Summary:
Genetic variability of hepatitis B virus: Distribution of HBV genotypes
and correlation with disease progression in patients with chronic HBV
infection
Introduction: The role of HBV genotypes and mutations in the core promoter
and/or precore region in the natural course of chronic HBV infection remains
controversial and data from our country are limited.
Aims: The aim of this cohort study was to evaluate the association of HBV
genotypes and core promoter and/or precore mutations with the clinical
phases of chronic HBV infection and the progression of liver disease.
Methods: Core promoter and precore sequences were analyzed and HBV
genotype was determined with direct sequencing in 255 patients (M/F:
188/67, mean age 43,5+14,3 years), 48 had HBeAg-positve chronic HBV
infection [10 HBeAg-positive with normal ALT (immune tolerance phase) and
38 HBeAg-positive chronic hepatitis B (CHB)] and 207 had HBeAg-negative
chronic HBV infection [147 HBeAg-negative chronic hepatitis B and 60 were
chronic inactive carriers. Median follow-up was 108 (6-484) months.
Results: All patients had genotype A or D. Genotype D was predominant in
all groups and it was found in 95.7% of study population. Although genotype A
was found only in 4.3% of total population, it was detected more frequently
(exclusively) in patients with HBeAg-positive CHB versus the others group
(29% vs 0%, 0%, 0%, P<0,001). The G1896A mutation was detected in
77.2% of the total population and it was found significantly more frequent in
29
patients with HBeAg-negative chronic HBV infection compared with patients
with HBeAg-positive chronic HBV infection (91.5% vs 10.5%, P<0,001). The
G1896A was not detected in any HBeAg-positive patient with normal ALT,
was found in 13% of patients with HBeAg-positive CHB, in 90% of inactive
carriers and in 92% of patients with HBeAg-negative CHB. The mutations
A1762Tand/orG1764A were detected in 68% of study population and their
frequency was higher, but not significantly in patients with HBeAg-negative
chronic HBV infection compared with patients with HBeAg-positive chronic
HBV infection (70.2% vs 55.3%, p=NS). Mutations in the basic core promoter
were detected in 28.6% of patients with HBeAg-positive with normal ALT, in
61.3% of patients with HBeAg-positive CHB, in 62.7% of inactive carriers and
in 73.4% of patients with HBeAg-negative CHB. The proportions of G1896A
precore mutation and of the core promoter mutations (A1762T and/orG1764A)
were similar between patients with HBeAg-negative CHB and inactive carriers
(92% vs 90% and 73.4% vs 62.7% respectively, p=NS). Hepatocellular
carcinoma (HCC) developed in 33 patients during follow-up. Patients who
developed HCC compared to those who did not, were more frequently older,
males and with HBeAg-negative rather than HBeAg-positive chronic HBV
infection. In addition, core promoter mutations were more commonly detected
in HCC than in non-HCC patients (95% vs 68%, P=0,015), while the
proportion of precore mutation was similar between these two groups.
During follow-up, 30/48 patients achieved HBeAg seroconversion. The rate of
HBeAg seroconversion was similar between genotype A and D, but patients
with genotype A seroconverted later (about one decade) than patients with
genotype D, with higher proportion (71%) of remission of liver disease andHBsAg
loss after HBeAg seroconversion. Patients with genotype A achieve
HBeAg seroconversion with the development of mutations in the BCP region
and no patient had G1896A. In patients with genotype D, the HBeAg
seroconversion was achieved with the development of G1896A and although
the mutations in the BCP region were frequent, no association with HBeAg
loss was found.
Conclusions: 1. HBV genotype D is endemic in Greece and is associated
with every phase of chronic HBV infection. The proportion of genotype A is
only 5% of chronic HBV cases overall, but it increases up to 29% in
HBeAgpositive
CHB. 2. Precore mutations are detected in a minority (10%) of our
HBeAg-positive chronic HBV patients, but core promoter mutations may be
present in up to 55% of them. However, precore and basic core promoter
mutations are detected in the majority of patients with HBeAg-negative
chronic HBV infection (90.5% vs 79.2% respectively). 3. The prevalence of
mutations in the precore and core promoter region seems to be similar
between patients with HBeAg-negative CHB and inactive carriers, but core
promoter mutations are significantly more frequently detected in patients who
develop HCC. 4. The rate of HBeAg seroconversion was similar between
genotype A and D, but patients with genotype A seroconvert later and have
higher proportion of remission of liver disease and of HBsAg loss after
seroconversion.
