Efficacy and Safety of an Extended Nevirapine Regimen in Infants of Breastfeeding Mothers With HIV-1 Infection for Prevention of HIV-1 Transmission (HPTN 046): 18-Month Results of a Randomized, Double-Blind, Placebo-Controlled Trial

Fowler, Mary Glenn MD, MPH*; Coovadia, Hoosen MD; Herron, Casey M. MS; Maldonado, Yvonne MD§; Chipato, Tsungai MBChB; Moodley, Dhayendre PhD; Musoke, Philippa MBchB, PhD#; Aizire, Jim MBChB, MS#; Manji, Karim MBBS**; Stranix-Chibanda, Lynda MBChB, MMed††; Fawzi, Wafaie MD‡‡; Chetty, Vani B Tech; Msweli, Lindiwe BA; Kisenge, Rodrick PhD**; Brown, Elizabeth ScD; Mwatha, Anthony MS; Eshleman, Susan H. MD*; Richardson, Paul MSc*; Allen, Melissa MPH#; George, Kathleen MPH‡‡; Andrew, Philip RN§§; Zwerski, Sheryl CRNP‖‖; Mofenson, Lynne M. MD¶¶; Jackson, J. Brooks MD, MBA*; for the HPTN 046 Protocol Team

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 March 2014 - Volume 65 - Issue 3 - p 366–374
doi: 10.1097/QAI.0000000000000052
Epidemiology and Prevention

Background: HPTN 046 compared the efficacy and safety of infant nevirapine (NVP) among HIV-exposed breastfed infants randomized at 6 weeks to 6 months to t NVP or placebo to prevent postnatal infection: we report final 18-month outcomes.

Methods: Randomized, placebo-controlled trial in 4 African countries. Infant diagnostic HIV testing was performed regularly from birth through 18 months. Kaplan–Meier analysis was used to assess 18-month cumulative infant HIV infection, HIV infection/or death, and mortality rates.

Results: Between 6 weeks and 6 months, postnatal HIV infection rates were significantly lower among infants receiving daily NVP from 6 weeks to 6 months 1.1% [95% confidence interval (CI): 0.2% to 1.8%], compared with placebo 2.4% (95% CI: 1.3% to 2.6%), P = 0.049, but not significantly lower thereafter. Eighteen-month postnatal infection rates were low: 2.2% (95% CI: 1.1% to 3.3%) versus 3.1% (95% CI: 1.9% to 4.4%), respectively, P = 0.28. Mortality and HIV infection/death did not differ between arms at any age. Infants of women receiving antiretroviral therapy (ART) for their own health had the lowest 18-month postnatal infection rates (0.5%, 95% CI: 0.0% to 1.1%). However, HIV infection/death rates at 18 months were not significantly different for infants of mothers on ART (3.7%, 95% CI: 1.9% to 5.5%), and infants of mothers with CD4 counts of ≥350 cells per cubic millimeter not receiving ART (4.8%, 95% CI: 2.7% to 6.8%; P = 0.46). There were no differences in adverse events between study arms.

Conclusions: This trial demonstrated early but not late differences in postnatal HIV transmission among infants randomized at age 6 weeks to extended NVP or placebo, underscoring the importance of continued prophylaxis throughout breastfeeding.

*Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD;

Maternal Adolescent and Child Health, University of the Witwatersrand, South Africa;

Fred Hutchinson Cancer Research Center, Seattle, WA;

§Department of Pediatrics, Stanford University School of Medicine, Stanford, CA;

Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe;

Centre for the AIDS Programme of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu Natal, Durban, South Africa;

#Makerere University, Johns Hopkins University, Research Collaboration, Kampala, Uganda;

**Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania;

††Department of Pediatrics, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe;

‡‡Department of Global Health and Population, Harvard University School of Public Health, Boston, MA;

§§Family Health International, Research Triangle Park, NC;

‖‖Division of HIV/AIDS, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, MD; and

¶¶Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD.

Correspondence to: Mary Glenn Fowler, MD, MPH, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (e-mail:mgfowler@mujhu.org).

Supported by the National Institutes of Health (National Institute of Allergy and Infectious Diseases, and Eunice Kennedy Shriver National Institute of Child Health and Human Development) Grant U01 AI068632. HIV Prevention Trials Network (HPTN) 046 (ClinicalTrials.gov Identifier: NCT00074412) was funded by the US National Institutes of Health, initially through the HPTN and later through the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group. The HPTN (U01AI46749) has been funded by the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Drug Abuse, and National Institute of Mental Health (NIMH). The IMPAACT Group (U01AI068632) has been funded by NIAID, NICHD, and NIMH. The study products were provided free of charge by Boehringer Ingelheim Pharmaceuticals.

Presented at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013), March 5, 2013, Atlanta, GA. Abstract no. U-1003.

The authors have no conflicts of interest to disclose.

The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or U.S. Department of Health and Human Services.

Received October 25, 2013

Accepted October 25, 2013

© 2014 by Lippincott Williams & Wilkins