Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention

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N Engl J Med. 2016 Nov 3;375(18):1726-1737.

Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention

Fowler MG¹, Qin M¹, Fiscus SA¹, Currier JS¹, Flynn PM¹, Chipato T¹, McIntyre J¹, Gnanashanmugam D¹, Siberry GK¹, Coletti AS¹, Taha TE¹, Klingman KL¹, Martinson FE¹, Owor M¹, Violari A¹, Moodley D¹, Theron GB¹, Bhosale R¹, Bobat R¹, Chi BH¹, Strehlau R¹, Mlay P¹, Loftis AJ¹, Browning R¹, Fenton T¹, Purdue L¹, Basar M¹, Shapiro DE¹, Mofenson LM¹; IMPAACT 1077BF/1077FF PROMISE Study Team.

• ¹From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children´s Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).

Abstract below; full text is at http://www.nejm.org/doi/full/10.1056/NEJMoa1511691

Background Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. Methods We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. Results The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART. Conclusions Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).