Abstract

Chronic hepatitis B virus (HBV) infection is a major health threat in Asia. In order to design a better therapeutic regimen, the underlying mechanism of HBV viral persistence must be understood. Immunological studies have found that impaired HBV virus-specific T cell reactivity is the major cause of chronic infection, whereas strong and multispecific T cell responses to HBV are associated with long-term control, but not elimination of the virus. Furthermore, in the serological clearance of hepatitis B surface antigen (HBsAg) in allogeneic haematopoietic cell transplantation, HBsAg seroconversion is associated with activation of the donor's hepatitis B core antigen-specific CD4+ T lymphocytes. This suggests that the donor's hepatitis B core antigen-specific CD4+ T cells provide 'intermolecular T cell help' for the HBsAg seroconversion. These findings are relevant to the future development of therapeutic vaccines or DNA vaccine as immunotherapy for chronic hepatitis B. Apart from interferon-alpha, thymosin alpha1 (Talpha1) has been investigated for treatment of chronic hepatitis B. Meta-analysis of 4 randomized controlled studies investigating the safety and efficacy of Talpha1 monotherapy for the treatment of chronic hepatitis B showed that 6 months treatment with Talpha1 (1.6 mg twice weekly) almost doubles the sustained response rate (36%) compared with controls (19%; P=0.04). However, more specific immunological approaches are being developed; notably, hepatitis B core antigen-based therapeutic vaccine was found to induce T cell proliferative responses in chronically infected hepatitis B patients to the T helper epitope included in the construct. However, the cytokine profile observed suggested the induction of a T helper 0/T helper 2 CD4+ T cell response rather than T helper 1 response. Thus, its combination with interferon-gamma or interleukin-12, which might reverse the CD4+T cell response, should be considered. In the future, it is likely that different types of combination therapy may have to be tailor-made for chronic HBV infection with different virological and immunological profiles and different degrees of liver damage.