Possible mechanisms of action and reasons for failure of antiviral therapyin chronic hepatitis C

The known mechanisms of hepatitis C virus (HCV) clearance and their failure in persistent infection are discussed. Interferon-alpha is the main treatm ent in chronic HCV but has shown poor sustained virological response rates when used as a monotherapy, The effects of interferon-alpha may include inh ibition of HCV virion production by an effect on viral RNA and protein synt hesis, enhancement of immune lysis of HCV infected cells, inhibition of hep atic fibrosis by an effect on TGF beta, and an effect on HCV induced carcin ogenesis, Mathematical modelling studies have provided insights into the me chanisms of action of interferon-alpha in chronic HCV. The two-phase plasma HCV RNA disappearance curve may reflect the presence of an interferon-resi stant second site of HCV replication either within or outside the liver. Cl inical observations and cerebral magnetic resonance scans provide evidence of functional cerebral impairment in HCV infected patients, raising the iss ue of the central nervous system (CNS) as a site for HCV replication, Recen t studies using ribavirin in combination with interferon suggest that this approach doubles the sustained response rates obtained without having a maj or effect on the initial rate of HCV clearance (see Zeuzem paper). The pote ntial mechanisms of action of ribavirin, although not yet fully understood, include inhibition of synthesis of GTP by an effect on inosine monophospha te dehydrogenase thereby limiting viral RNA synthesis, and enhancement of T H1 responses, which may assist viral clearance, There is no significant eff ect on HCV RNA polymerase activity, It is possible that ribavirin may have activity at extrahepatic sites of HCV infection, thus explaining the marked reduction in relapse rates with combination therapy without an appreciable effect on initial antiviral response.