© 2011 The Korean Academy of Medical Sciences.
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Precore and Core Promoter Mutations of the Hepatitis B Virus
Gene in Chronic Genotype C -Infected Children
The precore (G1896A) and core promoter (A1762T, G1764A) mutations of the hepatitis B
virus gene are known to be associated with changes in immunologic phase or the
progression to complicated liver disease in adults. We analyzed these mutations in
chronically HBV-infected children. Serum was collected from 37 children with chronic HBV
infection from March 2005 to September 2008. HBV DNA extraction and nested PCR were
followed by sequencing of the PCR products. The children were 6.7 ± 4.6 yr old. All of 37
children had HBV genotype C. Of the cohort, 31 (83.8%) were HBeAg-positive and 6
(16.2%) were HBeAg-negative; the former group comprised 18 (48.6%) who were in the
immune-tolerance phase (ITP) and 13 (35.2%) in the immune-clearance phase (ICP). Most
of the patients had HBV DNA levels of > 1.0 × 108 copies/mL. In the ITP group, only 1
(5.5%) had core promoter mutations, and none had the precore mutation. In the ICP
group, only 2 (15.4%) had core promoter mutations; the remaining 6 patients had HBV
DNA levels of < 2.0 × 103 copies/mL and no core promoter/precore mutations. The very
low incidence of the precore/core promoter gene mutation, in children, suggests that
these mutations may be the result of life-long chronic HBV infection.
Key Words: Hepatitis B Virus; Mutation; Child
Hyun Sik Kang1, Ki Soo Kang1,2,
and Byung-Cheol Song3
1Department of Pediatrics, 2Institute of Medical
Science, 3Department of Internal Medicine, Jeju
National University School of Medicine, Jeju, Korea
Received: 11 December 2010
Accepted: 8 February 2011
Address for Correspondence:
Ki Soo Kang, MD
Department of Pediatrics and Institute of Medical Science,
Jeju National University School of Medicine, 66 Jejudaehang-no,
Jeju 690-756, Korea
Tel: +82.64-717-1130, Fax:+82.64-717-1630
This work was supported by JNUH-2008 grant of Jeju National
DOI: 10.3346/jkms.2011.26.4.546 • J Korean Med Sci 2011; 26: 546-550
There are three phases in the natural history of chronic HBV in-
fection (1). The first is the immune-tolerant phase (ITP) defined
by hepatitis B e antigen (HBeAg)-positive, normal hepatic en-
zyme levels and high serum HBV DNA concentrations. The sec-
ond is the immune-clearance phase (ICP) defined by HBeAg-
positive, abnormal hepatic enzyme levels and falling serum
HBV DNA concentrations. The third is the HBeAg negative car-
rier stage defined by seroconversion from HBeAg to hepatitis B
e antibody (HBeAb), normal hepatic enzyme levels and low or
nondetectable serum HBV DNA concentrations. After the third
phase, reactivation may develop. The progression from the first
to the third or reactivation phase over several decades may cause
the development of complications of chronic HBV infection,
such as liver cirrhosis and hepatocellular carcinoma (2).
Precore mutations, such as G1896A (guanine-to-adenine mu-
tation at nucleotide 1,896), and core promoter (CP) mutations,
including A1762T (adenine-to-thymine mutation at nucleotide
1,762) and G1764A (guanine-to-adenine mutation at nucleo-
tide 1,764), are known to be associated with HBeAg status in
adults (3). The precore stop-codon mutation (G1896A) abolishes
HBeAg and the dual mutation in the CP region (A1762T, G1764A)
down-regulates HBeAg production. These mutations are also
reported to be associated with change of the immunologic phase
and the resulting severity of liver disease in adults with chronic
HBV infection (4, 5). However, the causal relationship between
these mutations and the change of the immunologic phase or
severity of liver disease has not been established definitively.
Some researchers have reported that these mutations are not
related to either immunologic change or liver disease (1, 6).
The aim of this study was to determine the incidence of pre-
core/CP mutations in relation to the change of the immunolog-
ic phase in young chronic infected children.
MATERIALS AND METHODS
Serum was collected from 37 children with chronic HBV infec-
tion who had been HBsAg-positive for over 6 months and had
visited Jeju National University Hospital (JNUH), Jeju, Korea
between March 2005 and September 2008. The number of blood
sampling from each patient was 3 to 5 times matching to every
visit to the pediatric clinic. Serum from patients who were tak-
ing antiviral agents, such as lamivudine or adefovir, was exclud-
ed from the analysis. All sera were immediately stored in a deep
freezer at -80.0°C until required for analysis. We also recorded
information regarding the patients’ serology, levels of aspartate
aminotransferase (AST), alanine aminotransferase (ALT), HBeAg/
HBeAb, and HBV DNA (copies/mL) in serum.
