viral loads urgent) reduced risk of HIV transmission when adjusting for potential confounders including receipt ofmaternal ARV medications; however, zidovudine alone was the regimen primarily used as prophylaxis (AOR0.30; P = 0.022).6Among infants born to 834 women with HIV RNA medications, 8 (1%) were HIV infected. In a more recent report from a comprehensive national surveillancesystem in the United Kingdom and Ireland, 3 (0.1%) of 2,309 and 12 (1.2%) of 1,023 infants born to womenwith HIV RNA levels 7The recent studies demonstrate that transmission can occur even at very low HIV RNA levels. However,given the low rate of transmission in this group, it is unclear whether scheduled cesarean delivery confersany additional benefit in reducing transmission. Although decisions about mode of delivery for women withHIV RNA levels and the mother, women should be informed that there is no evidence of benefit for scheduled cesareandelivery performed solely for prevention of perinatal transmission in women with HIV RNA copies/mL and that it is not routinely recommended in this group. Scheduled Cesarean Delivery in the Highly Active Antiretroviral Therapy EraIn surveillance data from the United Kingdom and Ireland, pregnant women receiving combination ARVregimens (meaning at least 3 drugs) had transmission rates of about 1%, unadjusted for mode of delivery.7Given the low transmission rates achievable with use of maternal combination ARV drug regimens, thebenefit of scheduled cesarean delivery is difficult to evaluate. Both the randomized clinical trial2and meta-analysis3documenting the benefits of cesarean delivery included mostly women who were receiving eitherno ARVs or zidovudine alone. However, other data partially address this issue.In a report from the European Collaborative Study that included data from 4,525 women, the overalltransmission rate in the subset of women on a combination ARV regimen was 1.2% (11 of 918).8In thesubset of 560 women with undetectable HIV RNA levels (≤50 to ≤200 copies/mL, depending on site),scheduled cesarean delivery was associated with a significant reduction in perinatal transmission inunivariate analysis (OR 0.07; 95% CI, 0.02–0.31; P = .0004). However, after adjustment for ARV drug use(none vs. any), the effect was no longer significant (AOR 0.52; 95% CI, 0.14–2.03; P = .359). Similarly, datafrom a European surveillance study did not demonstrate a statistically significant difference in transmissionrates between scheduled cesarean delivery and planned vaginal delivery (AOR 1.24; 95% CI, 0.34–4.5) inwomen on combination ARV regimens.7The transmission rate in all women who received at least 14 days ofARV medications was 0.8% (40 of 4,864), regardless of mode of delivery. Therefore, no evidence to datesuggests any benefit from scheduled cesarean delivery in women who have been receiving combination ARVmedications for several weeks and who have achieved virologic supression.When the delivery method selected is scheduled cesarean delivery and the maternal viral load is ≥400copies/mL, administer a 1-hour loading dose and continuous intravenous (IV) zidovudine for 2 hours (3hours total) before scheduled cesarean delivery. In a study of the pharmacokinetics of IV zidovudine in 28Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-6Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.pregnant women, the ratio of cord blood to maternal zidovudine levels increased significantly in women whoreceived IV zidovudine for 3 to 6 hours compared with 9This suggests that an interval of at least 3 hours may provide adequate time to reach equilibrium across theplacenta, although the relationship between specific cord blood zidovudine levels or cord blood-to-maternal-zidovudine levels and efficacy in preventing mother-to-child transmission of HIV is unknown.Because unscheduled cesarean delivery is performed for both maternal and fetal indications, when anunscheduled cesarean delivery is indicated in a woman who has a viral load ≥400 copies/ml, considerationcan be given to shortening the interval between initiation of IV zidovudine administration and delivery. Forexample, some experts recommend administering the 1-hour loading dose of IV zidovudine and not waitingto complete additional administration before proceeding with delivery.Women Presenting Late in Pregnancy HIV-infected women who present late in pregnancy and are not receiving ARV drugs may not have HIVRNA results available before delivery. Without current therapy, HIV RNA levels are unlikely to be copies/mL at baseline. Even if combination ARV medications were begun immediately, reduction in plasmaHIV RNA to undetectable levels usually takes several weeks, depending on the kinetics of viral decay for aparticular drug regimen.10In this instance, scheduled cesarean delivery is likely to provide additional benefitin reducing the risk of perinatal transmission of HIV for women, unless viral suppression can be documentedbefore 38 weeks’ gestation. Timing of Scheduled Cesarean Delivery In general, ACOG recommends that scheduled cesarean delivery not be performed before 39 weeks’gestation because of the risk of iatrogenic prematurity.11, 12However, in cases of cesarean delivery performedto prevent transmission of HIV, ACOG recommends scheduling cesarean delivery at 38 weeks’ gestation inorder to decrease the likelihood of onset of labor or rupture of membranes before delivery.1In all womenundergoing repeat cesarean delivery, the risk of any neonatal adverse event—including neonatal death,respiratory complications, hypoglycemia, newborn sepsis, or admission to the neonatal intensive care unit—is 15.3% at 37 weeks, 11.0% at 38 weeks, and 8.0% at 39 weeks.12Gestational age should be determined bybest obstetrical dating criteria, including last menstrual period and early ultrasound for dating purposes.Amniocentesis to document lung maturity should be avoided when possible in HIV-infected women and israrely indicated before scheduled cesarean section for prevention of HIV transmission.Among 1,194 infants born to HIV-infected mothers, 9 (1.6%) infants born vaginally had respiratory distresssyndrome (RDS) compared with 18 (4.4%) infants born by scheduled cesearean delivery (P was no statistically significant association between mode of delivery and infant RDS in an adjusted modelthat included infant gestational age and birth weight.13Although newborn complications may be increased inplanned births thought to outweigh the risks if the procedure is performed for prevention of HIV transmission. Whencesarean delivery is performed in HIV-infected women for an indication other than decreasing HIVtransmission, cesarean delivery should be scheduled at 39 weeks, based on ACOG guidelines.Risk of Maternal ComplicationsAdministration of perioperative antimicrobial prophylaxis is recommended for all women to decreasematernal infectious morbidity associated with cesarean delivery. Most studies have demonstrated that HIV-infected women have increased rates of postoperative complications, mostly infectious, compared withHIV-uninfected women and that risk of complications is related to degree of immunosuppression.14-19Furthermore, a Cochrane review of six studies of HIV-infected women concluded that urgent cesareandelivery was associated with the highest risk of postpartum morbidity, scheduled cesarean delivery wasRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-7Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-8intermediate in risk, and vaginal delivery had the lowest risk of morbidity.20Complication rates in moststudies 2, 21-25were within the range reported in populations of HIV-uninfected women with similar riskfactors and not of sufficient frequency or severity to outweigh the potential benefit of reduced perinatal HIVtransmission. Therefore, HIV-infected women should be counseled regarding the risks associated withundergoing cesarean delivery and the potential benefits in decreasing perinatal transmission of HIV if HIVRNA levels at term are >1,000 copies/mL.Management of Women Who Present in Early Labor or With Ruptured MembranesFew data are available to address the question of whether performing cesarean delivery after the onset oflabor or membrane rupture decreases risk of perinatal transmission of HIV. Most studies have shown asimilar risk of transmission for cesarean delivery performed for obstetric indications after labor andmembrane rupture and for vaginal delivery. In one study, the HIV transmission rate was similar in womenundergoing emergency cesarean delivery and those delivering vaginally (1.6% vs. 1.9%, respectively).7Ameta-analysis of HIV-infected women, most of whom were on zidovudine as a single drug or receiving noARV medications, demonstrated a 2% increased transmission risk for every additional hour of rupturedmembranes.26However, it is not clear how soon after the onset of labor or the rupture of membranes thebenefit of cesarean delivery is lost.27Therefore, the decision about whether to deliver by expeditiouscesarean section for prevention of perinatal transmission in women originally scheduled for cesareandelivery who then present with ruptured membranes or in labor must be individualized, taking into accountduration of rupture or labor upon presentation, plasma RNA level, and current ARV drug regimen status. TheARV drug regimen should be continued and IV zidovudine initiated, if previously planned. When membrane rupture occurs before 37 weeks’ gestation, decisions about timing of delivery should bebased on best obstetrical practices, taking into account risks to the infant of prematurity and of HIVtransmission. Steroids should be given, if appropriate, to accelerate fetal lung maturity because no data existto suggest that these recommendations need to be altered for HIV-infected women. When the decision ismade to deliver, route of delivery should be according to obstetrical indications.Table 8 summarizes recommendations regarding mode of delivery for different clinical scenarios.Table 8. Clinical Scenarios and Recommendations Regarding Mode of Delivery to Reduce PerinatalTransmission of HIV (page 1 of 2)Clinical Scenario RecommendationsHIV-infected women presenting late inpregnancy (after about 36 weeks’gestation), known to be HIV infected butnot receiving ARV medications, and whohave HIV RNA level and CD4 T-lymphocyte (CD4-cell) counts pendingbut unlikely to be available beforedelivery.• Start antiretroviral (ARV) medications as per Table 6.• Provide counseling on the likelihood that scheduled cesarean delivery will reducethe risk of mother-to-child transmission, if viral suppression cannot bedocumented before 38 weeks. Include information on increased maternal risksof cesarean delivery, including risks related to anesthesia and surgery andincreased rates of postoperative infection. • When the delivery method selected is scheduled cesarean, perform theprocedure at 38 weeks’ gestation, as determined by best obstetrical dating.• Administer a 1-hour intraveneous (IV) loading dose followed by continuous IVzidovudine for 2 hours (3 hours total)before scheduled cesarean.• Continue other ARV medications on schedule, as much as possible, before andafter surgery.• All standard cesarean delivery management should be recommended, includinguse of prophylactic antibiotics.Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-9Clinical Scenario RecommendationsHIV-infected women who began prenatalcare early in the third trimester, arereceiving combination ARV drugregimens, and have an initial virologicresponse but have HIV RNA levels thatremain substantially >1,000 copies/mLat 36 weeks’ gestation.• Continue the current combination ARV regimen if response in HIV RNA level isappropriate.• Consult an expert in HIV infection to determine the appropriateness of additionalARV agents to rapidly further decrease viral load.• Recommend scheduled cesarean delivery if viral load suppression is notachieved by 38 weeks because of the potential additional benefit in preventingintrapartum HIV transmission. Inform woman about the increased maternal risksassociated with cesarean delivery, including risks related to anesthesia andsurgery and increased rates of postoperative infection.• When the delivery method selected is scheduled cesarean, perform theprocedure at 38 weeks’ gestation by best obstetrical dating.• When the delivery method selected is scheduled cesarean delivery, administer a1-hour loading dose and continuous IV zidovudine for 2 hours (3 hours total)before scheduled cesarean.• Continue other ARV medications on schedule, as much as possible, before andafter surgery.• All standard cesarean delivery management should be recommended, includingthe use of prophylactic antibiotics.HIV-infected women on combinationARV drug regimens with undetectableHIV RNA levels at 36 weeks’ gestation.• Provide counseling on risk of perinatal transmission of HIV with a persistentlyundetectable HIV RNA level, which is 1% or less, even with vaginal delivery. Noevidence currently exists to show that this risk can be lowered further byperforming scheduled cesarean delivery.• Risk of complications is increased with cesarean delivery compared with vaginaldelivery, and the risks must be balanced against the uncertain benefits ofcesarean delivery in women with undetectable viral load.HIV-infected women with HIV RNA level>1,000 copies/mL who have electedscheduled cesarean delivery but presentafter rupture of membranes or onset oflabor at >37 weeks’ gestation.• Start IV zidovudine immediately.• Individualize the decision regarding mode of delivery based on clinical factors atpresentation including duration of rupture and/or labor, plasma RNA level, andcurrent ARV regimen. Management of vaginal delivery, if chosen, should beindividualized. Some clinicians may consider administration of oxytocin, ifclinically appropriate, in order to expedite delivery. Scalp electrodes and otherinvasive monitoring and operative delivery should be avoided, if possible, unlessthere are clear obstetric indications.• When cesarean delivery is chosen, administration of the loading dose of IVzidovudine ideally should be completed before the procedure. Table 8. Clinical Scenarios and Recommendations Regarding Mode of Delivery to Reduce PerinatalTransmission of HIV (page 2 of 2)References1. Committee on Obstetric Practice. ACOG committee opinion scheduled Cesarean delivery and the prevention of verticaltransmission of HIV infection. Number 234, May 2000 (replaces number 219, August 1999). Int J Gynaecol Obstet. Jun2001;73(3):279-281. Available at http://www.ncbi.nlm.nih.gov/pubmed/11424912.2. European Mode of Delivery Collaboration. Elective caesarean-section versus vaginal delivery in prevention of verticalHIV-1 transmission: a randomised clinical trial. Lancet. Mar 27 1999;353(9158):1035-1039. Available atDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.http://www.ncbi.nlm.nih.gov/pubmed/10199349.3. International Perinatal HIV Group. The mode of delivery and the risk of vertical transmission of humanimmunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies. The International Perinatal HIVGroup. N Engl J Med. Apr 1 1999;340(13):977-987. Available at http://www.ncbi.nlm.nih.gov/pubmed/10099139.4. American College of Obstetricians and Gynecologists. ACOG committee opinion. Scheduled cesarean delivery and theprevention of vertical transmission of HIV infection. Number 219, August 1999. Committee on Obstetric Practice.American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. Sep 1999;66(3):305-306. Available athttp://www.ncbi.nlm.nih.gov/pubmed/10580685.5. Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the riskof perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med. Aug 5 1999;341(6):394-402.Available at http://www.ncbi.nlm.nih.gov/pubmed/10432324.6. Ioannidis JP, Abrams EJ, Ammann A, et al. Perinatal transmission of human immunodeficiency virus type 1 by pregnantwomen with RNA virus loads http://www.ncbi.nlm.nih.gov/pubmed/11170978.7. Townsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-childtransmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS.May 11 2008;22(8):973-981. Available at http://www.ncbi.nlm.nih.gov/pubmed/18453857.8. European Collaborative Study. Mother-to-child transmission of HIV infection in the era of highly active antiretroviraltherapy. Clin Infect Dis. Feb 1 2005;40(3):458-465. Available at http://www.ncbi.nlm.nih.gov/pubmed/15668871.9. Rodman JH, Flynn PM, Robbins B, et al. Systemic pharmacokinetics and cellular pharmacology of zidovudine inhuman immunodeficiency virus type 1-infected women and newborn infants. J Infect Dis. Dec 1999;180(6):1844-1850.Available at http://www.ncbi.nlm.nih.gov/pubmed/10558940.10. European Collaborative Study, Patel D, Cortina-Borja M, Thorne C, Newell ML. Time to undetectable viral load afterhighly active antiretroviral therapy initiation among HIV-infected pregnant women. Clin Infect Dis. Jun 152007;44(12):1647-1656. Available at http://www.ncbi.nlm.nih.gov/pubmed/17516411.11. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 97: Fetal lung maturity. ObstetGynecol. Sep 2008;112(3):717-726. Available at http://www.ncbi.nlm.nih.gov/pubmed/18757686.12. Tita AT, Landon MB, Spong CY, et al. Timing of elective repeat cesarean delivery at term and neonatal outcomes. NEngl J Med. Jan 8 2009;360(2):111-120. Available at http://www.ncbi.nlm.nih.gov/pubmed/19129525.13. Livingston EG, Huo Y, Patel K, et al. Mode of delivery and infant respiratory morbidity among infants born to HIV-1-infected women. Obstet Gynecol. Aug 2010;116(2 Pt 1):335-343. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20664394.14. Grubert TA, Reindell D, Kastner R, Lutz-Friedrich R, Belohradsky BH, Dathe O. Complications after caesarean sectionin HIV-1-infected women not taking antiretroviral treatment. Lancet. Nov 6 1999;354(9190):1612-1613. Available athttp://www.ncbi.nlm.nih.gov/pubmed/10560681.15. Maiques-Montesinos V, Cervera-Sanchez J, Bellver-Pradas J, Abad-Carrascosa A, Serra-Serra V. Post-cesarean sectionmorbidity in HIV-positive women. Acta Obstet Gynecol Scand. Oct 1999;78(9):789-792. Available athttp://www.ncbi.nlm.nih.gov/pubmed/10535342.16. Rodriguez EJ, Spann C, Jamieson D, Lindsay M. Postoperative morbidity associated with cesarean delivery amonghuman immunodeficiency virus-seropositive women. Am J Obstet Gynecol. May 2001;184(6):1108-1111. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11349171.17. Semprini AE, Castagna C, Ravizza M, et al. The incidence of complications after caesarean section in 156 HIV-positivewomen. AIDS. Aug 1995;9(8):913-917. Available at http://www.ncbi.nlm.nih.gov/pubmed/7576327.18. Urbani G, de Vries MM, Cronje HS, Niemand I, Bam RH, Beyer E. Complications associated with cesarean section inHIV-infected patients. Int J Gynaecol Obstet. Jul 2001;74(1):9-15. Available atRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-10Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.http://www.ncbi.nlm.nih.gov/pubmed/11430935.19. Vimercati A, Greco P, Loverro G, Lopalco PL, Pansini V, Selvaggi L. Maternal complications after caesarean section inHIV infected women. Eur J Obstet Gynecol Reprod Biol. May 2000;90(1):73-76. Available athttp://www.ncbi.nlm.nih.gov/pubmed/10767514.20. Read JS, Newell MK. Efficacy and safety of cesarean delivery for prevention of mother-to-child transmission of HIV-1.Cochrane Database Syst Rev. 2005(4):CD005479. Available at http://www.ncbi.nlm.nih.gov/pubmed/16235405.21. Faucher P, Batallan A, Bastian H, et al. [Management of pregnant women infected with HIV at Bichat Hospital between1990 and 1998: analysis of 202 pregnancies]. Gynecol Obstet Fertil. Mar 2001;29(3):211-225. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11300046.22. Fiore S, Newell ML, Thorne C, European HIV in Obstetrics Group. Higher rates of post-partum complications in HIV-infected than in uninfected women irrespective of mode of delivery. AIDS. Apr 9 2004;18(6):933-938. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15060441.23. Marcollet A, Goffinet F, Firtion G, et al. Differences in postpartum morbidity in women who are infected with thehuman immunodeficiency virus after elective cesarean delivery, emergency cesarean delivery, or vaginal delivery. Am JObstet Gynecol. Apr 2002;186(4):784-789. Available at http://www.ncbi.nlm.nih.gov/pubmed/11967508.24. Read JS, Tuomala R, Kpamegan E, et al. Mode of delivery and postpartum morbidity among HIV-infected women: thewomen and infants transmission study. J Acquir Immune Defic Syndr. Mar 1 2001;26(3):236-245. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11242196.25. Watts DH, Lambert JS, Stiehm ER, et al. Complications according to mode of delivery among humanimmunodeficiency virus-infected women with CD4 lymphocyte counts of ≤500/microL. Am J Obstet Gynecol. Jul2000;183(1):100-107. Available at http://www.ncbi.nlm.nih.gov/pubmed/10920316.26. International Perinatal HIV Group. Duration of ruptured membranes and vertical transmission of HIV-1: a meta-analysisfrom 15 prospective cohort studies. AIDS. Feb 16 2001;15(3):357-368. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11273216.27. Jamieson DJ, Read JS, Kourtis AP, Durant TM, Lampe MA, Dominguez KL. Cesarean delivery for HIV-infectedwomen: recommendations and controversies. Am J Obstet Gynecol. Sep 2007;197(3 Suppl):S96-100. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17825656.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-11Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-12Other Intrapartum Management Considerations (Last updated July 31, 2012; lastreviewed July 31, 2012)If spontaneous rupture of membranes occurs before or early during the course of labor, interventions todecrease the interval to delivery, such as administration of oxytocin, can be considered in HIV-infectedwomen with viral suppression and no indications for cesarean delivery.Artificial rupture of membranes should be avoided and used only for a clear obstetric indication in womenwith intact membranes and detectable viral loads who present in labor and will be allowed to proceed tovaginal delivery. Data are limited on artificial rupture of membranes in women with undetectable viral loadsand planned vaginal delivery. In general, the procedure should be performed only for clear obstetricalindications because of the potential, albeit small, of an increased risk of HIV transmission.Obstetric procedures that increase the risk of fetal exposure to maternal blood, such as invasive fetalmonitoring, have been implicated in increasing vertical transmission rates by some, but not all, investigators,primarily in studies performed in the pre-antiretroviral therapy (ART) era.1-4Data are limited on routine useof fetal scalp electrodes in labor in women receiving suppressive antiretroviral (ARV) regimens who haveundetectable viral loads; routine use of fetal scalp electrodes for fetal monitoring should be avoided in thesetting of maternal HIV infection unless there are clear obstetric indications.Similarly, data are limited to those obtained in the pre-ART era regarding the potential risk of perinataltransmission of HIV associated with operative vaginal delivery with forceps or the vacuum extractor and/or useof episiotomy.2, 4These procedures should be performed only if there are clear obstetric indications. Delayedcord clamping has been associated with improved iron status in both term and preterm infants and benefits suchas decreased risk of intraventricular hemorrhage in preterm births to HIV-uninfected mothers.5-8Even thoughHIV-specific data on the practice are lacking, there is no reason to modify it in HIV-infected mothers.Panel’s Recommendations• The following should generally be avoided unless there are clear obstetric indications because of a potential increased riskof transmission:ºArtificial rupture of membranes (BIII)ºRoutine use of fetal scalp electrodes for fetal monitoring (BIII)ºOperative delivery with forceps or a vacuum extractor and/or episiotomy (BIII)• The antiretroviral drug regimen a woman is receiving should be taken into consideration when treating excessivepostpartum bleeding resulting from uterine atony:• In women who are receiving a cytochrome P (CYP) 3A4 enzyme inhibitor such as a protease inhibitor, methergineshould be used only if no alternative treatments for postpartum hemorrhage are available and the need forpharmacologic treatment outweighs the risks. If methergine is used, it should be administered in the lowest effectivedose for the shortest possible duration (BIII).• In women who are receiving a CYP3A4 enzyme inducer such as nevirapine, efavirenz, or etravirine, additionaluterotonic agents may be needed because of the potential for decreased methergine levels and inadequate treatmenteffect.Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Postpartum Hemorrhage, Antiretroviral Drugs, and Methergine UseOral or parenteral methergine or other ergot alkaloids are often used as first-line treatment for postpartumhemorrhage resulting from uterine atony. However, methergine should not be coadministered with drugs thatare potent cytochrome P (CYP) 3A4 enzyme inhibitors, including protease inhibitors (PIs). Concomitant useof ergotamines and PIs has been associated with exaggerated vasoconstrictive responses. When uterine atonyresults in excessive postpartum bleeding in women receiving PIs, methergine should be used only ifalternative treatments such as prostaglandin F 2 alpha, misoprostol, or oxytocin are unavailable. If noalternative medications are available and the need for pharmacologic treatment outweighs the risks,methergine should be used in as low a dose and for as short a period as possible. In contrast, additionalutertonic agents may be needed when other ARV drugs that are CYP3A4 inducers, such as nevirapine,efavirenz, and etravirine, are used because of the potential for decreased methergine levels and inadequatetreatment effect.References1. Boyer PJ, Dillon M, Navaie M, et al. Factors predictive of maternal-fetal transmission of HIV-1. Preliminary analysis ofzidovudine given during pregnancy and/or delivery. JAMA. Jun 22-29 1994;271(24):1925-1930. Available athttp://www.ncbi.nlm.nih.gov/pubmed/7911164.2. Mandelbrot L, Mayaux MJ, Bongain A, et al. Obstetric factors and mother-to-child transmission of humanimmunodeficiency virus type 1: the French perinatal cohorts. SEROGEST French Pediatric HIV Infection Study Group.Am J Obstet Gynecol. Sep 1996;175(3 Pt 1):661-667. Available at http://www.ncbi.nlm.nih.gov/pubmed/8828431.3. Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of human immunodeficiency virustype 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med. Aug 51999;341(6):385-393. Available at http://www.ncbi.nlm.nih.gov/pubmed/10432323.4. Shapiro DE, Sperling RS, Mandelbrot L, Britto P, Cunningham BE. Risk factors for perinatal human immunodeficiencyvirus transmission in patients receiving zidovudine prophylaxis. Pediatric AIDS Clinical Trials Group protocol 076Study Group. Obstet Gynecol. Dec 1999;94(6):897-908. Available at http://www.ncbi.nlm.nih.gov/pubmed/10576173.5. Oh W, Fanaroff AA, Carlo WA, et al. Effects of delayed cord clamping in very-low-birth-weight infants. J Perinatol.Apr 2011;31(Suppl 1):S68-71. Available at http://www.ncbi.nlm.nih.gov/pubmed/21448208.6. Rabe H, Reynolds G, Diaz-Rossello J. A systematic review and meta-analysis of a brief delay in clamping the umbilicalcord of preterm infants. Neonatology. 2008;93(2):138-144. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17890882.7. Mercer JS, Vohr BR, McGrath MM, Padbury JF, Wallach M, Oh W. Delayed cord clamping in very preterm infantsreduces the incidence of intraventricular hemorrhage and late-onset sepsis: a randomized, controlled trial. Pediatrics.Apr 2006;117(4):1235-1242. Available at http://www.ncbi.nlm.nih.gov/pubmed/16585320.8. Andersson O, Hellstrom-Westas L, Andersson D, Domellof M. Effect of delayed versus early umbilical cord clampingon neonatal outcomes and iron status at 4 months: a randomised controlled trial. BMJ. 2011;343:d7157. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22089242.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States G-13Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-1Postpartum CarePostpartum Follow-Up of HIV-Infected Women (Last updated July 31, 2012; lastreviewed July 31, 2012)The postpartum period provides an opportunity to review and optimize women’s health care. Comprehensivecare and support services are particularly important for women with HIV infection and their families, whooften face multiple medical and social challenges. Components of comprehensive care include the followingmedical and supportive care services as needed:• primary, gynecologic/obstetric, and HIV specialty care for an HIV-infected woman;• pediatric care for her infant;• family planning services;• mental health services;• substance abuse treatment;• support services; and• coordination of care through case management for a woman, her child(ren), and other family members.Support services should be tailored to individual women’s needs and can include case management; childcare; respite care; assistance with basic life needs, such as housing, food, and transportation; peer counseling;and legal and advocacy services. Ideally, this care should begin before pregnancy and continue throughoutpregnancy and the postpartum period.During the postpartum period, maternal medical services must be coordinated between obstetric careproviders and HIV specialists. It is especially critical to ensure continuity of the antepartum antiretroviral(ARV) drug regimen when such treatment is required for a woman’s health. The decision about whether tocontinue ARV drugs after delivery should be discussed with a woman and made before delivery.Panel’s Recommendations• Contraceptive counseling should be included in the prenatal period as well as immediately postpartum as a critical aspectof postpartum care (AIII).• Decisions about continuing antiretroviral (ARV) drugs after delivery should take into account current recommendationsfor initiation of antiretroviral therapy (ART), current and nadir CD4 T-lymphocyte counts and trajectory, HIV RNA levels,adherence issues, whether a woman has an HIV-uninfected sexual partner, and patient preference (AIII).• For women continuing ARV drugs postpartum, arrangements for new or continued supportive services should be madebefore hospital discharge because the immediate postpartum period poses unique challenges to adherence (AII).• Women with a positive rapid HIV antibody test during labor require immediate linkage to HIV care and comprehensivefollow-up, including confirmation of HIV infection. If infection is confirmed, a full health assessment is warranted,including evaluation for associated medical conditions, counseling related to newly diagnosed HIV infection, andassessment of need for ART and opportunistic infection prophylaxis (AII).