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

J Clin Virol. 2015 Jan:62:20-4. doi: 10.1016/j.jcv.2014.10.020. Epub 2014 Nov 20.

Abstract

Background: The 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.

Objectives: This study was designed to describe the proportions and quantities of NRTI and NNRTI-resistant variants in patients with successful first-line NNRTI therapy.

Study design: We 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).

Results: The mean HIV RNA concentration was 4.78 ± 0.74 log copies/mL and the mean CD4 cell count was 368 ± 184 CD4 cells/mm(3). 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 556 copies/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 715 copies/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.

Conclusions: First-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.

Keywords: Deep sequencing; Human immunodeficiency virus; Minority variants.

MeSH terms

  • Adult
  • Antiretroviral Therapy, Highly Active
  • CD4 Lymphocyte Count
  • Drug Resistance, Viral*
  • Female
  • Follow-Up Studies
  • Genetic Variation*
  • Genotype
  • HIV Infections / drug therapy*
  • HIV Infections / immunology
  • HIV Infections / virology*
  • HIV-1 / drug effects*
  • HIV-1 / genetics*
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • RNA, Viral
  • Reverse Transcriptase Inhibitors / therapeutic use*
  • Sequence Analysis, DNA
  • Viral Load

Substances

  • RNA, Viral
  • Reverse Transcriptase Inhibitors