Minority resistant HIV-1 variants and the response to first-line NNRTI therapy

Abstract

BackgroundThe presence of low-frequency HIV-1 variants with mutations making them resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTI) could influence the virological response to first-line NNRTI therapy. ObjectivesThis study was designed to describe the proportions and quantities of NRTI and NNRTI-resistant variants in patients with successful first-line NNRTI therapy. Study designWe evaluated the presence of drug-resistance mutations (DRMs) prior to treatment initiation in 131 naive chronically HIV-1-infected patients initiating NNRTI-based first-line therapy. DRMs were detected by ultradeep pyrosequencing (UDPS) on a GS Junior instrument (Roche). ResultsThe mean HIV RNA concentration was 4.78±0.74logcopies/mL and the mean CD4 cell count was 368±184 CD4cells/mm3. Patients were mainly infected with subtype B (68%) and 96% were treated with efavirenz. The sensitivity threshold for each mutation was 0.13–1.05% for 2000 reads. Major NRTI-resistant or NNRTI-resistant mutations were detected in 40 patients (33.6%). The median frequency of major NRTI-resistant mutations was 1.37% [IQR: 0.39–84.1], i.e.: a median of 556copies/mL [IQR: 123–37,553]. The median frequency of major NNRTI-resistant DRMs was 0.78% [IQR: 0.67–7.06], i.e.: a median of 715copies/mL [IQR: 391–3452]. The genotypic susceptibility score (GSS) of 9 (7.3%) patients with mutations to given treatment detected by UDPS was 1.5 or 2. ConclusionsFirst-line NNRTI-based treatment can produce virological success in naïve HIV-1-infected patients harboring low-frequency DRMs representing <1% of the viral quasispecies. Further studies are needed to determine the clinical cut-off of low-frequency resistant variants associated to virological failure.