Genomic variations in precore and cytotoxic T lymphocyte regions in chronic hepatitis B in relationship to interferon responsiveness.
OBJECTIVE
Treatment of chronic hepatitis B patients with interferon (IFN) alpha results in a sustained loss of viral replication in as many as 20-40% of cases. The resistance to antiviral treatment by some viruses is due to positive selection of variants harboring mutations that confer resistance. An HBV variant with a stop codon in the precore region (A1896 HBV) has been reported to be associated with the response to IFN therapy. Recently variations in amino acid residues 21 and 27 of the core protein that serve as either partial agonists or antagonists to cytotoxic T-lymphocyte (CTL) function have been demonstrated to affect response to IFN therapy. In this study, we investigated whether these genomic variations in precore and CTL regions can affect response to IFN therapy.


METHODS
Twenty-three patients with chronic hepatitis B were treated with IFN alpha. Of these 23 patients, 6 were responders (defined as showing seroconversion to anti-HBe, loss of serum HBV DNA and normalization of serum aminotransferase levels), and the remaining 17 were non-responders.


METHODS
A total of 75 serum samples (3 serial samples per patient collected before, at the end of therapy, and 6 months after therapy) were tested for core promoter and precore wildtype and mutant viral levels and for sequence in the CTL region.


RESULTS
There were no significant differences in precore wildtype and mutant viral levels before therapy between responders and non-responders, and both viral levels significantly decreased equally when measured at the end of therapy. Approximately 90% of non-responders with HLA-A2 had no amino acid substitutions in the CTL region before therapy. IFN therapy did not induce any specific mutations in this region.


CONCLUSIONS
These findings suggest that the precore wildtype and mutant had similar sensitivity to IFN, and that genomic variation in the CTL region does not appear to be associated with response to IFN therapy.
Shindo
M
M
Department of Internal Medicine, Akashi Municipal Hospital, Hyogo, Japan.
Okuno
T
T
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004279:DNA, Viral / Q000097:blood; D005260:Female; D014644:Genetic Variation; D016679:Genome, Viral; D006512:Hepatitis B Core Antigens / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D008099:Liver / Q000473:pathology; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000998:Antiviral Agents; D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins