Minority Quasispecies of Drug‐Resistant HIV‐1 That Lead to Early Therapy Failure in Treatment‐Naive and ‐Adherent Patients

TLDR

Early virological failure of antiretroviral therapy in treatment‑naive HIV‑1 patients is driven by the emergence of drug‑resistant variants, and minority quasispecies that are undetectable by standard sequencing can rapidly expand to dominate the viral population and precipitate failure. The study aimed to determine whether baseline minority drug‑resistant HIV‑1 quasispecies predict early virological failure in patients initiating first‑line therapy. Researchers quantified key reverse‑transcriptase mutations (K65R, K103N, Y181C, M184V, M184I) by allele‑specific real‑time PCR in plasma from 4 failing patients and 18 controls before and during treatment. Baseline minority M184V/I variants were present in all 4 failing patients (0.07–2.0 %) but only in 3 of 18 controls, and these variants rapidly rose to dominate the viral population within weeks, despite good adherence and normal drug levels.

Abstract

Early virological failure of antiretroviral therapy associated with the selection of drug-resistant human immunodeficiency virus type 1 in treatment-naive patients is very critical, because virological failure significantly increases the risk of subsequent failures. Therefore, we evaluated the possible role of minority quasispecies of drug-resistant human immunodeficiency virus type 1, which are undetectable at baseline by population sequencing, with regard to early virological failure.We studied 4 patients who experienced early virological failure of a first-line regimen of lamivudine, tenofovir, and either efavirenz or nevirapine and 18 control patients undergoing similar treatment without virological failure. The key mutations K65R, K103N, Y181C, M184V, and M184I in the reverse transcriptase were quantified by allele-specific real-time polymerase chain reaction performed on plasma samples before and during early virological treatment failure.Before treatment, none of the viruses showed any evidence of drug resistance in the standard genotype analysis. Minority quasispecies with either the M184V mutation or the M184I mutation were detected in 3 of 18 control patients. In contrast, all 4 patients whose treatment was failing had harbored drug-resistant viruses at low frequencies before treatment, with a frequency range of 0.07%-2.0%. A range of 1-4 mutations was detected in viruses from each patient. Most of the minority quasispecies were rapidly selected and represented the major virus population within weeks after the patients started antiretroviral therapy. All 4 patients showed good adherence to treatment. Nonnucleoside reverse-transcriptase inhibitor plasma concentrations were in normal ranges for all 4 patients at 2 separate assessment times.Minority quasispecies of drug-resistant viruses, detected at baseline, can rapidly outgrow and become the major virus population and subsequently lead to early therapy failure in treatment-naive patients who receive antiretroviral therapy regimens with a low genetic resistance barrier.