title: Polymorphism in Gag gene cleavage sites of HIV-1 non-B subtype and virological outcome of a first-line lopinavir/ritonavir single drug regimen.
abstract: Virological failure on a boosted-protease inhibitor (PI/r) first-line triple combination is usually not associated with the detection of resistance mutations in the protease gene. Thus, other resistance pathways are being investigated. First-line PI/r monotherapy is the best model to investigate in vivo if the presence of mutations in the cleavage sites (CS) of gag gene prior to any antiretroviral treatment might influence PI/r efficacy. 83 patients were assigned to initiate antiretroviral treatment with first-line lopinavir/r monotherapy in the randomised Monark trial. We compared baseline sequence of gag CS between patients harbouring B or non-B HIV-1 subtype, and between those who achieved viral suppression and those who experienced virological failure while on LPV/r monotherapy up to Week 96. Baseline sequence of gag CS was available for 82/83 isolates; 81/82 carried at least one substitution in gag CS compared to HXB2 sequence. At baseline, non-B subtype isolates were significantly more likely to harbour mutations in gag CS than B subtype isolates (p<0.0001). Twenty-three patients experienced virological failure while on lopinavir/r monotherapy. The presence of more than two substitutions in p2/NC site at baseline significantly predicted virological failure (p = 0.0479), non-B subtype isolates being more likely to harbour more than two substitutions in this specific site. In conclusion, gag cleavage site was highly polymorphic in antiretroviral-naive patients harbouring a non-B HIV-1 strain. We show that pre-therapy mutations in gag cleavage site sequence were significantly associated with the virological outcome of a first-line LPV/r single drug regimen in the Monark trial.
authors.affiliation: Paris Descartes University, EA 3620, Necker University Hospital, Paris, France. jade.ghosn@bct.aphp.fr
authors.forename: Jade
authors.initials: J
authors.lastname: Ghosn
authors.forename: Constance
authors.initials: C
authors.lastname: Delaugerre
authors.forename: Philippe
authors.initials: P
authors.lastname: Flandre
authors.forename: Julie
authors.initials: J
authors.lastname: Galimand
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cohen-Codar
authors.forename: François
authors.initials: F
authors.lastname: Raffi
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Delfraissy
authors.forename: Christine
authors.initials: C
authors.lastname: Rouzioux
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Chaix
mesh_terms: D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D061466:Lopinavir / Q000494:pharmacology* / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000187:drug effects*; D019438:Ritonavir / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; D061466:Lopinavir; D019438:Ritonavir