In the secondary analysis, which included all follow-up data, there were 8 cumulative infections among 1218 mother–infant pairs randomized to mART and 10 among the 1211 randomized to iNVP. For the 18 infected infants, the median infant age at HIV-1 infection was 38 weeks (range, 13–62 weeks) in the mART arm and 50.5 weeks (range, 6–75 weeks) in the iNVP arm. The cumulative probability of infection at 24 months was 0.9% (95% CI: 0.6% to 1.5%) (Fig. 1B and Table 2). The probability of infant HIV-1 infection/death at 24 months in the mART arm was 2.9% (95% CI: 2.0% to 4.1%), and in the iNVP arm was 2.3% (95% CI: 1.5% to 3.4%), resulting in HIV-1–free survival at 24 months of 97.1% in the mART and 97.7% in the iNVP arm (Fig. 1C and Table 2).
All 2431 women are included in the safety analysis; 15 had no postrandomization visit (9 in mART and 6 in iNVP) and were censored at date of randomization. There was no significant difference in time to the first composite safety endpoint between arms (P = 0.98 and P = 0.61) and the incidence rates of adverse events were similar in the 2 arms (Table 3). Sensitivity analyses that did not censor at the minimum recommended duration of breastfeeding provided similar results (not shown). Three maternal deaths occurred (2 in the mART and 1 in the iNVP arm) during the perinatal HIV-1 transmission risk period; no death was judged related to study intervention. Of the 1207 women in the mART arm who started on the study recommended regimen, 9 (<1%) stopped the recommended regimen because of toxicity.
All 2444 infants are included in the safety analysis; 4 had no postrandomization visit information (2 in each arm) and were censored at date of randomization. There was no significant difference in time to the first composite safety endpoint between arms (P = 0.99) and the incidence rates of adverse events were similar in the 2 arms (Table 3). Sensitivity analyses that did not censor at the minimum recommended duration of breastfeeding provided similar results (not shown). In addition, among infants randomized to iNVP, safety assessments beyond week 6 did not demonstrate increased incidence of liver or skin toxicity compared with the mART arm (Table 3). Of the 1204 infants in the iNVP arm who started on the study recommended regimen, 20 (<2%) stopped the recommended regimen because of toxicity.
The PROMISE study is the first randomized trial to conduct a head-to-head comparison of mART and iNVP for postnatal HIV-1 transmission through up to 18 months of breastfeeding in asymptomatic women with high CD4 counts who did not meet treatment criteria at the time the study was conducted. Although the cumulative postnatal HIV-1 transmission rates in both the mART and iNVP arms were much lower than anticipated in sample size calculations, which greatly limited the study's statistical power to detect a difference in transmission risk between arms, the findings demonstrate that both mART and iNVP regimens were highly efficacious, with 12- and 24-month postnatal infection rates of 0.6% and 0.9%, respectively, and high rates of HIV-1–free survival at 24 months (>97%). The high under-two year survival rates (1.7% infant mortality) were particularly noteworthy compared with prevailing rates in most of the settings where the study was conducted.24
Two contemporary studies, ANRS 12174 and the Uganda PROMOTE trial, demonstrated similar survival rates but at 50 weeks of follow-up. ANRS 12174 randomized HIV-1–uninfected breastfed infants to either LPV/r or 3 TC through cessation of breastfeeding or 50 weeks. HIV-1–free survival at 50 weeks was 96% in both study arms.11 HIV-1–infected women in the PROMOTE study were randomized between 12 and 28 weeks of pregnancy to either a LPV/r or efavirenz-based regimen that was continued for 48 weeks of breastfeeding. HIV-1–free infant survival at 8 weeks postpartum was 92.9% in the LPVr arm and 97.2% in the efavirenz arm.12
In addition, no safety concerns were observed in both mART and iNVP arms of the study. Less than 1% of women and 2% of infants discontinued their study regimen because of toxicity. Concerns have been raised about the potential infant toxicity from ingestion of ARVs in breastmilk of mothers receiving ART. Our study found no evidence of increased rates of toxicity in breastfeeding infants of mothers receiving tenofovir-based ART compared with breastfeeding infants whose mothers were not receiving ART. These data are also reassuring regarding the safety of TDF/FTC preexposure prophylaxis by breastfeeding, uninfected women at risk of HIV, and their infants.25–27 Similarly, the prolonged use of daily NVP prophylaxis by HIV-1–uninfected infants for up to 18 months was not associated with elevated infant toxicity, including skin and liver toxicity, compared with infants not receiving NVP.
