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

Sylvie Larrat 1 Sophie Vallet 2, 3 Sandra David-Tchouda 4 Alban Caporossi 1, 5 Jennifer Margier 4 Christophe Ramière 6, 7 Caroline Scholtès 7, 6 Stéphanie Haïm-Boukobza 8, 9 Anne-Marie Roque-Afonso 8, 9 Bernard Besse 10 Elisabeth André-Garnier 10 Sofiane Mohamed 11 Philippe Halfon 11 Adeline Pivert 12 Hélène Leguillou-Guillemette 12 Florence Abravanel 13 Matthieu Guivarch 13 Vincent Mackiewicz 14 Olivier Lada 14 Thomas Mourez 15 Jean-Christophe Plantier 15 Yazid Baazia 16 Sophie Alain 17 Sébastien Hantz 17 Vincent Thibault 18 Catherine Gaudy-Graffin 19, 20 Dorine Bouvet 19, 20 Audrey Mirand 21 Cécile Henquell 21 Joël Gozlan 22 Gisèle Lagathu 23 Charlotte Pronier 23 Aurélie Velay 24 Evelyne Schvoerer 24, 25 Pascale Trimoulet 26 Hervé Fleury 26 Magali Bouvier-Alias 27 Etienne Brochot 28 Gilles Duverlie 28 Sarah Maylin 29 Stéphanie Gouriou 4 Jean-Michel Pawlotsky 27 Patrice Morand 1
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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https://hal.univ-lorraine.fr/hal-02014295
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Submitted on : Monday, February 11, 2019 - 3:19:01 PM
Last modification on : Saturday, February 15, 2020 - 1:41:58 AM

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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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