Journal of Hepafology zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 1999: 31: (Suppl. 1): 152-159 Printed in Denmark AN rights reserved M unksgaard. Copenhagen Copyright 0 European Association for the Study of the Liver 1999 Journal of Hepatology ISSN 01694185 ISBN 87- 16- 16386- 9 Possible mechanisms of action and reasons for failure of antiviral therapy in chronic hepatitis C Howard. C. Thomas, M. E. mrok, D. M. Forton and S. D. Taylor-Robinson Hepatology Section, Department of Medicine A, Imperial College School of Medicine at St. Mary’s, London The known mechanisms of hepatitis C virus (HCV) clearance and their failure in persistent infection are discussed. Interferon-a is the main treatment in chronic HCV but has shown poor sustained virolo- gical response rates when used as a monotherapy. The effects of interferon-a may include inhibition of HCV virion production by an effect on viral RNA and pro- tein synthesis, enhancement of immune lysis of HCV infected cells, inhibition of hepatic fibrosis by an effect on TGF/?, and an effect on HCV induced carcino- genesis. Mathematical modelling studies have pro- vided insights into the mechanisms of action of inter- ferou-a in chronic HCY The two-phase plasma HCV RNA disappearance curve may reflect the presence of an interferon-resistant second site of HCV replication either within or outside the liver. Clinical observations and cerebral magnetic resonance scans provide evi- dence of functional cerebral impairment in HCV in- fected patients, raising the issue of the central nervous system (CNS) as a site for HCV replication. Recent zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIH I N ORDER TO understand the mechanisms of action of antiviral therapy in persistent HCV infection, the known mechanisms of HCV clearance and their failure in persistent infection will be briefly summarised (see earlier chapters). HCV causes a mild, often asymptomatic, hepatitis. The majority of patients develop persistent infection with only 20-25% of patients clearing the virus (1). The majority of patients are infected in adult life as a result of exposure to blood products, through intra- venous drug use or as a result of sexual contact. The virus is not directly cytopathic. The hepatitic Correspondence: Prof. H. C. Thomas, Hepatology Sec- tion, Department of Medicine A, Imperial College School of Medicine at St. Mary’s, 10th Floor QEQM Wing, South Wharf Road, London W2 INY, UK. Tel: +44 171 886 6454. Fax: +44 171 724 9360. studies using ribavirin in combination with interferon suggest that this approach doubles the sustained re- sponse rates obtained without having a major effect on the initial rate of HCV clearance (see Zeuzem paper). The potential mechanisms of action of ribavir- in, although not yet fully understood, include inhi- bition of synthesis of GTP by an effect on inosine monophosphate dehydrogenase thereby limiting viral RNA synthesis, and enhancement of THl responses, which may assist viral clearance. There is no signifl- cant effect on HCV RNA polymerase activity. It is possible that ribavirin may have activity at extrahep- atic sites of HCV infection, thus explaining the marked reduction in relapse rates with combination therapy, without an appreciable effect on initial anti- viral response. Key words: Extrahepatic site; Hepatitis C; Iuter- feron-a; Mathematical modelling; Mechanisms of ac- tion; Ribavirin. process appears to result from the immune recognition and destruction of infected hepatocytes (2). As this is probably a part of the recovery process, the enigma of protective immunity and tissue damaging immune responses occurring in parallel is seen in HCV infec- tion, as in many other viral diseases. Recovery from HCV infection is associated with cer- tain MHC class II alleles, suggesting a role for CD4+ T lymphocytes in this process (3,4). Approximately 40% of patients with persistent HCV infection do not have detectable proliferative responses to HCV anti- gens (5,6). However, patients with an acute infection who go on to normalise their transaminases have sig- nificantly more vigorous and more frequently detect- able responses to HCV core and non-structural pro- teins than those in whom transaminases remained elev- ated (5,7). This again suggests the importance of the CD4+ T cell response in control of viraemia and is 152