Hepatitis B virus infection

Mei-Hwei Chang*
Department of Pediatrics, National Taiwan University Hospital, 7F, No 7 Chung-Shan South Road, Taipei 100, Taiwan
KEYWORDS
Hepatitis B virus;
Mother-to-infant
transmission;
Chronic hepatitis B;
Hepatitis B e antigen;
Hepatitis B
immunoglogulin;
Hepatitis B vaccine
Summary Hepatitis B virus (HBV) infection is a worldwide health problem and may cause
acute, fulminant, chronic hepatitis, liver cirrhosis, or hepatocelullar carcinoma (HCC). Infec-
tion with HBV in infancy or early childhood may lead to a high rate of persistent infection (25e
90%), while the rates are lower if infection occurs during adulthood (5e10%). In most endemic
areas, infection occurs mainly during early childhood and mother-to-infant transmission
accounts for approximately 50% of the chronic infection cases.
Hepatitis B during pregnancy does not increase maternal mortality or morbidity or the risk of
fetal complications. Approximately 90% of the infants of HBsAg carrier mothers with positive
hepatitis B e-antigen (HBeAg) will become carriers if no immunoprophylaxis is given. Transpla-
cental HBeAg may induce a specic non-responsiveness of helper T cells and HBcAg. Spontane-
ous HBeAg seroconversion to anti-HBe may develop with time but liver damage may occur
during the process of the immune clearance of HBV and HBeAg.
Mother-to-infant transmission of HBV from HBeAg negative but HBsAg positive mothers is the
most important cause of acute or fulminant hepatitis B in infancy.
Although antiviral agents are available to treat and avoid the complications of chronic hep-
atitis B, prevention of HBV infection is the best way for control. Screening for maternal HBsAg
with/without HBeAg, followed by three to four doses of HBV vaccine in infancy and hepatitis B
immunoglobulin (HBIG) within 24 h of birth is the most effective way to prevent HBV infection.
In areas with a low prevalence of HBV infection or with limited resources, omitting maternal
screening but giving three doses of HBV vaccine universally in infancy can also produce good
protective efcacy. The rst universal HBV immunisation programme in the world was
launched in Taiwan 22 years ago. HBV infection rates, chronicity rates, incidence of HCC
and incidence of fulminant hepatitis in children have been effectively reduced.
2007 Elsevier Ltd. All rights reserved.
Hepatitis B virus (HBV) infection is a worldwide health
problem and may lead to acute, fulminant or chronic
hepatitis, liver cirrhosis and liver carcinoma.
1
It is most prev-
alent in Asia, Africa, Southern Europe and Latin America,
where the prevalence of hepatitis B surface antigen (HBsAg)
carriers in the general population ranges from 2e20%. HBV
infection occurs mainly during infancy and early childhood
in hyperendemic areas, where the effect of chronic HBV
infection usually begins early in life. An example of such a
hyperendemic area is Taiwan, where the HBsAg carrier
rate in the population is 10e20%. Before the universal HBV
* Tel.: 886 2 2312 3456x5131; fax: 886 2 2393 8871.
E-mail address: mhchang@ha.mc.ntu.edu.tw
1744-165X/$ - see front matter 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2007.01.013
avai l abl e at www. s ci encedi r ect . com
j our nal homepage: www. el s evi er. com/l ocat e/s i ny
Seminars in Fetal & Neonatal Medicine (2007) 12, 160e167
vaccination programme, the HBsAg seropositive (chronic
infection) rate in Taipei city was around 5% in infancy. It
reached 10% at 2 years of age and remained stationary
thereafter, while the total infection rate increased with
age and reached 50% by age 15.
2
This suggests that most
HBsAg carriers in the population were infected before
2 years of age. Another example is the rural community of
Senegal where the total HBV infection rate was 25% by
2 years of age. At 15 years of age, 80% of the population
was infected.
3
North America, Northern Europe and the Oceanic areas
are low prevalence areas (prevalence rate of around 0.1% in
the general population) for HBV infection. HBV infection in
those areas occurs mainly in adolescents and adults.
However, HBV infection in high-risk groups, such as men
who have sex with men, intravenous drug users and an
increasing number of immigrants from hyperendemic areas,
remain a problem to be solved.
Biology of HBV
HBV is a 3.2 kilobase (kb), circular, partially double-
stranded deoxyribonucleic acid (DNA) virus. HBV contains
four open reading frames, which encode major structural
and non-structural proteins for HBV. These are the poly-
merase gene region for polymerase, surface gene region
for three surface proteins (large, middle and major
surface proteins), precore and core gene regions for
hepatitis B core antigen (HBcAg) and hepatitis B e antigen
(HBeAg), as well as the X gene region for hepatitis B X
protein.
4,5
During active replication, viral particles appear in large
quantities in the serum in two forms: one is the complete
virion of 42 nm diameter, the other is a 22 nm empty viral
envelope, which contains only the HBsAg. A soluble anti-
gen, HBeAg, which is closely related to the non-secretory
capsid antigen HBcAg, also appears in the serum during
the highly replicative phase of HBV infection. HBeAg is a
serum marker that is used to identify highly infectious
mothers and also those subjects with active viral replica-
tion for antiviral therapy.
Route of transmission
HBV can be transmitted either perinatally or horizontally to
the child. Perinatal transmission from highly infectious
mothers to their neonates is an important route for HBV
infection in Asian countries and endemic areas.
6
It accounts
for about 40e50% of HBsAg carriers in Taiwan. Before the
vaccination era, mothers carrying HBsAg served as a reser-
voir for HBV, thus maintaining transmission of HBV from one
generation to the next.
