The contribution of low frequency drug-resistant HIV-1 variants to failure of antiretroviral therapy is not well-defined in treatment-experienced patients.
We sought to detect minor non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant variants at the onset of multidrug efavirenz-containing therapy in both NNRTI-naïve and NNRTI-experienced patients and to determine their association with virologic response.
Plasma samples at entry and virologic failure from patients enrolled in the AIDS Clinical Trials Group study 398 were analyzed by standard genotype, single-genome sequencing and allele-specific PCR (K103N and Y181C) to detect and quantify minor NNRTI-resistant variants.
Minor populations of NNRTI-resistant variants that were missed by standard genotype were detected more often at study entry in NNRTI-experienced patients than NNRTI-naïve patients by both single-genome sequencing (8 of 12 vs. 3 of 15; P=0.022) and allele-specific PCR (>1% Y181C: 5 of 22 vs. 3 of 72, respectively, P = 0.016). K103N variants at frequencies >1% were associated with inferior HIV-1 RNA response to efavirenz-containing therapy between entry and week 24 (+0.5 vs −1.1 log10 copies/ml; P <0.001).
Minor NNRTI-resistant variants were more prevalent in NNRTI-experienced patients and were associated with reduced virologic response to efavirenz-containing multidrug regimens.