R1626, a prodrug of the hepatitis C virus (HCV) RNA polymerase inhibitor R1479, showed time-dependent and dose-dependent reduction of HCV RNA levels in a previous study. The present study evaluated the efficacy and safety of R1626 administered for 4 weeks in combination with peginterferon alfa-2a Ψ ribavirin in HCV genotype 1-infected treatment-naive patients. Patients were randomized to: DUAL 1500 (1500 mg R1626 twice daily [bid] Ψ peginterferon alfa-2a; n β«Ψβ¬ 21); DUAL 3000 (3000 mg R1626 bid Ψ peginterferon alfa-2a; n β«Ψβ¬ 32); TRIPLE 1500 (1500 mg R1626 bid Ψ peginterferon alfa-2a Ψ ribavirin; n β«Ψβ¬ 31); or standard of care (SOC) (peginterferon alfa-2a Ψ ribavirin; n β«Ψβ¬ 20). At 4 weeks HCV RNA was undetectable (<15 IU/mL) in 29%, 69%, and 74% of patients in the DUAL 1500, DUAL 3000, and TRIPLE 1500 arms, respectively, compared with 5% of patients receiving SOC, with respective mean reductions in HCV RNA from baseline to week 4 of 3.6, 4.5, 5.2, and 2.4 log 10 IU/mL. Synergy was observed between R1626 and peginterferon alfa-2a and between R1626 and ribavirin. There was no evidence of development of viral resistance. Adverse events (AEs) were mainly mild or moderate; seven patients had nine serious AEs (including one patient with one serious AE in SOC). The incidence of Grade 4 neutropenia was 48%, 78%, 39%, and 10% in DUAL 1500, DUAL 3000, TRIPLE 1500, and SOC, respectively, and was the main reason for dose reductions. Conclusion: A synergistic antiviral effect was observed when R1626 was combined with peginterferon alfa-2a Ψ ribavirin; up to 74% of patients had undetectable HCV RNA at week 4. Dosing of R1626 was limited by neutropenia; a study of different dosages of R1626 in combination with peginterferon alfa-2a and ribavirin is underway. (HEPATOLOGY 2008;48:385-397.)
C ompared with genotypes 2 and 3, patients with hepatitis C virus (HCV) genotype 1 typically have a lower response to combination therapy of pegylated interferon and ribavirin. 1,2 Approximately half of patients with chronic HCV genotype 1 infection achieve a sustained viral response with the current standard of care (SOC) and response rates are even lower in patients coinfected with human immunodeficiency virus,