758 CHARACTERIZATION OF RESISTANT MUTANTS SELECTED IN VITRO BY THE HCV NS3/4A PROTEASE INHIBITOR BI 201335

Background: MP-424 (telaprevir) is a highly selective inhibitor of the hepatitis C virus (HCV) NS3–4A protease which is currently investigated in phase 3 trial in combination with peginterferon and ribavirin. We reported the first clinical study examining telaprevir monotherapy with an extended dosing period of 24 weeks in Japan (Ozeki I, et al: EASL 2009). After completing study drug therapy, patients were treated with peginterferon alfa-2b and ribavirin. Methods: Five naive patients were treated with telaprevir monotherapy at 750mg every 8 hours for up to 24 weeks. All patients, 48 to 68 years of age, had a chronic infection with HCV genotype 1b and their baseline serum HCVRNA levels were at least 1×105 IU/ml. Patients who met the definition of viral breakthrough (>2-log increase in HCVRNA above nadir) discontinued telaprevir dosing. RNA sequence was analyzed using the clonal sequencing method. After a withdrawal of MP-424, 4 of the 5 patients were enrolled in the off-study treatment with peginterferon alfa-2b and ribavirin within 4 weeks after the last administration of study drug. Results: At the initiation of off-study treatment, major NS3 protease variants in the patients were T54A, T54S+A156T, and A156V+V158I. All patients achieved undetectable HCVRNA levels by 12 weeks regardless of selected telaprevir-resistant variants. Sustained virologic response (SVR) was achieved in 2 patients who completed the assigned treatment for 48 weeks. The other 2 patients are now receiving peginterferon alfa-2b and ribavirin beyond 48 weeks for extended treatment period to 72 weeks. HCVRNA levels in these 2 patients continue to be undetectable. Conclusions: By the off-study treatment of standard peginterferon alfa-2b and ribavirin, all patients achieved complete EVR regardless of selected drug-resistant variants. Two patients who were typically treated for 48 weeks achieved an SVR. Updated results of this study will be presented.