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To describe the prevalence of HIV-1 drug resistance mutations at the time of treatment initiation in a large cohort of HIV-infected children previously exposed to single-dose nevirapine (sdNVP) for prevention of transmission.Drug resistance mutations were measured pretreatment in 255 infants and young children under 2 years of age in South Africa exposed to sdNVP and initiating ritonavir-boosted lopinavir-based therapy. Those who achieved viral suppression were randomized to either continue the primary regimen or to switch to a nevirapine-based regimen. Pretreatment samples were tested using population sequencing and real time allele-specific PCR (AS-PCR) to detect Y181C and K103N minority variants. Those with confirmed viremia more than 1000 copies/ml by 52 weeks postrandomization in the switch group were defined as having viral failure.Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, predominantly Y181C, were detected by either method in 62% of infants less than 6 months of age, in 39% of children 6–12 months of age, 22% 12–18 months, and 16% 18–24 months (P = <0.0001). NNRTI mutations detected by genotyping, but not K103N or Y181C mutations detected only by AS-PCR, were associated with viral failure in the switch group.The prevalence of mutations known to compromise primary NNRTI-based therapy is high in sdNVP-exposed children, supporting current guidelines recommending use of protease inhibitor-based regimens for young children. Standard genotyping is adequate to identify children who could benefit from switching to NNRTI-based therapy.