• Breastfeeding is not recommended for HIV-infected women in the United States, including those receiving ART (AII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.The postpartum period also is a critical time for addressing the issue of safer sex practices, secondarytransmission prevention, and contraception. It is important that comprehensive family planning andpreconception care be integrated into routine health visits. Women who receive family planning counselingduring prenatal care are more likely to use effective contraception postpartum.1Lack of breastfeeding isassociated with earlier return of fertility; ovulation returns as early as 6 weeks postpartum, and even earlier insome women, putting them at risk of pregnancy shortly after delivery.2Interpregnancy intervals of less than18 months have been associated with increased risk of poor perinatal and maternal outcomes in HIV-uninfected women.3Because of the stresses and demands of a new baby, women may be more receptive touse of effective contraception, yet simultaneously at higher risk of nonadherence to contraceptive use and,thus, unintended pregnancy.4This is an important concern in women who are on an efavirenz-containingregimen because of the potential risk of teratogencity in the first 5 to 6 weeks of pregnancy (the neural tubecloses at 36–39 days after the last menstrual period). A “dual-protection” strategy, such as use of condomsplus a second highly effective contraceptive, is ideal for HIV-infected women because it providessimultaneous protection against unintended pregnancy, transmission of HIV, and acquisition or transmissionof sexually transmitted disease.5Longer term reversible contraceptive methods, such as injectables, implants,and intrauterine devices (IUDs) should be included as options.Drug interactions have been documented between oral contraceptives and many ARV drugs (see Table 4inPreconception Counseling and Care for HIV-Infected Women of Childbearing Age); however, data primarilycome from pharmacokinetic (PK) studies and the clinical implications have not been well studied. Themagnitude of changes in contraceptive drug levels that may reduce contraceptive efficacy or increasecontraceptive-associated adverse effects is unknown. Hormonal contraceptives can be used withantiretroviral therapy (ART) in women who have no other contraindications. Additional or alternativemethods of contraception can be recommended where drug interactions are known. Estrogen-containinghormonal contraceptives significantly lower levels of amprenavir/fosamprenavir and, therefore,coadministration is not recommended. Whether low-dose ritonavir boosting raises amprenavir levelssufficiently to allow coadministration is unknown. Depot medroxyprogesterone acetate (Depo-Provera,DMPA) PKs are not significantly affected by nevirapine, efavirenz, or nelfinavir and levels of these drugswere not significantly altered by DMPA.6Adverse effects of DMPA are no different in HIV-infected womenon ARV drugs than in HIV-uninfected women.7In one study, DMPA use was associated with an increase inacquisition of HIV by uninfected women and transmission of HIV from infected women to male partners, butother studies have not seen this association and further studies are needed.8Other non-oral contraceptives,such as levonorgestrel implants, the combined contraceptive patch, the combined hormonal contraceptivevaginal ring, and the levonorgestrel IUD, are largely unstudied in combination with ARV drugs, but somedata do exist on lopinavir/ritonavir interactions with the estrogen patch.9ARV drug interactions may be ofless concern with contraceptive methods that exert primarily local activity and have minimal systemicabsorption, but there is still potential for interaction if metabolic or elimination pathways are shared.6, 10TheWorld Health Organization has summarized the research on hormonal contraception, IUD use, and risk ofHIV infection.11Permanent sterilization is appropriate only for women who are certain they do not desirefuture childbearing.Decisions about whether to continue ARV drugs after delivery should be made in consultation with the HIVprovider. Factors to be taken into consideration should include current recommendations for initiation ofART, current and nadir CD4-lymphocyte counts and trajectory, HIV RNA levels, adherence issues, partnerHIV status, and patient preference. Women with nadir CD4 T-lymphocyte (CD4-cell) counts less than thecurrently recommended threshold for institution of ART12and/or symptomatic HIV infection should beencouraged to continue their ARV regimens postpartum without interruption. The risks versus benefits ofstopping combination ART drug regimens postpartum in women with high CD4-cell counts are beingevaluated in the ongoing PROMISE study (clinical trial number NCT00955968). Unplanned changes in ARVRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-2Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.regimens and discontinuations of ART in the postpartum period have led to viral load rebound.4Recent data from the HPTN 052 clinical trial showed that earlier initiation of ARV drugs led to a significantreduction in sexual transmission of HIV to uninfected partners in serodiscordant couples (see PreconceptionCounseling). HPTN 052 evaluated immediate versus delayed initiation of ART to HIV-infected individualswith CD4-cell counts between 350 and 550 cells/mm3. Based on the results from that trial, continuedadministration of ARV drugs may be recommended for prevention of sexual transmission of HIV inpostpartum women who have CD4-cell counts between 350 and 550 cells/mm3and have HIV-uninfectedsexual partners, and it can be considered for those with CD4-cell counts greater than 550 cells/mm3withHIV-uninfected sexual partners. It is important to counsel the woman that no single method (includingtreatment of the infected partner) is fully protective against HIV transmission and safer sexual practicesshould be continued.Concerns have been raised about adherence to ARV regimens during the postpartum period, because anumber of studies have found significant decreases in adherence postpartum.13-16Women should becounseled that postpartum physical and psychological changes and the stresses and demands of caring for anew baby may make adherence more difficult and that additional support may be needed during thisperiod.17-19Health care providers should be vigilant for signs of depression and illicit drug or alcohol use thatmay require assessment and treatment and interfere with adherence. Poor adherence has been shown to beassociated with virologic failure, development of resistance, and decreased long-term effectiveness of ART.20-22Simplification of an ARV regimen (for example, to once-daily medications) can be considered. It may bepreferable to temporarily interrupt ART in women who are unable to adhere to their regimens while theywork with a provider on strategies to improve adherence. Efforts to maintain adequate adherence during thepostpartum period may prolong the effectiveness of therapy (see the section on Adherencein the Guidelinesfor the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents).For women whose antepartum regimen included a non-nucleoside reverse transcriptase inhibitor (NNRTI)and who plan to stop ARV prophylaxis after delivery, consideration should be given to stopping the NNRTIand continuing the other ARV drugs for a period of time before stopping electively. The optimal intervalbetween stopping an NNRTI and the other ARV drugs is unknown; a minimum of 7 days is recommended.Because efavirenz-based therapy has potential to result in prolonged, detectable NNRTI concentrations formore than 3 weeks, some experts recommend that patients receiving efavirenz continue their other ARVdrugs or substitute a protease inhibitor (PI) for the NNRTI drug in combination with their other ARV drugsfor up to 30 days after stopping efavirenz (see Stopping Antiretroviral Therapy during PregnancyandPrevention of Antiretroviral Drug Resistance). Women whose antepartum regimen did not include an NNRTIand who plan to stop ARV prophylaxis after delivery should stop all ARV drugs at the same time. Doses ofsome PIs may be increased during pregnancy. For women continuing therapy, available data suggest thatstandard doses can be used again, beginning immediately after delivery.Immediate linking to care, comprehensive medical assessment, counseling, and follow-up are required forwomen who test positive on rapid HIV antibody assay during labor or at delivery. To minimize the delay indefinitive diagnosis, confirmatory HIV antibody testing should be performed as soon as possible after an initialpositive rapid test.23Women who test positive on rapid HIV antibody assay should not breastfeed unless aconfirmatory HIV test is negative. Women with a new HIV diagnosis postpartum should receive the samethorough evaluation as other newly identified infected patients, including consideration of ART and prophylaxisfor opportunistic infections, as indicated. Other children and partner(s) should be referred for HIV testing.References1. Jackson E. Controversies in postpartum contraception: when is it safe to start oral contraceptives after childbirth?Thromb Res. Feb 2011;127(Suppl 3):S35-39. Available at http://www.ncbi.nlm.nih.gov/pubmed/21262436.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-3Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.2. Jackson E, Glasier A. Return of ovulation and menses in postpartum nonlactating women: a systematic review. ObstetGynecol. Mar 2011;117(3):657-662. Available at http://www.ncbi.nlm.nih.gov/pubmed/21343770.3. Sholapurkar SL. Is there an ideal interpregnancy interval after a live birth, miscarriage or other adverse pregnancyoutcomes? J Obstet Gynaecol. Feb 2010;30(2):107-110. Available at http://www.ncbi.nlm.nih.gov/pubmed/20143964.4. Sha BE, Tierney C, Cohn SE, et al. Postpartum viral load rebound in HIV-1-infected women treated with highly activeantiretroviral therapy: AIDS Clinical Trials Group Protocol A5150. HIV Clin Trials. Jan-Feb 2011;12(1):9-23. Availableat http://www.ncbi.nlm.nih.gov/pubmed/21388937.5. Cates W, Jr., Steiner MJ. Dual protection against unintended pregnancy and sexually transmitted infections: what is thebest contraceptive approach? Sex Transm Dis. Mar 2002;29(3):168-174. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11875378.6. Cohn SE, Park JG, Watts DH, et al. Depo-medroxyprogesterone in women on antiretroviral therapy: effectivecontraception and lack of clinically significant interactions. Clin Pharmacol Ther. Feb 2007;81(2):222-227. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17192768.7. Watts DH, Park JG, Cohn SE, et al. Safety and tolerability of depot medroxyprogesterone acetate among HIV-infectedwomen on antiretroviral therapy: ACTG A5093. Contraception. Feb 2008;77(2):84-90. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18226670.8. Heffron R, Donnell D, Rees H, et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospectivecohort study. Lancet Infect Dis. Jan 2012;12(1):19-26. Available at http://www.ncbi.nlm.nih.gov/pubmed/21975269.9. Vogler MA, Patterson K, Kamemoto L, et al. Contraceptive efficacy of oral and transdermal hormones when co-administered with protease inhibitors in HIV-1-infected women: pharmacokinetic results of ACTG trial A5188. J AcquirImmune Defic Syndr. Dec 2010;55(4):473-482. Available at http://www.ncbi.nlm.nih.gov/pubmed/20842042.10. Womack J, Williams A. Hormonal contraception in HIV-positive women. AIDS Read. Jul 2008;18(7):372-377, 381.Available at http://www.ncbi.nlm.nih.gov/pubmed/18655314.11. World Health Organization. Review of Priorities in Research on Hormonal Contraception and IUDs and HIV Infection.2010; Geneva. Available at http://whqlibdoc.who.int/hq/2010/WHO_RHR_10.21_eng.pdf. Accessed on June 29, 2012.12. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed on June 29, 2012.13. Kreitchmann R, Harris DR, Kakehasi F, et al. Antiretroviral Adherence During Pregnancy and Postpartum in LatinAmerica. AIDS Patient Care STDS. Jun 4 2012. Available at http://www.ncbi.nlm.nih.gov/pubmed/22663185.14. Kaida A, Kanters S, Chaworth-Musters T, et al. Antiretroviral adherence during pregnancy and postpartum among HIV-positive women receiving highly active antiretroviral therapy (HAART) in British Columbia (BC), Canada(1997-2008). Paper presented at: 6th International AIDS Society Conference on HIV Pathogenesis, Treatment andPrevention; July 17-20, 2011; Rome, Italy. Abstract CDB397-CD-ROM.15. Mellins CA, Chu C, Malee K, et al. Adherence to antiretroviral treatment among pregnant and postpartum HIV-infectedwomen. AIDS Care. Sep 2008;20(8):958-968. Available at http://www.ncbi.nlm.nih.gov/pubmed/18608073.16. Nachega J, Uthman C, Mills E, Muessig K, et al. Adherence to antiretroviral therapy (ART) during and after pregnancyin low, middle and high income countries: a systematic review and meta-analysis. Paper presented at: 19th Conferenceon Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle, WA. Abstract 1006.17. Cohn SE, Umbleja T, Mrus J, Bardeguez AD, Andersen JW, Chesney MA. Prior illicit drug use and missed prenatalvitamins predict nonadherence to antiretroviral therapy in pregnancy: adherence analysis A5084. AIDS Patient CareSTDS. Jan 2008;22(1):29-40. Available at http://www.ncbi.nlm.nih.gov/pubmed/18442305.18. Ickovics JR, Wilson TE, Royce RA, et al. Prenatal and postpartum zidovudine adherence among pregnant women withHIV: results of a MEMS substudy from the Perinatal Guidelines Evaluation Project. J Acquir Immune Defic Syndr. Jul 12002;30(3):311-315. Available at http://www.ncbi.nlm.nih.gov/pubmed/12131568.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-4Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.19. Bardeguez AD, Lindsey JC, Shannon M, et al. Adherence to antiretrovirals among US women during and afterpregnancy. J Acquir Immune Defic Syndr. Aug 1 2008;48(4):408-417. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18614923.20. Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIVinfection. Ann Intern Med. Jul 4 2000;133(1):21-30. Available at http://www.ncbi.nlm.nih.gov/pubmed/10877736.21. Le Moing V, Chene G, Carrieri MP, et al. Clinical, biologic, and behavioral predictors of early immunologic andvirologic response in HIV-infected patients initiating protease inhibitors. J Acquir Immune Defic Syndr.Aug 12001;27(4):372-376. Available at http://www.ncbi.nlm.nih.gov/pubmed/11468425.22. Murri R, Ammassari A, Gallicano K, et al. Patient-reported nonadherence to HAART is related to protease inhibitorlevels. J Acquir Immune Defic Syndr. Jun 1 2000;24(2):123-128. Available athttp://www.ncbi.nlm.nih.gov/pubmed/10935687.23. Centers for Disease Control and Prevention (CDC). Rapid HIV-1 antibody testing during labor and delivery for womenof unknown HIV status: a practical guide and model protocol. 2004. Available athttp://www.cdc.gov/hiv/topics/testing/resources/guidelines/pdf/Labor&DeliveryRapidTesting.pdf. Accessed July 3,2012.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-5Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-6Infants Born to Mothers with Unknown HIV Infection Status (Last updated July 31, 2012;last reviewed July 31, 2012)Rapid HIV antibody testing of mothers and/or infants is recommended as soon as possible after birth whenmaternal HIV status is unknown and rapid HIV antibody testing was not performed during labor. If rapidtesting is positive, infant antiretroviral (ARV) prophylaxis should be initiated immediately, without waitingfor the results of a confirmatory test. Rapid HIV antibody testing should be available on a 24-hour basis at allfacilities with a maternity service and/or neonatal intensive care or newborn nursery. A positive test result inmothers or infants should be presumed to indicate maternal HIV infection until standard antibodyconfirmatory testing clarifies maternal status. A standard confirmatory test (such as Western blot) should beperformed on mothers (or their infants) as soon as possible after the initial positive rapid test.1A positiveHIV antibody test in an infant indicates maternal but not necessarily infant HIV infection; diagnosis of HIVinfection in infants younger than age 18 months requires virologic testing. If the confirmatory test on amother (or infant) is negative, ARV prophylaxis can be discontinued. If the confirmatory test is positive, anHIV DNA polymerase chain reaction (PCR) assay should be obtained urgently from the newborn. If the HIVDNA PCR is positive, ARV prophylaxis should be promptly discontinued and the infant should receivetreatment for HIV infection with standard combination antiretroviral therapy according to establishedGuidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Reference1. Centers for Disease Control and Prevention (CDC). Rapid HIV-1 antibody testing during labor and delivery for womenof unknown HIV status: a practical guide and model protocol. 2004;http://www.cdc.gov/hiv/topics/testing/resources/guidelines/pdf/Labor&DeliveryRapidTesting.pdf.Panel’s Recommendations• For infants born to mothers with unknown HIV status, rapid HIV antibody testing of mothers and/or infants isrecommended as soon as possible after birth, with immediate initiation of infant antiretroviral (ARV) prophylaxis (seeInfant Antiretroviral Prophylaxis) if the rapid test is positive (AII). • In the setting of a positive test, standard antibody confirmatory testing such as a Western blot also should be performedon mothers (or their infants) as soon as possible. Clinicians should not wait for the results of the confirmatory test beforeinitiating postnatal prophylaxis. If the confirmatory test is negative, ARV prophylaxis can be discontinued (AIII). • If the HIV antibody confirmatory test is positive, a newborn HIV DNA polymerase chain reaction (PCR) assay should beperformed (AIII).• If the newborn HIV DNA PCR is positive, ARV prophylaxis should be discontinued and the infant promptly referred to apediatric HIV specialist for confirmation of the diagnosis and treatment of HIV infection with standard combinationantiretroviral therapy (AI).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-7Infant Antiretroviral Prophylaxis (Last updated July 31, 2012; last reviewed July 31, 2012)General Considerations for Choice of Infant ProphylaxisAll HIV-exposed infants should receive postpartum antiretroviral (ARV) drugs to reduce perinataltransmission of HIV. The 6-week neonatal zidovudine chemoprophylaxis regimen is recommended for allHIV-exposed infants.1, 2Table 9shows recommended zidovudine dosing based on the status of maternalantepartum ARV regimens. Infants born to mothers who have received standard antepartum and intrapartumARV prophylaxis and have undetectable viral loads are at very low risk of HIV transmission and shouldreceive the 6-week zidovudine regimen alone.The risk of transmission is increased when maternal viral load at delivery is high or maternal antepartumand/or intrapartum prophylaxis was not received. Most experts feel that the potential benefit of combiningzidovudine infant prophylaxis with additional ARV drugs may exceed the risk of multiple drug exposure toinfants born to:a. mothers who received antepartum and intrapartum ARV drugs but who had suboptimal viralsuppression at delivery, particularly if delivery was vaginal;b. mothers who received only intrapartum ARV drugs;c. mothers who received neither antepartum nor intrapartum ARV drugs; andd. mothers with known ARV drug-resistant virus.In each of these situations, there is a spectrum of transmission risk that depends on a number of maternal andinfant factors, including maternal viral load, mode of delivery, and gestational age at delivery. The risks andbenefits of infant exposure to ARV drugs in addition to zidovudine will differ depending on where thePanel’s Recommendations• The 6-week neonatal component of the zidovudine chemoprophylaxis regimen is recommended for all HIV-exposedneonates to reduce perinatal transmission of HIV (AI).• Zidovudine, at gestational age-appropriate doses, should be initiated as close to the time of birth as possible, preferablywithin 6 to 12 hours of delivery (AII).• Infants born to HIV-infected women who have not received antepartum antiretroviral (ARV) drugs should receiveprophylaxis with zidovudine given for 6 weeks combined with three doses of nevirapine in the first week of life (at birth,48 hours later, and 96 hours after the second dose), begun as soon after birth as possible (AI).• In other scenarios, the decision to combine other drugs with the 6-week zidovudine regimen should be made inconsultation with a pediatric HIV specialist, preferably before delivery, and should be accompanied by counseling of themother on the potential risks and benefits of this approach (BIII).• In the United States, the use of ARV drugs other than zidovudine and nevirapine cannot be recommended in prematureinfants because of lack of dosing and safety data (BIII).• The National Perinatal HIV Hotline (1-888-448-8765) provides free clinical consultation on all aspects of perinatal HIV,including infant care.Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.mother/child falls in the risk spectrum. For example, an infant delivered vaginally to a mother with an HIVRNA level ≥100,000 copies/mL at delivery has a higher risk of acquiring HIV infection than an infant bornby cesarean delivery to a mother with an HIV RNA level of approximately 10,000 copies/mL at delivery.Thus, a generic recommendation cannot be made regarding use of combination drug regimens for infantprophylaxis. Each situation needs to be considered individually, balancing potential benefits (in terms ofpreventing perinatal transmission of HIV) with risks (in terms of toxicity to the infant). In addition,appropriate drug formulations and dosing regimens for neonates are incompletely defined and data areminimal on the safety of combination drugs in the neonate (see Short-Term Antiretroviral Drug Safety andChoice for Neonatal Prophylaxisand the Guidelines for the Use of Antiretroviral Agents in Pediatric HIVInfection). Recent data from the NICHD-HPTN 040/PACTG 1043 study have provided guidance for management ofinfants born to women who received no ARV prophylaxis during pregnancy. In this study, 1,746 infants bornto HIV-infected women who did not receive any ARV drugs during pregnancy were randomized to 3 infantprophylaxis regimens: the standard 6-week zidovudine regimen; 6 weeks of zidovudine plus 3 doses ofnevirapine given during the first week of life (first dose at birth–48 hours, second dose 48 hours after firstdose, and third dose 96 hours after second dose); and 6 weeks of zidovudine plus 2 weeks oflamivudine/nelfinavir. The risk of intrapartum transmission was significantly lower compared with 6 weeksof zidovudine alone in the 2- and 3-drug arms (2.2% and 2.5%, respectively, vs. 4.9% for zidovudine alone;P = .046 for each experimental arm vs. zidovudine alone).3Although transmission rates with the 2combination regimens were similar, neutropenia was significantly more common with the 3-drug regimenthan with the 2-drug or zidovudine-alone regimen (27.5% vs. 15%, P higher rates of neutropenia and anemia have been reported with coadministration of zidovudine andlamivudine to infants.4Thus, based on comparable efficacy and reduced toxicity, the Panel recommends 6weeks of zidovudine plus 3 doses of nevirapine for infants whose mothers have not received antepartumARVs (Table 9).In all other scenarios, decisions about use of combination ARV prophylaxis in infants should be made inconsultation with a pediatric HIV specialist before delivery, if possible, and should be accompanied by adiscussion with the mothers about potential risks and benefits of this approach. Despite the paucity of available data, the use of combination ARV prophylaxis for infants in high-risksituations is increasing. Surveillance of obstetric and pediatric HIV infection in the United Kingdom andIreland through the National Study of HIV in Pregnancy and Childhood noted that between 2001 and 2004,9% of HIV-exposed infants received triple-drug prophylaxis compared with 13% between 2005 and 2008.5Similarly, in a web-based poll of 134 U.S.-based perinatal HIV service providers, 62% reported usingcombination postnatal prophylaxis in high-risk situations in the past year. Zidovudine, lamivudine, andnevirapine was the combination regimen used most often.6The National Perinatal HIV Hotline (1-888-448-8765)The National Perinatal HIV Hotlineis a federally funded service providing free clinical consultation toproviders caring for HIV-infected pregnant women and their infants.Recommendations for Infant Antiretroviral Prophylaxis in Specific Clinical SituationsInfants Born to Mothers Who Received Antepartum/Intrapartum Antiretroviral Drugs withEffective Viral SuppressionThe risk of HIV acquisition is small in infants born to women who received standard ARV prophylaxisregimens during pregnancy and labor and had undetectable viral loads at delivery or born by scheduledcesarean section to mothers with low viral loads at delivery. Such infants should receive the 6-weekRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-8Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.zidovudine infant prophylaxis regimen. In that situation, combining zidovudine with additional ARV drugs toreduce transmission risk is not recommended because the benefit would be very limited.Infants Born to Mothers Who Have Received Antepartum/Intrapartum Antiretroviral DrugsBut Have Suboptimal Viral Suppression Near DeliveryThe risk of perinatal transmission is related to maternal antepartum viral load in women on no ARV drugs aswell as women receiving ARVs.7-9Scheduled cesarean delivery is recommended for prevention of perinataltransmission in women who have received antepartum ARV drugs but have detectable viremia (HIV RNA>1,000 copies/mL) near the time of delivery (see Intrapartum Careand Transmission and Mode of Delivery).In PACTG 316, transmission occurred in 0% of 17 infants when maternal HIV RNA levels at delivery were>10,000 copies/mL and delivery was by scheduled cesarean delivery.2However, not all women withdetectable viremia near delivery will undergo cesarean delivery. The risk of acquisition of HIV will be higherin infants born to mothers with higher viral loads near delivery, particularly if delivery is vaginal. Thegradient of transmission risk is based on HIV RNA levels. In the Women and Infants Transmission Study(WITS), the risk of transmission of HIV was ≤1.8% in women who received triple-combination ARVprophylaxis and had HIV RNA levels HIV RNA levels ≥30,000 copies/mL.9All infants should receive zidovudine for 6 weeks. No specific data address whether a more intensivecombination infant prophylaxis regimen (2 or 3 drugs) provides additional protection against transmissionwhen maternal antepartum/intrapartum prophylaxis is received but viral replication near delivery issignificant. Elective cesarean section is recommended for pregnant women with HIV RNA levels >1,000copies/mL near delivery. Extrapolation of findings from the previously discussed NICHD-HPTN040/PACTG 1043 study3suggests that combination infant prophylaxis should be considered, depending onassessment of risk based on maternal viral load and mode of delivery. That decision should be made inconsultation with a pediatric HIV specialist before delivery and accompanied by maternal counseling on thepotential risks and benefits of this approach.Infants Born to Mothers Who Received Only Intrapartum Antiretroviral DrugsAll infants whose mothers have received only intrapartum ARV drugs should be given zidovudine for 6weeks. This infant prophylaxis regimen is a critical component of prevention when no maternal antepartumARV drugs have been received. The PETRA study demonstrated that intrapartum prophylaxis alone, withoutinfant prophylaxis, is ineffective in reducing perinatal transmission.10A study in Thailand indicated thatlonger infant prophylaxis with zidovudine (6 weeks vs. 3 days) is required for optimal efficacy whenmaternal antenatal exposure to zidovudine is 11Infant prophylaxis with zidovudine should beinitiated as soon after delivery as possible. In addition to zidovudine, three doses of nevirapine should beadministered in the first week of life (first dose at birth–48 hours, second dose 48 hours after first dose, andthird dose 96 hours after second dose). In the NICHD-HPTN 040/PACTG 043 trial previously discussed,41% of women received zidovudine during labor. Administration of intrapartum zidovudine did not affecttransmission rates.3Infants Born to Mothers Who Did Not Receive Antepartum or Intrapartum AntiretroviralDrugsThe two-drug regimen of 6 weeks of zidovudine plus three doses of nevirapine in the first week of life (firstdose at birth–48 hours, second dose 48 hours after first dose, and third dose 96 hours after second dose) isrecommended based on the results of the NICHD-HPTN 040/PACTG 1043 study, which demonstratedincreased efficacy of combination regimens in reducing intrapartum transmission compared with use ofzidovudine alone in infants.3Prophylaxis should be initiated as soon after delivery as possible.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-9Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.The interval during which infant prophylaxis can be initiated and still be of benefit is undefined. In the NewYork State study, when prophylaxis was delayed beyond 48 hours after birth, no efficacy could bedemonstrated. Data from animal studies indicate that the longer the delay in institution of prophylaxis, theless likely that infection will be prevented. In most studies of animals, ARV prophylaxis initiated 24 to 36hours after exposure usually has been ineffective in preventing infection, although a delay in administrationhas been associated with decreased viremia.12-14In the NICHD-HPTN 040/PACTG 1043 study, infantregimens were initiated within 48 hours of life and usually within 12 hours of life.3Initiation of infantprophylaxis after age 2 days is not likely to be efficacious in preventing transmission and, by age 14 days,infection already would be established in most infants.15Initiating prophylaxis as soon after delivery aspossible increases its potential efficacy and minimizes potential harm, such as development of resistant virus,if infection has occurred.Infants Born to Mothers with Antiretroviral Drug-Resistant VirusThe optimal prophylactic regimen for newborns delivered by women with ARV drug-resistant virus isunknown. ARV prophylaxis for infants born to mothers with known or suspected drug resistance should bedetermined in consultation with a pediatric HIV specialist before delivery. Data from the WITS suggest that in women who have mixed zidovudine-resistant and -sensitive viralpopulations, the zidovudine-sensitive rather than -resistant virus may be preferentially transmitted.16, 17Thus,the 6-week infant zidovudine prophylaxis (along with maternal intravenous intrapartum zidovudineprophylaxis) continues to be recommended, even when maternal zidovudine-resistant virus with thymidine-associated mutations is identified.Some studies have suggested that ARV drug-resistant virus may have decreased replicative capacity (reducedviral fitness) and transmissibility.17However, transmission from mother to child of multidrug-resistant virushas been reported.18-20For these newborns, use of zidovudine in combination with other ARV drugs, selected on the basis ofmaternal virus resistance testing, should be considered. The efficacy of this approach for prevention oftransmission, however, has not been proven in clinical trials, and for many drugs, appropriate dosingregimens for neonates have not been established. Decisions regarding use of additional drugs should be madein consultation with a pediatric HIV specialist and will depend on maternal history of past and current ARVdrug exposure, HIV RNA levels at or near delivery, current and previous maternal resistance testing, andavailability of drug formulation and dosing information in the infant. Short-Term Antiretroviral Drug Safety and Choice for Neonatal ProphylaxisInfant prophylaxis with zidovudine has been associated with only minimal toxicity, consisting primarily oftransient hematologic toxicity (mainly anemia), which generally resolves by age 12 weeks (see InitialPostnatal Management). Data are limited on the toxicity to infants of exposure to multiple ARV drugs. The latest information on neonatal dosing for ARV drugs can be found in the Guidelines for the Use ofAntiretroviral Agents in Pediatric HIV Infection. Other than zidovudine, lamivudine is the nucleoside reversetranscriptase inhibitor (NRTI) with the most experience in use for neonatal prophylaxis. In early studies,neonatal exposure to combination zidovudine/lamivudine was generally limited to 110, 21, 22or 2 weeks.3Sixweeks of infant zidovudine/lamivudine exposure also has been reported; these studies suggest thathematologic toxicity may be increased over that seen with zidovudine alone, although the infants also had inuteroexposure to maternal combination therapy. In a French study, more severe anemia and neutropenia were observed in infants exposed to 6 weeks ofzidovudine/lamivudine for prophylaxis plus maternal antepartum zidovudine/lamivudine than in a historicalRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-10Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.cohort exposed only to maternal and infant zidovudine. Anemia was reported in 15% and neutropenia in 18%of infants exposed to zidovudine/lamivudine, with 2% of infants requiring blood transfusion and 4%requiring treatment discontinuation for toxicity.4Similarly, in a Brazilian study of maternal antepartum and6-week infant zidovudine/lamivudine prophylaxis, neonatal hematologic toxicity was common, with anemiaseen in 69% and neutropenia in 13% of infants.23Experience with other NRTI drugs for neonatal prophylaxis is more limited.24, 25Hematologic andmitochondrial toxicity may be more common with exposure to multiple versus single NRTI drugs.4, 26-29Nevirapine is the only non-nucleoside reverse transcriptase inhibitor drug with a pediatric drug formulationand neonatal dosing information (see Guidelines for the Use of Antiretroviral Agents in Pediatric HIVInfection).30In rare cases, chronic multiple-dose nevirapine has been associated with severe and potentiallylife-threatening rash and hepatic toxicity. These toxicities have not been observed in infants receiving single-dose nevirapine, the two-drug zidovudine regimen plus three doses of nevirapine in the first week of life inNICHD-HPTN 040/PACTG 1043), or in breastfeeding infants receiving nevirapine prophylaxis daily for 6weeks to 6 months to prevent transmission of HIV via breast milk.3, 31-34Resistance to nevirapine can occur,however, with exposure to nevirapine in infants who become infected despite prophylaxis.35, 36ARV drug-resistance testing is recommended for all HIV-infected infants before initiation of antiretroviral therapy (seeGuidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection).Of the protease inhibitors (PIs), although nelfinavir, lopinavir/ritonavir, ritonavir, tipranavir, andfosamprenavir have pediatric drug formulations, their use in neonates is not recommended. Pharmacokinetic(PK) studies of nelfinavir in newborn infants show highly variable plasma concentrations and no single dosethat results in safe but adequate nelfinavir concentrations in all infants has been defined.25, 37, 38In addition,nelfinavir powder is no longer commercially available in the United States. No PK data are available for theother PIs in infants in the first 2 weeks of life. PK data are available for treatment of HIV-infected infants 2to 6 weeks of age with lopinavir/ritonavir. Although the lopinavir area under the curve (AUC) wassignificantly lower with dosing 300 mg lopinavir/75 mg ritonavir/m2body surface area twice daily thanobserved for infants >6 weeks of age, treatment was well tolerated and 80% of 10 infants had viral control at6 months.39Studies are ongoing but data are not yet available for infants premature infants (2 sets of twins) started on lopinavir/ritonavir from birth, heart block developed thatresolved after drug discontinuation.40, 41In studies of adults, both ritonavir and lopinavir/ritonavir cause dose-dependent prolongation of the PR interval, and cases of significant heart block, including complete heartblock, have been reported. Elevation of 17-hydroxyprogesterone and dehydroepiandrosterone-sulfate hasalso been associated with administration of lopinavir/ritonavir compared with zidovudine in the neonatalperiod. Levels of 17-hydroxyprogesterone were greater in infants who were also exposed tolopinavir/ritonavir in uterocompared with those exposed only in the neonatal period. Term infants wereasymptomatic but 3 premature newborns experienced life-threatening symptoms compatible with adrenalinsufficiency, including hyponatremia and hyperkalemia with, in 1 case, cardiogenic shock.42Based on theseand other post-marketing reports of cardiac toxicity (including complete atrioventricular block, bradycardia,and cardiomyopathy), lactic acidosis, acute renal failure, adrenal dysfunction, central nervous systemdepression, respiratory complications leading to death, and metabolic toxicity,43predominantly in pretermneonates, the Food and Drug Administration now recommends that lopinavir/ritonavir NOT be administeredto neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the timeelapsed after birth) of 42 weeks and a postnatal age of at least 14 days. