Effects of interferon alpha therapy on the catalytic domains of the polymerase gene and basal core promoter, precore and core regions of hepatitis B virus.
OBJECTIVE
The aim of the present study was to examine the catalytic domains of the polymerase gene, the basal core promoter and the precore and core regions of the hepatitis B virus (HBV) genome for specific mutations. These may account for the response to interferon alpha (IFN-alpha) treatment, which may have prognostic value.


METHODS
Multiple serum samples were collected prospectively from 30 patients with chronic active hepatitis B who were treated with IFN-alpha. Patients were assigned to one of three groups: group A (n = 11) and group B (n = 10) individuals were hepatitis B e antigen (HBeAg)-positive prior to treatment. Group A patients underwent HBeAg seroconversion after treatment while group B patients did not. Group C (n = 9) patients were HBeAg-negative prior to treatment. The HBV DNA was extracted from the sera collected before, during and after treatment and the various genomic regions were amplified, sequenced and examined for mutations.


RESULTS
During IFN-alpha therapy, multiple changes were found in the catalytic domains of the HBV polymerase gene in all groups. The frequency of mutations and associated amino acid changes were highest in virus from group C patients and lowest in group A patients. The interdomain regions of the viral polymerase were the most affected. Multiple mutations were also found in the precore, core and core promoter regions. However, no specific mutations were associated with clinical response or outcome.


CONCLUSIONS
During IFN-alpha treatment, multiple mutations occurred in the HBV genome, including the catalytic domains of the polymerase gene. Changes that did occur could not be correlated to the clinical response or treatment outcome. However, no mutations were found that have been linked to lamivudine escape, indicating that lamivudine therapy would be effective in IFN-alpha non-responder patients.
Chen
Robert Yung Ming
RY
Department of Gastroenterology, St Vincent's Hospital, Melbourne, Australia.
Bowden
Scott
S
Desmond
Paul Vincent
PV
Dean
Jo
J
Locarnini
Stephen A
SA
D000328:Adult; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D001315:Australia; D001483:Base Sequence; D020134:Catalytic Domain / Q000187:drug effects* / Q000235:genetics*; D018388:Codon, Terminator / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects* / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D016679:Genome, Viral; D005838:Genotype; D006512:Hepatitis B Core Antigens / Q000187:drug effects* / Q000235:genetics*; D006514:Hepatitis B Surface Antigens / Q000187:drug effects / Q000235:genetics; D006513:Hepatitis B e Antigens / Q000187:drug effects / Q000235:genetics; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D017354:Point Mutation / Q000187:drug effects / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000235:genetics*; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D013223:Statistics as Topic; D016896:Treatment Outcome; D014758:Viral Core Proteins / Q000187:drug effects* / Q000235:genetics*; D019562:Viral Load
D000998:Antiviral Agents; D018388:Codon, Terminator; D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D016898:Interferon-alpha; D018894:Reverse Transcriptase Inhibitors; D014758:Viral Core Proteins; D019259:Lamivudine; D004259:DNA-Directed DNA Polymerase