Hepatitis C: recent successes and continuing challenges in the development of improved treatment modalities

Abstract

Dramatic progress is being made toward the development of less-toxic and simpler alternatives to the current standard-of-care therapy for chronic hepatitis C, which involves a combination of pegylated interferon (peg-IFN) and ribavirin (RBV). Several accessible viral targets have been identified and licensure of the most advanced clinical compounds can be anticipated within the next several years. However, the highly replicative nature of HCV infection, coupled with error-prone viral RNA synthesis and considerable genome diversity, pose extraordinary challenges to drug development. Peg-IFN is likely to remain a mainstay of therapy for the foreseeable future, or until such time that multiple direct-acting antiviral (STAT-C) inhibitors are available and shown to provide a sufficiently high barrier to resistance when used in combination.

Figure 1

Organization of the HCV genome. (a) Organization of the single-stranded, positive-sense RNA genome of HCV. The polyprotein coding region (shown as a box) is flanked by short noncoding regulatory sequences. Potential antiviral targets are identified. (b) Organization of selectable subgenomic (top) and full-genome length HCV RNA replicons that are capable of autonomous amplification when transfected into Huh7 cells, and that are typically used in drug discovery research.