title: Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length Gag-protease genes.
abstract: OBJECTIVE
  Major protease mutations are rarely observed following first-line failure with PIs and interpretation of genotyping results in this context may be difficult. We performed extensive phenotyping of viruses from five patients failing lopinavir/ritonavir monotherapy in the MONARK study without major PI mutations by standard genotyping.
  
  
  METHODS
  Phenotypic susceptibility testing and viral infectivity assessments were performed using a single-cycle assay and fold changes (FC) relative to a lopinavir-susceptible reference strain were calculated.
  
  
  RESULTS
  >10-fold reduced baseline susceptibility to lopinavir occurred in two of five patients and >5-fold in another two. Four of five patients exhibited phylogenetic evidence of a limited viral evolution between baseline and failure, with amino acid changes at drug resistance-associated positions in one: T81A emerged in Gag with M36I in the protease gene, correlating with a reduction in lopinavir susceptibility from FC 7 (95% CI 6-8.35) to FC 13 (95% CI 8.11-17.8). Reductions in darunavir susceptibility (>5 FC) occurred in three individuals.
  
  
  CONCLUSIONS
  This study suggests both baseline reduced susceptibility and evolution of resistance could be contributing factors to PI failure, despite the absence of classical PI resistance mutations by standard testing methods. Use of phenotyping also reveals lower darunavir susceptibility, warranting further study as this agent is commonly used following lopinavir failure.
authors.affiliation: Public Health England, London, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Sutherland
authors.affiliation: Public Health England, London, UK.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Mbisa
authors.affiliation: Université Paris Descartes, EA 7327, Faculté de Médecine Site Necker, Paris, France APHP, UF de Thérapeutique en Immuno Infectiologie, CHU Hotel Dieu, Paris, France.
authors.forename: Jade
authors.initials: J
authors.lastname: Ghosn
authors.affiliation: Université Paris Descartes, EA 7327, Faculté de Médecine Site Necker, Paris, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Chaix
authors.affiliation: AbbVie Laboratory, Rungis, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cohen-Codar
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Stephane
authors.initials: S
authors.lastname: Hue
authors.affiliation: AP-HP, Department of Internal Medicine, Bicetre University Hospital, Le Kremlin-Bicetre, France.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Delfraissy
authors.affiliation: Virology, U941 INSERM Paris Diderot University, St Louis Hospital-APHP, Paris, France.
authors.forename: Constance
authors.initials: C
authors.lastname: Delaugerre
authors.affiliation: Division of Infection and Immunity, University College London, London, UK rebmrag@ucl.ac.uk.
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Gupta
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061466:Lopinavir / Q000627:therapeutic use*; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D019438:Ritonavir / Q000627:therapeutic use*; D017211:Treatment Failure; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D054301:gag Gene Products, Human Immunodeficiency Virus; D061466:Lopinavir; D016333:HIV Protease; D019438:Ritonavir
keywords: Gag; HIV; antiretroviral resistance; monotherapy; protease inhibitors
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