Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based ART: A multicohort European case-control study using centralized ultrasensitive 454 pyrosequencing

Alessandro Cozzi-Lepri, Marc Noguera-Julian, Francesca Di Giallonardo, Rob Schuurman, Martin Däumer, Sue Aitken, Francesca Ceccherini-Silberstein, Antonella D.Arminio Monforte, Anna Maria Geretti, Clare L. Booth, Rolf Kaiser, Claudia Michalik, Klaus Jansen, Bernard Masquelier, Pantxika Bellecave, Roger D. Kouyos, Erika Castro, Hansjakob Furrer, Anna Schultze, Huldrych F. GünthardFrancoise Brun-Vezinet, Roger Paredes, Karin J. Metzner, Norbert Brockmeyer

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Abstract

© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. Objectives: It is still debated if pre-existing minority drug-resistant HIV-1 variants (MVs) affect the virological outcomes of first-line NNRTI-containing ART. Methods: This Europe-wide case-control study included ART-naive subjects infected with drug-susceptible HIV-1 as revealed by population sequencing, who achieved virological suppression on first-line ART including one NNRTI. Cases experienced virological failure and controls were subjects from the same cohort whose viraemia remained suppressed at a matched time since initiation of ART. Blinded, centralized 454 pyrosequencing with parallel bioinformatic analysis in two laboratories was used to identify MVs in the 1%-25% frequency range. ORs of virological failure according to MV detection were estimated by logistic regression. Results: Two hundred and sixty samples (76 cases and 184 controls), mostly subtype B (73.5%),were used for the analysis. Identical MVs were detected in the two laboratories. 31.6% of cases and 16.8% of controls harboured pre-existing MVs. Detection of at least one MV versus no MVs was associated with an increased risk of virological failure (OR=2.75, 95% CI=1.35-5.60, P=0.005); similar associations were observed for at least one MV versus no NRTIMVs (OR=2.27, 95% CI=0.76-6.77, P=0.140) and at least oneMV versus no NNRTIMVs (OR=2.41, 95% CI=1.12-5.18, P=0.024). A dose-effect relationship between virological failure and mutational loadwas found. Conclusions: Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART.
Original languageEnglish
Article numberdku426
Pages (from-to)930-940
JournalJournal of Antimicrobial Chemotherapy
Volume70
Issue number3
DOIs
Publication statusPublished - 1 Jan 2015

Keywords

  • Antiretroviral therapy
  • CHAIN
  • European multicentre study
  • Minority drug-resistant HIV-1 variants

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