Hepatitis B: treatment for the 21st century

Hepatitis B virus (HBV) infection constitutes a worldwide public health problem, causing both acute and chronic liver infections. Although a vaccine has been developed that is effective in preventing HBV infection, this is of no benefit to the estimated 350 million carriers of the virus. Chronic hepatitis B infection may lead to cirrhosis of the liver and hepatocellular carcinoma. Therefore, there is a clear need for antiviral therapy. Alpha interferon was the first therapeutic agent used against HBV infection. However, its lack of efficacy in many patients and significant adverse event profile has prompted the development of alternative therapies. Nucleoside analogues are currently being investigated as potential anti-HBV agents, with two compounds, famciclovir and lamivudine, undergoing Phase III clinical trials of long-term use. In preclinical studies using the Pekin duck model for hepatitis B, both compounds have been found to reduce the amount of serum duck HBV DNA to sub-detectable levels during therapy. However, once therapy was stopped, the virus returned to pretreatment levels, making longterm treatment necessary. In clinical studies in chronic hepatis B patients, treatment with these agents also resulted in a significant reduction of HBV DNA levels but, again, the return of HBV DNA after discontinuing treatment indicates the need for long-term therapy. The need for long-term treatment means that the virus may develop resistance to the antiviral agents. Resistance mutations to both famciclovir and lamivudine are now being reported after treatment of chronic HBV infection with these agents. Combination therapy may be a strategy to overcome the development of resistance. Therapeutic vaccines and new antiviral agents are also being developed.