Abstract Body

Background: The majority of patients with inherited bleeding disorders who received blood-derived factor concentrates were infected with HCV with repeated exposures to multiple HCV species. It is hypothesized that wide quasispecies representation could affect treatment responses, and that lead-in might mitigate emergent viral breakthrough. The utility of lead-in vs. DAA-based therapy in hemophiliacs was evaluated using viral dynamic modeling methods.

Methods: Treatment-experienced subjects with hemophilia were treated with telaprevir/pegylated interferon alfa/weight-based ribavirin (T/P/R) and randomized to triple-drug start vs. lead-in for 1 month with P/R only. Intensive sampling of blood was performed at baseline, 3, 6, 12, 24, 48 and 72 hours after dosing, and again at days 7 and 10. Lead-in subjects underwent intensive sampling after addition of telaprevir (Week 5). Viral dynamic models were utilized for data analysis and treatment responses were assessed. Safety parameters studied included development of inhibitors to factor concentrates.

Results: Seven patients with hemophilia provided informed consent. Two were screen failures (spontaneous clearance/loss to f/u prior to drug start). Among the five treated subjects, all were male, 80% were Caucasian and 1 (20%) was black, non-Hispanic. Four subjects were IL28B genotype CT, and one was CC. The mean baseline HCV RNA titer was log 6.7 IU/ml. Three subjects were randomized to lead-in followed by addition of T after four weeks, and two received standard T/P/R therapy. The lead-in subjects’ mean HCV RNA titer prior to beginning telaprevir (week 5) was 4.97. The efficacy parameter (Æ) for lead-in ranged from 0 to 0.9745 (mean= 0.514). Addition of telaprevir resulted in a mean efficacy of more than 0.999. This was comparable to subjects who started all three medications simultaneously. Overall efficacy in those with hemophilia was higher than historical non-hemophilia controls not treated with ribavirin (data not shown). Ultimately, 4/5 subjects (80%) achieved SVR. Adverse event profiles were similar to that observed in non-hemophilia cohorts. There was no evidence of factor inhibitor formation.

Conclusions: T/P/R was highly effective in HCV clearance among hemophilic subjects. There was no evidence that lead-in provided benefit in terms of response efficacy, but addition of telaprevir led to rapid viral decline. These data support DAA-based therapy in those with inherited bleeding disorders.