Resistance to nevirapine and its impact on strategies to prevent and treat HIV infection in children living in resource -poor countries

Exposure to a single dose of nevirapine for prevention of mother-to-child HIV-1 transmission results in the emergence of resistance in infants who fail prophylaxis. Subsequently, resistance to nevirapine at high frequencies (≥20% of virus population) leads to poorer treatment outcomes when the drug is reused for treatment. We analyzed the risk of nevirapine resistance when prophylaxis was extended in infants for six weeks for prevention of HIV-1 transmission during breastfeeding. Using high throughput ultradeep pyrosequencing, we also assessed the impact of nevirapine resistance after a single dose on virologic suppression when nevirapine was reused as part of highly-active antiretroviral therapy (HAART) preceded by induction therapy with lopinivar/ritonavir (LPV/r).;Six weeks of nevirapine prophylaxis was significantly associated with an increased risk of high frequency nevirapine resistance compared with a single-dose regimen (92% of 12 vs. 38% of 29). Exposure to breast milk for up to 12 months from women who received a single dose of nevirapine was associated with acquiring infection with nevirapine resistant HIV-1 in 40% of infants. High frequency nevirapine resistance was found in 18.5% of 124 single-dose exposed South African children and was associated with a 3.5-fold higher risk of virologic failure upon switch to maintenance HAART with nevirapine following initial induction therapy with LPV/r. In contrast, low frequency nevirapine resistance was observed in 14.5% of children and did not lead to a higher risk of virologic failure. The frequencies with which nevirapine resistance persisted in long-lived cells (61% of 96 children) following induction with HAART correlated with frequencies in pretreatment plasma; however, cellular resistance was not predictive of virologic failure.;Given that nevirapine is a central part of efforts to prevent mother-to-child transmission and treat HIV-1 infected infants in resource-poor countries, insights into circumstances that allow recycling of nevirapine when resistance develops is critical. Our findings that a threshold frequency of plasma resistance above 20% was a strong predictor of poor virologic response, although present in only a small proportion of single-dose exposed children, suggests that standard drug resistance tests for high frequency resistance mutations may be sufficient to identify children likely to benefit from this novel induction-maintenance treatment approach.