Normal serum AST and ALT level was defined when lower
Kang HS, et al. • Precore and Core Promoter Mutations of the HBV Gene
than 45 IU/L. Immune tolerant phase was defined by normal
AST/AST level, HBeAg positive and high serum HBV DNA con-
centrations (7). The transient abnormal AST/ALT level caused
by other viral infections was also clarified to this phase in our
study. Immune clearance phase was defined by abnormal AST/
AST level, HBeAg positive and falling serum HBV DNA concen-
trations (7). Immune clearance phase was differentiated from
the transient nonspecific hepatitis caused by other viral infec-
tion in the children.
HBV DNA levels were quantified by a polymerase chain reac-
tion (PCR) assay with a lower limit of detection of 2×102 copies/
mL and a linearity range of 2 × 102-2 × 105 copies/mL (Cobas
Amplicor HBV Monitor, Roche Diagnostic Systems, Pleasanton,
CA, USA). All HBeAg-positive samples were prediluted up to
106-fold, and a 105-fold dilution was used for initial testing.
HBV DNA was extracted at room temperature from 200 μL
aliquots of each child’s serum (thawed at 4.0°C) using the High
Pure Viral Nucleic Acid Kit (Roche, Penzberg, Germany). The
extracted HBV DNA was immediately used for genotyping and
Using genotype-specific primers developed by Naito et al. (8),
the nucleotide sequences of the pre-S1 through S genes were
amplified. Genotyping was performed for only three (A-C) of
the six (A-F) types. The first PCR was performed using universal
primers, including P1 and S1-2, and was followed by a second
PCR, which was performed using the primer mixtures specify-
ing different genotypes, including A, B, and C. Finally, genotyp-
ing was performed based on the band sizes (type A, 281 bp; type
B, 122 bp; and type C, 68 bp) shown on electrophoresis (data
The tube for the first PCR of the precore and CP genes was
prepared using 50 μL aliquots of mixtures containing 10 μL of
extracted HBV DNA, 1 μL of 10 pM of external primers, each of
the four dNTPs at 0.2 mM, 1.5 mM MgCl2, 1 U of Taq polymerase,
5 μL of 10 LPCR buffer (Promega, Madison, WI, USA), and 32 μL
of nuclease-free water. The external primers were P1 (5´-CATA-
AGAGGACTCTTGGACT-3´, positions 1,653-1,672) and P2 (5´-
GGAAAGAAATCAGAAGGCA-3´, positions 1,974-1,956). The
mixture for the first PCR was put into the thermocycler and the
following PCR protocol used: denaturation at 94.0°C for 5 min;
followed by 40 cycles of denaturation at 94.0°C for 30 sec, an-
nealing at 54.0°C, and extension at 72.0°C for 45 sec; with a final
extension at 72.0°C for 10 min.
The tube for the second PCR was prepared using the 50 μL of
mixture comprising the first PCR product, 1 μL of 10 pM of in-
ternal primers, 0.2 mM of each of the four dNTPs, 1.5 mM MgCl2,
1 U of Taq polymerase, 5 μL of 10 LPCR buffer (Promega), and
40 μL of nuclease-free water. The internal primers were P3 (5´-
GGACTCTTGGACTCTCAGCAA-3´, positions 1,660-1,680) and
P4 (5’-TCCACAGAAGCTCCAAATTCTTT-3´, positions 1,941-
1,919). The protocol for the second PCR was the same as for the
first. The final PCR products were identified on electrophoresis
carried out using 1.0% agarose gel stained with ethidium bro-
Finally, the second PCR product was sequenced using an ABI
PRISM BigDye Terminator v3.1 cycle sequencing kit (Applied
Biosystems, Foster City, CA, USA) and then analyzed using a
genetic analyzer (ABI PRISM 3100, Applied Biosystems). The
PCR products, which included 4 μL of Terminator Ready Reac-
tion Mix, 1 μL of cleaned PCR product (20-40 ng of PCR prod-
uct), 1 μL of primer (5 pM), and sterile water to a total volume
of 10 μL, was placed in a reaction tube. Cycle sequencing was
then carried out as follows: 30 cycles of 96.0°C for 10 sec, 50.0°C
for 5 sec, and 60.0°C for 4 min. Precipitation and loading of the
samples were then performed according to the manufacturer’s
Results are expressed as the mean ± standard deviation (range).
Differences between categorical variables were analyzed using
chi-squared test. Kruskal-Wallis test was used for continous vari-
ables according to 3 immunologic phases. A P value of less than
0.05 (two-tailed) was considered statistically significant.
This study was reviewed and approved by the institutional re-
view board of Jeju National University Hospital (JNUH-IRB-07-
16). We received written informed consent from the parents of
all participating children.
