Impact of Ribavirin on HCV Replicon RNA Decline during Treatment with Interferon-α and the Protease Inhibitors Boceprevir or Telaprevir

Abstract

Ribavirin increases early and sustained virological response rates in patients chronically infected with HCV who receive pegylated interferon-α and novel HCV protease inhibitors. To better characterize antiviral efficacies of these upcoming therapies, Huh7 cells harbouring a subgenomic HCV replicon system were cultivated with various doses and combinations of ribavirin, interferon-α, and the protease inhibitors boceprevir and telaprevir. Antiviral efficacy parameters were estimated from HCV RNA decay, and synergistic effects of combination therapies were analysed with the Bliss independency model. Single-drug antiviral activities showed dose-dependent HCV RNA reductions in replicon cells (50% inhibitory concentration of 386.16 μM, 81.67 IU, 0.44 μM and 0.81 μM after 48 h for ribavirin, interferon-α, boceprevir and telaprevir, respectively). For the dual combination of ribavirin with either boceprevir or telaprevir, no deviation from additivity was observed whereas the reduction of HCV RNA was synergistic for ribavirin with interferon-α (P<0.001). Triple combinations with ribavirin, interferon-α and protease inhibitors showed the most profound HCV RNA decay. The beneficial in vitro antiviral effect of ribavirin with interferon-α and novel HCV protease inhibitors demonstrates that ribavirin may be required as an antiviral backbone in the near future.