Laboratoire de Virologie, CHU de Bordeaux, F-33000 Bordeaux, France. firstname.lastname@example.org.
Telaprevir (TVR) is a protease inhibitor (PI) used in chronic hepatitis C treatment with PEG-interferon plus ribavirin. We analyzed the prevalence and kinetic development of TVR resistance upon treatment.
Twenty-four 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.
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 W2 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); 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.
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.