Efficacy of short-course AZT plus 3TC to reduce nevirapine resistance in the prevention of mother-to-child HIV transmission: a randomized clinical trial.

BACKGROUND: Single-dose nevirapine (sdNVP)-which prevents mother-to-child transmission of HIV-selects non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance mutations in the majority of women and HIV-infected infants receiving it. This open-label, randomised trial examined the efficacy of short-course zidovudine (AZT) and lamivudine (3TC) with sdNVP in reducing NNRTI resistance in mothers, and as a secondary objective, in infants, in a setting where sdNVP was standard-of-care. METHODS AND FINDINGS: sdNVP alone, administered at the onset of labour and to the infant, was compared to sdNVP with AZT plus 3TC, given as combivir (CBV) for 4 (NVP/CBV4) or 7 (NVP/CBV7) days, initiated simultaneously with sdNVP in labour; their newborns received the same regimens. Women were randomised 1ratio1ratio1. HIV-1 resistance was assessed by population sequencing at: baseline, 2, and 6 wk after birth. An unplanned interim analysis resulted in early stopping of the sdNVP arm. 406 pregnant women were randomised and took study medication (sdNVP 74, NVP/CBV4 164, and NVP/CBV7 168). HIV-1 resistance mutations emerged in 59.2%, 11.7%, and 7.3% of women in the sdNVP, NVP/CBV4, and NVP/CBV7 arms by 6 wk postpartum; differences between NVP-only and both NVP/CBV arms were significant (p<0.0001), but the difference between NVP/CBV4 and NVP/CBV7 was not (p = 0.27). Estimated efficacy comparing combined CBV arms with sdNVP was 85.6%. Similar resistance reductions were seen in infants who were HIV-infected by their 6-wk visit. CONCLUSIONS: A short course of AZT plus 3TC, supplementing maternal and infant sdNVP, reduces emergent NNRTI resistance mutations in both mothers and their infants. However, this trial was not powered to detect small differences between the CBV arms. TRIAL REGISTRATION: www.ClinicalTrials.govNCT 00144183.

Selection and persistence of viral resistance in HIV-infected children after exposure to single-dose nevirapine.

BACKGROUND: Single-dose nevirapine (sd-NVP) is the mainstay of prevention of mother-to-child transmission programs in developing countries. Exposure to sd-NVP selects for resistance mutations, however. We longitudinally assessed these mutations in HIV-1-infected infants from Soweto and Durban, South Africa. METHODS: We prospectively followed 465 infants who received sd-NVP after enrolling their mothers when pregnant. If HIV infected, their virus was genotyped, using the ViroSeq HIV-1 Genotyping System, to detect resistant mutations. Those with resistance were genotyped at 6 months and then every 6 months out to 18 months if resistance was detected at the previous visit. RESULTS: Of 53 HIV-infected infants, 24 (45.3%) had detectable resistance at their first visit, when the most frequent mutations were Y181C (75%), K103N (25%), and Y188C (12%). Of those whose visit was before 12 weeks of age, 2 of 42 infants shared identical resistance mutations with their mothers. By 18 months of age, 11 of 24 infants with resistance had died and 1 still had the Y181C mutation. CONCLUSIONS: Resistant mutations were selected in half of the infants exposed to sd-NVP, but fewer were detected over time and, unlike the case in their mothers, Y181C dominated initially and persists. Transient resistance mutations may have a negative impact on highly active antiretroviral therapy in infants and children.