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Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin

2015; American Society for Microbiology; Volume: 53; Issue: 7 Linguagem: Inglês

10.1128/jcm.03633-14

1098-660X

Sylvie Larrat, Sophie Vallet, Sandra David‐Tchouda, Alban Caporossi, Jennifer Margier, Christophe Ramière, Caroline Scholtès, Stéphanie Haïm‐Boukobza, Anne‐Marie Roque‐Afonso, Bernard Besse, Elisabeth André‐Garnier, Sofiane Mohamed, Philippe Halfon, Adeline Pivert, Hélène Leguillou‐Guillemette, Florence Abravanel, Matthieu Guivarch, Vincent Mackiewicz, Olivier Lada, Thomas Mourez, Jean‐Christophe Plantier, Y. Baazia, Sophie Alain, Sébastien Hantz, Vincent Thibault, Catherine Gaudy‐Graffin, D. Bouvet, Audrey Mirand, Cécile Henquell, Joël Gozlan, Gisèle Lagathu, Charlotte Pronier, Aurélie Velay, Évelyne Schvoerer, Pascale Trimoulet, Hervé Fleury, Magali Bouvier‐Alias, Étienne Brochot, Gilles Duverlie, Sarah Maylin, S. Gouriou, Jean‐Michel Pawlotsky, Patrice Morand,

Chronic Lymphocytic Leukemia Research

ABSTRACT The pretherapeutic presence of protease inhibitor (PI) resistance-associated variants (RAVs) has not been shown to be predictive of triple-therapy outcomes in treatment-naive patients. However, they may influence the outcome in patients with less effective pegylated interferon (pegIFN)-ribavirin (RBV) backbones. Using hepatitis C virus (HCV) population sequence analysis, we retrospectively investigated the prevalence of baseline nonstructural 3 (NS3) RAVs in a multicenter cohort of poor IFN-RBV responders (i.e., prior null responders or patients with a viral load decrease of <1 log IU/ml during the pegIFN-RBV lead-in phase). The impact of the presence of these RAVs on the outcome of triple therapy was studied. Among 282 patients, the prevalances (95% confidence intervals) of baseline RAVs ranged from 5.7% (3.3% to 9.0%) to 22.0% (17.3% to 27.3%), depending to the algorithm used. Among mutations conferring a >3-fold shift in 50% inhibitory concentration (IC 50 ) for telaprevir or boceprevir, T54S was the most frequently detected mutation (3.9%), followed by A156T, R155K (0.7%), V36M, and V55A (0.35%). Mutations were more frequently found in patients infected with genotype 1a (7.5 to 23.6%) than 1b (3.3 to 19.8%) ( P = 0.03). No other sociodemographic or viroclinical characteristic was significantly associated with a higher prevalence of RAVs. No obvious effect of baseline RAVs on viral load was observed. In this cohort of poor responders to IFN-RBV, no link was found with a sustained virological response to triple therapy, regardless of the algorithm used for the detection of mutations. Based on a cross-study comparison, baseline RAVs are not more frequent in poor IFN-RBV responders than in treatment-naive patients and, even in these difficult-to-treat patients, this study demonstrates no impact on treatment outcome, arguing against resistance analysis prior to treatment.