Prevalence and evolution of low frequency HIV drug resistance mutations detected by ultra deep sequencing in patients experiencing first line antiretroviral therapy failure

PLoS One. 2014 Jan 27;9(1):e86771. doi: 10.1371/journal.pone.0086771. eCollection 2014.

Abstract

Objectives: Clinical relevance of low-frequency HIV-1 variants carrying drug resistance associated mutations (DRMs) is still unclear. We aimed to study the prevalence of low-frequency DRMs, detected by Ultra-Deep Sequencing (UDS) before antiretroviral therapy (ART) and at virological failure (VF), in HIV-1 infected patients experiencing VF on first-line ART.

Methods: Twenty-nine ART-naive patients followed up in the ANRS-CO3 Aquitaine Cohort, having initiated ART between 2000 and 2009 and experiencing VF (2 plasma viral loads (VL) >500 copies/ml or one VL >1000 copies/ml) were included. Reverse transcriptase and protease DRMs were identified using Sanger sequencing (SS) and UDS at baseline (before ART initiation) and VF.

Results: Additional low-frequency variants with PI-, NNRTI- and NRTI-DRMs were found by UDS at baseline and VF, significantly increasing the number of detected DRMs by 1.35 fold (p<0.0001) compared to SS. These low-frequency DRMs modified ARV susceptibility predictions to the prescribed treatment for 1 patient at baseline, in whom low-frequency DRM was found at high frequency at VF, and 6 patients at VF. DRMs found at VF were rarely detected as low-frequency DRMs prior to treatment. The rare low-frequency NNRTI- and NRTI-DRMs detected at baseline that correlated with the prescribed treatment were most often found at high-frequency at VF.

Conclusion: Low frequency DRMs detected before ART initiation and at VF in patients experiencing VF on first-line ART can increase the overall burden of resistance to PI, NRTI and NNRTI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Retroviral Agents / therapeutic use
  • Cohort Studies
  • DNA Primers / genetics
  • Drug Resistance, Viral / genetics*
  • Evolution, Molecular*
  • Female
  • HIV Infections / drug therapy
  • HIV Infections / epidemiology*
  • HIV Infections / virology*
  • HIV-1 / genetics*
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Male
  • Prevalence
  • Reverse Transcriptase Polymerase Chain Reaction
  • Viral Load

Substances

  • Anti-Retroviral Agents
  • DNA Primers

Grants and funding

This work was supported by the European Community's Seventh Framework Programme (FP7/2007–2013) under the project Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN) (grant no. 223131), the Agence Nationale de Recherche sur le SIDA et les Hépatites and the University Bordeaux Segalen - Centre national de la recherche scientifique UMR 5234. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.