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J Antimicrob Chemother. 2015 Mar;70(3):930-40. doi: 10.1093/jac/dku426. Epub 2014 Oct 21.

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.

Author information

1
University College London, London, UK.
2
Institut de Recerca de la SIDA IrsiCaixa i Unitat VIH, Universitat Autònoma de Barcelona, Universitat de Vic, Catalonia, Spain.
3
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
4
Department of Virology, University Medical Centre, Utrecht, The Netherlands.
5
Institut für Immunologie und Genetik, Kaiserslautern, Germany.
6
Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
7
Department of Health Sciences, Clinic of Infectious Diseases, 'San Paolo' Hospital, University of Milan, Milan, Italy.
8
Institute of Infection & Global Health, University of Liverpool, Liverpool, UK.
9
Department of Virology, Royal Free London NHS Foundation Trust, London, UK.
10
Institute of Virology, University of Cologne, Cologne, Germany.
11
Competence Network for HIV/AIDS, Bochum, Germany and Clinic for Dermatology, Venerology and Allergology of the Ruhr-Universität, Bochum, Germany Clinical Trial Centre (ZKS), University of Cologne, Cologne, Germany.
12
Competence Network for HIV/AIDS, Bochum, Germany and Clinic for Dermatology, Venerology and Allergology of the Ruhr-Universität, Bochum, Germany.
13
Laboratoire de Virologie, CHU de Bordeaux and MFP-UMR5234, Université Bordeaux 2, Bordeaux, France.
14
Addiction Medicine, Service of Community Psychiatry, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
15
Department of Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland.
16
Department of Virology, Bichat University Hospital, Paris, France.
17
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland karin.metzner@usz.ch.

Abstract

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 NRTI MVs (OR = 2.27, 95% CI = 0.76-6.77, P = 0.140) and at least one MV versus no NNRTI MVs (OR = 2.41, 95% CI = 1.12-5.18, P = 0.024). A dose-effect relationship between virological failure and mutational load was found.

CONCLUSIONS:

Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART.

KEYWORDS:

CHAIN; European multicentre study; antiretroviral therapy; minority drug-resistant HIV-1 variants

PMID:
25336166
PMCID:
PMC4319483
DOI:
10.1093/jac/dku426
[Indexed for MEDLINE]
Free PMC Article

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