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

作者：Trimoulet Pascale^*; Pinson Patricia; Papuchon Jennifer; Foucher Juliette; Vergniol Julien; Chermak Faiza; Wittkop Linda; Castaing Nadege; Merrouche Wassil; Reigadas Sandrine; Molimard Mathieu; Kann Michael; Fleury Herve; de Ledinghen Victor

来源：Antiviral Therapy, 2013, 18(5): 723-727.

DOI：10.3851/IMP2632

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.

• 出版日期2013