Journal Article

Polymorphism in Gag Gene Cleavage Sites of HIV-1 Non-B Subtype and Virological Outcome of a First-Line Lopinavir/Ritonavir Single Drug Regimen

Cohen-Codar, Isabelle, Chaix, Marie-Laure, Galimand, Julie, Raffi, François, Ghosn, Jade, Delaugerre, Constance, Flandre, Philippe, Rouzioux, Christine, Delfraissy, Jean-François

2011

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acquired immune deficiency syndrome / AIDS / Antiretroviral agents / Antiretroviral drugs / Antiviral drugs / Biology / Care and treatment / Cleavage / Collaboration / Comparative analysis / Failure / gag Gene Products, Human Immunodeficiency Virus - genetics / Gag protein / Gene polymorphism / Genes / Genetic polymorphisms / Highly active antiretroviral therapy / HIV / HIV Infections - drug therapy / HIV Infections - virology / HIV Protease Inhibitors - pharmacology / HIV Protease Inhibitors - therapeutic use / HIV-1 - drug effects / HIV-1 - genetics / Human immunodeficiency virus / Humans / In vivo methods and tests / Infections / Infectious diseases / Internal medicine / Lopinavir / Lopinavir - pharmacology / Lopinavir - therapeutic use / Medicine / Mutation / Mutation - genetics / Patient compliance / Patients / Polymorphism / Polymorphism, Genetic - drug effects / Protease / Protease inhibitors / Proteases / Proteinase inhibitors / Ritonavir / Ritonavir - pharmacology / Ritonavir - therapeutic use / Treatment Outcome / Virology