Immunomodulatory drugs and therapeutic vaccine in chronic hepatitis B infection.

The main risk of patients with chronic HBV infection is the occurrence of cirrhosis resulting in overmortality related to the development of hepatocellular carcinoma or non carcinomatous complications of cirrhosis (portal hypertension and liver failure). Control of viral replication significantly reduces these risks since pathology of HBV infection is mainly immune- mediated. The two approved therapies for chronic hepatitis with a clear clinical beneficial effect are interferon-alpha and lamivudine but they have some limitations. Interferon-alpha therapy, which combines antiviral and immunostimulant properties, results in a sustained suppression of HBV replication in only one third of patients. Lamivudine leads to a rapid and almost absolute discontinuation of HBV replication but short-term treatment leads to a frequent relapse of HBV replication and long-term treatment to virological breakthrough with a yearly incidence of 15 to 25%. These limitations of both antiviral therapies of HBV underline the need for alternative therapeutic approaches, including new nucleotide analogues and specific or non specific immunotherapeutic strategies in order to enhance or to broaden the defective T cell responses in chronically infected patients. These immunotherapic strategies are mainly the passive transfer of specific HBV immunity, immunomodulatory drugs (cytokines, thymic derivates, growth factors, polyadenur…) and therapeutic vaccines (recombinant anti-HBV vaccine, T-cell vaccine and DNA vaccine). We report the results of these unusual strategies based on limited number of patients. Thymosin treatment seems to be beneficial and vaccine therapy appears to be potentially efficient but have some limitations including safety issues associated with the injection of DNA and potential adverse effects (too strong cytotoxic response). These results point to the possibility of designing new ways for the treatment of HBV infections and a potential synergistic action of combined antiviral (lamivudine, adefovir), immunomodulatory (interferon-alpha, thymic derivates) and vaccine (DNA vaccines) therapeutic approaches.