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 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-alpha. In nine patients with chronic hepatitis B not responding to IFN-alpha monotherapy, we determined the virus-specific T-helper-cell responses during two consecutive therapeutic regimens: IFN-alpha alone and IFN-alpha in combination with a new potent inhibitor of HBV replication, lamivudine. By comparing the results obtained during the initial IFN-alpha 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-alpha monotherapy and during the combination of lamivudine plus IFN-alpha. 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.
Institute of Liver Studies, King's College School of Medicine and Dentistry, London, England.
G
G
Marinos
N V
NV
Naoumov
R
R
Williams
D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D002908:Chronic Disease; D004279:DNA, Viral / Q000097:blood; D004359:Drug Therapy, Combination; D006509:Hepatitis B / Q000276:immunology* / Q000628:therapy / Q000821:virology; D006512:Hepatitis B Core Antigens / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D019259:Lamivudine / Q000494:pharmacology*; D008297:Male; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D016898:Interferon-alpha; D019259:Lamivudine