Dynamic and rapid changes in viral quasispecies by UDPS in chronic hepatitis C patients receiving telaprevir-based therapy

Pascale Trimoulet (1, 2) , Patricia Pinson (1, 2) , Jennifer Papuchon (1, 2) , Juliette Foucher (3, 4) , Julien Vergniol (3, 4) , Faiza Chermak (3, 4) , Linda Wittkop (5, 6) , Nadège Castaing (7, 8) , Wassil Merrouche (3, 4) , Sandrine Reigadas (1, 2) , Mathieu Molimard (8, 7) , Michael Kann (1, 2) , Hervé Fleury (1, 2) , Victor de Lédinghen (4, 3)

1 Service de virologie et d'immunologie biologique
2 MFP - Microbiologie Fondamentale et Pathogénicité
3 Service d'Hépato-Gastro-Entérologie
4 Physiopathologie du cancer du foie
5 Epidémiologie et Biostatistique [Bordeaux]
6 Santé publique
7 Département Hospitalo-Universitaire de Pharmacologie de Bordeaux
8 Pharmacoepidemiologie et évaluation de l'impact des produits de santé sur les populations

Background: Telaprevir (TVR) is a protease inhibitor (PI) used in chronic hepatitis C treatment with pegylated interferon plus ribavirin. We analysed the prevalence and kinetic development of TVR resistance upon treatment. Methods: A total of 24 cirrhotic patients (genotype 1a, n=8; genotype 1b, n=16) previously non-responders to standard therapy were treated with TVR-based therapy. The distribution of TVR-resistant variants was assessed at every HCV-RNA-positive time point by 454 ultra-deep pyrosequencing (UDPS) during a mean follow-up period of 9.4 months. Results: A median of 6,837 reads/specimen was studied. Based on control UDPS, we considered mutations as real when present >0.4%. TVR-resistant variants were found at baseline in 8/24 patients (33.3%). Four of the 24 patients (16.7%), all genotype 1a, did not achieve HCV RNA<100 IU/ml between week (W)2 and W12 and stopped treatment. No statistical significant difference was observed in the prevalence of resistant mutants between responders and non-responders (25% [5/20] and 75% [3/4], respectively). The proportion of genotype 1a patients with R155K/T/Q at baseline was higher in non-responders than in responders (50% versus 0%). During treatment failure, significant enrichment in V36A/M and R155K/T/Q was observed but their frequency reverted back to baseline after TVR discontinuation. Conclusions: TVR-resistant variants are widely present at baseline. The presence of TVR-resistant mutants at baseline, even in high abundance (>20%), did not always preclude TVR treatment success. The detection of R155K/T/Q at baseline may predict failure in genotype 1a patients. At failure, which occurred in genotype 1a patients, a significant enrichment in V36A/M and R155K/T/Q was observed.

Domaines: Microbiologie et Parasitologie

Pascale Trimoulet, Patricia Pinson, Jennifer Papuchon, Juliette Foucher, Julien Vergniol, et al.. Dynamic and rapid changes in viral quasispecies by UDPS in chronic hepatitis C patients receiving telaprevir-based therapy. Antiviral Therapy, 2012, 18, pp.723-727. ⟨10.3851/IMP2632⟩. ⟨hal-01101200⟩