Among the 37 children with chronic HBV infections (age 6.7 ±
4.6 yr, mean ± SD; range 10 months-15.8 yr), vertical infection
was the most common route of infection (n = 31, 83.8%), followed
by another member of the family (n = 3, 8.1%); the origin of in-
fection was unknown in three patients (8.1%).
Of the cohort, 18 patients (48.6%) were in the ITP, with high
viral replication and normal ALT levels (Table 1), and 13 (35.2%)
were in the ICP, with viral replication and elevated ALT levels.
Six patients (16.2%) were in the HBeAg negative carrier state
(Table 1). There was no significant association between gender
and immunologic phase (P = 0.189, chi-squared test). The mean
age was highest in the HBeAg negative carrier group, followed
by the ICP and ITP groups (Table 1).
Hepatic enzyme levels, including AST and ALT, were all near
the upper limit of normal in the ITP group, three or five times
the upper limit of normal in the ICP group, and near the lower
limit of normal in those in the HBeAg negative carrier state. The
distribution of the two hepatic enzymes differed significantly
between the three immunologic phase groups (P < 0.001, Krus-
kal-Wallis test; Table 1).
In the ITP and ICP groups, most patients had high HBV DNA
levels (i.e., more than 1.0 × 108 copies/mL). In the HBeAg nega-
Kang HS, et al. • Precore and Core Promoter Mutations of the HBV Gene
tive carrier group, all of the patients had low HBV DNA levels
(range 102-105 copies/mL; Table 1). The distribution of HBV DNA
levels differed significantly between the groups (P < 0.001, chi-
squared test; Table 1).
All of the 37 patients had HBV genotype C. Only 3 of the 37
patients exhibited CP mutations. Only one (5.5%) of the 18 ITP
patients had the G1764A mutation and 1 had the A1762T/G1764A
mutation (Table 2). Of the 13 patients in the ICP group, only two
(15.4%) exhibited CP mutations, including one A1762T/G1764A
mutation. None of the patients in the HBeAg negative carrier
group had any CP mutations.
Only one of the entire cohort exhibited a precore mutation: an
ICP patient (7.7%). The distributions of both the precore and CP
mutations did not differ significantly (A1762T, P = 0.788; G1764A,
P = 0.447; G1896A, P = 0.387, chi-squared test; Table 2).
Precore and CP gene mutations frequently occur over several
decades of chronic HBV infection. The common mutations of
the CP genes are the adenine-to-thymine mutation at nucleo-
tide 1762 (A1762T) and/or the guanine-to-adenine mutation at
nucleotide 1764 (G1764A) (9-11). In the precore gene, the gua-
nine-to-adenine mutation at nucleotide 1896 (G1896A) is the
most prevalent (3, 11).
There are many conflicting reports regarding the association
between these gene mutations and disease severity in chronic
HBV infection, with progression from the immune tolerant phase
to the HBeAg negative carrier or reactivation phase (12). There
are some reports that precore/CP mutations are correlated with
the patient’s immunological and/or disease status (4, 5, 13-17),
but others that those mutations have no significant correlation
with viral replication or liver damage (1, 6).
The prevalence of CP mutations is higher than that of precore
mutations (4) among Koreans, in whom only the C genotype
is expressed (18). In Korean adults (4), CP mutations (A1762T,
G1654A) were found in 95.0% of ICP patients, in 67% of HBeAg
negative carriers, and in 30.0% of ITP patients. The precore mu-
tation (G1896A) was less prevalent than CP mutations (i.e., 5%
of ICP patients, 32.5% of HBeAg negative carriers, and 22.5% of
ITP patients). In Taiwanese adults with HBeAg negative chronic
hepatitis B (19), the overall prevalence of the precore stop codon
mutant and basal core promoter mutant was 67% and 60%, re-
spectively. Genotype B and C are major strains in Taiwan.
In German adults with HBeAg negative chronic hepatitis B
(20), the overall prevalence of the precore stop codon mutant
and basal core promoter mutant was 46% and 59%, respective-
ly. Genotype A and D are major strains in Germany. In the anal-
ysis of these mutation rates of 3 countries, it seems to be similar
results in HBeAg negative carriers.
