Background:  As part of a prospective, randomized, double-blind controlled trial in India to address efficacy of extended-dose nevirapine (NVP) prophylaxis in preventing breast-milk transmission of HIV-1, we compared NVP resistance among infants exposed to extended-dose NVP vs single-dose NVP by timing of HIV-1 infection and receipt of maternal single-dose NVP.

Methods: Single-dose NVP-exposed infants were randomized and masked to receive Eextended-dose NVP + multivitamins or multivitamins alone once daily from day 8 until 42 of life. HIV-1 DNA polymerase chain reaction (PCR) was done at 48 hours and week 1, 2, 4, 6, 10, and 14 and month 6, 9, and 12 of age. Timing of infection was based on 4 groups:  in utero (IU: positive by 48 hours; n = 23); peripartum/early breastfeeding (positive at week 1 to 6; n = 19); late breast-fed ( positive at week10 to 14; n = 18), and very late breast-fed (positive at ≥6 months; n = 19). HIV-1 population-based genotyping was done on infant plasma samples collected on visit following positive DNA PCR. NVP resistance between and among extended-dose NVP and single-dose NVP exposed infant groups were compared using Fishers exact tests. Multivariate logistic regression modeled correlates of NVP resistance.

Results:  Of 99 plasma samples, 89 (90%) were available for study. Population-based genotyping was successful in 86 (97%); 79 (92%) had samples that were a median of 28 days since HIV diagnosis. Extended-dose NVP infants infected within 6 weeks of age had higher NVP resistance than single-dose NVP infants (11 of 12 [92%] vs 12 of 30 [40%]; p = 0.005). However, extent (>1 mutation) and type of NVP resistance were not different for all infant groups at the population level; extended-dose NVP in 5 of 13 (38%) vs single-dose NVP in 4 of 16 (25%); Y181C (40% vs 32%) being the most common, followed by K103N (30% vs 21%) and Y188C (16% vs 10%); p>0.5. NVP resistance in infants infected within 14 weeks of age and born to women with and without NVP receipt was also similar (infant extended-dose NVP 6 of 11 [55%] vs 5 of 7 [71%], p = 0.64; infant single-dose NVP 10 of 25 [40%] vs 5 of 17 [29%]; p = 0.48). After adjusting for infant treatment by receipt of maternal NVP with or without antepartum zidovudine, late breast-fed and very late breast-fed infants were less likely to have NVP resistance than infants infected early (intrauterine, post-partum, and early breast-fed) (late breast-fed, OR = 0.15; 0.03 to 0.64; very late breast-fed, OR = 0.06; 0.01 to 0.34).

Conclusions:  Higher rates of NVP resistance were seen in extended-dose NVP-exposed infants infected within 6 weeks of life. However, among infants who escaped early infection, wild type HIV-1 is predominantly transmitted through breast milk. Maternal single-dose NVP receipt, however, did not seem to influence this finding in our study. These results may be important for use of extended-dose NVP prophylaxis for preventing breast-milk transmission and subsequent therapy for infants.