Beneficial Effect and the Related Immune Reaction of Prednisolone Withdrawal Followed by Telbivudine Therapy in Chronic Hepatitis B Patients with ALT Level between 2 to 5 Times Upper Limit of Normal

A follow-up study in our patients has shown that spontaneous HBeAg seroclearance occurs within 18 months in ＞60% of patients in whom alanine aminotransferase (ALT) was ＞5 times the upper limit of normal (ULN). However, it was only 9% in patients with ALT level between 2 to 5 x ULN. Clearly the former requires closed observation and the latter is needed to receive antiviral therapy. Our previous study using lamivudine in the treatment of patients with chronic hepatitis B virus (HBV) infection has shown that patients with a pretherapy ALT level over fivefold the ULN have a HBeAg seroconversion rate of 64%. Several studies in the literature have also documented that patients with higher ALT level achieved better HBeAg response after conventional IFN-α therapy. In view of the pathogenic mechanism of ALT elevation in chronic HBV infection, these findings suggest that an adequate host immune response leading to eradication of the residue cccDNA may be a prerequisite for HBV clearance by antiviral agent alone. It is therefore suggested that manipulation of the host immune response against HBV in combination with or followed by antiviral agent may be required for a better response in patients with lower ALT levels. It is well known that withdrawal of a short course of corticosteroid is usually followed by an ALT flare and decrease in HBV replication, as the results of an immune rebound that induces lysis of hepatocytes expressing HBV antigen. It has been shown that corticosteroid priming may enhance the therapeutic efficacy of lamivudine, in patients with chronic HBV infection, particularly in those with lower ALT. Recently, the efficacy of 1-year and 2-year telbivudine therapy has been shown superior to lamivudine treatment in terms of HBeAg seroconversion rate, HBV DNA seroclearance rate and the sustained virological response. Hence, it is worth to investigate whether ALT rebound following corticosteroid priming enhances complete response to 3-year telbivudine therapy in chronic hepatitis B patients with lower ALT level. In addition, telbivudine therapy demonstrated the immunomodulatory effect in murine hepatitis virus type 3 (MHV-3) infected C3H mice. However, the exact effects of immunomodulation using telbivudine in treating chronic HBV-infected patients are largely unknown. On the other hand, HBV specific CD8+T cells were exhausted in patients with chronic HBV hepatitis, which is attributed to regularity T cells and high level of programmed cell death-1 (PD-1) expression in HBV-specific CD8+T cells. And regulatory T cells was shown to inhibit the interferon-γ synthesis, one of the key molecules in inhibiting HBV replication, in these exhausted CD8+T cells. High PD-1 expression on HBV specific CD8+T cells also has negative impact of interferon-γ secretion. In this proposal, we will investigate the cellular and molecular mechanisms of the restoration of effector T cell function by prednisolone priming followed by telbivudine in order to provide solid information for immunomodulation against chronic HBV infection. Furthermore, we aimed to investigate the therapeutic effect of prednisolone priming followed by telbivudine and correlate it with regulatory T cell function and the association of improved CD8+T cell function.

Project ID:PC9908-0398
External Project ID:NSC99-2314-B182-030