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-11Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Neonatal Antiretroviral Drug DosingTable 9. Recommended Neonatal Dosing for Prevention of Mother-to-Child Transmission of HIVThe recommended dose of zidovudine for post-exposure prophylaxis in full-term neonates is 4 mg/kg bodyweight orally (PO) twice daily for the first 6 weeks of life, beginning as soon after birth as possible andpreferably within 6 to 12 hours of delivery.10, 31, 44-51(Table 9) If the infant is unable to tolerate oralmedications, the 6-week zidovudine prophylaxis regimen can be administered intravenously (IV). Thezidovudine dosing requirements differ for premature infants and term infants (see Antiretroviral Drug Dosingfor Premature Infants).In the United Kingdom and many other European countries, a 4-week neonatal chemoprophylaxis regimen isrecommended for infants born to mothers who have received antenatal combination ARV drug regimens.52, 53This approach also can be considered in cases where adherence to or toxicity from the 6-week zidovudineprophylaxis regimen is a concern. In an Irish observational study, a transmission rate of 1.1% was observedin 916 infants who received 4 weeks of zidovudine infant prophylaxis following antenatal maternalcombination ARV prophylaxis. That is the standard regimen in Ireland and the transmission rate was similarto that observed in the United States, where 6 weeks of infant zidovudine prophylaxis is standard.53Aprospective, observational study reported that the 4-week zidovudine regimen allowed earlier recovery fromanemia in otherwise healthy infants compared with the 6-week zidovudine regimen.54The optimal durationRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-12All HIV-Exposed Infants (initiated as soon after delivery as possible)Zidovudine (ZDV) Dosing DurationZDV ≥35 weeks’ gestation at birth:4 mg/kg/dose PO twicedaily, started as soon after birth as possible and preferablywithin 6–12 hours of delivery (or, if unable to tolerate oralagents, 3 mg/kg/dose IV, beginning within 6–12 hours ofdelivery, then every 12 hours) Birth through 6 weeksZDV ≥30 to (or 1.5 mg/kg/dose IV), started as soon after birth aspossible, preferably within 6–12 hours of delivery, thenevery 12 hours, advanced to 3 mg/kg/dose PO (or 2.3mg/kg/dose IV) every 12 hours at age 15 daysBirth through 6 weeksZDV PO (or 1.5 mg/kg/dose IV) started as soon after birth aspossible, preferably within 6–12 hours of delivery, thenevery 12 hours, advanced to 3 mg/kg/dose PO (or 2.3mg/kg/dose IV) every 12 hours after age 4 weeks Birth through 6 weeksAdditional Antiretroviral Prophylaxis Agents for HIV-Exposed Infants of Women who Received No AntepartumAntiretroviral Prophylaxis (initiated as soon after delivery as possible)In addition to ZDV as shownabove, administerNevirapine (NVP)Birth weight 1.5–2 kg: 8 mg/dose POBirth weight >2 kg: 12 mg/dose PO3 doses in the first week of life• 1st dose within 48 hours ofbirth (birth–48 hours)• 2nd dose 48 hours after 1st • 3rd dose 96 hours after 2nd Key to Abbreviations:IV = intravenously; NVP = nevirapine; PO = orally; ZDV = zidovudineDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.of neonatal zidovudine chemoprophylaxis, however, has not been established in clinical trials, and in theUnited States, the standard 6-week infant zidovudine regimen is recommended unless there are concernsabout adherence or toxicity. Consultation with an expert in pediatric HIV infection is advised if earlydiscontinuation of prophylaxis is considered.PKs and safety of the single-dose nevirapine regimen to mother and infant55and chronic nevirapineadministration to infants to prevent HIV transmission during breastfeeding have been studied.56The 3-doseextended nevirapine regimen that was used in NICHD-HPTN 040/PACTG 1043 and is recommended for HIV-exposed infants whose mothers did not receive ARV during the antepartum period has also been studied.30Inthe NICHD-HPTN 040/PACTG 1043 study, nevirapine concentrations were measured in 14 newbornsparticipating in a PK substudy during the second week of life and in single samples from 30 more newborns onDays 10 to 14. The median nevirapine elimination half-life was 30.2 hours (range: 17.8–50.3 hours) and theconcentration remained greater than the target of 100 ng/mL in all infants through Day 10 of life.30Antiretroviral Drug Dosing for Premature InfantsDosing recommendations for premature infants is available for only zidovudine and nevirapine (see Table 9).Zidovudine is primarily cleared through hepatic glucuronidation to an inactive metabolite; this metabolicpathway is immature in neonates, leading to prolonged zidovudine half-life and clearance compared witholder infants. Clearance is further prolonged in premature infants because their hepatic metabolic function iseven less mature than in term infants.57, 58The recommended zidovudine dosage for infants less than 35weeks’ gestation at birth is 2 mg/kg body weight per dose PO every 12 hours (or 1.5 mg/kg/dose IV every 12hours), increasing to 3 mg/kg/dose PO (or 2.3 mg/kg/dose IV) every 12 hours at age 15 days. For infantsborn at less than 30 weeks’ gestation, 2 mg/kg/dose PO (or 1.5 mg/kg/dose IV) started as soon after birth aspossible, preferably within 6 to 12 hours of delivery, then every 12 hours, advanced to 3 mg/kg/dose PO (or2.3 mg/kg/dose IV) every 12 hours after age 4 weeks is recommended.PKs in low birth weight infants receiving a single dose of nevirapine have been described. In a study of 81infants less than 37 weeks’ gestation, of which 29.6% were small for gestational age, half-lives were verylong—median 59 hours in infants whose mothers received single-dose nevirapine and 69 hours in infants whosemothers did not receive single-dose nevirapine. AUC of nevirapine was higher and clearance lower (Pin small-for-gestational-age infants.59Use of ARV drugs other than zidovudine and nevirapine cannot be recommended at this time in prematureinfants because data on dosing and safety are lacking. Immature renal and hepatic metabolism can increasethe risk of overdosing and toxicity. However, in situations where there is a high risk of infant HIV infection,consultation with a pediatric HIV specialist is recommended to determine if the benefits of combination ARVprophylaxis other than zidovudine and nevirapine outweigh the potential risks.Breastfeeding Infants of Mothers Diagnosed with HIV Infection PostpartumBreastfeeding should be stopped until infection is confirmed or ruled out in women who are breastfeeding atthe time of HIV diagnosis or suspected to be HIV infected. Pumping and temporarily discarding breast milkcan be recommended to mothers who are suspected of being HIV infected but whose infection is not yetconfirmed and who want to continue to breastfeed. If HIV infection is ruled out, breastfeeding can resume.The risk of acquisition of HIV associated with breastfeeding depends on multiple infant and maternal factors,including maternal viral load and CD4 T-lymphocyte (CD4-cell) count.60Infants of women who developacute HIV infection while breastfeeding are at greater risk of becoming infected than are those of womenwith chronic HIV infection61because acute HIV infection is accompanied by a rapid increase in viral loadand a corresponding decrease in CD4-cell count.62Other than discontinuing breastfeeding, optimal strategies for managing infants born to HIV-infected mothersRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-13Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.who breastfed their infants before HIV diagnosis have yet to be defined. Some experts would consider theuse of post-exposure prophylaxis in infants for 4 to 6 weeks after cessation of breastfeeding. Post-exposureprophylaxis, however, is less likely to be effective in this circumstance compared with other nonoccupationalexposures because the exposure to breast milk is likely to have occurred over a prolonged period rather thanin a single exposure.63Several studies of infants breastfed by women with chronic HIV infection have shown that daily infantnevirapine or nevirapine plus zidovudine can reduce the risk of postnatal infection during breastfeeding.31-33The NICHD-HPTN 040/PACTG 043 study demonstrated that combination ARV prophylaxis was moreeffective than zidovudine prophylaxis alone for preventing intrapartum transmission in mothers who havenot received antepartum ARV drugs.3However, whether the combination regimens in this trial are effectivefor preventing transmission after cessation of breastfeeding in mothers with acute HIV infection is unknown. An alternative approach favored by some experts would be to offer a combination ARV regimen that wouldbe effective for treatment of HIV should the infant become infected. If this route is chosen, currentrecommendations for treatment should guide selection of an appropriate combination ARV regimen (seeGuidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection). Regardless of whether post-exposure prophylaxis or “preemptive therapy” is chosen, the optimal duration of the intervention isunknown. A 28-day course may be reasonable based on current recommendations for nonoccupational HIVexposure.63As in other situations, decisions regarding administration of a prophylactic or preemptivetreatment regimen should be accompanied by consultation with a pediatric HIV specialist and maternalcounseling on the potential risks and benefits of this approach.Infants should be tested for HIV infection at baseline and 4 to 6 weeks, 3 months, and 6 months afterrecognition of maternal infection to determine HIV status. In infants younger than age 18 months, HIV DNAor RNA polymerase chain reaction (PCR) tests should be used for diagnosis. HIV DNA PCR is preferable forinfants who are receiving combination ARV prophylaxis or preemptive treatment. HIV antibody assays canbe used in infants older than age 18 months. 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Pediatr Infect Dis J. Sep 2011;30(9):769-772. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21666540.39. Chadwick EG, Pinto J, Yogev R, et al. Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age:pharmacokinetics and 24-week safety and efficacy. Pediatr Infect Dis J. Mar 2009;28(3):215-219. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19209098.40. Lopriore E, Rozendaal L, Gelinck LB, Bokenkamp R, Boelen CC, Walther FJ. Twins with cardiomyopathy andcomplete heart block born to an HIV-infected mother treated with HAART. AIDS. Nov 30 2007;21(18):2564-2565.Available at http://www.ncbi.nlm.nih.gov/pubmed/18025905.41. McArthur MA, Kalu SU, Foulks AR, Aly AM, Jain SK, Patel JA. Twin preterm neonates with cardiac toxicity related tolopinavir/ritonavir therapy. Pediatr Infect Dis J. Dec 2009;28(12):1127-1129. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19820426.42. Simon A, Warszawski J, Kariyawasam D, et al. Association of prenatal and postnatal exposure to lopinavir-ritonavir andadrenal dysfunction among uninfected infants of HIV-infected mothers. JAMA. Jul 6 2011;306(1):70-78. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21730243.43. Boxwell D, Cao K, Lewis L, Marcus K, Nikhar B. Neonatal toxicity of Kaletra oral solution: LPV, ethanol orprophylene glycol? Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February27-Mar 2, 2011; Boston, MA. Abstract 708.44. Taha TE, Kumwenda NI, Hoover DR, et al. Nevirapine and zidovudine at birth to reduce perinatal transmission of HIVin an African setting: a randomized controlled trial. JAMA. Jul 14 2004;292(2):202-209. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15249569.45. Taha TE, Kumwenda NI, Gibbons A, et al. Short postexposure prophylaxis in newborn babies to reduce mother-to-childtransmission of HIV-1: NVAZ randomised clinical trial. Lancet. Oct 11 2003;362(9391):1171-1177. Available athttp://www.ncbi.nlm.nih.gov/pubmed/14568737.46. Shapiro RL, Thior I, Gilbert PB, et al. Maternal single-dose nevirapine versus placebo as part of an antiretroviralstrategy to prevent mother-to-child HIV transmission in Botswana. AIDS. Jun 12 2006;20(9):1281-1288. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16816557.47. Gray GE, Urban M, Chersich MF, et al. A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers. AIDS. Aug 12 2005;19(12):1289-1297. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16052084.48. Kilewo C, Karlsson K, Ngarina M, et al. Prevention of mother-to-child transmission of HIV-1 through breastfeeding bytreating mothers with triple antiretroviral therapy in Dar es Salaam, Tanzania: the Mitra Plus study. J Acquir ImmuneDefic Syndr. Nov 1 2009;52(3):406-416. Available at http://www.ncbi.nlm.nih.gov/pubmed/19730269.49. Peltier CA, Ndayisaba GF, Lepage P, et al. Breastfeeding with maternal antiretroviral therapy or formula feeding toprevent HIV postnatal mother-to-child transmission in Rwanda. AIDS. Nov 27 2009;23(18):2415-2423. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19730349.50. Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N EnglJ Med. Jun 17 2010;362(24):2282-2294. Available at http://www.ncbi.nlm.nih.gov/pubmed/20554983.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-17Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.51. Kesho Bora Study Group, de Vincenzi I. Triple antiretroviral compared with zidovudine and single-dose nevirapineprophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Borastudy): a randomised controlled trial. Lancet Infect Dis. Mar 2011;11(3):171-180. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21237718.52. de Ruiter A, Mercey D, Anderson J, et al. British HIV Association and Childrens HIV Association guidelines for themanagement of HIV infection in pregnant women 2008. HIV Med. Aug 2008;9(7):452-502. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18840151.53. Ferguson W, Goode M, Walsh A, Gavin P, Butler K. Evaluation of 4 weeks neonatal antiretroviral prophylaxis as acomponent of a prevention of mother-to-child transmission program in a resource-rich setting. Pediatr Infect Dis J. May2011;30(5):408-412. Available at http://www.ncbi.nlm.nih.gov/pubmed/21266939.54. Lahoz R, Noguera A, Rovira N, et al. Antiretroviral-related hematologic short-term toxicity in healthy infants:implications of the new neonatal 4-week zidovudine regimen. Pediatr Infect Dis J. Apr 2010;29(4):376-379. Availableat http://www.ncbi.nlm.nih.gov/pubmed/19949355.55. Mirochnick M, Dorenbaum A, Blanchard S, et al. Predose infant nevirapine concentration with the two-doseintrapartum neonatal nevirapine regimen: association with timing of maternal intrapartum nevirapine dose. J AcquirImmune Defic Syndr. Jun 1 2003;33(2):153-156. Available at http://www.ncbi.nlm.nih.gov/pubmed/12794547.56. Shetty AK, Coovadia HM, Mirochnick MM, et al. Safety and trough concentrations of nevirapine prophylaxis givendaily, twice weekly, or weekly in breast-feeding infants from birth to 6 months. J Acquir Immune Defic Syndr. Dec 152003;34(5):482-490. Available at http://www.ncbi.nlm.nih.gov/pubmed/14657758.57. Capparelli EV, Mirochnick M, Dankner WM, et al. Pharmacokinetics and tolerance of zidovudine in preterm infants. JPediatr. Jan 2003;142(1):47-52. Available at http://www.ncbi.nlm.nih.gov/pubmed/12520254.58. Mirochnick M, Capparelli E, Connor J. Pharmacokinetics of zidovudine in infants: a population analysis across studies.Clin Pharmacol Ther. Jul 1999;66(1):16-24. Available at http://www.ncbi.nlm.nih.gov/pubmed/10430105.59. Mugabo P, Els I, Smith J, et al. Nevirapine plasma concentrations in premature infants exposed to single-dosenevirapine for prevention of mother-to-child transmission of HIV-1. S Afr Med J. Sep 2011;101(9):655-658. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21920159.60. Kuhn L, Reitz C, Abrams EJ. Breastfeeding and AIDS in the developing world. Curr Opin Pediatr. Feb 2009;21(1):83-93. Available at http://www.ncbi.nlm.nih.gov/pubmed/19242244.61. Van de Perre P, Lepage P, Homsy J, Dabis F. Mother-to-infant transmission of human immunodeficiency virus by breastmilk: presumed innocent or presumed guilty? Clin Infect Dis. Sep 1992;15(3):502-507. Available athttp://www.ncbi.nlm.nih.gov/pubmed/1445596.62. Daar ES. Virology and immunology of acute HIV type 1 infection. AIDSRes Hum Retroviruses. Oct 1998;14(Suppl3):S229-234. Available at http://www.ncbi.nlm.nih.gov/pubmed/9814948.63. Smith DK, Grohskopf LA, Black RJ, et al. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, orother nonoccupational exposure to HIV in the United States: recommendations from the U.S. Department of Health andHuman Services. MMWR Recomm Rep. Jan 21 2005;54(RR-2):1-20. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15660015.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-18Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-19Initial Postnatal Management of the HIV-Exposed Neonate (Last updated July 31, 2012;last reviewed July 31, 2012)A complete blood count (CBC) and differential should be performed on HIV-exposed newborns beforeinitiation of infant antiretroviral (ARV) drug prophylaxis. Decisions about the timing of hematologicmonitoring of infants after birth depend on a number of factors, including baseline hematologic values,gestational age at birth, clinical condition of the infants, which ARV drugs are being administered, receipt ofconcomitant medications, and maternal antepartum ARV drug regimen. Anemia is the primary complicationseen in neonates given the standard 6-week postnatal zidovudine regimen. In PACTG 076, infants in thezidovudine group had lower hemoglobin at birth than those in the placebo group, with the maximaldifference (1 g/dL) occurring at age 3 weeks.1The lowest mean value for hemoglobin levels (10 g/dL)occurred at age 6 weeks in the zidovudine group. By age 12 weeks, hemoglobin values in both groups weresimilar. No significant differences in other laboratory parameters were observed between groups.Some experts recheck hematologic values in healthy infants receiving zidovudine prophylaxis only ifsymptoms are present. Hematologic safety data are limited on administration of 4 mg/kg of zidovudine twicePanel’s Recommendations• A complete blood count and differential should be performed on newborns as a baseline evaluation (BIII).• Decisions about the timing of subsequent monitoring of hematologic parameters in infants depend on baselinehematologic values, gestational age at birth, clinical condition of the infants, the zidovudine dose being administered,receipt of other ARV drugs and concomitant medications, and maternal antepartum ARV therapy (CIII).• If hematologic abnormalities are identified in infants receiving prophylaxis, decisions on whether to continue infantantiretroviral (ARV) prophylaxis need to be individualized. Consultation with an expert in pediatric HIV infection is advisedif early discontinuation of prophylaxis is considered (CIII).• Some experts recommend more intensive monitoring of hematologic and serum chemistry and liver function assays atbirth and when diagnostic HIV polymerase chain reaction tests are obtained in infants exposed to combination ARV drugregimens in utero or during the neonatal period (CIII).• A recheck of hemoglobin and neutrophil counts is recommended 4 weeks after initiation of prophylaxis for infants whoreceive combination zidovudine/lamivudine-containing ARV prophylaxis regimens (AI).• Routine measurement of serum lactate is not recommended. However, measurement can be considered if an infantdevelops severe clinical symptoms of unknown etiology (particularly neurologic symptoms) (CIII).• Virologic tests are required to diagnose HIV infection in infants first 14 to 21 days of life, at 1 to 2 months, and at 4 to 6 months of age (AII).• To prevent Pneumocystis jirovecii pneumonia (PCP), all infants born to women with HIV infection should begin PCPprophylaxis at ages 4 to 6 weeks, after completing their ARV prophylaxis regimen, unless there is adequate testinformation to presumptively exclude HIV infection (see USPHS/IDSA Guidelines for the Prevention and Treatment ofOpportunistic Infections in HIV-Exposed and Infected Children) (AII).• Health care providers should routinely inquire about premastication of foods fed to infants, instruct HIV-infectedcaregivers to avoid this practice, and advise on safer feeding options (AII).Rating of Recommendations: A = Strong; B = Moderate; C = OptionalRating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.daily in infants. When administering this dosing regimen, some experts recheck hemoglobin and neutrophilcounts routinely after 4 weeks of zidovudine prophylaxis and/or when diagnostic HIV polymerase chainreaction (PCR) tests are obtained.In uteroexposure to maternal combination ARV drug regimens may be associated with some increase inanemia and/or neutropenia compared with that seen in infants exposed to zidovudine alone.2-5In PACTG316, where 77% of mothers received antenatal combination therapy, significant Grade 3 or higher anemiawas noted in 13% and neutropenia in 12% of infants, respectively. Depending on the combination regimenthe mother has received, some experts advise more intensive laboratory monitoring, including serumchemistry and transaminases at birth plus a CBC at the time of diagnostic HIV PCR testing; monitoring ofbilirubin levels may be considered for infants exposed antenatally to atazanavir. In addition, data are limited on infants receiving zidovudine in combination with other ARVs forprophylaxis. However, higher rates of hematologic toxicity have been observed in infants receivingzidovudine/lamivudine combination prophylaxis compared with those receiving zidovudine alone orzidovudine plus nevirapine.6A recheck of hemoglobin and neutrophil counts, therefore, is recommended forinfants who receive combination zidovudine/lamivudine-containing ARV prophylaxis regimens 4 weeks afterinitiation of prophylaxis and/or at the time that diagnostic HIV PCR testing is done.7If hematologic abnormalities are found, decisions on whether to continue infant ARV prophylaxis need to beindividualized. Considerations include the extent of the abnormality, whether related symptoms are present,duration of infant prophylaxis, risk of HIV infection (as assessed by the mother’s history of ARVprophylaxis, viral load near delivery, and mode of delivery), and the availability of alternative interventionssuch as erythropoietin and transfusion. Consideration can be given to reducing the duration of infantprophylaxis from 6 to 4 weeks, as is the case in many European centers. In a recent prospective,observational study, the 4-week regimen was found to allow earlier recovery from anemia in otherwisehealthy infants compared with the 6-week regimen.8Consultation with an expert in pediatric HIV infection isadvised if discontinuation of prophylaxis is considered.Hyperlactatemia has been reported in infants with in uteroexposure to ARVs, but it appears to be transientand, in most cases, asymptomatic.9, 10Routine measurement of serum lactate is not recommended inasymptomatic neonates to assess for potential mitochondrial toxicity because the clinical relevance isunknown and the predictive value for toxicity appears poor.9, 10Serum lactate measurement should beconsidered, however, for infants who develop severe clinical symptoms of unknown etiology, particularlyneurologic symptoms. In infants with symptoms, if the levels are significantly abnormal (>5 mmol/L), ARVprophylaxis should be discontinued and an expert in pediatric HIV infection should be consulted regardingpotential alternate prophylaxis.To prevent Pneumocystis jiroveciipneumonia, all infants born to women with HIV infection should begintrimethoprim-sulfamethoxazole prophylaxis at age 6 weeks, after completion of the infant ARV prophylaxisregimen, unless there is adequate virologic test information to presumptively exclude HIV infection (seeUSPHS/IDSA Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed andInfected Children).11HIV infection in infants should be diagnosed using HIV DNA PCR or RNA virologic assays. Maternal HIVantibody crosses the placenta and will be detectable in all HIV-exposed infants up to age 18 months;therefore, standard antibody tests should not be used for HIV diagnosis in newborns. HIV virologic testingshould be performed within the first 14 to 21 days of life, at 1 to 2 months, and at 4 to 6 months of age.12Some experts also perform a virologic test at birth, especially in women who have not had good virologiccontrol during pregnancy or if adequate follow-up of the infant may not be assured. A positive HIV virologictest should be confirmed as soon as possible with a second HIV virologic test on a different specimen. TwoRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-20Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.positive HIV tests constitute a diagnosis of HIV infection. Data do not indicate any delay in HIV diagnosiswith HIV DNA PCR assays in infants who have received the zidovudine regimen.1, 13However, the effect ofmaternal or infant exposure to combination ARV drug regimens on the sensitivity of infant virologicdiagnostic testing—particularly using HIV RNA assays—is unknown. Therefore, although HIV RNA assaysmay be acceptable for diagnosis (particularly in older infants), HIV DNA PCR assays may be optimal fordiagnosing infection in the neonatal period. Any newly diagnosed infant should undergo viral resistancetesting by genotype and/or phenotype to assess for susceptibility to combination antiretroviral therapy.HIV may be presumptively excluded with two or more negative tests, one at age 14 days or older and theother at age 1 month or older. Definitive exclusion of HIV in non-breastfed infants can be based on twonegative virologic tests at age 1 month or older and at age 4 months or older. Many experts confirm HIV-negative status with an HIV antibody test at ages 12 to 18 months. Alternative algorithms exist forpresumptive and definitive HIV exclusion.12This testing algorithm applies mainly to exposure to HIVsubtype B, which is the predominant viral subtype found in the United States. Non-subtype B virusespredominate in some other parts of the world. Non-subtype B infection may not be detected by manycommercially available nucleic acid tests, particularly HIV DNA PCR. Many of the newer HIV RNA assayshave improved detection of non-subtype B HIV, but there are still variants that are either poorly detected orundetectable. If non-subtype B HIV infection is suspected based on maternal origins, then newer HIV RNAassays that have improved ability to detect non-subtype B HIV should be used as part of the initial diagnosticalgorithm. Exposed infants also should be closely monitored and undergo definitive HIV serologic testing atage 18 months (see the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, IssuesRelated to Diagnosis of Non-Subtype B HIV Infectionfor additional information).Following birth, HIV-exposed infants should have a detailed physical examination, and a thorough maternalhistory should be obtained. HIV-infected mothers may be coinfected with other pathogens that can betransmitted from mother to child, such as cytomegalovirus, herpes simplex virus, hepatitis B, hepatitis C,syphilis, toxoplasmosis, or tuberculosis. Infants born to mothers with such coinfections should undergoappropriate evaluation, as indicated by maternal CD4 T-lymphocyte count and evidence of disease activity, torule out transmission of additional infectious agents. The routine primary immunization schedule should befollowed for HIV-exposed infants born to HIV-infected mothers. Modifications in the schedule for live virusvaccines may be required for infants with known HIV infection (see USPHS/IDSA Guidelines for thePrevention and Treatment of Opportunistic Infections in HIV-Exposed and Infected Children).Infant Feeding Practices and Risk of HIV TransmissionIn the United States, where safe infant feeding alternatives are available and free for women in need, HIV-infected women should not breastfeed their infants. Maternal receipt of combination ARV regimens is likelyto reduce free virus in the breast milk, but the presence of cell-associated virus (intracellular HIV DNA)remains unaffected and, therefore, may continue to pose a transmission risk.14Late HIV transmission events in infancy have been reported in HIV-infected children suspected of acquiringHIV infection as a result of consuming premasticated food given to them by their caregivers. Phylogeneticcomparisons of virus from cases and suspected sources and supporting clinical history and investigationsidentified the practice of feeding premasticated foods to infants as a potential risk factor for HIVtransmission. Health care providers should routinely inquire about premastication, instruct HIV-infectedcaregivers against this feeding practice, and advise on safer feeding options.15, 16References1. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virustype 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. NovRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-21Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.3 1994;331(18):1173-1180. Available at http://www.ncbi.nlm.nih.gov/pubmed/7935654.2. Feiterna-Sperling C, Weizsaecker K, Buhrer C, et al. Hematologic effects of maternal antiretroviral therapy andtransmission prophylaxis in HIV-1-exposed uninfected newborn infants. J Acquir Immune Defic Syndr. May 12007;45(1):43-51. Available at http://www.ncbi.nlm.nih.gov/pubmed/17356471.3. El Beitune P, Duarte G. Antiretroviral agents during pregnancy: consequences on hematologic parameters in HIV-exposed, uninfected newborn infant. Eur J Obstet Gynecol Reprod Biol. Sep-Oct 2006;128(1-2):59-63. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16876310.4. Watson WJ, Stevens TP, Weinberg GA. Profound anemia in a newborn infant of a mother receiving antiretroviraltherapy. Pediatr Infect Dis J. May 1998;17(5):435-436. Available at http://www.ncbi.nlm.nih.gov/pubmed/9613665.5. Dryden-Peterson S, Shapiro RL, Hughes MD, et al. Increased risk of severe infant anemia after exposure to maternalHAART, Botswana. J Acquir Immune Defic Syndr. Apr 15 2011;56(5):428-436. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21266910.6. Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIVinfection. N Engl J Med. Jun 21 2012;366(25):2368-2379. Available at http://www.ncbi.nlm.nih.gov/pubmed/22716975.7. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudine-zidovudine combination for prevention ofmaternal-infant transmission of HIV-1. JAMA. Apr 25 2001;285(16):2083-2093. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11311097.8. Lahoz R, Noguera A, Rovira N, et al. Antiretroviral-related hematologic short-term toxicity in healthy infants:implications of the new neonatal 4-week zidovudine regimen. Pediatr Infect Dis J. Apr 2010;29(4):376-379. Availableat http://www.ncbi.nlm.nih.gov/pubmed/19949355.9. Ekouevi DK, Toure R, Becquet R, et al. Serum lactate levels in infants exposed peripartum to antiretroviral agents toprevent mother-to-child transmission of HIV: Agence Nationale de Recherches Sur le SIDA et les Hepatites Virales1209 study, Abidjan, Ivory Coast. Pediatrics. Oct 2006;118(4):e1071-1077. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16950945.10. Noguera A, Fortuny C, Munoz-Almagro C, et al. Hyperlactatemia in human immunodeficiency virus-uninfected infantswho are exposed to antiretrovirals. Pediatrics. Nov 2004;114(5):e598-603. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15492359.11. Mofenson LM, Brady MT, Danner SP, et al. Guidelines for the Prevention and Treatment of Opportunistic Infectionsamong HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIVMedicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and theAmerican Academy of Pediatrics. MMWR Recomm Rep. Sep 4 2009;58(RR-11):1-166. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19730409.12. Schneider E, Whitmore S, Glynn KM, et al. Revised surveillance case definitions for HIV infection among adults,adolescents, and children aged years—United States, 2008. MMWR Recomm Rep. Dec 5 2008;57(RR-10):1-12. