title: HIV-1 subtype influences susceptibility and response to monotherapy with the protease inhibitor lopinavir/ritonavir.
abstract: OBJECTIVE
  PI susceptibility results from a complex interplay between protease and Gag proteins, with Gag showing wide variation across HIV-1 subtypes. We explored the impact of pre-treatment susceptibility on the outcome of lopinavir/ritonavir monotherapy.
  
  
  METHODS
  Treatment-naive individuals who experienced lopinavir/ritonavir monotherapy failure from the MONARK study were matched (by subtype, viral load and baseline CD4 count) with those who achieved virological response ('successes'). Successes were defined by viral load <400 copies/mL after week 24 and <50 copies/mL from week 48 to week 96. Full-length Gag-protease was amplified from patient samples for in vitro phenotypic susceptibility testing, with susceptibility expressed as fold change (FC) relative to a subtype B reference strain.
  
  
  RESULTS
  Baseline lopinavir susceptibility was lower in viral failures compared with viral successes, but the differences were not statistically significant (median lopinavir susceptibility: 4.4 versus 8.5, respectively, P = 0.17). Among CRF02_AG/G patients, there was a significant difference in lopinavir susceptibility between the two groups (7.1 versus 10.4, P = 0.047), while in subtype B the difference was not significant (2.7 versus 3.4, P = 0.13). Subtype CRF02_AG/G viruses had a median lopinavir FC of 8.7 compared with 3.1 for subtype B (P = 0.001).
  
  
  CONCLUSIONS
  We report an association between reduced PI susceptibility (using full-length Gag-protease sequences) at baseline and subsequent virological failure on lopinavir/ritonavir monotherapy in antiretroviral-naive patients harbouring subtype CRF02_AG/G viruses. We speculate that this may be important in the context of suboptimal adherence in determining viral failure.
authors.affiliation: Virus Reference Department, Public Health England, London, UK Department of Infection, University College London, London, UK.
authors.forename: K A
authors.initials: KA
authors.lastname: Sutherland
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: J
authors.initials: J
authors.lastname: Ghosn
authors.affiliation: Department of Medical Statistics, London School of Hygiene and Tropical Medicine, UK.
authors.forename: J
authors.initials: J
authors.lastname: Gregson
authors.affiliation: Virus Reference Department, Public Health England, London, UK.
authors.forename: J L
authors.initials: JL
authors.lastname: Mbisa
authors.affiliation: Université Paris Descartes, EA 7327, Faculté de Médecine site Necker, Paris, France.
authors.forename: M L
authors.initials: ML
authors.lastname: Chaix
authors.affiliation: AbbVie Laboratory, Rungis, France.
authors.forename: I
authors.initials: I
authors.lastname: Cohen Codar
authors.affiliation: AP-HP, Department of Internal Medicine, Bicetre University Hospital, Le Kremlin-Bicetre, France.
authors.forename: J F
authors.initials: JF
authors.lastname: Delfraissy
authors.affiliation: Virology, U941 INSERM Paris Diderot University, St Louis Hospital-APHP, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Delaugerre
authors.affiliation: Department of Infection, University College London, London, UK ravindra.gupta@ucl.ac.uk.
authors.forename: R K
authors.initials: RK
authors.lastname: Gupta
mesh_terms: D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D061466:Lopinavir / Q000627:therapeutic use*; D008297:Male; D008826:Microbial Sensitivity Tests; D019438:Ritonavir / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; D061466:Lopinavir; D016333:HIV Protease; D019438:Ritonavir
keywords: antiretroviral therapy; gag; protease inhibitor; resistance