Nevirapine Resistance and Breast-Milk HIV Transmission: Effects of Single and Extended-Dose Nevirapine Prophylaxis in Subtype C HIV-Infected Infants

Anitha Moorthy,Sandesh Patil,Madhuri Thakar,Usha Balasubramaniam,Deborah Persaud,Ramesh Bhosale,Renu Bharadwaj,Arvind V Bhore,Varadharajan Venkataramani,Nishi Suryavanshi,Smita Kulkarni,Anju Kagal,Vandana Kulkarni,Jayagowri Sastry,Nikhil Gupte,Srikanth Tripathy,Amita Gupta,Carrie Ziemniak,Robert C Bollinger

doi:10.1371/journal.pone.0004096

Abstract

BackgroundDaily nevirapine (NVP) prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the “six-week extended-dose nevirapine” (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life.Methods/FindingsStandard population sequencing and cloning for viral subpopulations present at ≥5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infant's blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00) and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission.Conclusions/SignificanceUse of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not differ between SD-NVP and SWEN groups. As with SD-NVP, the value of preventing HIV infection in a large number of infants should be considered alongside the high risk of resistance associated with extended NVP prophylaxis.Trial RegistrationClinicalTrials.gov NCT00061321

Highlights

In 2007, an estimated 420,000 infants worldwide were infected with human immunodeficiency virus (HIV) through in utero, peripartum, or breast-milk transmission [1]
In an ‘‘as-treated’’ analysis, we found that infants diagnosed with HIV infection in the first six weeks of life who received six-week extended-dose nevirapine’’ (SWEN) were significantly more likely to have NVP resistance (NVP-R) mutations detected by standard population sequencing compared to infants who received single-dose NVP (SD-NVP) (92% of 12 vs. 38% of 29; p = 0.002; Figure 1)
Within the context of the SWEN trial to prevent breast-milk HIV transmission, we found that prevalence of NVP-R was higher for Indian infants who became subtype C HIV-infected in the first six weeks of life despite receiving daily NVP than for those who had received SD-NVP, a relationship that held even when low-frequency variants were considered

Summary

Introduction

In 2007, an estimated 420,000 infants worldwide were infected with human immunodeficiency virus (HIV) through in utero, peripartum, or breast-milk transmission [1]. The overall risk of HIV transmission through breastfeeding is estimated to be 10%, with the greatest risk by the first six to 14 weeks of life, a period in which 60–70% of breast-milk transmission occurs [6]. Despite this risk, the World Health Organization (WHO) recommends that HIV-infected mothers exclusively breastfeed for at least six months to improve infant survival [7,8]. We assessed NVP-resistance in Indian infants enrolled in the ‘‘six-week extended-dose nevirapine’’ (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who acquired subtype C HIV infection during the first year of life

Methods

Results

Conclusion