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19052530.13. Kovacs A, Xu J, Rasheed S, et al. Comparison of a rapid nonisotopic polymerase chain reaction assay with fourcommonly used methods for the early diagnosis of human immunodeficiency virus type 1 infection in neonates andchildren. Pediatr Infect Dis J. Nov 1995;14(11):948-954. Available at http://www.ncbi.nlm.nih.gov/pubmed/8584360.14. Gaillard P, Fowler MG, Dabis F, et al. Use of antiretroviral drugs to prevent HIV-1 transmission through breast-feeding:from animal studies to randomized clinical trials. J Acquir Immune Defic Syndr. Feb 1 2004;35(2):178-187. Available athttp://www.ncbi.nlm.nih.gov/pubmed/14722452.15. Ivy W, 3rd, Dominguez KL, Rakhmanina NY, et al. Premastication as a route of pediatric HIV transmission: case-control and cross-sectional investigations. J Acquir Immune Defic Syndr. Feb 1 2012;59(2):207-212. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22027873.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-22Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.16. Gaur AH, Dominguez KL, Kalish ML, et al. Practice of feeding premasticated food to infants: a potential risk factor forHIV transmission. Pediatrics. Aug 2009;124(2):658-666. Available at http://www.ncbi.nlm.nih.gov/pubmed/19620190.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-23Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-24Long-Term Follow-Up of Antiretroviral Drug-Exposed Infants (Last updated July 31,2012; last reviewed July 31, 2012)Data remain insufficient to address the effect that exposure to zidovudine or other antiretroviral (ARV)agents in utero might have on long-term risk of neoplasia or organ system toxicities in children. Data fromfollow-up of PACTG 076 infants through age 6 years do not indicate any differences in immunologic,neurologic, and growth parameters between infants who were exposed to the zidovudine regimen and thosewho received placebo, and no malignancies have been seen.1-3As discussed earlier in NRTI Drugs andMitochondrial Toxicity, data are conflicting regarding whether mitochondrial dysfunction is associated withperinatal exposure to ARVs. Children with in utero exposure to ARVs who develop significant organ systemabnormalities of unknown etiology, particularly of the nervous system or heart, should be evaluated forpotential mitochondrial dysfunction.4-6Follow-up of children with exposure to ARVs should continue intoadulthood because of the theoretical concerns regarding the potential for carcinogenicity of the nucleosideanalogue ARV drugs. Long-term follow-up should include annual physical examinations of all childrenexposed to ARV drugs. Innovative methods are needed to provide follow-up of infants with in utero exposureto ARV drugs. Information regarding such exposure should be part of ongoing permanent medical records forchildren, particularly those who are uninfected. Evaluation is ongoing of early and late effects of in utero exposure to ARVs, including the PediatricHIV/AIDS Cohort Study, Surveillance Monitoring of Antiretroviral Toxicity Study, natural history studies,and HIV/AIDS surveillance conducted by state health departments and the Centers for Disease Control andPrevention. Because most of the available follow-up data relate to in utero exposure to antenatal zidovudinealone and most HIV-infected pregnant women currently receive combination ARV drug regimens, it iscritical that studies to evaluate potential adverse effects of in utero drug exposure continue to be supported.HIV surveillance databases from states that require HIV reporting provide an opportunity to collectpopulation-based information concerning in utero exposure to ARVs. To the extent permitted by federal lawand regulations, data from these confidential registries can be compared with information from birth defectand cancer registries to identify potential adverse outcomes.References1. Culnane M, Fowler M, Lee SS, et al. Lack of long-term effects of in utero exposure to zidovudine among uninfectedchildren born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams. JAMA. Jan 131999;281(2):151-157. Available at http://www.ncbi.nlm.nih.gov/pubmed/9917118.2. Hanson IC, Antonelli TA, Sperling RS, et al. Lack of tumors in infants with perinatal HIV-1 exposure and fetal/neonatalexposure to zidovudine. J Acquir Immune Defic Syndr Hum Retrovirol. Apr 15 1999;20(5):463-467. Available atPanel’s Recommendations• Children with in utero/neonatal exposure to antiretroviral (ARV) drugs who develop significant organ systemabnormalities of unknown etiology, particularly of the nervous system or heart, should be evaluated for potentialmitochondrial dysfunction (CIII).• Follow-up of children with exposure to ARVs should continue into adulthood because of the theoretical concernsregarding the potential for carcinogenicity of nucleoside analogue ARV drugs (CIII).Rating of Recommendations:A = Strong; B = Moderate; C = OptionalRating of Evidence:I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One ormore well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinionDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.http://www.ncbi.nlm.nih.gov/pubmed/10225228.3. Brogly S, Williams P, Seage GR, 3rd, Van Dyke R. In utero nucleoside reverse transcriptase inhibitor exposure andcancer in HIV-uninfected children: an update from the pediatric AIDS clinical trials group 219 and 219C cohorts. JAcquir Immune Defic Syndr. Apr 1 2006;41(4):535-536. Available at http://www.ncbi.nlm.nih.gov/pubmed/16652068.4. Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviralnucleoside analogues. Lancet. Sep 25 1999;354(9184):1084-1089. Available athttp://www.ncbi.nlm.nih.gov/pubmed/10509500.5. Barret B, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants:clinical screening in a large prospective cohort. AIDS. Aug 15 2003;17(12):1769-1785. Available athttp://www.ncbi.nlm.nih.gov/pubmed/12891063.6. Spector SA, Saitoh A. Mitochondrial dysfunction: prevention of HIV-1 mother-to-infant transmission outweighs fear.AIDS. Aug 22 2006;20(13):1777-1778. Available at http://www.ncbi.nlm.nih.gov/pubmed/16931943.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States H-25Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-1Supplement: Safety and Toxicity of Individual Antiretroviral Agentsin PregnancyNucleoside and Nucleotide Analogue Reverse Transcriptase InhibitorsSix nucleoside analogue reverse transcriptase inhibitors (nucleoside NRTIs) and one nucleotide reversetranscriptase inhibitor (nucleotide NRTI) are currently approved (zalcitabine is no longer available in theUnited States). Data are available from clinical trials in human pregnancy for the nucleoside NRTIszidovudine, abacavir, lamivudine, didanosine, emtricitabine, and stavudine and the nucleoside NRTItenofovir. The nucleoside analogue drugs require three intracellular phosphorylation steps to form thetriphosphate nucleoside, which is the active drug moiety. Tenofovir, an acyclic nucleotide analogue drug,contains a monophosphate component attached to the adenine base and, hence, requires only twophosphorylation steps to form the active moiety.For information regarding the nucleoside analogue drug class and potential mitochondrial toxicity inpregnancy and to the infant, see NRTI Drugs and Mitochondrial Toxicityin the perinatal guidelines.Abacavir (Ziagen, ABC)is classified as Food and Drug Administration (FDA) Pregnancy Category C.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesAbacavir is mutagenic and clastogenic in some in vitroand in vivoassays. In long-term carcinogenicitystudies in mice and rats, malignant tumors of the preputial gland of males and the clitoral gland offemales were observed in both species, and malignant hepatic tumors and nonmalignant hepatic andthyroid tumors were observed in female rats. The tumors were seen in rodents at doses that were 6 to 32times that of human therapeutic exposure.• Reproduction/fertilityNo effect of abacavir on reproduction or fertility in male and female rodents has been seen at doses of upto 500 mg/kg/day (about 8 times that of human therapeutic exposure based on body surface area).• Teratogenicity/developmental toxicityAbacavir is associated with developmental toxicity (decreased fetal body weight and reduced crown-rump length) and increased incidence of fetal anasarca and skeletal malformations in rats treated withabacavir during organogenesis at doses of 1000 mg/kg (about 35 times that of human therapeuticexposure based on area under the curve [AUC]). Toxicity to the developing embryo and fetus (increasedresorptions and decreased fetal body weight) occurred with abacavir administration of 500 mg/kg/day toGlossary of Terms for SupplementCarcinogenic = producing or tending to produce cancer• Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic.• Genetic mutations and/or chromosomal damage can contribute to cancer formation.Clastogenic = causing disruption of or breakages in chromosomesGenotoxic = damaging to genetic material such as DNA and chromosomesMutagenic = inducing or capable of inducing genetic mutationTeratogenic = interfering with fetal development and resulting in birth defectsDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.pregnant rodents. The offspring of female rats were treated with 500 mg/kg of abacavir, beginning atembryo implantation and ending at weaning. In these animals, an increased incidence of stillbirth andlower body weight was seen throughout life. However, in the rabbit, no evidence of drug-relateddevelopmental toxicity was observed and no increase in fetal malformations was observed at doses up to700 mg/kg (about 8.5 times that of human therapeutic exposure).In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to abacavir inhumans have been monitored to be able to detect at least a 2-fold increase in risk of overall birth defects.No such increase in birth defects has been observed with abacavir. Among cases of first-trimesterabacavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was3.0% (25 of 823 births; 95% confidence interval [CI], 2.0%–4.5%) compared with 2.7% in the U.S.population, based on Centers for Disease Control and Prevention (CDC) surveillance.1• Placental and breast milk passageAbacavir crosses the placenta and is excreted into the breast milk of lactating rats.• Human studies in pregnancyA Phase I study of abacavir in pregnant women indicates that the AUC drug concentration duringpregnancy was similar to that at 6 to 12 weeks postpartum and in non-pregnant individuals.2Thus, nodose adjustment for abacavir is needed during pregnancy. Serious hypersensitivity reactions have beenassociated with abacavir therapy in non-pregnant adults and have rarely been fatal; symptoms includefever, skin rash, fatigue, and gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominalpain. Abacavir should not be restarted following a hypersensitivity reaction because more severesymptoms will occur within hours and may include life-threatening hypotension and death.References1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.2. Best BM, Mirochnick M, Capparelli EV, et al. Impact of pregnancy on abacavir pharmacokinetics. AIDS. Feb 282006;20(4):553-560. Available at http://www.ncbi.nlm.nih.gov/pubmed/16470119.Didanosine (Videx, ddI)is classified as FDA Pregnancy Category B.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesDidanosine is both mutagenic and clastogenic in several in vitroand in vivoassays. Long-term animalcarcinogenicity screening studies at human exposures of 0.7 to 1.7 times in mice and 3 times in rats havebeen negative.• Reproduction/fertilityAt approximately 12 times the estimated human exposure, didanosine was slightly toxic to female ratsand their pups during mid and late lactation. These rats showed reduced food intake and body weightgains; however, the physical and functional development of the offspring was not impaired and therewere no major changes in the F2 generation.• Teratogenicity/developmental toxicityNo evidence of teratogenicity or toxicity was observed with administration of didanosine at 12 and 14times human exposure, respectively, in pregnant rats and rabbits. Among cases of first-trimesterdidanosine exposure reported to the Antiretroviral Pregnancy Registry, prevalence of birth defects wasRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-2Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.4.6% (19 of 409 births; 95% CI, 2.8%–7.2%) compared with 2.7% in the U.S. population, based on CDCsurveillance.1All defects were reviewed in detail by the Registry, and no pattern of defects wasdiscovered. The rate and types of defects will continue to be closely monitored.• Placental and breast milk passagePlacental transfer of didanosine was limited in a Phase I/II safety and pharmacokinetic (PK) study.2Thiswas confirmed in a study of 100 HIV-infected pregnant women who were receiving NRTIs (generally aspart of a two- or three-drug combination antiretroviral [ARV] regimen). At the time of delivery, cord-to-maternal blood ratio for didanosine (n = 10) was 0.38 (range 0.0–2.0) and in 15 of 24 (62%) samples,cord blood concentrations for didanosine were below the limits of detection.3A study in rats showed thatdidanosine and/or its metabolites are transferred to the fetus through the placenta. It is not known ifdidanosine is excreted in human breast milk.• Human studies in pregnancyA Phase I study (PACTG 249) of didanosine was conducted in 14 HIV-infected pregnant women enrolledat gestational age 26 to 36 weeks and treated through 6 weeks postpartum.2The drug was well toleratedduring pregnancy by the women and the fetuses. PK parameters after oral administration were notsignificantly affected by pregnancy, and dose modification from the usual adult dosage is not needed.Lactic acidosis, in some cases fatal, has been described in pregnant women receiving the combination ofdidanosine and stavudine along with other ARV agents;4-6the FDA and Bristol-Myers Squibb have issued awarning to health care professionals that pregnant women may be at increased risk of fatal lactic acidosiswhen prescribed didanosine and stavudine in combination. These two drugs should be prescribed togetherto pregnant women only when the potential benefit clearly outweighs the potential risk. Clinicians shouldprescribe this ARV combination in pregnancy with caution and generally only when other nucleosideanalog drug combinations have failed or have caused unacceptable toxicity or side effects.References1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.2. Wang Y, Livingston E, Patil S, et al. Pharmacokinetics of didanosine in antepartum and postpartum humanimmunodeficiency virus—infected pregnant women and their neonates: an AIDS clinical trials group study. J Infect Dis.1999;180(5):1536-1541. Available athttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10515813.3. Chappuy H, Treluyer JM, Jullien V, et al. Maternal-fetal transfer and amniotic fluid accumulation of nucleosideanalogue reverse transcriptase inhibitors in human immunodeficiency virus-infected pregnant women. AntimicrobAgents Chemother. Nov 2004;48(11):4332-4336. Available at http://www.ncbi.nlm.nih.gov/pubmed/15504861.4. Mandelbrot L, Kermarrec N, Marcollet A, et al. Case report: nucleoside analogue-induced lactic acidosis in the thirdtrimester of pregnancy. AIDS. Jan 24 2003;17(2):272-273. Available at http://www.ncbi.nlm.nih.gov/pubmed/12545093.5. Sarner L, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positivewomen taking antiretroviral medication. Sex Transm Infect. Feb 2002;78(1):58-59. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11872862.6. Bristol-Myers Squibb Company. Healthcare Provider Important Drug Warning Letter. January 5, 2001. Available athttp://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm173947.htm.Accessed on June 25, 2012.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-3Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Emtricitabine (Emtriva, FTC)is classified as FDA Pregnancy Category B.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesEmtricitabine was neither mutagenic nor clastogenic in a series of in vitroand animal in vivoscreeningtests. In long-term oral carcinogenicity studies of emtricitabine, no drug-related increases in tumorincidence were found in mice at doses up to 26 times the human systemic exposure at a therapeutic doseof 200 mg/day or in rats at doses up to 31 times the human systemic exposure at the therapeutic dose.• Reproduction/fertilityNo effect of emtricitabine on reproduction or fertility was observed with doses that produced systemicdrug exposures (as measured by AUC) approximately 60-fold higher in female mice and 140-fold higherin male mice than observed with human exposure at the recommended therapeutic dose. • Teratogenicity/developmental toxicityIncidence of fetal variations and malformations was not increased with emtricitabine dosing in mice thatresulted in systemic drug exposure 60-fold higher than observed with human exposure at recommendeddoses or in rabbits with dosing resulting in drug exposure 120-fold higher than human exposure.In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to emtricitabinein humans have been monitored to be able to detect at least a 2-fold increase in risk of overall birthdefects. No such increase in birth defects has been observed with emtricitabine. Among cases of first-trimester emtricitabine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence ofbirth defects was 2.3% (21 of 899 births; 95% CI, 1.4%–3.5%) compared with a 2.7% total prevalence inthe U.S. population, based on CDC surveillance.1• Placental and breast milk passageEmtricitabine has been shown to cross the placenta in mice and rabbits; the average fetal/maternal drugconcentration was 0.4 in mice and 0.5 in rabbits.2Emtricitabine has been shown to have excellentplacental transfer in pregnant women. In 18 women who received 200 mg emtricitabine once dailyduring pregnancy, mean cord blood concentration was 300 ± 268 ng/mL and mean ratios of cordblood/maternal emtricitabine concentrations were 1.17 ± 0.6 (n = 9).3When 35 women wereadministered 400 mg of emtricitabine in combination with tenofovir at delivery, median maternal andcord concentrations were 1.02 (0.034–2.04) and 0.74 (0.0005–1.46) mg/L, respectively.4Similarly, in astudy of 26 women in P1026s who received emtricitabine during pregnancy, the mean cord:maternalblood ratio was 1.2 (90% CI, 1.0–1.5).5It is unknown if emtricitabine is excreted in human milk.• Human studies in pregnancyEmtricitabine PKs have been evaluated in 18 HIV-infected pregnant women receiving antiretroviral therapyincluding emtricitabine (200 mg once daily) at 30 to 36 weeks’ gestation and 6 to 12 weeks postpartum.3Emtricitabine exposure was modestly lower during the third trimester (8.6 µg*h/mL [5.2–15.9]) comparedwith the postpartum period (9.8 µg*h/mL [7.4–30.3]). Two-thirds (12 of 18) of pregnant women versus100% (14 of 14) of postpartum women met the AUC target (10th percentile in non-pregnant adults).Trough emtricitabine levels were also lower during pregnancy (minimum plasma concentration [Cmin] 52ng/mL [14–180]) compared with the postpartum period (86 ng/mL [women who received 400 mg of emtricitabine with tenofovir at delivery, median population AUC,maximum plasma concentration (Cmax), and Cminwere 14.3 µg*h/mL, 1,680 ng/mL, and 76 ng/mL,respectively.4In the P1026s study, 26 women had emtricitabine PKs assessed during the third trimester(median 35 weeks) and 22 postpartum (mean 8 weeks postpartum).5Comparing PKs during pregnancywith postpartum, higher emtricitabine clearance (25.0 vs. 20.6 liters/hour during pregnancy vs. postpartum,respectively) and lower 24-hour post-dose levels (0.058 vs. 0.085 mg/liter) were seen but the 24-hour post-Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-4Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.dose levels were well above the inhibitory concentration 50% (IC50) in all patients. Thus, these changesare not believed to be large enough to warrant dosage adjustment during pregnancy.References1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.2. Szczech GM, Wang LH, Walsh JP, Rousseau FS. Reproductive toxicology profile of emtricitabine in mice and rabbits.Reprod Toxicol. Jan-Feb 2003;17(1):95-108. Available at http://www.ncbi.nlm.nih.gov/pubmed/12507664.3. Hirt D, Urien S, Rey E, et al. Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Antimicrob Agents Chemother. Mar 2009;53(3):1067-1073. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19104016.4. Best B, Stek A, Hu C, et al. High-dose lopinavir and standard-dose emtricitabine pharmacokinetics during pregnancyand postpartum. Paper presented at: 15th Conference on Retroviruses and Opportunistic Infections (CROI); February 3-8, 2008; Boston, MA. Abstract 629.5. Stek AM, Best BM, Luo W, et al. Effect of pregnancy on emtricitabine pharmacokinetics. HIV Med. Apr2012;13(4):226-235. Available at http://www.ncbi.nlm.nih.gov/pubmed/22129166.Lamivudine (Epivir, 3TC)is classified as FDA Pregnancy Category C. (Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesLamivudine has weak mutagenic activity in one in vitroassay but no evidence of in vivogenotoxicity inrats at 35 to 45 times human exposure. Long-term animal carcinogenicity screening studies at 10 and 58times human exposure have been negative in mice and rats, respectively.• Reproduction/fertilityLamivudine administered to rats at doses up to 4000 mg/kg/day, producing plasma levels 47 to 70 timesthose in humans, revealed no evidence of impaired fertility and no effect on the offsprings’ survival,growth, and development up to the time of weaning.• Teratogenicity/developmental toxicity studiesThere is no evidence of lamivudine-induced teratogenicity at 35 times human plasma levels in rats andrabbits. Early embryolethality was seen in rabbits at doses similar to human therapeutic exposure but notin rats at 35 times the human exposure level.In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to lamivudine inhumans have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in the most commonly occurring birth defects, such as defects of the cardiovascular andgenitourinary systems. No such increase in birth defects has been observed with lamivudine. Amongcases of first-trimester lamivudine exposure reported to the Antiretroviral Pregnancy Registry, theprevalence of birth defects was 3.1% (127 of 4,088 births; 95% CI, 2.6%–3.7%) compared with a 2.7%total prevalence in the U.S. population, based on CDC surveillance.1• Placental and breast milk passageLamivudine readily crosses the placenta in humans, achieving comparable cord blood and maternalconcentrations.2In a study of 123 mother/infant pairs, the placental transfer expressed as fetal-to-maternal AUC ratio was 0.86, and the lamivudine amniotic fluid accumulation, expressed as the amnioticfluid-to-fetal AUC ratio, was 2.9.3Other studies have also noted amniotic fluid accumulation ofRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-5Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.lamivudine.4This is likely secondary to renal excretion of lamivudine by the fetus; lamivudine diffusesfrom maternal to fetal blood through the placenta and the fetal kidney removes lamivudine from fetalblood and concentrates it in urine, with fetal micturition causing a rise in the concentration of lamivudinein amniotic fluid.Lamivudine is excreted into human breast milk. In a study in Kenya of 67 HIV-infected nursing mothersreceiving a combination regimen of zidovudine, lamivudine, and nevirapine, the median breast milklamivudine concentration was 1214 ng/mL and the median ratio of lamivudine concentration in breastmilk to that in plasma was 2.56.5In infants who received lamivudine only via breast milk, median plasmalamivudine concentration was 23 ng/mL (half-maximal IC50of wild-type HIV against lamivudine = 0.6–21 ng/mL).• Human studies in pregnancyTwo studies have evaluated lamivudine PKs in HIV-infected pregnant women, one evaluating drug levelsin 57 mother/infant pairs on the day of delivery4and the other evaluating PKs in 20 women startinglamivudine/zidovudine at 38 weeks gestation.2These studies concluded that there was a lack of effect ofpregnancy on lamivudine PKs after 38 weeks of pregnancy. In a larger study of 114 pregnant women,123 women in labor, and 47 non-pregnant women receiving a lamivudine-containing regimen who hadsamples collected for therapeutic drug monitoring (given as 150 mg twice daily with zidovudine or 300mg once daily with abacavir), data were retrospectively analyzed using a population PK approach.3Pregnant women had a 22% higher apparent clearance than non-pregnant and postpartum women, butthis increase did not lead to subtherapeutic exposure; the level of lamivudine exposure in pregnantwomen, although lower than exposure in non-pregnant and parturient women, was relatively close todata reported previously for non-pregnant adults. Thus, no dose adjustment in pregnancy is necessary.References1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.2. Moodley J, Moodley D, Pillay K, et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or whencoadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring.J Infect Dis. Nov 1998;178(5):1327-1333. Available at http://www.ncbi.nlm.nih.gov/pubmed/9780252.3. Benaboud S, Treluyer JM, Urien S, et al. Pregnancy-related effects on lamivudine pharmacokinetics in a populationstudy with 228 women. Antimicrob Agents Chemother. Feb 2012;56(2):776-782. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22106227.4. Mandelbrot L, Peytavin G, Firtion G, Farinotti R. Maternal-fetal transfer and amniotic fluid accumulation of lamivudinein human immunodeficiency virus-infected pregnant women. Am J Obstet Gynecol. Jan 2001;184(2):153-158. Availableat http://www.ncbi.nlm.nih.gov/pubmed/11174495.5. Mirochnick M, Thomas T, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of mothersreceiving highly active antiretroviral therapy. Antimicrob Agents Chemother. Mar 2009;53(3):1170-1176. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19114673.Stavudine (Zerit, d4T)is classified as FDA Pregnancy Category C. (Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesStavudine is clastogenic in in vitroand in vivoassays but not mutagenic in in vitroassays. In 2-yearcarcinogenicity studies in mice and rats, stavudine was noncarcinogenic in doses producing exposures 39Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-6Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.(mice) and 168 (rats) times human exposure at the recommended therapeutic dose. At higher levels ofexposure (250 [mice] and 732 [rats] times human exposure at therapeutic doses), benign and malignantliver tumors occurred in mice and rats and urinary bladder tumors occurred in male rats.• Reproduction/fertilityStavudine has not been shown to have an effect on reproduction or fertility in rodents. A dose-relatedcytotoxic effect has been observed on preimplantation mouse embryos, with inhibition of blastocystformation at a concentration of 100 µM and of postblastocyst development at 10 µM.1• Teratogenicity/developmental toxicity studiesNo evidence of teratogenicity was noted in rats or rabbits with exposures (based on Cmax) up to 399 and183 times, respectively, of that seen at a clinical dosage of 1 mg/kg/day. In rat fetuses, the incidence of acommon skeletal variation—unossified or incomplete ossification of sternebra—was increased with 399times human exposure, although no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times human exposure, with no effect noted at approximately 135times human exposure. An increase in early rat neonatal mortality (birth to Day 4) occurred at 399 timeshuman exposure, although survival of neonates was unaffected at approximately 135 times the humanexposure. A study in rats showed that stavudine is transferred to the fetus through the placenta. Theconcentration in fetal tissue was approximately one-half the concentration in maternal plasma.In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to stavudine inhumans have been monitored to be able to detect at least a 2-fold increase in risk of overall birth defects.No such increase in birth defects has been observed with stavudine. Among cases of first-trimesterstavudine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was2.5% (20 of 801 births; 95% CI, 1.5%–3.8%) compared with a total prevalence in the U.S. population of2.7%, based on CDC surveillance.2• Placental and breast milk passageStavudine crosses the rat placenta in vivoand the human placenta ex vivo, resulting in a fetal/maternalconcentration of approximately 0.50. In primates (pigtailed macaques), fetal/maternal plasmaconcentrations were approximately 0.80.3Stavudine is excreted into the breast milk of lactating rats.• Human studies in pregnancyA Phase I/II safety and PK study has been conducted of combination stavudine and lamivudine inpregnant HIV-infected women and their infants (PACTG 332). Both drugs were well tolerated, withstavudine PKs similar to those in non-pregnant adults.4Data from primate studies also indicated thatpregnancy did not affect the PKs of stavudine.5Lactic acidosis, in some cases fatal, has been described in pregnant women receiving the combination ofdidanosine and stavudine along with other ARV agents.6-8The FDA and Bristol-Myers Squibb haveissued a warning to health care professionals that pregnant women may be at increased risk of fatal lacticacidosis when prescribed didanosine and stavudine in combination (see NRTI Drugs and MitochondrialToxicityin the perinatal guidelines). These drugs should be prescribed together for pregnant women onlywhen the potential benefit clearly outweighs the potential risk. Clinicians should prescribe this ARVcombination in pregnancy with caution and generally only when other nucleoside analog drugcombinations have failed or have caused unacceptable toxicity or side effects.References1. Toltzis P, Mourton T, Magnuson T. Comparative embryonic cytotoxicity of antiretroviral nucleosides. J Infect Dis. May1994;169(5):1100-1102. Available at http://www.ncbi.nlm.nih.gov/pubmed/8169400.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-7Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.2. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.3. Odinecs A, Nosbisch C, Keller RD, Baughman WL, Unadkat JD. In vivomaternal-fetal pharmacokinetics of stavudine(2,3-didehydro-3-deoxythymidine) in pigtailed macaques (Macaca nemestrina). Antimicrob Agents Chemother. Jan1996;40(1):196-202. Available at http://www.ncbi.nlm.nih.gov/pubmed/8787905.4. Wade NA, Unadkat JD, Huang S, et al. Pharmacokinetics and safety of stavudine in HIV-infected pregnant women andtheir infants: Pediatric AIDS Clinical Trials Group protocol 332. J Infect Dis. Dec 15 2004;190(12):2167-2174.Available at http://www.ncbi.nlm.nih.gov/pubmed/15551216.5. Odinecs A, Pereira C, Nosbisch C, Unadkat JD. Prenatal and postpartum pharmacokinetics of stavudine (2,3-didehydro-3-deoxythymidine) and didanosine (dideoxyinosine) in pigtailed macaques (Macaca nemestrina). AntimicrobAgents Chemother. Oct 1996;40(10):2423-2425. Available at http://www.ncbi.nlm.nih.gov/pubmed/8891157.6. Bristol-Myers Squibb Company. Healthcare Provider Important Drug Warning Letter. January 5, 2001. 2001. Availableat http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm173947.htm7. Sarner L, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positivewomen taking antiretroviral medication. Sex Transm Infect. Feb 2002;78(1):58-59. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11872862.8. Mandelbrot L, Kermarrec N, Marcollet A, et al. Case report: nucleoside analogue-induced lactic acidosis in the thirdtrimester of pregnancy. AIDS. Jan 24 2003;17(2):272-273. Available at http://www.ncbi.nlm.nih.gov/pubmed/12545093.Tenofovir disoproxil fumarate (Viread, TDF)is classified as FDA Pregnancy Category B. (Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesTenofovir is mutagenic in one of two in vitroassays and has no evidence of clastogenic activity. Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at 16times (mice) and 5 times (rats) human exposure. In female mice, liver adenomas were increased atexposures 16 times that observed in humans at therapeutic doses. In rats, the study was negative forcarcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.• Reproduction/fertilityReproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the humandose based on body surface area comparisons and revealed no evidence of impaired fertility or harm tothe fetus associated with tenofovir. There were also no effects on fertility, mating performance, or earlyembryonic development when tenofovir disoproxil fumarate was administered to male rats (600mg/kg/day; equivalent to 10 times the human dose based on body surface area) for 28 days before matingand to female rats for 15 days before mating through Day 7 of gestation. There was, however, analteration of the estrous cycle in female rats administered 600 mg/kg/day.• Teratogenicity/developmental toxicityChronic exposure of fetal monkeys to tenofovir at a high dose of 30 mg/kg (exposure equivalent to 25times the AUC achieved with therapeutic dosing in humans) from Days 20 to 150 of gestation did notresult in gross structural abnormalities.1However, significantly lower fetal circulating insulin-like growthfactor (IGF)-1 (a primary regulator of linear growth) and higher IGF binding protein-3 levels were shownand were associated with overall body weights approximately 13% lower than untreated controls. Aslight reduction in fetal bone porosity was also observed. Effects on these parameters were observedwithin 2 months of maternal treatment. Significant changes in maternal monkey bone biomarkers werenoted but were primarily limited to the treatment period and were reversible.