Therapeutic modalities in hepatitis C: challenges and development

Our understanding of the pathogenicity of hepatitis C virus (HCV) is based on patients infected chronically for >20 years. The lack of a suitable animal model, the narrow host range of the virus, and the protracted onset of liver disease induced by HCV have hampered advances in treatment. In spite of these problems, we identified patient and viral characteristics that predict responses to current therapies, including HCV genotype, viral load, body weight, age, liver histology, co-infection with HIV and treatment adherence and tolerance. Interferon (IFN) alpha was the first therapy for chronic HCV infection. The combination of IFN plus ribavirin increases sustained virological response rates compared with IFN alone. Two pegylated IFNs have been developed and are widely approved for the treatment of chronic hepatitis C: peginterferon alpha-2a (40 KD), and pegylated IFN alpha-2b (12 KD). These products have reduced systemic clearance, prolonged half-lives and reduced antigenicity compared with conventional IFN. The reduced clearance results in sustained plasma levels of the drug and allows for once-weekly dosing. Pegylated IFN alpha-2b (12 KD) has a small, linear polyethylene glycol (PEG) moiety and has an intermediate duration of activity; peginterferon alpha-2a (40 KD) incorporates a large, branched-chain PEG moiety and has a longer half-life than both conventional IFN alpha and pegylated IFN alpha-2b (12 KD). The combination of a pegylated IFN plus ribavirin significantly increases sustained virological response rates compared with conventional IFN plus ribavirin in patients with chronic hepatitis C and is now recognized as the standard of care for these patients.