Our data underline the importance of providing postpartum support for women receiving ART because we observed a continuing risk of infant postnatal infection for the duration of breastfeeding even when effective interventions were being provided. A variety of approaches will be needed to achieve an HIV-1–free generation, including interventions to support ART adherence and postpartum retention in care for women and ensuring the availability of equally effective and safe infant prophylaxis alternatives for situations in which maternal ART may be insufficient to protect the breastfeeding infant.
The PROMISE team gratefully acknowledges the contributions of the mothers and their infants who participated in the study. The team also acknowledges the support and donation of study products of Gilead, GSK/Viiv/Healthcare, Abbvie, and Boehringer Ingelheim pharmaceutical companies. The authors gratefully acknowledge the contributions of the study staff, site investigators, and site staff who conducted IMPAACT 1077BFstudy.
PROMISE Study Team Members
Judith Currier, Katherine Luzuriaga, Adriana Weinberg, James McIntyre, Tsungai Chipato, Karin Klingman, Renee Browning, Mireille Mpoudi-Ngole, Jennifer S. Read, George Siberry, Heather Watts, Lynette Purdue, Terrence Fenton, Linda Barlow-Mosha, Mary Pat Toye, Mark Mirochnick, William B. Kabat, Benjamin Chi, Marc Lallemant, Karin Nielsen; Statistical and Data Analysis Center, Harvard T.H. Chan School of Public Health: K.B., Konstantia Angelidou, MS, and Sean Brummel, PhD. FHI360: Melissa Allen, Anne Coletti, Megan Valentine, Kathleen George; Frontier Science Data Management Center: Michael Basar, Amy Jennings, Adam Manzella, Amanda Zadzilka; Retroviral Core Laboratory, University of North Carolina Virology Laboratory: Amy James.
INDIA. Byramjee Jeejeebhoy Medical College: Ajay Sahebrao Chandanwale, MS; Pradip Wamanrao Sambarey, MD PhD; Uma Nitin Wankhede, MD. MALAWI. Blantyre: T.E.T.; B.M.; Rachel Chamanga, MBBS; Newton Kumwenda, MPH, PhD. Lilongwe/UNC: C.M.; Godwin Chikopa, MBBS, MSC Paeds; Ezylia Makina, RNM. SOUTH AFRICA. Durban Paediatric: Sajeeda Mawlana, MBChB, Post Graduate Diploma in Clinical HIV/AIDS Management Nozibusiso Rejoice Sikhosana, BN; Kimesh Naidoo, MBChB, DCH, FCPaed. Family Clinical Research Unit: Jeanne Louw, MSc; Magdel Rossouw, MNutr, MBChB; Lindi Rossouw, MBChB. Shandukani Research: Janet Grab, BPharm; Lee Fairlie, MBChB, FCPaeds (SA), MMED (Paeds); Hermien Gous, PharmD; Gurpreet Kindra, MBBS. Soweto: Sylvia Dittmer, MD; M.N.; Nasreen Abrahams, MBA. Umlazi: Megeshinee Naidoo, MBChB; Vani Chetty, BscHon; Alicia Catherine Desmond, BPharm, MPharm; TANZANIA. Kilimanjaro Christian Medical Centre Blandina Theophil Mmbaga, MD, MMed, PhD; Boniface Njau, MPH; Julitha Kimbi, RN. UGANDA. MU-JHU Research Collaboration: Moreen Kamateeka, MBChB, MPH; Dorothy Sebikari, MBChB, MPH; Philippa Musoke, PhD. ZAMBIA. George Clinic: Mwangelwa Mubiana-Mbewe, MBChB, MMed, MBA; Felistas M. Mbewe, RN, BSc; Bethany Freeman, MSPH, MSW. ZIMBABWE. Harare Family Care: Tapiwa Mbengeranwa, MBChB; Tsungai Mhembere, BPharm; Sukunena Maturure, SRN, MS; T.V. Seke North: L.S.-C.; T.N.; Suzen Maonera, SRN, MS; Vongai Chanaiwa, BPharm. St. Mary's: Tsungai Chipato, MB, ChB, FRCOG; Bangani Kusakara, MBChB; Mercy Mutambanengwe, BPharm; Emmie Marote, SRN, MA.
The PROMISE team dedicates this article to Dr Edward Handelsman, Division of AIDS, NIH, Dr Stephen Lagakos from the Center for Biostatistics in AIDS Research, Harvard School of Public Health, and Mrs. Linda Millar from The Frontier Science & Technology Research Foundation, Amherst, NY in grateful memory of their many contributions to the PROMISE 1077 trial and HIV/AIDS research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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