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-8Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Continued administration of tenofovir at 30 mg/kg/day to infant monkeys resulted in significant growthrestriction and severe bone toxicity in 2 of 8 (25%) infants and effects on bone biomarkers and defectivebone mineralization in all animals. Chronic administration of tenofovir to immature animals of multiplespecies has resulted in reversible bone abnormalities; these effects were dose, exposure, age, and speciesspecific. Abnormalities ranged from minimal decrease in bone mineral density and content (with oraldosing in rats and dogs that achieved drug exposures 6 to 10 times that achieved with therapeutic dosingin humans) to severe, pathologic osteomalacia (with subcutaneous [SQ] dosing given to monkeys).Juvenile monkeys given chronic SQ tenofovir at 30 mg/kg/day (exposure equivalent to 25 times the AUCachieved with therapeutic dosing in humans) developed osteomalacia, bone fractures, and markedhypophosphatemia. However, no clinical or radiologic bone toxicity was seen when juvenile monkeysreceived SQ dosing of 10 mg/kg/day (exposure equivalent to 8 times the AUC achieved with therapeuticdosing in humans). Evidence of nephrotoxicity was observed in newborn and juvenile monkeys giventenofovir in doses resulting in exposures 12 to 50 times higher than the human dose, based on bodysurface area comparisons.In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to tenofovir inhumans have been monitored to be able to detect at least a 2-fold increase in risk of overall birth defects.No such increase in birth defects has been observed with tenofovir. Among cases of first-trimestertenofovir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was2.3% (31 of 1,370 births; 95% CI, 1.5%–3.2%) compared with a 2.7% total prevalence in the U.S.population, based on CDC surveillance.2• Placental and breast milk passageStudies in rats have demonstrated that tenofovir is secreted in milk. Intravenous administration oftenofovir to pregnant cynomolgus monkeys resulted in a fetal/maternal concentration of 17%,demonstrating that tenofovir does cross the placenta.3In studies of pregnant women on chronic dosing,the cord-to-maternal blood ratio ranged from 0.60 to 1.03, indicating high placental transfer.4-7In a studyof 31 pregnant women receiving single-dose tenofovir (with and without emtricitabine) in labor, thedrugs were well-tolerated and the median tenofovir cord-to-maternal blood ratio at delivery was 0.73(range, 0.26 to 1.95).8In a study evaluating intracellular tenofovir levels in newborns, intracellulartenofovir concentrations were detected in the peripheral blood mononuclear cells from cord blood in allinfants after a maternal single dose of 600 mg tenofovir with 400 mg emtricitabine, but intracellulartenofovir diphosphate was detectable in only 2 (5.5%) of 36.9Neonatal dosing of tenofovir resulted intenofovir and tenofovir diphosphate levels similar to those in adults.9Among women receiving a single 600-mg dose during labor, tenofovir was detectable in only 4 of 25(16%) breast milk samples during the first week after delivery, with a median concentration of 13 (range6–18) ng/mL.8In another study, 16 breast milk samples were obtained from 5 women who received 600mg of tenofovir at the start of labor followed by 300 mg daily for 7 days. Tenofovir levels in breast milkranged from 5.8 to 16.3 ng/mL, and nursing infants received an estimated 0.03% of the proposed oraldose of tenofovir for neonates.10• Human studies in pregnancyA retrospective population PK study was performed on samples collected for therapeutic drug monitoringfrom 46 pregnant women and 156 non-pregnant women receiving combination regimens includingtenofovir.11Pregnant women had a 39% higher apparent clearance compared with non-pregnant women,which decreased slightly but significantly with increasing age. In study P1026s, tenofovir PKs wereevaluated in 19 pregnant women receiving tenofovir-based combination therapy at 30 to 36 weeks’gestation and 6 to 12 weeks postpartum.4The percentage of women with tenofovir AUC exceeding thetarget of 2 μg*hour/mL (the 10th percentile in non-pregnant adults) was lower in the third trimester(74%, 14 of 19 women) than postpartum (86%, 12 of 14 women) (P= .02); however, trough levels wereRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-9Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.similar in the two groups. At the present time, standard dosing during pregnancy continues to berecommended.A recent case series found tenofovir to be well tolerated among 76 pregnant women, with only 2 stoppingtherapy, 1 for rash and the other for nausea. All 78 infants were healthy with no signs of toxicity, and allwere HIV uninfected.12A follow-up study of 20 of the tenofovir-exposed infants and 20 controls foundno differences between the groups in renal function, including cystatin C levels, through age 2 years.13Aretrospective review of 16 pregnancy outcomes in 15 heavily ARV experienced women demonstratedthat tenofovir was well tolerated by the women and associated with normal growth and development inthe infants.14In a cross-sectional study of 68 HIV-exposed uninfected infants who had in uteroexposureto combination regimens with (N = 33) or without (N = 35) tenofovir, the incidence of low birth weightand length measurements (thpercentile) was comparable in the two groups and evaluation ofquantitative bone ultrasound and parameters of bone metabolism gave similar measures betweengroups.15The Pediatric HIV/AIDS Cohort Study from the United States reported on the association oftenofovir use during pregnancy with early growth parameters in 449 HIV-exposed but -uninfectedinfants.16Of 2,029 infants, 449 (21%) had in uteroexposure to tenofovir. There was no difference atbirth between those exposed to combination drug regimens with or without tenofovir for low birthweight, small-for-gestational-age, and newborn length-for-age and head circumference-for-age z-scores(LAZ and HCAZ, respectively). At age 1 year, infants exposed to combination regimens with tenofovirhad a slight but significantly lower adjusted mean LAZ and HCAZ than those without tenofovir exposure(LAZ: -0.17 vs. -0.03, P= .04; HCAZ: 0.17 vs. 0.42, P= .02), but not lower weight-for-age z-score.However, there were no significant differences between those with and without tenofovir exposure at age1 year when defining low LAZ or HCAZ as HCAZ scores are of uncertain significance.References1. Tarantal AF, Castillo A, Ekert JE, Bischofberger N, Martin RB. Fetal and maternal outcome after administration oftenofovir to gravid rhesus monkeys (Macaca mulatta). J Acquir Immune Defic Syndr. Mar 1 2002;29(3):207-220.Available at http://www.ncbi.nlm.nih.gov/pubmed/11873070.2. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.3. Tarantal AF, Marthas ML, Shaw JP, Cundy K, Bischofberger N. Administration of 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) to gravid and infant rhesus macaques (Macaca mulatta): safety andefficacy studies. J Acquir Immune Defic Syndr Hum Retrovirol. Apr 1 1999;20(4):323-333. Available athttp://www.ncbi.nlm.nih.gov/pubmed/10096575.4. Burchett S, Best B, Mirochnick M, et al.Tenofovir pharmacokinetics during pregnancy, at delivery, and postpartum.Paper presented at: 14th Conference on Retroviruses and Opportunistic Infections (CROI); February 25-28, 2007; LosAngeles, CA. Abstract 738b.5. Bonora S, de Requena DG, Chiesa E, et al.Transplacental passage of tenofovir and other ARVs at delivery. Paperpresented at: 14th Conference on Retoviruses and Opportunistic Infections (CROI); February 25-28, 2007; Los Angeles,CA. Abstract 738a.6. Hirt D, Urien S, Rey E, et al. Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Antimicrob Agents Chemother. Mar 2009;53(3):1067-1073. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19104016.7. Colbers A, Taylor G, et al.A comparison of the pharmacokinetics of tenofovir during pregnancy and post-partum. Paperpresented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; April 16-18, 2012; Barcelona,Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-10Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Spain. Abstract P34.8. Flynn PM, Mirochnick M, Shapiro DE, et al. Pharmokinetics and Safety of Single-Dose Tenofovir Disoproxil Fumarateand Emtricitabine in HIV-1-Infected Pregnant Women and Their Infants. Antimicrob Agents Chemother. Dec2011;55(12):5914-22. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232794/?tool=pmcentrez.9. Hirt D, Ekouevi DK, Pruvost A, et al. Plasma and intracellular tenofovir pharmacokinetics in the neonate (ANRS 12109trial, step 2). Antimicrob Agents Chemother. Jun 2011;55(6):2961-2967. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21464249.10. Benaboud S, Pruvost A, Coffie PA, et al. Concentrations of tenofovir and emtricitabine in breast milk of HIV-1-infectedwomen in Abidjan, Cote dIvoire, in the ANRS 12109 TEmAA Study, Step 2. Antimicrob Agents Chemother. Mar2011;55(3):1315-1317. Available at http://www.ncbi.nlm.nih.gov/pubmed/21173182.11. Benaboud S, Hirt D, Launay O, et al. Pregnancy-related effects on tenofovir pharmacokinetics: a population study with186 women. Antimicrob Agents Chemother. Feb 2012;56(2):857-862. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22123690.12. Haberl A, Linde R, Reittner A, et al. Safety and efficacy of tenofovir in pregnant women. Paper presented at: 15thConference on Retroviruses and Opportunistic Infections (CROI); February 3-6, 2008; Boston, MA. Abstract 627a.13. Linde R, Konigs C, Rusicke E, Haberl A, Reitter A, Dreuz W. Tenofovir therapy during pregnancy does not affect renalfunction in HIV-exposed children. Paper presented at: 17th Conference on Retoviruses and Opportunistic Infections(CROI); February 27-March 2, 2010; San Francisco, CA. Abstract 925.14. Nurutdinova D, Onen NF, Hayes E, Mondy K, Overton ET. Adverse effects of tenofovir use in HIV-infected pregnantwomen and their infants. Ann Pharmacother.Nov 2008;42(11):1581-1585. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18957630.15. Vigano A, Mora S, Giacomet V, et al. In uteroexposure to tenofovir disoproxil fumarate does not impair growth andbone health in HIV-uninfected children born to HIV-infected mothers. Antivir Ther. 2011;16(8):1259-1266. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22155907.16. Siberry GK, Williams PL, Mendez H, et al. Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS. Jun 1 2012;26(9):1151-1159. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22382151.Zalcitabine (HIVID, ddC)is no longer available in the United States.(Last updated September 14, 2011; last reviewed July 31, 2012)Zidovudine (Retrovir, AZT, ZDV)is classified as FDA Pregnancy Category C.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesZidovudine was shown to be mutagenic in two in vitroassays and clastogenic in one in vitroand two invivoassays, but not cytogenic in a single-dose in vivorat study. Long-term carcinogenicity studies havebeen performed with zidovudine in mice and rats.1In mice, seven late-appearing (>19 months) vaginalneoplasms (five nonmetastasizing squamous cell carcinomas, one squamous cell papilloma, and onesquamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papillomaoccurred in the vagina of an animal given an intermediate dose. No vaginal tumors were found at thelowest dose. In rats, two late-appearing (>20 months), nonmetastasizing vaginal squamous cell carcinomasoccurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats.No other drug-related tumors were observed in either sex in either species. At doses that produced tumorsin mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse)Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-11Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4hours. How predictive the results of rodent carcinogenicity studies may be for humans is unknown.Two transplacental carcinogenicity studies were conducted in mice.2, 3In one study, zidovudine wasadministered at doses of 20 mg/kg/day or 40 mg/kg/day from gestation Day 10 through parturition andlactation, with postnatal dosing continuing in offspring for 24 months.3The drug doses administered inthis study produced zidovudine exposures approximately 3 times the estimated human exposure atrecommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with noincrease in tumors in the liver or lung or any other organ in either gender. These findings are consistentwith results of the standard oral carcinogenicity study in mice, as described earlier. In a second study,zidovudine was administered at maximum tolerated doses of 12.5 mg/day or 25 mg/day (~1000 mg/kgnon-pregnant body weight or ~450 mg/kg of term body weight) to pregnant mice from Days 12 to 18 ofgestation.2There was an increase in the number of tumors in the lung, liver, and female reproductivetracts in the offspring of mice receiving the higher dose level of zidovudine.• Reproduction/fertilityWhen administered to male and female rats at doses up to 7 times the usual adult dose based on bodysurface area, zidovudine had no effect on fertility, as judged by rates of conception.Zidovudine has been shown to have no effect on reproduction or fertility in rodents. A dose-relatedcytotoxic effect on preimplantation mouse embryos can occur, with inhibition of blastocyst andpostblastocyst development at zidovudine concentrations similar to levels achieved with humantherapeutic doses.4• Teratogenicity/developmental toxicityOral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence ofteratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity, as evidenced byan increase in the incidence of fetal resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500mg/kg/day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations(after one-half of the daily dose) in rats 66 to 226 times and in rabbits 12 to 87 times mean steady-statepeak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommendeddaily dose (100 mg every 4 hours). In an in vitroexperiment with fertilized mouse oocytes, zidovudineexposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratologystudy in rats, a dose of 3000 mg/kg/day (very near the oral median lethal dose in rats of 3683 mg/kg)caused marked maternal toxicity and an increase in incidence of fetal malformations. This dose resultedin peak zidovudine plasma concentrations 350 times peak human plasma concentrations. (EstimatedAUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day.) No evidenceof teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less. Increased fetal resorption occurred in pregnant rats and rabbits treated with zidovudine doses thatproduced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100-mg dose of zidovudine. No otherdevelopmental anomalies were reported. In another developmental toxicity study, pregnant rats receivedzidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak humanplasma concentrations (300 times the daily AUC in humans given 600 mg/day zidovudine). This dosewas associated with marked maternal toxicity and an increased incidence of fetal malformations.However, there were no signs of teratogenicity at doses up to one-fifth the lethal dose.In humans, in the placebo-controlled perinatal trial PACTG 076, the incidence of minor and majorcongenital abnormalities was similar between zidovudine and placebo groups and no specific patterns ofdefects were seen.5, 6A report from the Women and Infants Transmission Study, a cohort study enrollingRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-12Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.women during pregnancy, described an association between first-trimester exposure to zidovudine and a10-fold increased risk of hypospadias.7However, in the Antiretroviral Pregnancy Registry, sufficientnumbers of first-trimester exposures to zidovudine have been monitored to be able to detect at least a1.5-fold increase in risk of overall birth defects and a 2-fold increase in defects in the more commonclasses, defects of the cardiovascular and genitourinary systems. No such increase in birth defects hasbeen observed with zidovudine. With first-trimester zidovudine exposure, the prevalence of birth defectswas 3.3% (124 of 3,789 births; 95% CI, 2.7%–3.9%) compared with a total prevalence in the U.S.population of 2.7%, based on CDC surveillance.8• Placental and breast milk passageZidovudine rapidly crosses the human placenta, achieving cord-to-maternal blood ratios of about 0.80.Zidovudine is excreted into human breast milk. In one study in Kenya in 67 mothers receiving acombination regimen of zidovudine, lamivudine, and nevirapine, zidovudine concentration in the breastmilk of mothers averaged 9 ng/mL and the ratio of breast milk to maternal plasma zidovudineconcentration averaged 44%.9No zidovudine was detectable in the plasma of the nursing infants, whoreceived zidovudine only via breast milk. • Human studies in pregnancyZidovudine is well tolerated in pregnancy at recommended adult doses and in the full-term neonate at 2mg/kg body weight orally every 6 hours.5, 10Long-term data on the safety of in uterodrug exposure inhumans are not available for any ARV drug; however, short-term data on the safety of zidovudine arereassuring. In PACTG 076, no difference in disease progression was seen between women who receivedzidovudine and those who received placebo, based on follow-up through 4 years postpartum.11Additionally, no differences in immunologic, neurologic, or growth parameters were seen betweeninfants with in uterozidovudine exposure and those who received placebo, based on nearly 6 years offollow-up.6, 12References1. Ayers KM, Clive D, Tucker WE, Jr., Hajian G, de Miranda P. Nonclinical toxicology studies with zidovudine: genetictoxicity tests and carcinogenicity bioassays in mice and rats. Fundam Appl Toxicol. Aug 1996;32(2):148-158. Availableat http://www.ncbi.nlm.nih.gov/pubmed/8921318.2. Olivero OA, Anderson LM, Diwan BA, et al. Transplacental effects of 3-azido-2,3-dideoxythymidine (AZT):tumorigenicity in mice and genotoxicity in mice and monkeys. J Natl Cancer Inst. 1997;89(21):1602-1608. Available athttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9362158&dopt=Abstract.3. Ayers KM, Torrey CE, Reynolds DJ. A transplacental carcinogenicity bioassay in CD-1 mice with zidovudine. FundamAppl Toxicol. Aug 1997;38(2):195-198. Available at http://www.ncbi.nlm.nih.gov/pubmed/9299194.4. Toltzis P, Marx CM, Kleinman N, Levine EM, Schmidt EV. Zidovudine-associated embryonic toxicity in mice. J InfectDis. Jun 1991;163(6):1212-1218. Available at http://www.ncbi.nlm.nih.gov/pubmed/2037787.5. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virustype 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. Nov3 1994;331(18):1173-1180. Available at http://www.ncbi.nlm.nih.gov/pubmed/7935654.6. Sperling RS, Shapiro DE, McSherry GD, et al. Safety of the maternal-infant zidovudine regimen utilized in thePediatric AIDS Clinical Trial Group 076 Study. AIDS. Oct 1 1998;12(14):1805-1813. Available athttp://www.ncbi.nlm.nih.gov/pubmed/9792381.7. Watts DH, Li D, Handelsman E, et al. Assessment of birth defects according to maternal therapy among infants in theWomen and Infants Transmission Study. J Acquir Immune Defic Syndr. Mar 1 2007;44(3):299-305. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17159659.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-13Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.8. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.9. Mirochnick M, Thomas T, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of mothersreceiving highly active antiretroviral therapy. Antimicrob Agents Chemother. Mar 2009;53(3):1170-1176. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19114673.10. OSullivan MJ, Boyer PJ, Scott GB, et al. The pharmacokinetics and safety of zidovudine in the third trimester ofpregnancy for women infected with human immunodeficiency virus and their infants: phase I acquiredimmunodeficiency syndrome clinical trials group study (protocol 082). Zidovudine Collaborative Working Group. Am JObstet Gynecol. 1993;168(5):1510-1516. Available athttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8098905.11. Bardeguez AD, Shapiro DE, Mofenson LM, et al. Effect of cessation of zidovudine prophylaxis to reduce verticaltransmission on maternal HIV disease progression and survival. J Acquir Immune Defic Syndr. Feb 1 2003;32(2):170-181. Available at http://www.ncbi.nlm.nih.gov/pubmed/12571527.12. Culnane M, Fowler M, Lee SS, et al. Lack of long-term effects of in uteroexposure to zidovudine among uninfectedchildren born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams. JAMA. Jan 131999;281(2):151-157. Available at http://www.ncbi.nlm.nih.gov/pubmed/9917118.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-14Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-15Non-Nucleoside Reverse Transcriptase Inhibitors Five non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) currently are approved (delavirdineis no longer available in the United States). Nevirapine and efavirenz have been studied in human pregnancy.No adequate and well-controlled studies of etravirine or rilpivirine use in pregnant women have beenconducted.For information about potential interactions between NNRTIs and methergine, see Postpartum Hemorrhage,Antiretroviral Drugs, and Methergine Use in the perinatal guidelines. For more information regardingnevirapine hepatic/rash toxicity, see Nevirapine and Hepatic/Rash Toxicity in the perinatal guidelines.Delavirdine (Rescriptor, DLV) is no longer available in the United States.(Last updated September 14, 2011; last reviewed July 31, 2011)Efavirenz (Sustiva, EFV) is classified as Food and Drug Administration (FDA) Pregnancy Category D.(Last updated July 31, 2011; last reviewed July 31, 2011)• Animal carcinogenicity studiesEfavirenz was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests.Long-term animal carcinogenicity studies with efavirenz have been completed in mice and rats. Atsystemic drug exposures approximately 1.7-fold higher than in humans receiving standard therapeuticdoses, no increase in tumor incidence above background was observed in male mice, but in female mice,an increase above background was seen in hepatocellular adenomas and carcinomas and pulmonaryalveolar/bronchiolar adenomas. No increase in tumor incidence above background was observed in maleand female rats with systemic drug exposures lower than that in humans receiving therapeutic doses.• Reproduction/fertility animal studiesNo effect of efavirenz on reproduction or fertility in rodents has been seen. • Teratogenicity/developmental toxicityAn increase in fetal resorption was observed in rats at efavirenz doses that produced peak plasmaconcentrations and area under the curve (AUC) values in female rats equivalent to or lower than thoseachieved in humans at the recommended human dose (600 mg once daily). Efavirenz produced noreproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrationssimilar to and AUC values approximately half of those achieved in humans administered efavirenz (600Glossary of Terms for SupplementCarcinogenic = producing or tending to produce cancer• Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic.• Genetic mutations and/or chromosomal damage can contribute to cancer formation.Clastogenic = causing disruption of or breakages in chromosomesGenotoxic = damaging to genetic material such as DNA and chromosomesMutagenic = inducing or capable of inducing genetic mutationTeratogenic = interfering with fetal development and resulting in birth defectsDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.mg once daily). Central nervous system (CNS) malformations and cleft palate were observed in 3 of 20infants born to pregnant cynomolgus monkeys receiving efavirenz from gestational Days 20 to 150 at adose of 30 mg/kg twice daily (resulting in plasma concentrations comparable to systemic humantherapeutic exposure).1The malformations included anencephaly and unilateral anophthalmia in onefetus, microphthalmia in another fetus, and cleft palate in a third fetus.• Placental and breast milk passageEfavirenz crosses the placenta in rats, rabbits, and primates, producing cord blood concentrations similarto concentrations in maternal plasma. In a study of 13 women in Rwanda, efavirenz was given during thelast trimester of pregnancy and for 6 months after delivery.2Efavirenz concentrations were measured inmaternal plasma, breast milk, and infant plasma. Efavirenz passed into breast milk with a ratio of 0.54(mean breast milk to mean maternal plasma concentration) and 4.08 (mean skim milk to mean newbornplasma concentration). Mean infant plasma efavirenz concentrations were 13.1% of maternal plasmalevels. No data currently are available about efavirenz in neonates. • Human studies in pregnancyIn pregnancies with prospectively reported exposure to efavirenz-based regimens in the AntiretroviralPregnancy Registry through January 2012, birth defects were observed in 18 of 679 live births with first-trimester exposure (2.7%, 95% confidence interval [CI], 1.6%–4.2%).3Although these data providesufficient numbers of first-trimester exposures to rule out a 2-fold or greater increase in the risk ofoverall birth defects, the low incidence of neural tube defects in the general population means that alarger number of exposures are still needed to be able to definitively rule out an increased risk of thisspecific defect. Prospective reports to the Antiretroviral Pregnancy Registry of defects after first-trimester efavirenz exposure have documented 1 neural tube defect case (sacral aplasia,myelomeningocele, and hydrocephalus with fetal alcohol syndrome) and 1 case of bilateral facial clefts,anophthalmia, and amniotic band.3Among retrospective cases, there are 6 reports of CNS defects,including 3 cases of meningomyelocele in infants born to mothers receiving efavirenz during the firsttrimester.4Retrospective reports can be biased toward reporting of more unusual and severe cases and areless likely to be representative of the general population experience.In an updated meta-analysis of 19 studies (including the Antiretroviral Pregnancy Registry data)reporting on birth outcomes among women exposed to efavirenz during the first trimester, there were 39infants with birth defects among live births in 1,437 women receiving first-trimester efavirenz (rate ofoverall birth defects, 2.0%, 95% CI, 0.8–3.2%).5The rate of overall birth defects was similar amongwomen exposed to efavirenz-containing regimens (1,290 live births) and non-efavirenz containingregimens (8,122 births) during the first trimester (pooled relative risk [RR] 0.85, 95% CI, 0.61–1.20).Across all births (1,437 live births with first-trimester efavirenz exposure), 1 neural tube defect(myelomeningocele) was observed, giving a point prevalence of 0.07% (95% CI, 0.002–0.39), within therange reported in the general population. However, the number of reported first-trimester efavirenzexposures still remains insufficient to rule out a significant increase in low-incidence birth defects(incidence of neural tube defects in the general U.S. population is 0.02%–0.2%).In contrast to the meta-analysis, the Pediatric AIDS Clinical Trials Protocols (PACTG) 219 and 219Cstudies reported a higher defect rate among infants with first-trimester exposure to efavirenz comparedwith those without such exposure (adjusted odds ratio 4.31, 95% CI, 1.56–11.86). However, only 32infants had efavirenz exposure. The PACTG protocol P1025 is a companion study of PACTG 219 withconsiderable overlap of the cases enrolled. Whereas the P1025 study reported a significant increased riskof congenital anomalies in infants born between 2002 and 2007 with first-trimester exposure toefavirenz, there is overlap in the defect cases between the two studies and only 42 infants are included inthis analysis. Thus, additional data are needed on first-trimester efavirenz exposures to more conclusivelyRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-16Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.determine if risk of neural tube defects is elevated.Efavirenz is classified as FDA Pregnancy Category D, which means that there is positive evidence ofhuman fetal risk based on studies in humans, but potential benefits may warrant use of the drug in pregnantwomen despite potential risks. Although the limited data on first-trimester efavirenz exposure cannot ruleout a 2- or 3-fold increased incidence of a rare outcome, such as neural tube defects, the available data fromthe meta-analysis on >1,400 births suggest that there is not a large increase (such as a 10-fold increase) inthe risk of neural tube defects with first-trimester exposure. Because of the potential for teratogenicity,pregnancy should be avoided in women receiving efavirenz, and treatment with efavirenz should beavoided during the first trimester (the primary period of fetal organogenesis) whenever possible. Women ofchildbearing potential should undergo pregnancy testing before initiation of efavirenz and should becounseled about the potential risk to the fetus and desirability of avoiding pregnancy. Alternateantiretroviral (ARV) regimens that do not include efavirenz should be strongly considered in women whoare planning to become pregnant or who are sexually active and not using effective contraception if suchalternative regimens are acceptable to provider and patient and will not compromise the woman’s health.However, given that the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy (theneural tube closes at 36–39 days after last menstrual period), pregnancy is rarely recognized before 4 to 6weeks of pregnancy, and ARV drug changes in pregnancy may be associated with loss of viral control andthus increase risk of transmission to the infant,6efavirenz can be continued in pregnant women receivingefavirenz-based antiretroviral therapy (ART) who present for antenatal care in the first trimester, providedthat the regimen produces virologic suppression. In such situations, additional fetal monitoring (such assecond-trimester ultrasound) should be considered to evaluate fetal anatomy.Higher rates of failure for hormonal contraceptives containing estrogen and progesterone may beassociated with ARV drugs such as efavirenz. Alternate ARV regimens that do not include efavirenzshould be strongly considered in women who are planning to become pregnant or who are sexuallyactive and not using effective contraception if such alternative regimens are acceptable to provider andpatient and will not compromise the woman’s health. Barrier contraception should always be used incombination with other methods of contraception such as hormonal contraceptives and intrauterinedevices. A study evaluating the interaction between efavirenz and depot medroxyprogesetrone (DMPA)in 17 women found no change in the pharmacokinetic (PK) profile of either efavirenz or DMPA withconcomitant use.7DMPA levels remained above the level needed for inhibition of ovulation throughoutthe dosing interval.Limited PK data exist for efavirenz in pregnancy. In a study of 25 pregnant women receiving efavirenzduring the third trimester as part of clinical care, efavirenz clearance was increased and clearance after 24hours was decreased compared with postpartum. These differences are not of sufficient magnitude towarrant dose adjustment during pregnancy.8References1. Nightingale SL. From the Food and Drug Administration. JAMA. Nov 4 1998;280(17):1472.Available athttp://www.ncbi.nlm.nih.gov/pubmed/9809716.2. Schneider S, Peltier A, Gras A, et al. Efavirenz in human breast milk, mothers, and newborns plasma. J Acquir ImmuneDefic Syndr. Aug 1 2008;48(4):450-454. Available at http://www.ncbi.nlm.nih.gov/pubmed/18614925.3. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center. 2012. Available athttp://www.APRegistry.com.4. Bristol-Myers Squibb Company. Efavirenz drug label. Revised June 2012. Available atRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-17Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020972s041,021360s029lbl.pdf. Accessed on June 25, 2012.5. Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review andmeta-analysis. AIDS. Nov 28 2011;25(18):2301-2304. Available at http://www.ncbi.nlm.nih.gov/pubmed/21918421.6. Floridia M, Ravizza M, Pinnetti C, et al. Treatment change in pregnancy is a significant risk factor for detectable HIV-1RNA in plasma at end of pregnancy. HIV Clin Trials. Nov-Dec 2010;11(6):303-311. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21239358.7. Cohn SE, Park JG, Watts DH, et al. Depo-medroxyprogesterone in women on antiretroviral therapy: effectivecontraception and lack of clinically significant interactions. Clin Pharmacol Ther. Feb 2007;81(2):222-227. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17192768.8. Cressey TR, Stek A, Capparelli E, et al. Efavirenz pharmacokinetics during the third trimester of pregnancy andpostpartum. J Acquir Immune Defic Syndr. Mar 1 2012;59(3):245-252. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22083071.Etravirine (Intelence, ETV) is classified as FDA Pregnancy Category B. (Last updated July 31, 2011; last reviewed July 31, 2011)• Animal carcinogenicity studiesEtravirine was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests.Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for upto approximately 104 weeks. Daily doses of 50, 200, and 400 mg/kg were administered to mice anddoses of 70, 200, and 600 mg/kg were administered to rats in the initial period of approximately 41 to 52weeks. The high and middle doses were subsequently adjusted because of tolerability and reduced by50% in mice and by 50% to 66% in rats to allow for completion of the studies. In the mouse study,statistically significant increases in the incidences of hepatocellular carcinoma and incidences ofhepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, nostatistically significant increases in tumor findings were observed in either sex. The relevance to humansof these liver tumor findings in mice is unknown. Because of tolerability of the formulation in theserodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those inhumans at the clinical dose (400 mg/day), with animal versus human AUC ratios being 0.6-fold (mice)and 0.2 to 0.7-fold (rats).