Compared with reports in Korean adults (4), the CP mutation
rate of our study was very low: 9.1% of the ITP group, 11.1% of
the ICP, and 0% of those in the HBeAg negative carrier state. The
incidence of the precore mutation was extremely low (4.1%), and
was found only in the ITP group. There are a few reports associ-
ated with precore or core promoter mutation of HBV in chronic
infected children in other countries (21-24). In the analysis for
89 sera from 32 chronic HBV infected Taiwanese children (24),
precore stop codon mutant was found in 10%-25% of children
before HBeAg seroconversion and in 39% of children after sero-
conversion. Core promoter mutations rates of Taiwanese chil-
dren (22) were 9.1% in seroconverters (HBeAg negative carrier)
and 5.5% in the nonseroconverters. In the analysis of 155 Euro-
pean children (21), 2 (2.2%) of 90 HBeAg positive patients and 5
Table 1. Baseline characteristics of the 37 patients with chronic hepatitis B virus
(n = 18)
(n = 13)
(n = 6)
HBV DNA (copies/mL)||
*P = 0.189 (χ2 test); †P = 0.061 (Kruskal-Wallis test);‡P < 0.001 (Kruskal-Wallis test);
§P < 0.001 (Kruskal-Wallis test); ||P ≤ 0.001 (χ2 test); ¶Mean ± 2SD. ITP, immune
tolerance phase; ICP, immune clearance phase; AST, aspartate aminotransferase; ALT,
alanine aminotransferase; high, > 108 copies/mL; moderate, 105-108 copies/mL; low,
102-105 copies/mL; negative, < 102 copies/mL. From 3 to 5 samples of each patient,
the highest value out of laboratory data and the value at the time of mutation were
selected in the patients without and with precore/core gene mutation, respectively.
40.6 ± 17.7¶
40.6 ± 22.1¶
7.5 ± 3.9
103.9 ± 78.9
170.5 ± 162.9
10.1 ± 4.6
28.2 ± 10.0
17.2 ± 6.3
Table 2. Distribution of genotypes and precore/CP gene mutations in relation to the
clinical status of chronic HBV infection
(n = 18)
(n = 13)
(n = 6)
CP mutations, No. (%)
Precore mutations, No. (%)
*P = 0.788 (χ2 test); †P = 0.447 (χ2 test); ‡P = 0.387 (χ2 test). nt, nucleotide.
0 (0%)1 (7.7%)0 (0%)
Kang HS, et al. • Precore and Core Promoter Mutations of the HBV Gene
(7.7%) of 65 anti-HBe positive children had precore stop codon
In the HBeAg negative carriers, the mutation rates of precore
stop codon and basal core promoter genes are high in adult and
low in children. This wide disparity suggest that these mutations
may be the result of life-long chronic HBV infection.
These low mutation rates in our study may originate from the
mutated HBV gene of the patient’s mother when the patient
was born. Unfortunately, the incidence of these gene mutations
in the mothers of all 37 children was not analyzed. The actual
mutation rate of these genes may thus be nearly 0%, despite the
changes in immunologic phase. These findings suggest that pre-
core/CP mutation is a only secondary occurrence, and not the
cause of immunological change in patients with chronic HBV
infection. These findings also support the opinion of Chang et
al. (24), who stated that “The precore stop codon mutant is se-
lected by host immune pressure, but is not an initiator of the loss
of immune tolerance during chronic HBV infection in children” .
Although HBeAg seroconversion is estimated to be affected
by age (Table 1), the age distribution did not differ significantly
with the immunologic phase (P = 0.061, Kruskal-Wallis test). This
may be due to the small size of each group and the wide stan-
There are limitations in our study. The first is small sample size.
The second is that direct sequencing of DNA samples of nested
PCR performed in our study reflects the major strains of HBV. It
is possible that the prevalence of precore/core promoter gene
mutation in these samples is underestimated when the mutant
strains are minor strains. HBV viral quasi-species evolution in
the precore/core gene before and after HbeAg seroconversion
in chronic HBV infected patients was reported (25). They sug-
gested that the high viral diversity, including the entire mutant
strains, may be associated with the change from the immune
tolerance pahse to the immune clearance phase (25).
HBeAg-negative chronic hepatitis B, which represents the
reactivation phase, is common in adults and is associated with
a high prevalence of precore/CP mutations (26). However, as
confirmed in the present study, this type is rare in children (27).
The geographical distribution of HBV genotypes reveals a high
prevalence of genotypes B and C in East Asia (12, 28, 29), and
countries that have many immigrants of East Asiatic origin, such
as Canada (30). Only genotype C was found in previous Korean
studies (18, 28). In our study, all 37 patients had genotype C.
In conclusion, the very low incidence of the precore/core pro-
moter gene mutation, in children, suggests that these mutations
may be the result of life-long chronic HBV infection.
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Precore and Core Promoter Mutations of the Hepatitis B Virus Gene in the Chronic
Genotype C -Infected Child
Hyun Sik Kang, Ki Soo Kang, and Byung-Cheol Song
The precore (G1896A) and core promoter (A1762T, G1764A) mutations of the hepatitis B virus gene are known to be associated
with changes in immunologic phase or the progression to complicated liver disease in adults. In contrast to the high mutation
rates in adults, our study in children revealed the very low mutation rates of precore and core promoter gene. Such results suggest
that these mutations may be the result of life-long chronic HBV infection.