Use of immunomodulatory therapy (other than interferon) for the treatment of chronic hepatitis B virus infection

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Abstract
Chronic hepatitis B virus (HBV) infection is a major health threat in Asia. In order to design a better therapeutic regimen, the underlyng 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‐α, thymosin α1 (Tα1) has been investigated for treatment of chronic hepatitis B. Meta‐analysis of 4 randomized controlled studies investigating the safety and efficacy of Tα1 monotherapy for the treatment of chronic hepatitis B showed that 6 months treatment with Tα1 (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‐γ 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.