Hepatitis C virus directly acting antivirals: current developments with NS3/4A HCV serine protease inhibitors

Chronic hepatitis C virus (HCV) infection is a global health problem, but the current therapy is effective in <50% of patients infected with genotype 1. With advances in cell culture systems over the past decade, the development of directly acting antivirals (DAAs) for HCV has become possible. There are currently >50 active clinical trials in this therapeutic area and NS3/4A protease inhibitors are now entering Phase III study. To date, we have learned that DAAs are potent inhibitors of HCV replication, resulting in rapid declines in serum HCV RNA levels, and have the potential to allow shortening of therapy. However, these agents drive selective pressure for mutant viruses that can develop rapidly and have reduced susceptibility to the drug. Therefore, for now, the current standard of care including pegylated interferon α (pegIFN) and ribavirin remains a crucial part of new drug development. Furthermore, the adverse event profile for the early DAAs has added to the concerns of tolerability that are so common for the current standard of care. Ongoing issues include the optimal duration of therapy, how and when to combine DAAs, and the long-term role of pegIFN and ribavirin. Here, we summarize the current information regarding the effectiveness of protease inhibitors in treating chronic HCV and discuss the key challenges now facing the field.