IMPACT OF COMPLETE INHIBITION OF VIRAL REPLICATION ON THE CELLULAR IMMUNE-RESPONSE IN CHRONIC HEPATITIS-B VIRUS-INFECTION

Interferon alfa (IFN-alpha) treatment is effective in only a proportio n of patients with chronic hepatitis B virus (HBV) infection, The mech anisms for therapeutic failure remain unknown but high levels of HBV r eplication are known to inhibit the immunopotentiating effects of IFN- alpha, In nine patients with chronic hepatitis B not responding to IFN -alpha monotherapy, we determined the virus-specific T-helper-cell res ponses during two consecutive therapeutic regimens: IFN-alpha alone an d IFN-alpha in combination with a new potent inhibitor of HBV replicat ion, lamivudine, By comparing the results obtained during the initial IFN-alpha monotherapy to those during the combination treatment, it wa s investigated whether complete inhibition of virus replication will e nhance the interferon-induced immunoreactivity to HBV, Despite the rap id reduction to undetectable serum HBV DNA in all nine patients during the combination treatment, none sustained permanent hepatitis B e ant igen (HBeAg) clearance during subsequent 12-month follow-up, HLA class II-restricted T-helper-cell responses to hepatitis B core antigen (HB cAg) showed no difference during IFN-alpha monotherapy and during the combination of lamivudine plus IFN-alpha. In contrast, a delayed T-cel l activation occurred after a rebound in serum HBV DNA postcombination treatment, which lead to increased hepatocytolysis. These findings su ggest 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.