HIV-1 drug resistance at antiretroviral treatment initiation in children previously exposed to single-dose nevirapine

Abstract

Objective: 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.

Design: 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.

Results: 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.

Conclusion: 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.

Figure 1. Pattern of HIV-1 drug resistance mutations detected by population sequencing among 255 sdNVP-exposed children initiating antiretroviral therapy

All major PI, NRTI and NNRTI mutations are shown (black bars). Minor mutations are shown in grey. Mutations are categorized as per the December 2009 IAS mutation list [25]

Figure 2. Comparison of Y181C and K103N AS-PCR quantitative value relative to population genotype

The actual quantitative values of the percent of the viral population found to be Y181C (left panel) and K103N (right panel) by AS-PCR stratified by genotype result are shown. Solid horizontal lines indicate the median quantitative value of AS-PCR positive samples in each group. 173 and 221 samples were negative for Y181C and K103N by population sequencing and AS-PCR, respectively.

Figure 3. Overall prevalence of NNRTI mutations among 255 sdNVP-exposed children initiating antiretroviral therapy

Data show the prevalence of NNRTI mutations by genotyping (black bars) plus the additional prevalence when including samples that were only identified using the Y181C or the K103N AS-PCR (grey bars). Samples classified as indeterminate by Y181C AS-PCR were excluded.