Progress towards improving antiviral therapy for hepatitis C with hepatitis C virus polymerase inhibitors. Part I: Nucleoside analogues

With an increasing worldwide burden of liver failure and liver cancer from chronic hepatitis C virus (HCV) infection, discovery and development efforts for new antiviral medicines for HCV are expanding rapidly. Two HCV protease inhibitors (PIs), telaprevir (VX950) and boceprevir (SCH503034), are now furthest along in clinical development, with Phase II data suggesting a potential treatment advance with triple combination regimens comprising a protease inhibitor, pegylated interferon and ribavirin. However, the current data suggest that such regimens will fail to produce sustained virologic responses in > or = 30 - 40% of patients, and tolerance of interferon/ribavirin treatment regimens is often problematic; hence, there is a need for continued development of new anti-HCV agents to further optimize treatment efficacy and safety. The HCV polymerase (HCV Pol) is an attractive target for antiviral therapy because the gene sequences encoding HCV Pol are relatively conserved across the six main HCV genotypes and the emergence of viral resistance is expected to be relatively slow for pharmaceutical agents, such as nucleoside analogues, that are targeted to the active (catalytic) site of HCV Pol.

This review (Part I) of HCV Pol inhibitors focuses on the scientific rationale and recent development progress for nucleoside-type HCV Pol inhibitors; a subsequent review (Part II) will assess progress with non-nucleosidic HCV Pol inhibitors.

Early clinical data for several nucleosides targeted to HCV Pol indicate marked antiviral effects and a likelihood of relatively slow HCV resistance, consistent with the profile of nucleosidic inhibitors of HIV and hepatitis B virus infection and supporting potentially important roles for nucleoside agents in optimizing combination therapies for HCV infection. Optimally effective future anti-HCV therapies are likely to be based on multi-class treatment regimens combining polymerase and PIs, together with pegylated interferon and ribavirin or pharmaceutical agents from other mechanistic classes.