title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: University College London, London, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cozzi-Lepri
authors.affiliation: Institut de Recerca de la SIDA IrsiCaixa i Unitat VIH, Universitat Autònoma de Barcelona, Universitat de Vic, Catalonia, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Noguera-Julian
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Giallonardo
authors.affiliation: Department of Virology, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Schuurman
authors.affiliation: Institut für Immunologie und Genetik, Kaiserslautern, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Däumer
authors.affiliation: Department of Virology, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Sue
authors.initials: S
authors.lastname: Aitken
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.affiliation: Department of Health Sciences, Clinic of Infectious Diseases, 'San Paolo' Hospital, University of Milan, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: D'Arminio Monforte
authors.affiliation: Institute of Infection & Global Health, University of Liverpool, Liverpool, UK.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Geretti
authors.affiliation: Department of Virology, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Booth
authors.affiliation: Institute of Virology, University of Cologne, Cologne, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kaiser
authors.affiliation: 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.
authors.forename: Claudia
authors.initials: C
authors.lastname: Michalik
authors.affiliation: Competence Network for HIV/AIDS, Bochum, Germany and Clinic for Dermatology, Venerology and Allergology of the Ruhr-Universität, Bochum, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Jansen
authors.affiliation: Laboratoire de Virologie, CHU de Bordeaux and MFP-UMR5234, Université Bordeaux 2, Bordeaux, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Masquelier
authors.affiliation: Laboratoire de Virologie, CHU de Bordeaux and MFP-UMR5234, Université Bordeaux 2, Bordeaux, France.
authors.forename: Pantxika
authors.initials: P
authors.lastname: Bellecave
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Kouyos
authors.affiliation: Addiction Medicine, Service of Community Psychiatry, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Erika
authors.initials: E
authors.lastname: Castro
authors.affiliation: Department of Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.affiliation: University College London, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Schultze
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.affiliation: Department of Virology, Bichat University Hospital, Paris, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Brun-Vezinet
authors.affiliation: Institut de Recerca de la SIDA IrsiCaixa i Unitat VIH, Universitat Autònoma de Barcelona, Universitat de Vic, Catalonia, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Paredes
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland karin.metzner@usz.ch.
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Metzner
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D016022:Case-Control Studies; D015331:Cohort Studies; D019295:Computational Biology; D024882:Drug Resistance, Viral; D005060:Europe; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D018570:Risk Assessment; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D018894:Reverse Transcriptase Inhibitors
keywords: CHAIN; European multicentre study; antiretroviral therapy; minority drug-resistant HIV-1 variants