HBV infection is a major cause of liver cirrhosis and hepatocellular carcinoma. Although HBV infection can be efficiently prevented by vaccination, and treatments are available, to date there is no reliable cure for the >240 million individuals that are chronically infected worldwide. Current treatments can only achieve viral suppression, and lifelong therapy is needed in the majority of infected persons. In the framework of the French National Agency for Research on AIDS and Viral Hepatitis 'HBV Cure' programme, a scientific workshop was held in Paris in June 2014 to define the state-of-the-art and unanswered questions regarding HBV pathobiology, and to develop a concerted strategy towards an HBV cure. This review summarises our current understanding of HBV host-interactions leading to viral persistence, as well as the roadblocks to be overcome to ultimately address unmet medical needs in the treatment of chronic HBV infection.

The possibility of inducing an immune response to a protein expressed directly from an introduced gene represents an alternative to classic vaccination. We evaluated the ability of plasmid-based eukaryotic expression vectors to produce the Hepatitis B surface antigen (HBsAg) after injection of pure DNA into mouse tibialis anterior muscles. DNA was injected into either normal mature muscle, or regenerating muscle following cardiotoxin-induced degeneration. The sera obtained from these animals contained significant levels of HBsAg as early as 10 days after gene transfer, at which time low levels of antibodies to HBsAg (anti-HBsAg) were already present. Between 15-60 d after DNA transfer, serum levels of anti-HBsAg steadily increased whereas those for HbsAg fell, most likely due to the neutralizing effect of the antibodies. Analysis of proportions of HBs-seropositive mice showed that within 2 wk of injection of 100 micrograms pCMV-HBs in regenerating muscle, 91% of the mice were seropositive [defined as having more than 1 milli-International Unit/ml (mIU/ml) of anti-HBsAg]. Even at that early time, 68% had titers of anti-HBsAg greater than 10 mlU/ml, a level that is recognized as being sufficient in humans to confer protection against natural Hepatitis B virus infection. The proportion of seropositive animals rose to 95% by 4 wk, and 100% by 8 wk, at which time all mice had greater than 100 mIU anti-HBsAg in their sera. We have thus demonstrated that direct intramuscular injection of a plasmid vector encoding the HBsAg will give rise to secretion of the viral surface protein into the circulation which leads to an appropriate antibody response.(ABSTRACT TRUNCATED AT 250 WORDS)

In a pilot study, it was established that specific therapy by standard anti-hepatitis B virus (HBV) vaccination may be effective in reducing HBV replication and canceling the immune tolerance to hepatitis B surface antigen (HBsAg) particles in about 50% of persons with chronic active HBV replication. In the present study, the vaccine-induced immune responses were analyzed during an ongoing controlled multicenter vaccine trial. Vaccination elicited peripheral blood mononuclear cell proliferative responses specific for envelope antigen in 7 of 27 subjects given HBsAg. The responses induced by the vaccines were mediated by CD4+ T lymphocytes, and at least three different epitopes were recognized. HBV-specific CD4+ T lymphocytes produced high levels of interferon-gamma [corrected] and belonged to a T helper 1 subset. Reduction of serum HBV DNA in some of these persons suggests that induction of CD4+ T cell responses could be important in controlling viremia during vaccine therapy of chronic HBV carriers.