• Reproduction/fertilityNo effect on fertility and early embryonic development was observed when etravirine was tested in ratsat maternal doses up to 500 mg/kg/day, resulting in systemic drug exposure equivalent to therecommended human dose (400 mg/day).• Teratogenicity/developmental toxicityAnimal reproduction studies in rats and rabbits at systemic exposures equivalent to those at therecommended human dose of 400 mg/day revealed no evidence of fetal toxicity or altered development.Developmental toxicity studies were performed in rabbits (at oral doses up to 375 mg/kg/day) and rats (atoral doses up to 1000 mg/kg/day). In both species, no treatment-related embryo-fetal effects, includingmalformations, were observed. In addition, no treatment effects were observed in a separate pre- andpostnatal study performed in rats at oral doses up to 500 mg/kg/day. The systemic exposures achieved inthese animal studies were equivalent to those at the recommended human dose (400 mg/day).• Placental and breast milk passageThere are no data on whether etravirine crosses the placenta or is excreted in breast milk in humans.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-18Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.• Human studies in pregnancyNo adequate and well-controlled studies of etravirine use in pregnant women have been conducted andvery limited case report data are available on etravirine use in pregnancy. One small study described useof etravirine in combination with darunavir/ritonavir and other ARV drugs in four pregnant women; PKsampling was done to determine etravirine plasma concentration during the third trimester.1PK data fromthese women were similar to those in non-pregnant adults. Data on etravirine in postpartum cord bloodand concurrent maternal plasma specimens were available for one patient with values of 112 ng/mL and339 ng/mL (cord/maternal blood ratio 0.33). No maternal, fetal, or neonatal toxicity was reported; oneinfant was born with a small accessory auricle on the right ear with no other malformations; no birthdefects were noted in the other children. Placental passage of etravirine was noted in another report ofuse of etravirine, darunavir/ritonavir, and enfuvirtide in a pregnant woman who gave birth to twins (cordblood levels 414 ng/mL in Twin 1 and 345 ng/mL in Twin 2).2In a separate report on two womenreceiving etravirine, darunavir/ritonavir, and raltegravir during pregnancy, no perinatal transmission ofHIV or congenital abnormalities were observed.3References1. Izurieta P, Kakuda TN, Feys C, Witek J. Safety and pharmacokinetics of etravirine in pregnant HIV-1-infected women.HIV Med. Apr 2011;12(4):257-258. Available at http://www.ncbi.nlm.nih.gov/pubmed/21371239.2. Furco A, Gosrani B, Nicholas S, et al. Successful use of darunavir, etravirine, enfuvirtide and tenofovir/emtricitabine inpregnant woman with multiclass HIV resistance. AIDS. Jan 28 2009;23(3):434-435. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19188762.3. Jaworsky D, Thompson C, Yudin MH, et al. Use of newer antiretroviral agents, darunavir and etravirine with or withoutraltegravir, in pregnancy: a report of two cases. Antivir Ther. 2010;15(4):677-680. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20587860.Nevirapine (Viramune, NVP) is classified as FDA Pregnancy Category B.(Last updated July 31, 2012; last reviewed July 13, 2012)• Animal carcinogenicity studiesNevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivostudies. Hepatocellular adenomas and carcinomas were increased at all doses in male mice and rats andat higher doses in female mice and rats. Systemic exposure at all doses studied was lower than systemicexposure in humans receiving therapeutic nevirapine doses. Given the lack of genotoxic activity ofnevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine-treated mice and rats isunknown.• Reproduction/fertilityEvidence of impaired fertility was seen in female rats at nevirapine doses providing systemic exposurecomparable to human therapeutic exposure.• Teratogenicity/developmental toxicityTeratogenic effects of nevirapine have not been observed in reproductive studies with rats and rabbits atsystemic exposures approximately equivalent to or 50% greater than the recommended human dose(based on AUC). In rats, however, a significant decrease in fetal weight occurred at doses producingsystemic concentrations approximately 50% higher than human therapeutic exposure.In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to nevirapine inRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-19Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.humans have been monitored to be able to detect at least a 1.5-fold increase in risk of overall birthdefects and a 2-fold increase in risk of birth defects in the more common classes, cardiovascular andgenitourinary systems. No such increase in birth defects has been observed with nevirapine. Amongcases of first-trimester nevirapine exposure reported to the Antiretroviral Pregnancy Registry, theprevalence of birth defects was 2.7% (28 of 1,020 births; 95% CI, 1.8%–4.0 %) compared with a totalprevalence of 2.7% in the U.S. population, based on Centers for Disease Control and Preventionsurveillance.1• Placental and breast milk passageNevirapine crosses the placenta and achieves neonatal blood concentrations equivalent to that in themother (cord-to-maternal blood ratio approximately 0.90).2Nevirapine is excreted into human breastmilk; the median concentration in 4 breast milk samples obtained from 3 women during the first weekafter delivery was approximately 76% (range 54%–104%) of serum levels.2In 19 women receivingcombination therapy with nevirapine, lamivudine, and zidovudine, breast milk nevirapine concentrationwas 6,795 ng/mL, which was 0.67 times that of maternal serum.3Median nevirapine breast milkconcentration was 4,564 ng/mL in a Kenyan study of 67 HIV-infected nursing mothers receiving acombination of zidovudine, lamivudine, and nevirapine.3The median nevirapine concentration was 734ng/mL in the infants who received the drug only via breast milk.• Human studies in pregnancyShort-Term Peripartum Prophylaxis:A Phase I study (PACTG 250) evaluated the safety and PKs of nevirapine administered to infectedpregnant women as a single 200-mg dose at the onset of labor and as a single 2-mg/kg dose to infantsaged 48 to 72 hours.2No adverse effects were seen in the women or the infants. The PK parameters of intrapartum nevirapine were similar in pregnant women and in non-pregnantadults, but variability was increased during pregnancy. Nevirapine elimination was prolonged in theinfants. The regimen maintained serum concentrations associated with antiviral activity in the infants forthe first week of life.The safety, toxicity, and PKs of nevirapine were also studied in HIV-infected pregnant women beginningchronic therapy late in the third trimester and their infants.4Initial-dose PK profiles in pregnant womenwere similar to those seen in non-pregnant adults. Serum nevirapine concentrations fell below the 100ng/mL target concentration by Day 7 of life in four of eight infants, suggesting that nevirapineelimination was accelerated in infants whose mothers received chronic nevirapine administrationcompared with newborns whose mothers received only a single intrapartum dose.The HIVNET 012 study in Uganda compared nevirapine (200 mg orally to the mother at the onset oflabor and 2 mg/kg to the neonate within 72 hours of birth) with zidovudine (600 mg orally to the motherat the onset of delivery and 300 mg every 3 hours until delivery, and 4 mg/kg orally twice daily for thefirst 7 days of life to the neonate). In this study, nevirapine lowered the risk of transmission of HIV bynearly 50% during the first 14 to 16 weeks of life compared with zidovudine.5However, the women inthis African trial were not receiving any other ARV drugs. In the United States, most infected women who know their HIV status during pregnancy receivecombination ARV prophylaxis regimens, usually including zidovudine, as well as intravenous zidovudineduring delivery, with 6 weeks of zidovudine given to their infant. A Phase III perinatal trial (PACTG 316)conducted in the United States, Europe, the Bahamas, and Brazil evaluated whether the HIVNET 012single-dose nevirapine regimen in combination with standard combination prophylaxis regimens (atminimum the PACTG 076 zidovudine regimen; 77% of women in the trial received combination ARVRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-20Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.regimens) would provide additional benefits in reducing transmission. Transmission was not significantlydifferent between those who received single-dose nevirapine (1.4%) and those who did not (1.6%).6Therefore, use of the single-dose nevirapine regimen is not recommended in women receivingcombination regimens in the United States.Longer-Term Antenatal Combination Therapy (See also Nevirapine and Hepatic/Rash Toxicity):The PKs of nevirapine have been evaluated in pregnant women receiving nevirapine as part of ARTduring pregnancy. A study that determined nevirapine PKs in 26 women during pregnancy (7 secondtrimester, 19 third trimester) and again in the same women 4 to 12 weeks after delivery found thatpregnancy did not alter nevirapine PK parameters.7In contrast, nevirapine clearance was 20% greater,AUC was 28% lower, and maximum plasma concentration was 30% lower in 16 pregnant womencompared with 13 non-pregnant women, based on nevirapine PK data from a therapeutic drugmonitoring program that included 12-hour sampling.8Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatichepatitis, hepatic necrosis, and hepatic failure and severe, life-threatening hypersensitivity skin reactions,including Stevens-Johnson syndrome, have been reported in HIV-infected patients receiving nevirapinein combination with other drugs for treatment of HIV disease and in a small number of individualsreceiving nevirapine as part of a combination regimen for post-exposure prophylaxis of nosocomial orsexual exposure to HIV.9These toxicities have not been reported in women or infants receiving two-dosenevirapine (the HIVNET 012 regimen) for prevention of perinatal transmission. The greatest risk ofsevere rash or hepatic events occurs during the first 6 to 18 weeks of therapy, although the risk of toxicitycontinues past this period and monitoring should continue at frequent intervals.Incidence of severe nevirapine-associated skin rash has been reported to be 5.5 to 7.3 times morecommon in women than men and has been reported in pregnant women.10-12Other studies have foundthat hepatic adverse events with systemic symptoms (often rash) were 3.2-fold more common in womenthan men.13Several studies suggest that the degree of risk of hepatic toxicity varies with CD4 T-lymphocyte (CD4-cell) count. In a summary analysis of data from 17 clinical trials of nevirapine therapy,women with CD4 counts >250 cells/mm3were 9.8 times more likely than women with lower CD4-cellcounts to experience symptomatic, often rash-associated, nevirapine-related hepatotoxicity.13HigherCD4-cell counts have also been associated with increased risk of severe nevirapine-associated skinrash.11Rates of hepatotoxicity and rash similar to those in U.S. studies have been seen in internationalcohorts of non-pregnant women but not in association with CD4-cell counts >250 cells/mm3.14Ingeneral, in controlled clinical trials, clinical hepatic events, regardless of severity, occurred in 4.0%(range 2.5%–11.0%) of patients who received nevirapine; however, the risk of nevirapine-associatedliver failure or hepatic mortality has been lower, in the range of 0.04% to 0.40%.13, 15Severe or life-threatening rash occurs in approximately 2% of patients receiving nevirapine.15Although deaths as a result of hepatic failure have been reported in HIV-infected pregnant women receivingnevirapine as part of a combination ARV regimen, it is uncertain if pregnancy increases the risk ofhepatotoxicity in women receiving nevirapine or other ARV drugs.16In an analysis of two multicenterprospective cohorts, pregnancy itself was a risk factor for liver enzyme elevations (RR 4.7; 95% CI, 3.4–6.5),although nevirapine use was not, regardless of pregnancy status.17Additional data from the same cohorts didnot show any increased risk of hepatotoxicity in HIV-infected pregnant women receiving nevirapine-basedART versus non-nevirapine-based ART.18In a cohort of 612 pregnant and non-pregnant women startingnevirapine-based therapy, CD4-cell count at initiation of therapy but not liver enzyme elevation was apredictor of rash; pregnancy was not an independent risk factor for the development of toxicity.19These datasuggest that nevirapine is no more toxic in pregnant women than in non-pregnant women. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-21Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Women initiating nevirapine with CD4-cell counts >250 cells/mm3, including pregnant women receivingARV drugs solely for prevention of transmission, are at increased risk of developing symptomatic, oftenrash-associated, nevirapine-related hepatotoxicity, which can be severe, life threatening, and in somecases fatal.20Therefore, nevirapine should be used as a component of a combination regimen in thissetting only if the benefit clearly outweighs the risk. Women with CD4-cell counts 3can receivenevirapine-based regimens, and women who become pregnant while taking nevirapine and who aretolerating their regimens well can continue therapy, regardless of CD4-cell count. Hepatic toxicity hasnot been seen in women receiving single-dose nevirapine during labor for prevention of perinataltransmission of HIV.Because pregnancy itself can mimic some of the early symptoms of hepatotoxicity, health care providerscaring for women receiving nevirapine during pregnancy should be aware of this potential complication.Frequent and careful monitoring of clinical symptoms and hepatic transaminases (that is, alanineaminotransferase [ALT] and aspartate aminotransferase [AST]) is necessary, particularly during the first18 weeks of therapy. Some clinicians measure serum transaminases at baseline, every 2 weeks for thefirst month, monthly through 4 months, and every 1 to 3 months thereafter (Adult AntiretroviralGuidelines); in patients with pre-existing liver disease, monitoring should be performed more frequentlywhen initiating therapy and monthly thereafter.21Transaminase levels should be checked in all womenwho develop a rash while receiving nevirapine. Patients who develop suggestive clinical symptomsaccompanied by elevation in serum transaminase levels (ALT and/or AST) or have asymptomatic butsevere transaminase elevations should stop nevirapine and not receive the drug in the future.References1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.2. Mirochnick M, Fenton T, Gagnier P, et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 250 Team. J Infect Dis. Aug1998;178(2):368-374. Available at http://www.ncbi.nlm.nih.gov/pubmed/9697716.3. Shapiro RL, Holland DT, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of women inBotswana receiving antiretroviral treatment. J Infect Dis. Sep 1 2005;192(5):720-727. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16088821.4. Mirochnick M, Siminski S, Fenton T, Lugo M, Sullivan JL. Nevirapine pharmacokinetics in pregnant women and intheir infants after in utero exposure. Pediatr Infect Dis J. Aug 2001;20(8):803-805. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11734746.5. Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine forprevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet. Sep4 1999;354(9181):795-802. Available at http://www.ncbi.nlm.nih.gov/pubmed/10485720.6. Dorenbaum A, Cunningham CK, Gelber RD, et al. Two-dose intrapartum/newborn nevirapine and standardantiretroviral therapy to reduce perinatal HIV transmission: a randomized trial. JAMA. Jul 10 2002;288(2):189-198.Available at http://www.ncbi.nlm.nih.gov/pubmed/12095383.7. Capparelli EV, Aweeka F, Hitti J, et al. Chronic administration of nevirapine during pregnancy: impact of pregnancy onpharmacokinetics. HIV Med. Apr 2008;9(4):214-220. Available at http://www.ncbi.nlm.nih.gov/pubmed/18366444.8. von Hentig N, Carlebach A, Gute P, et al. A comparison of the steady-state pharmacokinetics of nevirapine in men,nonpregnant women and women in late pregnancy. Br J Clin Pharmacol. Nov 2006;62(5):552-559. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17061962.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-22Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.9. Patel SM, Johnson S, Belknap SM, Chan J, Sha BE, Bennett C. Serious adverse cutaneous and hepatic toxicitiesassociated with nevirapine use by non-HIV-infected individuals. J Acquir Immune Defic Syndr. Feb 1 2004;35(2):120-125. Available at http://www.ncbi.nlm.nih.gov/pubmed/14722442.10. Mazhude C, Jones S, Murad S, Taylor C, Easterbrook P. Female sex but not ethnicity is a strong predictor of non-nucleoside reverse transcriptase inhibitor-induced rash. AIDS. Jul 26 2002;16(11):1566-1568. Available athttp://www.ncbi.nlm.nih.gov/pubmed/12131201.11. Bersoff-Matcha SJ, Miller WC, Aberg JA, et al. Sex differences in nevirapine rash. Clin Infect Dis. Jan 2001;32(1):124-129. Available at http://www.ncbi.nlm.nih.gov/pubmed/11118391.12. Knudtson E, Para M, Boswell H, Fan-Havard P. Drug rash with eosinophilia and systemic symptoms syndrome andrenal toxicity with a nevirapine-containing regimen in a pregnant patient with human immunodeficiency virus. ObstetGynecol. May 2003;101(5 Pt 2):1094-1097. Available at http://www.ncbi.nlm.nih.gov/pubmed/12738113.13. Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL. A comprehensive hepatic safety analysis ofnevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr. Sep 2003;34(Suppl 1):S21-33. Available at http://www.ncbi.nlm.nih.gov/pubmed/14562855.14. Peters PJ, Stringer J, McConnell MS, et al. Nevirapine-associated hepatotoxicity was not predicted by CD4 count ≥250cells/muL among women in Zambia, Thailand and Kenya. HIV Med. Nov 2010;11(10):650-660. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20659176.15. Boehringer-Ingelheim Pharmaceuticals Inc. Viramune drug label. Revised March 25, 2011. Available athttp://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201152s000lbl.pdf. Accessed on June 25, 2012.16. Lyons F, Hopkins S, Kelleher B, et al. Maternal hepatotoxicity with nevirapine as part of combination antiretroviraltherapy in pregnancy. HIV Med. May 2006;7(4):255-260. Available at http://www.ncbi.nlm.nih.gov/pubmed/16630038.17. Ouyang DW, Shapiro DE, Lu M, et al. Increased risk of hepatotoxicity in HIV-infected pregnant women receivingantiretroviral therapy independent of nevirapine exposure. AIDS. Nov 27 2009;23(18):2425-2430. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19617813.18. Ouyang DW, Brogly SB, Lu M, et al. Lack of increased hepatotoxicity in HIV-infected pregnant women receivingnevirapine compared with other antiretrovirals. AIDS. Jan 2 2010;24(1):109-114. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19926957.19. Aaron E, Kempf MC, Criniti S, et al. Adverse events in a cohort of HIV infected pregnant and non-pregnant womentreated with nevirapine versus non-nevirapine antiretroviral medication. PLoS One. 2010;5(9):e12617. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20838641.20. Grimbert S, Fisch C, Deschamps D, et al. Effects of female sex hormones on mitochondria: possible role in acute fattyliver of pregnancy. Am J Physiol. Jan 1995;268(1 Pt 1):G107-115. Available athttp://www.ncbi.nlm.nih.gov/pubmed/7840191.21. Kontorinis N, Dieterich DT. Toxicity of non-nucleoside analogue reverse transcriptase inhibitors. Semin Liver Dis. May2003;23(2):173-182. Available at http://www.ncbi.nlm.nih.gov/pubmed/12800070.Rilpivirine (Edurant, RPV) is classified as FDA Pregnancy Category B.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesRilpivirine was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screeningtests. Rilpivirine was not carcinogenic in rats when administered at doses 3 times higher than exposure inhumans at the recommended dose of 25 mg once daily. Hepatocellular neoplasms were observed in bothmale and female mice at doses 21 times that of human therapeutic exposure; the observed hepatocellularfindings in mice may be rodent specific.1Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-23Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.• Reproduction/fertilityNo effect on fertility was observed when rilpivirine was tested in rats at maternal doses up to 400mg/kg/day, resulting in systemic drug exposure equivalent to 40 times the recommended human dose.• Teratogenicity/developmental toxicityNo evidence of embryonic or fetal toxicity or an effect on reproductive function was observed in rat andrabbit dams treated with rilpivirine during pregnancy and lactation at doses 15 and 70 times higher,respectively, than exposure in humans at the recommended dose of 25 mg once daily.• Placental and breast milk passageNo data exist on whether rilpivirine crosses the placenta or is excreted in breast milk in humans. Studiesin lactating rats and their offspring indicate that rilpivirine is present in rat milk.• Human studies in pregnancyNo adequate and well-controlled studies of rilpivirine use in pregnant women have been conducted.Reference1. Tibotec. Edurant (rilpivirine) drug label. 2011. Available athttp://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf. Accessed on June 25, 2012.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-24Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-25Protease InhibitorsTen protease inhibitors (PIs) are currently approved (amprenavir is no longer available in the United States).Data are available from clinical trials in human pregnancy for atazanavir, lopinavir/ritonavir, nelfinavir,ritonavir, and saquinavir. Data in pregnancy are limited for darunavir, fosamprenavir, and indinavir. Verylimited data in pregnancy are available for tipranavir.For information regarding the PI class of drugs and potential metabolic complications during pregnancy andpregnancy outcome, see Protease Inhibitor Therapy and Hyperglycemiaand Combination AntiretroviralTherapy and Pregnancy Outcomein the perinatal guidelines.Amprenavir (Agenerase, APV)is no longer available in the United States.(Last updated September 14, 2011; last reviewed July 31, 2012)Atazanavir (Reyataz, ATV)is classified as Food and Drug Administration (FDA) Pregnancy Category B.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesIn in vitroand in vivoassays, atazanavir shows evidence of clastogenicity but not mutagenicity. Two-year carcinogenicity studies in mice and rats were conducted with atazanavir. In female mice, theincidence of benign hepatocellular adenomas was increased at systemic exposures 2.8- to 2.9-fold higherthan those in humans at the recommended therapeutic dose (300 mg/day atazanavir boosted with 100mg/kg/day ritonavir). There were no increases in the incidence of tumors in male mice at any dose. Inrats, no significant positive trends in the incidence of neoplasms occurred at systemic exposures up to1.1-fold (males) or 3.9-fold (females) higher than those in humans at the recommended therapeutic dose.• Reproduction/fertilityNo effect of atazanavir on reproduction or fertility in male and female rodents was seen at systemic drugexposures. The area under the curve (AUC) at this exposure level in rats was 0.9-fold in males and 2.3-fold in females compared with the exposures achieved in humans at the recommended therapeutic dose.• Teratogenicity/developmental toxicityIn animal reproduction studies, there was no evidence of teratogenicity in offspring born to animals atsystemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the humanclinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In developmental toxicityGlossary of Terms for SupplementCarcinogenic = producing or tending to produce cancer• Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic.• Genetic mutations and/or chromosomal damage can contribute to cancer formation.Clastogenic = causing disruption of or breakages in chromosomesGenotoxic = damaging to genetic material such as DNA and chromosomesMutagenic = inducing or capable of inducing genetic mutationTeratogenic = interfering with fetal development and resulting in birth defectsDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.studies in rats, maternal dosing that resulted in maternal toxicity and produced systemic drug exposure1.3 times the human exposure also resulted in weight loss or suppression of weight gain in the offspring.However, offspring were unaffected at lower maternal doses that produced systemic drug exposureequivalent to that observed in humans at the recommended therapeutic dose.In a retrospective analysis from London of atazanavir used in 31 women during 33 pregnancies (20 ofwhom were receiving atazanavir at conception), there were 2 miscarriages at 12 and 16 weeks, 26 infantsborn, and 5 women still pregnant.1No infant required phototherapy and no birth defects were seen; noneof the infants was HIV infected. In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposure to atazanavir in humans have been monitored to be able to detect at least a 2-foldincrease in risk of overall birth defects. No such increase in birth defects has been observed withatazanavir. The prevalence of birth defects with first-trimester atazanavir exposure was 1.9% (13 of 669births; 95% confidence interval [CI], 1.0%–3.3%) compared with a 2.7% total prevalence in the U.S.population, based on Centers for Disease Control and Prevention (CDC) surveillance.2Elevation in indirect (unconjugated) bilirubin attributable to atazanavir-related inhibition of hepaticuridine diphosphate glucuronosyltransferase (UGT) enzyme occurs frequently during treatment withatazanavir. Studies have demonstrated that infants born to mothers who received atazanavir duringpregnancy do not have pathologic or dangerous bilirubin elevations in the neonatal period.1, 3-7• Placental and breast milk passageIn studies of women receiving atazanavir/ritonavir-based combination therapy during pregnancy, cordblood atazanavir concentration averaged 13% to 21% of maternal serum levels at delivery.3, 5, 6Atazanavir is excreted in the milk of lactating rats. In a study of three women, the median ratio of breastmilk atazanavir concentration to that in plasma was 13%.8• Human studies in pregnancySeveral studies have investigated the pharmacokinetics (PKs) of atazanavir with ritonavir in pregnancy. Insome of these studies, virological results were also analyzed. Overall, most pregnant patients were able toachieve HIV RNA less than 50 copies/mL at time of delivery.9In some studies, almost all pregnant patientsachieved HIV RNA 4, 6, 7In a retrospective study reporting troughatazanavir concentrations in 19 pregnant women receiving atazanavir 300 mg and ritonavir 100 mg/day at amedian of 30 weeks’ gestation (14 in the third trimester), all but 2 women had a trough atazanavirconcentration >100 ng/mL.1Three studies have evaluated full PK profiles of atazanavir when administereddaily as 300 mg with 100 mg ritonavir during pregnancy. In all of these studies, atazanavir AUC was lowerduring pregnancy than in historic data from HIV-infected non-pregnant patients.3-5In 1 of the 3 studies,there was no difference between atazanavir AUC during pregnancy and postpartum, but AUC at both timeswas lower than in non-pregnant HIV-infected historic controls.3In the other 2 studies, atazanavir AUC was25% lower during pregnancy than in the same patients postpartum.4, 5, 9However, in both these studies(BMS AI424182 and IMPAACT P1026 atazanavir cohort), the postpartum AUC was elevated comparedwith non-pregnant HIV-infected historic control patients. For example, in study AI424182, 34 women weretreated with 300 mg atazanavir plus 100 mg ritonavir at 4 to 12 weeks postpartum and were observed tohave a 34% increase in geometric AUC compared with the historic control of HIV-infected, non-pregnantpatients (62 μg*hr/mL vs. 46.1 μg*hr/mL respectively).6Because of the postpartum elevation in AUC inthis study, the atazanavir drug label recommends that postpartum patients should be closely monitored foradverse events during the first 2 months after delivery.Although use of atazanavir with ritonavir combined with tenofovir and emtricitabine as a complete once-a-day dosing combination antiretroviral (ARV) regimen is becoming increasingly common in pregnancy,tenofovir reduces atazanavir exposure by 25% in non-pregnant adults.10This drug-drug interaction also isRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-26Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.present during pregnancy, with a 25% reduction in atazanavir AUC in pregnant women also receivingtenofovir compared with the same women postpartum and a 50% reduction compared with postpartumlevels in women who did not receive tenofovir.5Use of an increased dose of atazanavir of 400 mg with 100 mg ritonavir during pregnancy has beeninvestigated in two studies.4, 5In both studies pregnant women receiving the increased dose withouttenofovir had an atazanavir AUC equivalent to that seen in historic non-pregnant HIV-infected controlsreceiving standard-dose atazanavir without tenofovir. Pregnant women receiving the increased atazanavirdose with tenofovir had an AUC equivalent to that seen in non-pregnant HIV-infected patients receivingstandard-dose atazanavir and tenofovir.9In the prescribing information for atazanavir,6the dose recommended for most pregnant women is 300mg with 100 mg of ritonavir. For additional details about dosing with interacting concomitantmedications, please see Table 5(Antiretroviral Drug Use in Pregnant HIV-Infected Women:Pharmacokinetic and Toxicity Data in Human Pregnancy and Recommendations for Use in Pregnancy).Neonatal elevations in bilirubin have been reported in some—but not all—studies of infants born tomothers receiving atazanavir during pregnancy.3-5Phototherapy was needed to controlhyperbilirubinemia in 5 of 29 infants in 1 study.7In study AI424182, 6 of 39 infants receivedphototherapy.4Decisions to use phototherapy to treat infants with hyperbilirubinemia frequently aresubjective and guidelines for phototherapy of infants vary between countries, making it difficult,therefore, to compare the severity of hyperbilirubinemia between patients within a study and in differentstudies. Elevated neonatal bilirubin is more likely in infants with uridine diphosphateglucuronosyltransferase 1 genotypes associated with decreased UGT function.4Hypoglycemia (glucose delivery, or sepsis has been reported in 3 of 38 atazanavir-exposed infants with glucose samples collectedin the first day of life. All three hypoglycemic infants’ glucose samples were adequately collected andprocessed in a timely fashion (Bristol-Myers Squibb Reyataz product label). This finding of infanthypoglycemia is similar to a prior report in which 2 (both nelfinavir) of 14 infants exposed to PIs(nelfinavir, saquinavir, and indinavir) developed hypoglycemia in the first day of life.11References1. Natha M, Hay P, Taylor G, et al. Atazanavir use in pregnancy: a report of 33 cases. Paper presented at: 14th Conferenceon Retoviruses and Opportunistic Infections (CROI); February 25-28, 2007; Los Angeles, CA. Abstract 750.2. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.3. Ripamonti D, Cattaneo D, Maggiolo F, et al. Atazanavir plus low-dose ritonavir in pregnancy: pharmacokinetics andplacental transfer. AIDS. Nov 30 2007;21(18):2409-2415. Available at http://www.ncbi.nlm.nih.gov/pubmed/18025877.4. Conradie F, Zorrilla C, Josipovic D, et al. Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women. HIV Med. 2011 Oct;12(9):570-9. Available at:http://www.ncbi.nlm.nih.gov/pubmed/21569187.5. Mirochnick M, Best BM, Stek AM, et al. Atazanavir pharmacokinetics with and without tenofovir during pregnancy. JAcquir Immune Defic Syndr.Apr 15 2011;56(5):412-419. Available at http://www.ncbi.nlm.nih.gov/pubmed/21283017.6. Bristol-Myers Squibb Company. Reyataz package insert. 2011;http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021567s025lbl.pdf. Accessed on June 27, 2012.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-27Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.7. Mandelbrot L, Mazy F, Floch-Tudal C, et al. Atazanavir in pregnancy: impact on neonatal hyperbilirubinemia. Eur JObstet Gynecol Reprod Biol. Jul 2011;157(1):18-21. Available at http://www.ncbi.nlm.nih.gov/pubmed/21492993.8. Spencer L, Neely M, Mordwinkin N, et al. Intensive pharmacokinetics of zidovudine, lamivudine, and atazanavir andHIV-1 viral load in breast milk and plasma in HIV+ women receiving HAART. Paper presented at: 16th Conference onRetroviruses and Opportunistic Infections (CROI); February, 8-11, 2009; Montreal, Canada. Abstract 942.9. Mirochnick M, Stek A, Capparelli EV, et al. Pharmacokinetics of increased dose atazanavir with and without tenofovirduring pregnancy. Paper presented at: 12th International Workshop on Clinical Pharmacology of HIV Therapy; April13-15, 2011; Miami, FL. Abstract O10.10. Taburet AM, Piketty C, Chazallon C, et al. