S. Zeuzem; M. S. Sulkowski; F. Zoulim; K. E. Sherman; A. Alberti; L. J. Wei; B. van Baelen; J. Sullivan; T. L. Kieffer; S. De Meyer; G. Picchio; F. Tomaka; C. S. Graham; J. G. McHutchison
Background: Telaprevir (TVR) is a potent, specific hepatitis C virus (HCV) protease inhibitor that in combination with pegylated interferon alfa-2a (P) and ribavirin (R) led to higher sustained virologic response (SVR) rates than PR alone in both treatment-naïve and treatment-experienced genotype 1 HCV patients in Phase 2 clinical trials. EXTEND is a 3-year virology follow-up study on some of these patients. Here, we report an interim analysis of durability of virologic response in patients who had achieved SVR as well as changes in HCV variants in patients who had not achieved SVR.
Methods: 867 patients who received at least one dose of TVR in PROVE1, PROVE2, PROVE3 or Study 107 and from whom baseline HCV sequences were available were eligible for enrollment; 202 entered the study. Patients who achieved SVR (n=123) were observed for a median time of 22 months post-SVR. Patients who did not achieve an SVR as defined in previous studies (n=79) were observed for a median time of 22 months after the end of the prior study. HCV RNA levels were assessed with the COBAS TaqMan® HCV Test (version 2.0). Viral sequence was determined by nested RT-PCR followed by population sequencing of the NS3 protease (detecting variants present in >~20% of viral population). Amino acid (AA) positions 36, 54, 155, and 156 that are associated with decreased susceptibility to TVR in genotype 1 HCV patients were analyzed. We report on patients who possessed identified variants with decreased susceptibility to TVR at time of treatment failure.
Results: Ninety-nine percent (122 out of 123) of patients maintained SVR during follow-up; one patient from PROVE2 experienced a late relapse 47 weeks after early discontinuation from study dosing, as previously presented. Variants were no longer detectable in 89% (50 out of 56) of patients who had NS3 variants after failing to achieve an SVR. NS3 variants in each of the four AA positions associated with decreased susceptibility to TVR were no longer detectable in 89% of patients. In this cohort, there was no evidence to suggest that the time to undetectability of variants varied as a function of treatment arm, duration of TVR dosing, or non-response type (e.g., virologic breakthrough on treatment versus relapse).
During the follow-up period there were no serious clinical events observed in the group who achieved an SVR. In the Non-SVR group, two patients developed: patient one with cirrhosis at the beginning of the study, developed HCC and liver decompensation (ascites) with liver transplant. Patient two who had bridging fibrosis at the beginning of the study, developed hepatic encephalopathy.
· In this final analysis, SVR after telaprevir-based therapy was durable, with 122 of 123 subjects maintaining HCV RNA undetectable during a median 22 months follow-up.
· In patients who did not achieve SVR during telaprevir treatment, resistant variants were replaced withWT virus:
· 89% of subjects no longer had detectable resistant variants (median follow-up time: 25 months from the end of prior study.