Therapy of Viral Hepatitis

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Abstract
Worldwide viral hepatitis is the most common cause of jaundice, chronic liver disease cirrhosis and hepatocellular carcinoma. While important advances have been made in prevention of viral hepatitis, therapy of this disease remains unsatisfactory. There are no specific therapies of proven benefit for acute hepatitis, although use of alpha-interferon during the acute phase of hepatitis C may result in a decrease in the rate of chronicity. For chronic viral hepatitis, alpha-interferon has been widely used, but is expensive, poorly tolerated and limited in effectiveness. New antiviral agents and use of combinations of antivirals are now being evaluated and promise to provide a therapy that is effective in the majority of patients. The currently recommended therapy of chronic hepatitis B is a 4- to 6-month course of alpha-interferon in doses of 5–10 million units three times a week; a regimen that results in sustained clearance of hepatitis B virus (HBV) DNA and hepatitis B e antigen (HBeAg) from serum in approximately one-third and a loss of hepatitis B surface antigen (HBsAg) in one-tenth of patients. Long-term follow-up of patients who respond to interferon treatment with clearance of HBeAg indicate that the majority ultimately clear HBsAg as well and have continued remission in the liver disease, although low levels of HBV DNA can commonly be detected in liver tissue. Better therapies of hepatitis B are needed. Recently, several oral ‘second-generation’ nucleoside analogues have been developed that have potent activity against HBV. The best studied is lamivudine (3-thiacytidine) which results in marked inhibition of HBV DNA levels and improvement in serum aminotransferases and hepatic histology in the majority of patients. When stopped, however, most patients relapse and the shortcomings of long-term therapy have been the development of viral resistance in up to one-quarter of patients within a year and a higher percentage with more prolonged therapy. Future approaches of therapy of promise for hepatitis B are combinations of lamivudine with interferon and other antiviral nucleoside analogues. The currently recommended therapy of chronic hepatitis C is a 12- to 18-month course of alpha interferon in doses of 3 million units three times a week: a regimen that results in sustained clearance of hepatitis C virus (HCV) RNA in approximately 20% of patients. Sustained responses have been associated with marked improvements in hepatic histology and long-term studies indicate that the majority of patients remain free of virus in serum and liver, suggesting a ‘cure’ of infection. Responses to interferon correlate to some degree with clinical and virological features, including young age, absence of hepatic fibrosis, low levels of HCV RNA in serum and HCV genotypes 2 and 3. Most recently, combinations of alpha interferon and ribavirin, an oral nucleoside analogue, have been evaluated and shown to increase the sustained response rate to 30–40%. Better therapies are still needed, as the majority of patients with hepatitis C do not have a sustained response to therapy. Extensive research on the molecular structure of HCV indicates several potential means of inhibition of viral replication, including use of protease and helicase inhibitions. What is most needed to advance the field of therapeutics in hepatitis C is development of animal models and cell culture systems with which to study this important viral cause of liver disease.