Nevirapine resistance and breast-milk HIV transmission: effects of single and extended-dose nevirapine prophylaxis in subtype C HIV-infected infants

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

Abstract

Background: Daily 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/findings: Standard population sequencing and cloning for viral subpopulations present at > or =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/significance: Use 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 registration: ClinicalTrials.gov NCT00061321.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. SWEN and SD-NVP exposed HIV-infected…
Figure 1. SWEN and SD-NVP exposed HIV-infected infants diagnosed within the first six weeks of life with NVP-R.
SWEN = up to six weeks of extended-dose nevirapine; SD-NVP = single-dose nevirapine; NVP-R = nevirapine resistance. P-values generated using Fisher's exact test.
Figure 2. SWEN and SD-NVP exposed infants…
Figure 2. SWEN and SD-NVP exposed infants infected with HIV after six weeks of age through late-breastfeeding with NVP-R.
SWEN = up to six weeks of extended-dose nevirapine; SD-NVP = single-dose nevirapine; NVP-R = nevirapine resistance. P-values generated using Fisher's exact test.

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