Abstract
Background & AimsTelaprevir, a hepatitis C virus NS3/4A protease inhibitor has significantly improved sustained viral response rates when given in combination with pegylated interferon alfa-2a and ribavirin, compared with current standard of care in hepatitis C virus genotype 1 infected patients. In patients with a failed sustained response, the emergence of drug-resistant variants during treatment has been reported. It is unclear to what extent these variants persist in untreated patients. The aim of this study was to assess using ultra-deep pyrosequencing, whether after 4 years follow-up, the frequency of resistant variants is increased compared to pre-treatment frequencies following 14 days of telaprevir treatment.MethodsFifteen patients from 2 previous telaprevir phase 1 clinical studies (VX04-950-101 and VX05-950-103) were included. These patients all received telaprevir monotherapy for 14 days, and 2 patients subsequently received standard of care. Variants at previously well-characterized NS3 protease positions V36, T54, R155 and A156 were assessed at baseline and after a follow-up of 4±1.2 years by ultra-deep pyrosequencing. The prevalence of resistant variants at follow-up was compared to baseline.ResultsResistance associated mutations were detectable at low frequency at baseline. In general, prevalence of resistance mutations at follow-up was not increased compared to baseline. Only one patient had a small, but statistically significant, increase in the number of V36M and T54S variants 4 years after telaprevir-dosing.ConclusionIn patients treated for 14 days with telaprevir monotherapy, ultra-deep pyrosequencing indicates that long-term persistence of resistant variants is rare.
Highlights
Worldwide, an estimated 170 million people are chronically infected with hepatitis C virus (HCV) [1]
In patients treated for 14 days with telaprevir monotherapy, ultra-deep pyrosequencing indicates that longterm persistence of resistant variants is rare
In patients infected with HCV genotype 1, the most prevalent genotype in developed countries, treatment for 48 weeks results in rates of sustained virologic response (SVR) of only 40-50%
Summary
An estimated 170 million people are chronically infected with hepatitis C virus (HCV) [1]. The current standard of care, pegylated interferon-a-2a/b (PEG-IFN) combined with ribavirin (RBV), has limited efficacy and causes significant side effects. In patients infected with HCV genotype 1, the most prevalent genotype in developed countries, treatment for 48 weeks results in rates of sustained virologic response (SVR) of only 40-50%. Efforts to improve patients’ outcomes have resulted in the development of direct-acting antiviral agents (DAAs) such as nonstructural protein 3/4A (NS3/4A) serine protease inhibitors. Telaprevir, a hepatitis C virus NS3/4A protease inhibitor has significantly improved sustained viral response rates when given in combination with pegylated interferon alfa-2a and ribavirin, compared with current standard of care in hepatitis C virus genotype 1 infected patients. In patients with a failed sustained response, the emergence of drug-resistant variants during treatment has been reported. The aim of this study was to assess using ultra-deep pyrosequencing, whether after 4 years follow-up, the frequency of resistant variants is increased compared to pre-treatment frequencies following 14 days of telaprevir treatment
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