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreatedhuman immunodeficiency virus-infected patients. Antimicrob Agents Chemother. Jun 2004;48(6):2091-2096. Availableat http://www.ncbi.nlm.nih.gov/pubmed/15155205.11. Dinsmoor MJ, Forrest ST. Lack of an effect of protease inhibitor use on glucose tolerance during pregnancy. Infect DisObstet Gynecol. 2002;10(4):187-191. Available at http://www.ncbi.nlm.nih.gov/pubmed/12648312.Darunavir (Prezista, DRV)is classified as FDA Pregnancy Category C.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesDarunavir was neither mutagenic nor clastogenic in a series of in vitroand animal in vivoscreeningtests. A dose-related increase in the incidence of hepatocellular adenomas and carcinomas was observedin both male and female mice and rats as well as an increase in thyroid follicular cell adenomas in malerats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans.Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increasedthyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At thehighest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4- and 0.7-fold (mice) and 0.7-and 1-fold (rats) of those observed in humans at the recommended therapeutic doses(600/100 mg twice daily or 800/100 mg/day).• Reproduction/fertilityNo effects on fertility and early embryonic development were seen with darunavir in rats.• Teratogenicity/developmental toxicityNo embryotoxicity or teratogenicity was seen in mice, rats, or rabbits. Because of limited bioavailabilityof darunavir in animals and dosing limitation, the plasma exposures were approximately 50% (mice andrats) and 5% (rabbits) of those obtained in humans. In the rat pre- and postnatal development study, areduction in pup weight gain was observed with darunavir alone or with ritonavir exposure via breastmilk during lactation. In juvenile rats, single doses of darunavir (20 mg/kg–160 mg/kg at ages 5–11 days)or multiple doses of darunavir (40 mg/kg–1000 mg/kg at age 12 days) caused mortality. The deaths wereassociated with convulsions in some of the animals. Within this age range, exposures in plasma, liver,and brain were dose and age dependent and were considerably greater than those observed in adult rats.These findings were attributed to the ontogeny of the cytochrome P450 liver enzymes involved in themetabolism of darunavir and the immaturity of the blood-brain barrier. Sexual development, fertility, ormating performance of offspring was not affected by maternal treatment. Fewer than 200 first-trimesterpregnancy exposures have been reported to the Antiretroviral Pregnancy Registry; therefore, noconclusions can be made about risk of birth defects.• Placental and breast milk passageNo animal studies of placental passage of darunavir have been reported. Although variable transplacentalRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-28Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.transfer of darunavir has been observed in some case reports, in a study of 14 mother/infant pairs themedian (range) ratio of darunavir concentration in cord blood to that in maternal delivery plasma was24% (6%–58%).1, 2, 3, 4, 5Passage of darunavir into breast milk has been noted in rats. It is unknown ifbreast milk passage of darunavir occurs in humans. • Human studies in pregnancyCurrently, limited data exist about darunavir in pregnancy.1-11Three intensive PK studies ofdarunavir/ritonavir administered as 600 mg/100 mg twice a day or 800 mg/100 mg once a day duringpregnancy demonstrate 17% to 35% reductions in darunavir plasma concentration during the thirdtrimester compared with postpartum.1, 4, 11Because of low trough levels with once-daily dosing, twice-daily dosing of darunavir is recommended during pregnancy. A study of use of an increased twice-dailydarunavir dose during pregnancy is under way. Darunavir plasma protein binding decreases duringpregnancy, which increases the unbound plasma darunavir fraction and may partially mitigate thedecrease in total darunavir concentration.11References1. Capparelli EV, Best BM, Stek A, et al. Pharmacokinetics of darunavir once or twice daily during pregnancy andpostpartum. Paper presented at: 3rd International Workshop on HIV Pediatrics; July 15-16, 2011; Rome, Italy. AbstractP72.2. Ripamonti D, Cattaneo D, Cortinovis M, Maggiolo F, Suter F. Transplacental passage of ritonavir-boosted darunavir intwo pregnant women. Int J STD AIDS. Mar 2009;20(3):215-216. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19255280.3. Pinnetti C, Tamburrini E, Ragazzoni E, De Luca A, Navarra P. Decreased plasma levels of darunavir/ritonavir in avertically infected pregnant woman carrying multiclass-resistant HIV type-1. Antivir Ther. 2010;15(1):127-129.Available at http://www.ncbi.nlm.nih.gov/pubmed/20167999.4. Colbers A, Taylor G, et al. A comparison of the pharmacokinetics of tenofovir during pregnancy and post-partum. Paperpresented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; April 16-18, 2012; Barcelona,Spain. Abstract P34.5. Courbon E, Matheron S, et al. . Safety, efficacy, and pharmacokinetic of darunavir/ritonavir-containing regimen inpregnant HIV+ women. Paper presented at: 19th Conference on Retroviruses and Opportunistic Infections (CROI);March 5-8, 2012; Seattle, WA. Abstract 1011.6. Jaworsky D, Thompson C, Yudin MH, et al. Use of newer antiretroviral agents, darunavir and etravirine with or withoutraltegravir, in pregnancy: a report of two cases. Antivir Ther. 2010;15(4):677-680. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20587860.7. Ivanovic J, Bellagamba R, Nicastri E, et al. Use of darunavir/ritonavir once daily in treatment-naive pregnant woman:pharmacokinetics, compartmental exposure, efficacy and safety. AIDS. Apr 24 2010;24(7):1083-1084. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20386380.8. Pacanowski J, Bollens D, Poirier JM, et al. Efficacy of darunavir despite low plasma trough levels during latepregnancy in an HIV-hepatitis C virus-infected patient. AIDS. Sep 10 2009;23(14):1923-1924. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19710560.9. Furco A, Gosrani B, Nicholas S, et al. Successful use of darunavir, etravirine, enfuvirtide and tenofovir/emtricitabine inpregnant woman with multiclass HIV resistance. AIDS. Jan 28 2009;23(3):434-435. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19188762.10. Sued O, Lattner J, Gun A, et al. Use of darunavir and enfuvirtide in a pregnant woman. Int J STD AIDS. Dec2008;19(12):866-867. Available at http://www.ncbi.nlm.nih.gov/pubmed/19050223.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-29Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.11. Zorrilla C, Wright R, et al. Total and unbound darunavir pharmacokinetics in HIV-1+ pregnant women. Paper presented at:19th Conference on Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle, WA. Abstract 1012.Fosamprenavir (Lexiva, FPV)is classified as FDA Pregnancy Category C.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesFosamprenavir and amprenavir were neither mutagenic nor clastogenic in a series of in vitroand animal invivoscreening tests. Carcinogenicity studies of fosamprenavir showed an increase in incidence ofhepatocellular adenomas and carcinomas at all doses tested in male mice and at the highest dose tested infemale mice. In rats, the incidence of hepatocellular adenomas and thyroid follicular cell adenomas in males(all doses tested) and in females (two highest doses tested) was also increased. Repeat-dose studies in ratsproduced effects consistent with enzyme activation, which predisposes rats, but not humans, to thyroidneoplasms. In rats only there was an increase in interstitial cell hyperplasia at higher doses and an increasein uterine endometrial adenocarcinoma at the highest dose tested. The incidence of endometrial findings wasslightly increased over concurrent controls but was within background range for female rats. Thus therelevance of the uterine endometrial adenocarcinomas is uncertain. Exposures in the carcinogenicity studieswere 0.3- to 0.7-fold (mice) and 0.7- to 1.4-fold (rats) those in humans given 1400 mg twice daily offosamprenavir alone, and 0.2- to 0.3-fold (mice) and 0.3- to 0.7-fold (rats) those in humans given 1400 mgonce daily of fosamprenavir plus 200 mg ritonavir once daily or 0.1- to 0.3-fold (mice) and 0.3- to 0.6-fold(rats) those in humans given 700 mg of fosamprenavir plus 100 mg ritonavir twice daily.• Reproduction/fertilityNo impairment of fertility or mating was seen in rats at doses providing 3 to 4 times the human exposureto fosamprenavir alone or exposure similar to that with fosamprenavir and ritonavir dosing in humans. Atthose doses, no effect was seen on the development or maturation of sperm in rats.• Teratogenicity/developmental toxicityFosamprenavir was studied in rabbits at 0.8 times and in rats at twice the exposure in humans tofosamprenavir alone and at 0.3 (rabbits) and 0.7 (rats) times the exposure in humans to the combinationof fosamprenavir and ritonavir. In rabbits administered fosamprenavir (alone or in combination) theincidence of abortion was increased. In contrast, administration of amprenavir at a lower dose in rabbitswas associated with fetal loss and an increased incidence of minor skeletal variations from deficientossification of the femur, humerus, and trochlea. Fosamprenavir administered to pregnant rats (at twicehuman exposure) was associated with a reduction in pup survival and body weights in rats. F1 femalerats had an increased time to successful mating, an increased length of gestation, a reduced number ofuterine implantation sites per litter, and reduced gestational body weights compared with controls.The number of first-trimester exposures to fosamprenavir that have been monitored to date in theAntiretroviral Pregnancy Registry is insufficient to allow conclusions to be drawn regarding risk of birthdefects.1• Placental and breast milk passageIn a small study of women receiving fosamprenavir during pregnancy, the median (range) amprenavirconcentration in cord blood was 0.27 (0.09–0.60) mcg/mL and the median (range) ratio of amprenavirconcentration in cord blood to that in maternal plasma at the time of delivery was 0.24 (0.06–0.93).2Amprenavir is excreted in the milk of lactating rats; it is not known if it is excreted in human milk.• Human studies in pregnancyVery limited data exist on fosamprenavir in pregnant women. Fosamprenavir PK data have been reportedRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-30Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.in 16 women during pregnancy and postpartum. Following standard dosing with fosamprenavir 700 mgand ritonavir 100 mg, amprenavir AUC and 12-hour trough concentrations were somewhat lower duringpregnancy and higher postpartum compared with historical data. Amprenavir exposure during pregnancyappeared to be adequate for patients without PI resistance mutations.2A pediatric liquid formulation of fosamprenavir has been approved for children older than age 2 years,but there is no dosing information for neonates. References1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.2. Capparelli EV, Stek A, Best B, et al. Boosted fosamprenavir pharmacokinetics during pregnancy. Paper presented at:17th Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA.Abstract 908.Indinavir (Crixivan, IDV)is classified as FDA Pregnancy Category C.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesIndinavir is neither mutagenic nor clastogenic in both in vitroand in vivoassays. No increased incidenceof any tumor types occurred in long-term studies in mice. At the highest dose studied in rats (640mg/kg/day or 1.3-fold higher than systemic exposure at human therapeutic doses), thyroid adenomaswere seen in male rats.• Reproduction/fertilityNo effect of indinavir has been seen on reproductive performance, fertility, or embryo survival in rats.• Teratogenicity/developmental toxicityThere has been no evidence of teratogenicity or treatment-related effects on embryonic/fetal survival orfetal weights of indinavir in rats, rabbits, or dogs at exposures comparable to or slightly greater thantherapeutic human exposure. In rats, developmental toxicity manifested by an increase in supernumeraryand cervical ribs was observed at doses comparable to those administered to humans. No treatment-related external or visceral changes were observed in rats. No treatment-related external, visceral, orskeletal changes were seen in rabbits (fetal exposure limited, approximately 3% of maternal levels) ordogs (fetal exposure approximately 50% of maternal levels). Indinavir was administered to pregnantRhesus monkeys during the third trimester (at doses up to 160 mg/kg twice daily) and to neonatal Rhesusmonkeys (at doses up to 160 mg/kg twice daily). When administered to neonates, indinavir exacerbatedthe transient physiologic hyperbilirubinemia seen in this species after birth; serum bilirubin values wereapproximately 4-fold greater than controls at 160 mg/kg twice daily. A similar exacerbation did not occurin neonates after in uteroexposure to indinavir during the third trimester. In Rhesus monkeys, fetalplasma drug levels were approximately 1% to 2% of maternal plasma drug levels approximately 1 hourafter maternal dosing at 40, 80, or 160 mg/kg twice daily.In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposure to indinavir inhumans have been monitored to be able to detect at least a 2-fold increase in risk of overall birth defects.No such increase in birth defects has been observed with indinavir. Among cases of first-trimesterRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-31Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.indinavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was2.1% (6 of 286 births; 95% CI, 0.8%–4.5%) compared with a 2.7% total prevalence in the U.S.population, based on CDC surveillance.1• Placental and breast milk passageSignificant placental passage of indinavir occurs in rats and dogs, but only limited placental transferoccurs in rabbits. In studies of pregnant women receiving unboosted indinavir and their infants,transplacental passage of indinavir was minimal.2, 3In a study of Thai pregnant women receivingindinavir boosted with ritonavir, median cord blood indinavir concentration was 0.12 mcg/mL, medianmaternal plasma delivery concentration was 0.96 mcg/mL, and the median ratio between indinavirconcentrations in cord blood and maternal plasma at delivery was 12%.4Indinavir is excreted in the milkof lactating rats at concentrations slightly greater than maternal levels (milk-to-plasma ratio 1.26–1.45);it is not known if indinavir is excreted in human milk. • Human studies in pregnancyThe optimal dosing regimen for use of indinavir in pregnant patients has not been established. Two studiesof the PKs of unboosted indinavir (800 mg 3 times a day) during pregnancy demonstrated significantlylower indinavir plasma concentrations during pregnancy than postpartum.2, 5Use of unboosted indinavir isnot recommended in HIV-infected pregnant patients because of the substantially lower antepartumexposures observed in these studies and the limited experience in this patient population.Several reports investigate the use of indinavir with ritonavir boosting during pregnancy. In an intensive PKstudy of 26 Thai pregnant women receiving 400 mg indinavir/100 mg ritonavir twice a day, indinavir plasmaconcentrations were significantly lower during pregnancy than postpartum. The median trough indinavirconcentration was 0.13 mcg/mL; 24% of subjects had trough concentrations below 0.10 mcg/mL, the targettrough concentration used in therapeutic drug monitoring (TDM) programs; and 81% had RNA viral loads4In a study of French pregnant women receiving 400 mg indinavir/100 mgritonavir twice a day, the median indinavir trough concentration was 0.16 mcg/mL, 18% of subjects hadtrough concentrations below 0.12 mcg/mL, and 93% had HIV RNA level 6In asmall study of 2 women who received indinavir 800 mg and ritonavir 200 mg twice daily, third-trimesterindinavir AUC exceeded that for historical non-pregnant controls.7Based on these data, indinavir can beused in pregnancy with ritonavir boosting. Given the limited data on appropriate dosing, HIV RNA levelsand trough indinavir concentrations should be monitored during indinavir use in pregnancy.References1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.2. Unadkat JD, Wara DW, Hughes MD, et al. Pharmacokinetics and safety of indinavir in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother.Feb 2007;51(2):783-786. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17158945.3. Mirochnick M, Dorenbaum A, Holland D, et al. Concentrations of protease inhibitors in cord blood after in uteroexposure. Pediatr Infect Dis J. Sep 2002;21(9):835-838. Available at http://www.ncbi.nlm.nih.gov/pubmed/12352805.4. Cressey TR, Kreitchman R, et al. Effect of pregnancy on pharmacokinetics of indinavir boosted ritonavir. Paperpresented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; April 16-18, 2012; Barcelona,Spain. Abstract P37.5. Hayashi S, Beckerman K, Homma M, Kosel BW, Aweeka FT. Pharmacokinetics of indinavir in HIV-positive pregnantwomen. AIDS. May 26 2000;14(8):1061-1062. Available at http://www.ncbi.nlm.nih.gov/pubmed/10853990.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-32Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.6. Ghosn J, De Montgolfier I, Cornélie C, et al. Antiretroviral therapy with a twice-daily regimen containing 400 milligramsof indinavir and 100 milligrams of ritonavir in human immunodeficiency virus type 1-infected women during pregnancy.Antimicrob Agents Chemother. 2008 Apr;52(4):1542-4. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18250187.7. Kosel BW, Beckerman KP, Hayashi S, Homma M, Aweeka FT. Pharmacokinetics of nelfinavir and indinavir in HIV-1-infectedpregnant women. AIDS. May 23 2003;17(8):1195-1199. Available at http://www.ncbi.nlm.nih.gov/pubmed/12819521.Lopinavir + Ritonavir (Kaletra, LPV/r)is classified as FDA Pregnancy Category C.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesNeither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery of in vitroand invivoassays. The lopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavageadministration to mice and rats for up to 104 weeks. Results showed an increased incidence of benignhepatocellular adenomas and increased combined incidence of hepatocellular adenomas plus carcinoma inmale and female mice and male rats at doses that produced approximately 1.6 to 2.2 times (mice) and 0.5times (rats) the human exposure at the recommended therapeutic dose of 400 mg/100 mg (based onAUC0–24hrmeasurement). Administration of lopinavir/ritonavir did not cause a statistically significantincrease in incidence of any other benign or malignant neoplasm in mice or rats.• Reproduction/fertilityLopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and femalerats with exposures approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures inhumans at the recommended therapeutic dose.• Teratogenicity/developmental toxicityNo evidence exists of teratogenicity with administration of lopinavir/ritonavir to pregnant rats or rabbits.In rats treated with a maternally toxic dosage (100 mg lopinavir/50 mg ritonavir/kg/day), embryonic andfetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight,increased incidence of skeletal variations, and skeletal ossification delays) were observed. Drug exposurein the pregnant rats was 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at therecommended therapeutic dose. In a peri- and postnatal study in rats, a decrease in survival of pupsbetween birth and postnatal Day 21 occurred with exposure to 40 mg lopinavir/20 mg ritonavir/kg/day orgreater. In rabbits, no embryonic or fetal developmental toxicities were observed with a maternally toxicdosage, where drug exposure was 0.6-fold for lopinavir and 1-fold for ritonavir of the exposures inhumans at the recommended therapeutic dose.In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures tolopinavir/ritonavir have been monitored for detection of at least a 2-fold increase in risk of overall birthdefects. No such increase in birth defects has been observed with lopinavir/ritonavir. Among cases of first-trimester lopinavir/ritonavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence ofbirth defects was 2.4% (21 of 883; 95% CI, 1.5%–3.6%) compared with a total prevalence of 2.7% in theU.S. population, based on CDC surveillance.1• Placental and breast milk passageLopinavir crosses the human placenta; in the P1026s PK study, the average ratio of lopinavirconcentration in cord blood to maternal plasma at delivery was 0.20 ± 0.13. For ritonavir, data in humansindicate only minimal transplacental passage (see ritonavir). Lopinavir and ritonavir are secreted in thebreast milk of lactating rats; it is not known if either drug is excreted in human milk. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-33Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.• Human studies in pregnancyThe original capsule formulation of lopinavir/ritonavir has been replaced by a new tablet formulation thatis heat stable, has improved bioavailability characteristics, and does not have to be administered withfood.2, 3PK studies of standard adult lopinavir/ritonavir doses (400 mg/100 mg twice a day ) using eitherthe capsule or tablet formulations in pregnant women have demonstrated a reduction in lopinavir plasmaconcentrations during pregnancy of around 30% compared with that in non-pregnant adults.4-6Increasinglopinavir/ritonavir doses during pregnancy to either 533 mg/133 mg (capsules) or 600 mg/150 mg(tablets) results in lopinavir plasma concentrations equivalent to those seen in non-pregnant adultsreceiving standard doses.7, 8Reports of clinical experience suggest that most but not all pregnant womenreceiving standard lopinavir/ritonavir tablet dosing during pregnancy will have trough lopinavirconcentrations that exceed 1.0 mcg/mL, the usual trough concentration target used in therapeutic drugmonitoring programs for ARV-naive subjects, but not the higher trough concentrations recommended forPI-experienced subjects.2, 5Lopinavir plasma protein binding is reduced during pregnancy, but theresulting increase in free (unbound) drug is insufficient to make up for the reduction in total plasmalopinavir concentration associated with pregnancy.9, 10These PK studies suggest that lopinavir/ritonavir doses should be increased to 600 mg/150 mg twice aday in all HIV-infected pregnant women during the second and third trimesters. If standard doses oflopinavir/ritonavir are used during pregnancy, virologic response and lopinavir drug concentrations, ifavailable, should be monitored. An alternative strategy for increasing lopinavir/ritonavir exposure duringpregnancy is to add a pediatric lopinavir/ritonavir tablet (100/25 mg) to the standard dose of two adult200/50 mg tablets.10Once-daily dosing of lopinavir/ritonavir is notrecommended in pregnancy becauseno data exist to address whether drug levels are adequate with such administration.Lopinavir/ritonavir oral solution contains 42.4% (volume/volume) alcohol and 15.3% (weight/volume)propylene glycol. Reduced hepatic metabolic and kidney excretory function in newborns can lead toaccumulation of lopinavir as well as alcohol and propylene glycol, resulting in adverse events such asserious cardiac, renal, metabolic, or respiratory problems. Preterm babies may be at increased riskbecause their metabolism and elimination of lopinavir, propylene glycol, and alcohol are further reduced.Postmarketing surveillance has identified 10 neonates (babies prematurely, who received lopinavir/ritonavir and experienced life-threatening events.11In a separatereport comparing 50 HIV-exposed newborns treated with lopinavir/ritonavir after birth to 108 HIV-exposed neonates treated with zidovudine alone, elevated concentrations of 17-hydoxyprogesterone anddehydroepiandrosterone-sulfate, consistent with impairment of 21α-hydroxylase activity, were seen onlyin the lopinavir-exposed infants. All term infants were asymptomatic but 3 of 8 preterm infants had life-threatening symptoms, including hyponatremia, hyperkalemia, and cardiogenic shock, consistent withadrenal insufficiency.12Lopinavir/ritonavir oral solution should not be administered to neonates before apostmenstrual age (first day of the mother’s last menstrual period to birth, plus the time elapsed afterbirth) of 42 weeks and a postnatal age of at least 14 days has been attained.References1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.2. Khuong-Josses MA, Azerad D, Boussairi A, Ekoukou D. Comparison of lopinavir level between the two formulations(soft-gel capsule and tablet) in HIV-infected pregnant women. HIV Clin Trials. Jul-Aug 2007;8(4):254-255. Available athttp://www.ncbi.nlm.nih.gov/pubmed/17720666.3. Else LJ, Douglas M, Dickinson L, Back DJ, Khoo SH, Taylor GP. Improved oral bioavailability of lopinavir in melt-Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-34Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.extruded tablet formulation reduces impact of third trimester on lopinavir plasma concentrations. Antimicrob AgentsChemother. Feb 2012;56(2):816-824. Available at http://www.ncbi.nlm.nih.gov/pubmed/22106215.4. Stek AM, Mirochnick M, Capparelli E, et al. Reduced lopinavir exposure during pregnancy. AIDS. Oct 32006;20(15):1931-1939. Available at http://www.ncbi.nlm.nih.gov/pubmed/16988514.5. Bouillon-Pichault M, Jullien V, Azria E, et al. Population analysis of the pregnancy-related modifications in lopinavirpharmacokinetics and their possible consequences for dose adjustment. J Antimicrob Chemother. Jun 2009;63(6):1223-1232. Available at http://www.ncbi.nlm.nih.gov/pubmed/19389715.6. Ramautarsing RA, van der Lugt J, Gorowara M, et al. Thai HIV-1-infected women do not require a dose increase oflopinavir/ritonavir during the third trimester of pregnancy. AIDS. Jun 19 2011;25(10):1299-1303. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21516029.7. Mirochnick M, Best BM, Stek AM, et al. Lopinavir exposure with an increased dose during pregnancy. J AcquirImmune Defic Syndr. Dec 15 2008;49(5):485-491. Available at http://www.ncbi.nlm.nih.gov/pubmed/18989231.8. Best BM, Stek AM, Mirochnick M, et al. Lopinavir tablet pharmacokinetics with an increased dose during pregnancy. JAcquir Immune Defic Syndr. Aug 2010;54(4):381-388. Available at http://www.ncbi.nlm.nih.gov/pubmed/20632458.9. Aweeka FT, Stek A, Best BM, et al. Lopinavir protein binding in HIV-1-infected pregnant women. HIV Med. Apr2010;11(4):232-238. Available at http://www.ncbi.nlm.nih.gov/pubmed/20002783.10. Patterson KB, Dumond JB, Prince HA, et al. Pharmacokinetics of the LPV/r tablet in HIV-infected pregnant women: alongitudinal investigation of protein bound and unbound drug exposure with empiric dosage adjustment. Paperpresented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011;Boston, MA. Abstract 645.11. Boxwell D, Cao K, Lewis L, Marcus K, Nikhar B. Neonatal toxicity of Kaletra oral solution: LPV, ethanol orprophylene glycol? Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February27-Mar 2 2011; Boston, MA. Abstract 708.12. Simon A, Warszawski J, Kariyawasam D, et al. Association of prenatal and postnatal exposure to lopinavir-ritonavir andadrenal dysfunction among uninfected infants of HIV-infected mothers. JAMA. Jul 6 2011;306(1):70-78. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21730243.Nelfinavir (Viracept, NFV)is classified as FDA Pregnancy Category B.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesNelfinvair was neither mutagenic nor clastogenic in a series of in vitroand animal in vivoscreeningtests. However, incidence of thyroid follicular cell adenomas and carcinomas was increased over baselinein male rats receiving nelfinavir dosages of 300 mg/kg/day or higher (equal to a systemic exposuresimilar to that in humans at therapeutic doses) and female rats receiving 1000 mg/kg/day (equal to asystemic exposure 3-fold higher than that in humans at therapeutic doses).• Reproduction/fertilityNo effect of nelfinavir has been seen on reproductive performance, fertility, or embryo survival in rats atexposures comparable to human therapeutic exposure. Additional studies in rats indicated that exposureto nelfinavir in females from midpregnancy through lactation had no effect on the survival, growth, anddevelopment of the offspring to weaning. Maternal exposure to nelfinavir also did not affect subsequentreproductive performance of the offspring.• Teratogenicity/developmental toxicityNo evidence of teratogenicity has been observed in pregnant rats at exposures comparable to humanexposure and in rabbits with exposures significantly less than human exposure.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-35Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to nelfinavirhave been monitored to be able to detect at least a 2-fold increase in risk of overall birth defects. No suchincrease in birth defects has been observed with nelfinavir. Among cases of first-trimester nelfinavirexposure reported to the Antiretroviral Pregnancy Registry, prevalence of birth defects was 3.9% (47 of1,204 births; 95% CI, 2.9%–5.2%) compared with a 2.7% total prevalence in the U.S. population, basedon CDC surveillance.1• Placental and breast milk transferIn a Phase I study in pregnant women and their infants (PACTG 353, see below), transplacental passageof nelfinavir was minimal.2In addition, in a study of cord blood samples from 38 women treated withnelfinavir during pregnancy, the cord blood nelfinavir concentration was less than the assay limit ofdetection in 24 (63%), and the cord blood concentration was low (median, 0.35 µg/mL) in the remaining14 women.3Nelfinavir is excreted in the milk of lactating rats; it is not known if it is excreted in humanmilk. • Human studies in pregnancyA Phase I/II safety and PK study (PACTG 353) of nelfinavir in combination with zidovudine andlamivudine was conducted in pregnant HIV-infected women and their infants.2In the first nine pregnantHIV-infected women enrolled in the study, nelfinavir administered at a dose of 750 mg three times dailyproduced drug exposures that were variable and generally lower than those reported in non-pregnantadults with both twice- and three-times-daily dosing. Therefore, the study was modified to evaluate anincreased dose of nelfinavir given twice daily (1250 mg twice daily), which resulted in adequate levels ofthe drug in pregnancy. However, in two other small studies of women given 1250 mg nelfinavir twicedaily in the second and third trimesters, drug concentrations in the second and third trimesters weresomewhat lower than in non-pregnant women.4, 5In a PK study of combination therapy including the new nelfinavir 625-mg tablet formulation (given as1250 mg twice daily) in 25 women at 30 to 36 weeks’ gestation (and 12 at 6–12 weeks postpartum), peaklevels and AUC were lower in the third trimester than postpartum.6Only 16% (4 of 25) of women duringthe third trimester and 8% (1 of 12) women postpartum had trough values greater than the suggestedminimum trough of 800 ng/mL; however, viral load was trimester and 86% postpartum.Some nelfinavir manufactured before 2008 may have contained low levels of ethyl methane sulfonate(EMS), a process-related impurity. EMS is teratogenic, mutagenic, and carcinogenic in animals, althoughno data exist in humans and no increase in birth defects has been observed in the AntiretroviralPregnancy Registry. All nelfinavir manufactured and released since March 31, 2008, meets the new finalEMS limits established by the FDA for prescribing to all patient populations, including pregnant womenand pediatric patients. References1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.2. Bryson YJ, Mirochnick M, Stek A, et al. Pharmacokinetics and safety of nelfinavir when used in combination withzidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol353. HIV Clin Trials. Mar-Apr 2008;9(2):115-125. Available at http://www.ncbi.nlm.nih.gov/pubmed/18474496.3. Mirochnick M, Dorenbaum A, Holland D, et al. Concentrations of protease inhibitors in cord blood after in uteroRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-36Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.exposure. Pediatr Infect Dis J. Sep 2002;21(9):835-838. Available at http://www.ncbi.nlm.nih.gov/pubmed/12352805.4. Villani P, Floridia M, Pirillo MF, et al. Pharmacokinetics of nelfinavir in HIV-1-infected pregnant and nonpregnantwomen. Br J Clin Pharmacol. Sep 2006;62(3):309-315. Available at http://www.ncbi.nlm.nih.gov/pubmed/16934047.5. Fang A, Valluri SR, OSullivan MJ, et al. Safety and pharmacokinetics of nelfinavir during the second and thirdtrimesters of pregnancy and postpartum. HIV Clin Trials. Jan-Feb 2012;13(1):46-59. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22306587.6. Read JS, Best BM, Stek AM, et al. Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy andpostpartum. HIV Med. Nov 2008;9(10):875-882. Available at http://www.ncbi.nlm.nih.gov/pubmed/18795962.Ritonavir (Norvir, RTV)is classified as FDA Pregnancy Category B.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesRitonavir was neither mutagenic nor clastogenic in a series of in vitroand animal in vivoscreening tests.Carcinogenicity studies in mice and rats have been completed. In male mice, a dose-dependent increase inadenomas of the liver and combined adenomas and carcinomas of the liver was observed at levels of 50, 100,or 200 mg/kg/day; based on AUC, exposure in male mice at the highest dose was approximately 0.3-fold thatin male humans at the recommended therapeutic dose. No carcinogenic effects were observed in female micewith exposures 0.6-fold that of female humans at the recommended therapeutic dose. No carcinogenic effectswere observed in rats at exposures up to 6% of recommended therapeutic human exposure.