Impact of complete inhibition of viral replication on the cellular immune response in chronic hepatitis B virus infection

Abstract

Interferon alfa (IFN-α) treatment is effective in only a proportion of patients with chronic hepatitis B virus (HBV) infection. The mechanisms for therapeutic failure remain unknown but high levels of HBV replication are known to inhibit the immunopotentiating effects of IFN-α. In nine patients with chronic hepatitis B not responding to IFN-α monotherapy, we determined the virus-specific T-helper-cell responses during two consecutive therapeutic regimens: IFN-α alone and IFN-α in combination with a new potent inhibitor of HBV replication, lamivudine. By comparing the results obtained during the initial IFN-α monotherapy to those during the combination treatment, it was investigated whether complete inhibition of virus replication will enhance the interferon-induced immunoreactivity to HBV. Despite the rapid reduction to undetectable serum HBV DNA in all nine patients during the combination treatment, none sustained permanent hepatitis B e antigen (HBeAg) clearance during subsequent 12-month follow-up. HLA class II-restricted T-helper-cell responses to hepatitis B core antigen (HBcAg) showed no difference during IFN-α monotherapy and during the combination of lamivudine plus IFN-α. In contrast, a delayed T-cell activation occurred after a rebound in serum HBV DNA postcombination treatment, which lead to increased hepatocytolysis. These findings suggest that the profound inhibition of HBV replication by a nucleoside analogue does not restore the impaired virus-specific T-cell response in chronic HBV infection.