Mutations in the hepatitis B virus (HBV) core gene may influence disea
se activity by altering immune recognition sites or level of virus rep
lication. Sera from 69 Chinese patients with chronic HBV infection wer
e analyzed by direct sequencing of polymerase chain reaction amplifica
tion of NBV DNA to determine the frequency and location of naturally o
ccurring HBV core gene mutations. All but one patient had nucleotide c
hanges, and 44 (64%) patients had at least one amino acid change (mean
, 3.7; range, 1-13) when compared with published sequences. Multiple r
egression analysis showed that the frequency of core gene mutations wa
s significantly associated with precore stop-codon mutation, hepatitis
B e antigen negativity, and active liver disease, but not patients' a
ge. The mean number of amino acid changes/ patient for hepatitis B e a
ntigen (HBeAg)-positive patients with elevated versus normal aminotran
sferase levels were, respectively, 2.8 +/- 0.4 and 0.6 +/- 0.2. The co
rresponding values for HBeAg-negative patients were, respectively, 5.0
+/- 1.2 and 6.0 +/- 1.5. Thirteen patients were serially studied, the
mean rates of amino acid substitution in HBeAg-positive patients who
did or did not clear HBeAg during follow-up were 5.7 +/- 0.8 and 0 per
codon/yr. Most of the mutations were clustered in the middle of the c
ore gene that harbor several major B- and helper T-cell epitopes. Very
few mutations were found in the C-terminal part of the core gene. In
summary, mutations in the core gene can be frequently detected in pati
ents with chronic HBV infection. These mutations occur predominantly a
round the time of HBeAg clearance when liver disease is most active.