Impact of maternal and infant antiretroviral drug regimens on drug resistance in HIV-infected breastfeeding infants

Abstract

Background: The HIV Prevention Trials Network (HPTN) 046 trial evaluated the efficacy of extended infant nevirapine (NVP) administration for prevention of HIV transmission through breastfeeding. Infants received daily NVP up to 6 weeks of age. HIV-uninfected infants (the intent-to-treat group) received daily NVP or placebo up to 6 months of age. We analyzed emergence of NVP resistance in infants who acquired HIV infection despite prophylaxis.

Methods: HIV genotyping was performed using the ViroSeq HIV Genotyping System. Medians and proportions were used to summarize data. Two-sided Fisher exact tests were used to evaluate associations between categorical variables.

Results: NVP resistance was detected in 12 (92.3%) of 13 infants who were HIV-infected by 6 weeks and in 7 (28%) of 25 infants who were HIV-uninfected at 6 weeks and HIV-infected at 6 months of age (6/8 = 75% in the NVP arm, 1/17 = 5.9% in the placebo arm, P = 0.001). Among those 25 infants, 4 had mothers who initiated an antiretroviral treatment regimen by 6 months postpartum. In all 4 cases, the treatment regimen included a non-nucleoside reverse transcriptase inhibitor (NVP or efavirenz). NVP resistance was detected in all 4 of those infants by 6 months of age (4/4 = 100%). In contrast, only 3 (14.2%) of the remaining 21 HIV-infected infants whose mothers did not initiate antiretroviral treatment developed NVP resistance (P = 0.003).

Conclusions: Extended NVP prophylaxis significantly increased the risk of NVP resistance in infants who acquired HIV infection after 6 weeks of age. Treatment of maternal HIV infection was also associated with emergence of NVP resistance in HIV-infected, breastfed infants.

Figure 1

HIV genotyping results obtained for maternal plasma, breast milk, and infant plasma samples from eight mother-infant pairs where the mother started highly active antiretroviral therapy (HAART) by 6 months postpartum; all available samples were tested. Samples were collected at 6 weeks, and at 3 and 6 months postpartum. Shaded boxes indicate the study visits the mother was on HAART. HIV genotyping was not performed for maternal samples that had <400 copies/ml (c/ml) HIV RNA (VL<400c/ml). (a) A nested polymerase chain reaction (PCR) procedure was required for amplification. (b) HIV genotyping results for this infant did not include amino acids 8 to 32 in HIV reverse transcriptase. No major non-nucleoside reverse transcriptase inhibitor (NNRTI) or nucleoside / nucleotide reverse transcriptase inhibitor (NRTI) resistance mutations occur in that region of the reverse transcriptase protein.