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

Sylvie Larrat 1 Sophie Vallet 2 Sandra David-Tchouda 3 Alban Caporossi 4 Jennifer Margier 5 Christophe Ramière 6 Caroline Scholtès 7 Stéphanie Haïm-Boukobza Anne-Marie Roque-Afonso 8 Bernard Besse 4 Elisabeth André-Garnier 9 Sofiane Mohamed 10 Philippe Halfon 11 Adeline Pivert 12 Hélène Leguillou-Guillemette Florence Abravanel 13 Matthieu Guivarch Vincent Mackiewicz 14 Olivier Lada 15 Thomas Mourez 16 Jean-Christophe Plantier 16 Yazid Baazia 17 Sophie Alain 18 Sébastien Hantz 19 Vincent Thibault 20 Catherine Gaudy-Graffin 21 Dorine Bouvet Audrey Mirand 22 Cécile Henquell 23 Joël Gozlan 24 Gisèle Lagathu 20 Charlotte Pronier 20 Aurélie Velay 25 Evelyne Schvoerer 26, 27 Pascale Trimoulet 28 Hervé Fleury 29 Magali Bouvier-Alias 30 Etienne Brochot 31 Gilles Duverlie 32 Sarah Maylin 33 Stéphanie Gouriou 2 Jean-Michel Pawlotsky 34 Patrice Morand 35 Christophe Plantier Y.-W. Tang
6 Biologie cellulaire des infections virales – Cell biology of viral infection
CIRI - Centre International de Recherche en Infectiologie - UMR
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 (IC50) 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.
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Sylvie Larrat, Sophie Vallet, Sandra David-Tchouda, Alban Caporossi, Jennifer Margier, et al.. Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin. Journal of Clinical Microbiology, American Society for Microbiology, 2015, 53 (7), pp.2195-2202. ⟨10.1128/JCM.03633-14⟩. ⟨hal-02014295⟩



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