• Reproduction/fertilityNo effect of ritonavir has been seen on reproductive performance or fertility in rats at drug exposures40% (male) and 60% (female) of that achieved with human therapeutic dosing; higher doses were notfeasible because of hepatic toxicity in the rodents.• Teratogenicity/developmental toxicityNo ritonavir-related teratogenicity has been observed in rats or rabbits. Developmental toxicity, includingearly resorptions, decreased body weight, ossification delays, and developmental variations such as wavyribs and enlarged fontanelles, was observed in rats; however, these effects occurred only at maternally toxicdosages (exposure equivalent to 30% of human therapeutic exposure). In addition, a slight increase incryptorchidism was also noted in rats at exposures equivalent to 22% of the human therapeutic dose. Inrabbits, developmental toxicity (resorptions, decreased litter size, and decreased fetal weight) was observedonly at maternally toxic doses (1.8 times human therapeutic exposure based on body surface area).In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to ritonavir havebeen monitored to be able to detect at least a 2-fold increase in risk of overall birth defects. No suchincrease in birth defects has been observed with ritonavir. Among cases of first-trimester ritonavirexposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.2% (39of 1,741 births; 95% CI, 1.6%–3.0%) compared with a total prevalence of 2.7% in the U.S. population,based on CDC surveillance.1• Placental and breast milk transferTransplacental passage of ritonavir has been observed in rats with fetal tissue-to-maternal-serum ratios>1.0 at 24 hours post-dose in mid- and late-gestation fetuses. In a human placental perfusion model, theclearance index of ritonavir was very low, with little accumulation in the fetal compartment and noaccumulation in placental tissue.2In a Phase I study of pregnant women and their infants (PACTG 354,see below), transplacental passage of ritonavir was minimal.3Additionally, in a study of cord bloodsamples from six women treated with ritonavir during pregnancy, the cord blood concentration was lessRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I_37Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.than the assay limit of detection in 83% and was only 0.38 µg/mL in the remaining woman.4Ritonavir isexcreted in the milk of lactating rats; it is unknown if it is excreted in human milk. • Human studies in pregnancyA Phase I/II safety and PK study (PACTG 354) of ritonavir (500 or 600 mg twice daily) in combination withzidovudine and lamivudine in pregnant HIV-infected women and their infants showed lower levels ofritonavir during pregnancy than postpartum.3Ritonavir concentrations are also reduced during pregnancyversus postpartum when the drug is used at a low dose (100 mg) to boost the concentrations of other PIs.5, 6References1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.2. Casey BM, Bawdon RE. Placental transfer of ritonavir with zidovudine in the ex vivo placental perfusion model. Am JObstet Gynecol. Sep 1998;179(3 Pt 1):758-761. Available at http://www.ncbi.nlm.nih.gov/pubmed/9757985.3. Scott GB, Rodman JH, Scott WA, et al. Pharmacokinetic and virologic response to ritonavir (RTV) in combination withzidovudine (ZDV) and lamivudine (3TC) in HIV-10-infected pregnant women and their infants. Paper presented at: 9thConference on Retroviruses and Opportunistic Infections (CROI); February 24-28, 2002; Seattle, WA. Abstract 794.4. Mirochnick M, Dorenbaum A, Holland D, et al. Concentrations of protease inhibitors in cord blood after in uteroexposure. Pediatr Infect Dis J. Sep 2002;21(9):835-838. Available at http://www.ncbi.nlm.nih.gov/pubmed/12352805.5. Best BM, Stek AM, Mirochnick M, et al. Lopinavir tablet pharmacokinetics with an increased dose during pregnancy. JAcquir Immune Defic Syndr.Aug 2010;54(4):381-388. Available at http://www.ncbi.nlm.nih.gov/pubmed/20632458.6. Mirochnick M, Best BM, Stek AM, et al. Atazanavir pharmacokinetics with and without tenofovir during pregnancy. JAcquir Immune Defic Syndr.Apr 15 2011;56(5):412-419. Available at http://www.ncbi.nlm.nih.gov/pubmed/21283017.Saquinavir (Invirase, SQV)is classified as FDA Pregnancy Category B.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesSaquinavir was neither mutagenic nor clastogenic in a series of in vitroand animal in vivoscreeningtests. Carcinogenicity studies found no indication of carcinogenic activity in rats and mice administeredsaquinavir for approximately 2 years at plasma exposures approximately 60% of those obtained inhumans at the recommended therapeutic dose (rats) and at exposures equivalent to those in humans at therecommended therapeutic dose (mice). • Reproduction/fertilityNo effect of saquinavir has been seen on reproductive performance, fertility, or embryo survival in rats.Because of limited bioavailability of saquinavir in animals, the maximal plasma exposures achieved inrats were approximately 26% of those obtained in humans at the recommended clinical dose boostedwith ritonavir.• Teratogenicity/developmental toxicityNo evidence of embryotoxicity or teratogenicity of saquinavir has been found in rabbits or rats. Becauseof limited bioavailability of saquinavir in animals and/or dosing limitations, the plasma exposures (AUCvalues) in the respective species were approximately 29% (using rat) and 21% (using rabbit) of thoseobtained in humans at the recommended clinical dose boosted with ritonavir. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-38Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Too few first-trimester saquinavir exposures have been monitored by the Antiretroviral PregnancyRegistry to be able to accurately calculate the prevalence of birth defects in exposed cases.1• Placental and breast milk transferPlacental transfer of saquinavir in the rat and rabbit was minimal. In a Phase I study in pregnant womenand their infants (PACTG 386, see below), transplacental passage of saquinavir was minimal.2In addition,in a study of cord blood samples from eight women treated with saquinavir during pregnancy, the cordblood concentration of saquinavir was less than the assay limit of detection in samples from all women.3Saquinavir is excreted in the milk of lactating rats; it is not known if it is excreted in human milk. • Human studies in pregnancyThree studies have evaluated PKs of saquinavir-hard gel capsules (HGC) combined with low-doseritonavir (saquinavir-HGC 1000 mg/ritonavir 100 mg given twice daily) in a total of 19 pregnant women;trough levels were greater than the target in all but 1 woman.4, 5In a small study of 2 women whoreceived saquinavir-HGC 1200 mg/ritonavir 100 mg given once daily, trough levels were 285 and 684ng/mL and the AUC0–24were 28,010 and 16,790 ng hour/mL, greater than the target AUC of 10,000 nghour/mL.6Thus, the limited available data suggest that saquinavir-HGC 1000 mg/ritonavir 100 mg giventwice daily should achieve adequate trough levels in HIV-infected pregnant women. Data are too limitedto recommend once-daily dosing at present. However, a recent analysis of saquinavir HGC administeredonce daily at 1200 mg/100 mg ritonavir combined with various nucleoside reverse transcriptaseinhibitors during 46 pregnancies demonstrated saquinavir levels greater than the target minimum plasmaconcentration in 46 (93.4%) of pregnancy episodes and undetectable viral load at delivery in 88% ofepisodes.7Target levels were achieved in the other 3 women with a dose of 1600 mg/100 mg. The drugwas well tolerated. The PKs of the new 500-mg tablet formulation of saquinavir boosted with ritonavir in a dose ofsaquinavir 1000 mg/ritonavir 100 mg given twice daily were studied in 37 HIV-infected pregnant womenat 20 and 33 weeks’ gestation and 6 weeks postpartum; PK parameters were comparable duringpregnancy and postpartum.8However, in a smaller study of saquinavir tablets boosted with ritonavirgiven to 14 HIV-infected pregnant women, the saquinavir exposure during the third trimester wasreduced by about 50%, yet no woman experienced loss of virologic control and all but 1 maintainedadequate trough levels of saquinavir.9Thus, it does not appear that any adjustment of saquinavir boostedwith ritonavir is necessary during pregnancy.One study of a saquinavir/ritonavir-based combination ARV drug regimen in 42 women duringpregnancy reported abnormal transaminase levels in 13 women (31%) within 2 to 4 weeks of treatmentinitiation, although the abnormalities were mild (toxicity Grade 1–2 in most, Grade 3 in 1 woman).10References 1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available athttp://www.APRegistry.com.2. Zorrilla CD, Van Dyke R, Bardeguez A, et al. Clinical response and tolerability to and safety of saquinavir with low-dose ritonavir in human immunodeficiency virus type 1-infected mothers and their infants. Antimicrob AgentsChemother. Jun 2007;51(6):2208-2210. Available at http://www.ncbi.nlm.nih.gov/pubmed/17420209.3. Mirochnick M, Dorenbaum A, Holland D, et al. Concentrations of protease inhibitors in cord blood after in uteroexposure. Pediatr Infect Dis J. Sep 2002;21(9):835-838. Available at http://www.ncbi.nlm.nih.gov/pubmed/12352805.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-39Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.4. Hanlon M, ODea S, Woods S, et al. Evaluation of saquinavir/ritonavir based regimen for prevention of MTCT of HIV.Paper presented at: 13th Conference on Retroviruses and Opportunistic Infections (CROI); February 5-8, 2006; Denver,CO. Abstract 721.5. Khan W, Hawkins DA, Moyle G, et al. Pharmacokinetics (PK), safety, tolerability and efficacy of saquinavir hard-gelcapsules/ritonavir (SQV/r) plus 2 nucleosides in HIV-infected pregnant women. Paper presented at: XV InternationalAIDS Conference; July 11-16, 2004; Bangkok, Thailand.6. Lopez-Cortes LF, Ruiz-Valderas R, Pascual R, Rodriguez M, Marin Niebla A. Once-daily saquinavir-hgc plus low-doseritonavir (1200/100 mg) in HIV-infected pregnant women: pharmacokinetics and efficacy. HIV Clin Trials. May-Jun2003;4(3):227-229. Available at http://www.ncbi.nlm.nih.gov/pubmed/12815561.7. Lopez-Cortes LF, Ruiz-Valderas R, Rivero A, et al. Efficacy of low-dose boosted saquinavir once daily plus nucleosidereverse transcriptase inhibitors in pregnant HIV-1-infected women with a therapeutic drug monitoring strategy. TherDrug Monit. Apr 2007;29(2):171-176. Available at http://www.ncbi.nlm.nih.gov/pubmed/17417070.8. van der Lugt J, Colbers A, Molto J, et al. The pharmacokinetics, safety and efficacy of boosted saquinavir tablets in HIVtype-1-infected pregnant women. Antivir Ther. 2009;14(3):443-450. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19474478.9. Martinez-Rebollar M, Lonca M, Perez I, et al. Pharmacokinetic study of saquinavir 500 mg plus ritonavir (1000/100 mgtwice a day) in HIV-positive pregnant women. Ther Drug Monit. Dec 2011;33(6):772-777. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22105596.10. Hanlon M, ODea S, Clarke S, et al. Maternal hepatotoxicity with boosted saquinavir as part of combination ART inpregnancy. Paper presented at: 14th Conference on Retoviruses and Opportunistic Infections (CROI); February 25-28,2007; Los Angeles, CA. Abstract 753.Tipranavir (Aptivus, TPV)is classified as FDA Pregnancy Category C.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesTipranavir was neither mutagenic nor clastogenic in a battery of five in vitroand animal in vivoscreening tests. Long-term carcinogenicity studies in mice and rats have been conducted with tipranavir.Mice were administered 30, 150, or 300 mg/kg/day tipranavir, 150/40 mg/kg/day tipranavir/ritonavir incombination, or 40 mg/kg/day ritonavir. Incidence of benign hepatocellular adenomas and combinedadenomas/carcinomas was increased in females of all groups except females given the low dose oftipranavir. Such tumors also were increased in male mice at the high dose of tipranavir and in thetipranavir/ritonavir combination group. Incidence of hepatocellular carcinoma was increased in femalemice given the high dose of tipranavir and in both sexes receiving tipranavir/ritonavir. The combinationof tipranavir and ritonavir caused an exposure-related increase in this same tumor type in both sexes. Theclinical relevance of the carcinogenic findings in mice is unknown. Systemic exposures in mice (basedon AUC or maximum plasma concentration) at all dose levels tested were below those in humansreceiving the recommended dose level. Rats were administered 30, 100, or 300 mg/kg/day tipranavir,100/26.7 mg/kg/day tipranavir/ritonavir in combination, or 10 mg/kg/day ritonavir. No drug-relatedfindings were observed in male rats. At the highest dose of tipranavir, an increased incidence of benignfollicular cell adenomas of the thyroid gland was observed in female rats. Based on AUC measurements,exposure to tipranavir at this dose level in rats is approximately equivalent to exposure in humans at therecommended therapeutic dose. This finding is probably not relevant to humans because thyroidfollicular cell adenomas are considered a rodent-specific effect secondary to enzyme induction.• Reproduction/fertilityTipranavir had no effect on fertility or early embryonic development in rats at exposure levels similar toRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-40Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.human exposures at the recommended clinical dose (500/200 mg/day of tipranavir/ritonavir).• Teratogenicity/developmental toxicityNo teratogenicity was detected in studies of pregnant rats and rabbits at exposure levels approximately1.1-fold and 0.1-fold human exposure. Fetal toxicity (decreased ossification and body weights) wasobserved in rats exposed to 400 mg/kg/day or more of tipranavir (~0.8-fold human exposure). Fetaltoxicity was not seen in rats and rabbits at levels of 0.2-fold and 0.1-fold human exposures. In rats, noadverse effects on development were seen at levels of 40 mg/kg/day (~0.2-fold human exposure), but at400 mg/kg/day (~0.8-fold human exposure), growth inhibition in pups and maternal toxicity were seen.• Placental and breast milk transferNo animal studies of placental or breast milk passage of tipranavir have been reported. It is unknown ifplacental or breast milk passage of tipranavir occurs in humans. • Human studies in pregnancyNo studies of tipranavir have been completed in pregnant women or neonates. A case report with PKmeasurements of tipranavir used in a single pregnancy showed relatively high levels of tipranavir thirdtrimester and relatively high placental transfer (0.41), as measured by cord blood.1It is unclear whetherthis finding will be applicable to other pregnancies.Reference1. Weizsaecker K, Kurowski M, Hoffmeister B, Schurmann D, Feiterna-Sperling C. Pharmacokinetic profile in latepregnancy and cord blood concentration of tipranavir and enfuvirtide. Int J STD AIDS. May 2011;22(5):294-295.Available at http://www.ncbi.nlm.nih.gov/pubmed/21571982.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-41Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-42Entry InhibitorsTwo drugs have been approved in this new class of antiretroviral (ARV) drugs aimed at inhibiting viralbinding or fusion of HIV to host target cells. Binding of the viral envelope glycoprotein (gp)120 to the CD4receptor induces conformational changes that enable gp120 to interact with a chemokine receptor such asCCR5 or CXCR4 on the host cell; binding of gp120 to the coreceptor causes subsequent conformationalchanges in the viral transmembrane gp41, exposing the “fusion peptide” of gp41, which inserts into the cellmembrane. A helical region of gp41, called HR1, then interacts with a similar helical region, HR2, on gp41,resulting in a “zipping” together of the two helices and mediating the fusion of cellular and viral membranes.Enfuvirtide, which requires subcutaneous (SQ) administration, is a synthetic 36-amino-acid peptide derivedfrom a naturally occurring motif within the HR2 domain of viral gp41, and the drug binds to the HR1 region,preventing the HR1-HR2 interaction and correct folding of gp41 into its secondary structure, therebyinhibiting virus-cell fusion. Enfuvirtide was approved for use in combination with other ARV drugs to treatadvanced HIV infection in adults and children 6 years of age or older. Maraviroc interferes with viral entry atthe chemokine coreceptor level; it is a CCR5 coreceptor antagonist approved for combination therapy forHIV infection in adults infected with CCR5-tropic virus.Enfuvirtide (Fuzeon, T-20)is classified as Food and Drug Administration (FDA) Pregnancy Category B. (Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesEnfuvirtide was neither mutagenic nor clastogenic in a series of in vitroand animal in vivoscreeningtests. Long-term animal carcinogenicity studies of enfuvirtide have not been conducted.• Reproduction/fertility animal studiesReproductive toxicity has been evaluated in rats and rabbits. Enfuvirtide produced no adverse effects onfertility of male or female rats at doses up to 30 mg/kg/day administered SQ (1.6 times the maximumrecommended adult human daily dose on an m2body surface area basis).• Teratogenicity/developmental toxicity animal studiesStudies in rats and rabbits revealed no evidence of harm to the fetus from enfuvirtide administered indoses up to 27 times and 3.2 times, respectively, the adult human daily dose on an m2basis.• Placental and breast milk passageStudies of radiolabeled enfuvirtide administered to lactating rats indicated radioactivity in the milk;Glossary of Terms for SupplementCarcinogenic = producing or tending to produce cancer• Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic.• Genetic mutations and/or chromosomal damage can contribute to cancer formation.Clastogenic = causing disruption of or breakages in chromosomesGenotoxic = damaging to genetic material such as DNA and chromosomesMutagenic = inducing or capable of inducing genetic mutationTeratogenic = interfering with fetal development and resulting in birth defectsDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.however, it is not known if this reflected radiolabeled enfuvirtide or metabolites (such as amino acid andpeptide fragments) of enfuvirtide. It is not known if enfuvirtide crosses the human placenta or is excretedin human milk. A published case report of two peripartum pregnant patients and their neonates and datafrom an ex vivohuman placental cotyledon perfusion model suggest that enfuvirtide does not cross theplacenta.1, 2• Human studies in pregnancyVery limited data exist on the use of enfuvirtide in pregnant women.1, 3-5There is a single case reportdetecting no placental transfer of drug based on cord blood measurements.5References1. Brennan-Benson P, Pakianathan M, Rice P, et al. Enfurvitide prevents vertical transmission of multidrug-resistant HIV-1in pregnancy but does not cross the placenta. AIDS. Jan 9 2006;20(2):297-299. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16511429.2. Ceccaldi PF, Ferreira C, Gavard L, Gil S, Peytavin G, Mandelbrot L. Placental transfer of enfuvirtide in the ex vivohuman placenta perfusion model. Am J Obstet Gynecol. Apr 2008;198(4):433 e431-432. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18241815.3. Cohan D, Feakins C, Wara D, et al. Perinatal transmission of multidrug-resistant HIV-1 despite viral suppression on anenfuvirtide-based treatment regimen. AIDS. Jun 10 2005;19(9):989-990. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15905684.4. Meyohas MC, Lacombe K, Carbonne B, Morand-Joubert L, Girard PM. Enfuvirtide prescription at the end ofpregnancy to a multi-treated HIV-infected woman with virological breakthrough. AIDS. Sep 24 2004;18(14):1966-1968.Available at http://www.ncbi.nlm.nih.gov/pubmed/15353987.5. Weizsaecker K, Kurowski M, Hoffmeister B, Schurmann D, Feiterna-Sperling C. Pharmacokinetic profile in latepregnancy and cord blood concentration of tipranavir and enfuvirtide. Int J STD AIDS. May 2011;22(5):294-295.Available at http://www.ncbi.nlm.nih.gov/pubmed/21571982.Maraviroc (Selzentry, MVC)is classified as FDA Pregnancy Category B.(Last updated September 14, 2011; last reviewed July 31, 2012)• Animal carcinogenicity studiesMaraviroc was neither mutagenic nor clastogenic in a series of in vitroand animal in vivoscreeningtests. Long-term animal carcinogenicity studies found no increase in tumor incidence in mice (transgenicrasH2 mice) and rats at exposures up to 11-fold higher than experienced with human therapeuticexposure at the recommended clinical dose (300 mg twice daily).• Reproduction/fertility animal studiesReproductive toxicity has been evaluated in rats. Maraviroc produced no adverse effects on fertility ofmale or female rats or sperm of male rats at exposures up to 20-fold higher than experienced with humantherapeutic exposure at the recommended clinical dose (300 mg twice daily). • Teratogenicity/developmental toxicity animal studiesStudies in rats and rabbits revealed no evidence of harm to the fetus from maraviroc administered indoses up to 20-fold higher in rats and 5-fold higher in rabbits than experienced with human therapeuticexposure at the recommended clinical dose (300 mg twice daily). • Placental and breast milk passageIt is unknown if maraviroc crosses the placenta in humans. In a study of four macaques, a single oralRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-43Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.dose of 60 mg/kg or 100 mg/kg was given 2 hours before cesarean delivery. Median maternalconcentration at delivery was 974 ng/mL (range 86–2830 ng/mL) and median infant concentration was22 ng/mL (range 4–99 ng/mL) for a cord/maternal ratio of .023.1Maternal levels were detectable for 48hours after a single dose, whereas infant levels were detectable for only 3.5 hours after birth. Studies inlactating rats indicate that maraviroc is extensively secreted into rat milk.• Human studies in pregnancyNo studies of maraviroc have been conducted in pregnant women or neonates.• Additional concernsAlthough no increase in cancer has been observed with maraviroc, the drug has the potential to increaserisk because of its mechanism of action and possible effects on immune surveillance.Reference1. Winters MA, Van Rompay KK, Kashuba AD, Shulman NS, Holodniy M. Maternal-fetal pharmacokinetics anddynamics of a single intrapartum dose of maraviroc in rhesus macaques. Antimicrob Agents Chemother. Oct2010;54(10):4059-4063. Available at http://www.ncbi.nlm.nih.gov/pubmed/20696881.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-44Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-45Integrase InhibitorsOne drug has been approved in this new class of antiretroviral (ARV) drugs aimed at inhibiting integrase, theviral enzyme that catalyzes the two-step process of insertion of HIV DNA into the genome of the host cell.Integrase catalyzes a preparatory step that excises two nucleotides from one strand at both ends of the HIVDNA and a final “strand transfer” step that inserts the viral DNA into the exposed regions of cellular DNA.The integrase inhibitor drug class targets this second step in the integration process. Integration is requiredfor the stable maintenance of the viral genome as well as for efficient viral gene expression and replication.Integrase also affects retrotranscription and viral assembly. Host cells lack the integrase enzyme. BecauseHIV integrase represents a distinct therapeutic target, integrase inhibitors would be expected to maintainactivity against HIV that is resistant to other classes of ARV drugs.Raltegravir (Isentress)is classified as Food and Drug Administration Pregnancy Category C.(Last updated July 31, 2012; last reviewed July 31, 2012)• Animal carcinogenicity studiesRaltegravir was neither mutagenic nor clastogenic in a series of in vitroand animal in vivoscreeningtests. Long-term animal carcinogenicity studies of raltegravir are ongoing.• Reproduction/fertility animal studiesRaltegravir produced no adverse effects on fertility of male or female rats at doses up to 600 mg/kg/day(providing exposures 3-fold higher than the exposure at the recommended adult human dose).• Teratogenicity/developmental toxicity animal studiesStudies in rats and rabbits revealed no evidence of treatment-related effects on embryonic/fetal survivalor fetal weights from raltegravir administered in doses producing systemic exposures approximately 3- to4-fold higher than the exposure at the recommended adult human daily dose. In rabbits, no treatment-related external, visceral, or skeletal changes were observed. However, treatment-related increases in theincidence of supernumerary ribs were seen in rats given raltegravir at 600 mg/kg/day (providingexposures 3-fold higher than the exposure at the recommended human daily dose).• Placental and breast milk passagePlacental transfer of raltegravir was demonstrated in both rats and rabbits. In rats given a maternal doseof 600 mg/kg/day, mean fetal blood concentrations were approximately 1.5- to 2.5-fold higher than inmaternal plasma at 1 and 24 hours post-dose, respectively. However, in rabbits, the mean drugconcentrations in fetal plasma were approximately 2% of the mean maternal plasma concentration atGlossary of Terms for SupplementCarcinogenic = producing or tending to produce cancer• Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic.• Genetic mutations and/or chromosomal damage can contribute to cancer formation.Clastogenic = causing disruption of or breakages in chromosomesGenotoxic = damaging to genetic material such as DNA and chromosomesMutagenic = inducing or capable of inducing genetic mutationTeratogenic = interfering with fetal development and resulting in birth defectsDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.both 1 and 24 hours following a maternal dose of 1000 mg/kg/day. In humans, raltegravir appears toreadily cross the placenta. In P1026s, maternal and cord blood from six deliveries of mothers receivingraltegravir-based therapy during pregnancy were evaluated; the ratio of cord blood to maternal plasmawas 0.98 (95% confidence interval, 0.09–2.26).1Other case reports have shown similarly high cordblood/maternal blood drug level ratios of 1.00 to 1.06.2, 3In a report of three pregnant women withmultiresistant HIV-1 who were given raltegravir in late pregnancy to rapidly reduce maternal viral load,raltegravir concentrations within 3 hours of delivery in the neonates of two patients were approximately7 and 9.5 times higher than in the mother’s paired sample; in the third infant, maternal plasma was notavailable but neonatal concentration was still high 2.5 hours after delivery.4However, no adversereactions were observed in mothers or infants. Raltegravir is secreted in the milk of lactating rats, withmean drug concentrations in milk about 3-fold higher than in maternal plasma at a maternal dose of 600mg/kg/day. No effects in rat offspring were attributable to raltegravir exposure through breast milk.Whether raltegravir is secreted in human milk is unknown.• Human studies in pregnancyOnly limited data exist on the use of raltegravir in pregnancy. Raltegravir pharmacokinetics (PKs) wereevaluated in 10 women in the IMPAACT P1026s study. Raltegravir PKs showed extensive variability butdid not appear to be consistently altered during the third trimester compared with postpartum andhistorical data in non-pregnant individuals; thus the standard dose appears appropriate in pregnancy.1In acase series of 5 pregnant women treated with raltegravir in combination with 2 or 3 other ARV drugsbecause of persistent viremia or late presentation, the drug was well tolerated and led to rapid reductionin HIV RNA levels.5Drug levels were not measured in that study.References1. Best BM, Capparelli EV, Stek A, et al. Raltegravir pharmacokinetics during pregnancy. Paper presented at: 50thInterscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2010; Boston, MA.2. Pinnetti C, Baroncelli S, Villani P, et al. Rapid HIV-RNA decline following addition of raltegravir and tenofovir toongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 ofpregnancy. J Antimicrob Chemother. Sep 2010;65(9):2050-2052. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20630894.3. Croci L, Trezzi M, Allegri MP, et al. Pharmacokinetic and safety of raltegravir in pregnancy. Eur J Clin Pharmacol.Mar 1 2012. Available at http://www.ncbi.nlm.nih.gov/pubmed/22382989.4. McKeown DA, Rosenvinge M, Donaghy S, et al. High neonatal concentrations of raltegravir following transplacentaltransfer in HIV-1 positive pregnant women. AIDS. Sep 24 2010;24(15):2416-2418. Available athttp://www.ncbi.nlm.nih.gov/pubmed/20827058.5. Taylor N, Touzeau V, Geit M, et al. Raltegravir in pregnancy: a case series presentation. Int J STD AIDS. Jun2011;22(6):358-360. Available at http://www.ncbi.nlm.nih.gov/pubmed/21680678.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-46Downloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States I-47Antiretroviral Pregnancy Registry (Last updated September 14, 2011; last reviewedJuly 31, 2012)The Antiretroviral Pregnancy Registry is an epidemiologic project to collect observational, nonexperimentaldata on antiretroviral (ARV) drug exposure during pregnancy for the purpose of assessing the potentialteratogenicity of these drugs. Registry data will be used to supplement animal toxicology studies and assistclinicians in weighing the potential risks and benefits of treatment for individual patients. The registry is acollaborative project of the pharmaceutical manufacturers with an advisory committee of obstetric andpediatric practitioners.It is strongly recommended that health care providers who are treating HIV-infected pregnant women andtheir newborns report cases of prenatal exposure to ARV drugs (either alone or in combination) to theAntiretroviral Pregnancy Registry. The registry does not use patient names, and birth outcome follow-up isobtained from the reporting physician by registry staff.Referrals should be directed to: Antiretroviral Pregnancy RegistryResearch Park1011 Ashes DriveWilmington, NC 28405Telephone: 1–800–258–4263Fax: 1–800–800–1052http://www.APRegistry.comDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States J-1Appendix B: Acronyms 3TC lamivudineABC abacavirACOG American College of Obstetricians and GynecologistsALT alanine aminotransferaseanti-HBc hepatitis B core antibodyanti-HBs hepatitis B surface antibodyAOR adjusted odds ratioAP antepartumART antiretroviral therapyARV antiretroviralAST aspartate aminotransferaseATV atazanavirATV/r atazanavir/ritonavirAUC area under the curveAZT zidovudineBID twice dailyBMI body mass indexCBC complete blood countCDC Centers for Disease Control and PreventionCI confidence intervalCmaxmaximum plasma concentrationCminminimum plasma concentrationCNS central nervous systemCVS chorionic villus samplingCYP cytochrome PCYP3A4 cytochrome P450 3A4d4T stavudineddI didanosineDMPA depot medroxyprogesterone acetateDRV darunavirDRV/r darunavir/ritonavirDSMB Data and Safety Monitoring BoardEC enteric coatedECG electrocardiogramEFV efavirenzEMS ethyl methane sulfonateETR etravirineFDA Food and Drug AdministrationFPV fosamprenavirFPV/r fosamprenavir/ritonavirFTC emtricitabineDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States J-2gp glycoproteinHAV hepatitis A virusHBIG hepatitis B immune globulinHBsAg hepatitis B surface antigenHBV hepatitis B virusHCV hepatitis C virusHELLP hemolysis, elevated liver enzymes, and low plateletsHGC hard gel capsuleHR hazard ratioHRSA Health Resources and Services AdministrationIC50inhibitory concentration 50%IDV indinavirIGF insulin-like growth factorIP intrapartumIQR interquartile rangeIRIS immune reconstitution inflammatory syndromeIUD intrauterine deviceIV intravenous/intravenouslyLPV/r lopinavir/ritonavirMAC Mycobacterium aviumcomplexMACDP Metropolitan Atlanta Congenital Defects ProgramMIRIAD Mother-Infant Rapid Intervention at Delivery (study)MTCT mother-to-child transmissionmtDNA mitochondrial DNAMVC maravirocNFV nelfinavirNIH National Institutes of HealthNNRTI non-nucleoside reverse transcriptase inhibitor/non-nucleoside analogue reverse transcriptase inhibitorNRTI nucleoside reverse transcriptase inhibitor/nucleoside analogue reverse transcriptase inhibitorNtRTI nucleotide analogue reverse transcriptase inhibitorNVP nevirapineOC oral contraceptiveOI opportunistic infectionOR odds ratioPACTG Pediatric AIDS Clinical Trials GroupPCP Pneumocystis jiroveciipneumoniaPCR polymerase chain reactionPI protease inhibitorPK pharmacokineticPMTCT prevention of mother-to-child transmissionPP postpartumPPI proton pump inhibitorDownloaded from http://aidsinfo.nih.gov/guidelines on 12/27/2012 EST.PrEP pre-exposure prophylaxisPTD preterm deliveryRAL raltegravirRDS respiratory distress syndromeRPV rilpivirineRR relative riskRTV ritonavirsd single doseSQ subcutaneous SQV saquinavirSQV/r saquinavir/ritonavirSTD sexually transmitted diseaseT20 enfuvirtideTDF tenofovir disoproxil fumarateTDM therapeutic drug monitoringTID three times dailyTPV tipranavirTPV/r tipranavir/ritonavirUGT uridine diphosphate glucuronosyltransferaseWHO World Health OrganizationWITS Women and Infants Transmission StudyZDV zidovudineRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States J-3
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