In Africa, where HBV infection is also hyperendemic,
horizontal infection during early childhood is the main
route of transmission. The two most important sources of
horizontal infection in children are highly infectious family
members, particularly siblings, and infection through non-
sterile syringes or needles.
7
Other sources include close
contact among institutionalised children, skin piercing
and multiple blood transfusions.
Hepatitis B during pregnancy
Acute hepatitis B or exacerbation of chronic HBV disease
may occur during pregnancy. Although the early literature
reported an increased risk of mortality or morbidity of the
fetus, later data denied this.
8
Pregnancy neither increased
maternal mortality or morbidity from hepatitis B nor the
risk of fetal complications, such as fetal death, abortion,
or congenital anomalies. However, pre-term labour was re-
ported to be increased in mothers with acute hepatitis B
during pregnancy. Although infection is rarely symptomatic,
70e90% of babies infected from their mothers will remain
chronically infected into adult life, if immunoprophylaxis
is not given.
Mother-to-infant transmission
The age at which HBV infection occurs is an important
factor affecting the outcome (Table 1). The earlier the in-
fection occurs, the higher is the risk for chronicity. With
no immunoprophylaxis, more than 90% of infants who
were infected by their HBeAg/HBsAg positive mothers will
develop chronic HBV infection during follow-up (Table 2).
6
This may be explained by the very high virus amount trans-
mitted to the neonate with a physiologically immature
immune system. The chronicity rate after HBV infection
decreases to approximately one quarter (23%) in children
infected at preschool age
9
and to 2.7% in young adults.
10
Perinatal transmission decreased to <5% if the mother
was HBsAg positive but HBeAg negative.
Intrauterine infection occurs rarely in <5% of the infants
born to HBeAg and HBsAg positive mothers. In our study in
Taiwan, over a 10 year period, 2.4% of the 665 infants of
HBeAg and HBsAg positive mothers were sero-positive for
HBsAg at birth, suggesting intrauterine infection.
11
They re-
mained HBsAg positive at 12 months of age. Transplacental
leakage of HBeAg-positive maternal blood, which is induced
by uterine contractions during pregnancy and the disrup-
tion of placental barriers, is the most likely route for caus-
ing HBV intrauterine infection.
12
Perinatal transmission of HBV and immune
tolerance
HBeAg is a secretary small antigen produced by HBV. It can
cross the placental barrier from the mother to the infant.
Transplacental HBeAg from the mother induces a specic
unresponsiveness of helper T cells to HBeAg and HBcAg in
neonates born to HBeAg-positive HBsAg carrier mothers.
13
Table 1 Effect of infection age on the chronicity rate of
the infected subjects
Chronicity rate
Perinatal infection
a
>90%
b
Preschool age: 23%
b
Adolescents/adults: 2.7e10%
b
a
From HBeAg positive HBsAg carrier mothers.
b
Source: Beasley et al. (1983).
10
Hepatitis B virus infection 161
This may be one explanation for the fact that 90% of the in-
fants of HBeAg positive carrier mothers became chronic
carriers, while only approximately <5% of the infants of
HBeAg negative HBsAg carrier mothers become chronic car-
riers. The immune tolerance state persists for years to
decades after neonatal infection.
Perinatal transmission of HBV and
fulminant or acute hepatitis B
Acute or fulminant hepatitis B can occur in infancy. Mother-
to-infant transmission, mainly from HBeAg negative, HBsAg
positive mothers, is the most important route of trans-
mission for acute or fulminant hepatitis in infancy.
14,15
The
incidence of fulminant hepatitis B is higher in infancy than
in other age periods.
15
An incubation period of 6 weeks
to 6 months usually precedes the presentation of acute or
fulminant hepatitis B. HBV is not considered to be an aetio-
logical agent of neonatal viral hepatitis, which has its symp-
tom onset before 1e2 months of age and is caused mostly
by cytomegalovirus, herpes virus, rubella, etc.
Fulminant hepatitis B should be considered if signs of liver
failure, including coagulopathy, increasing bilirubin levels
with declining aminotransferase levels, a decreasing liver
size and hepatic encephalopathy, develop within 8 weeks of
the onset of symptoms of acute hepatitis B without previous
history of chronic liver disease. Hepatitis B core IgMantibody
(IgM anti-HBc) is a helpful marker for the diagnosis of acute
or fulminant hepatitis B. Serum HBsAg is often positive at
presentation. However, absence of this marker does not ex-
clude the possibility of fulminant hepatitis B since serocon-
version of HBsAg to anti-HBs may occur rapidly.
The mortality rate of fulminant hepatitis B is very high
(around67%),
16
yet it is lower thanthat inadults (around90%).
Liver transplantation is indicated if recovery is not possible.
Natural course of HBV infection
HBV infection may run an acute course with complete
recovery, or a fulminant course due to hepatic failure with
a high mortality rate. Alternatively it may last for more
than 6 months and become a chronic infection.
Acute HBV infection
Acute infection can be symptomatic or asymptomatic. In
asymptomatic cases, biochemical abnormalities such as the
elevation of aminotransferase levels are usually undetected
unless a routine check-up is performed. In symptomatic
cases, the prodromal symptoms include general malaise,
anorexia, nausea, vomiting and fever, which may last for
several days to weeks. Right upper quadrant discomfort or
u-like symptoms may also present. The patient may then
have jaundice (icteric hepatitis), or be jaundice free
(unicteric hepatitis). The stool colour may become light
yellowish when jaundice deepens. Physical examination
usually reveals hepatomegaly and mild tenderness over the
liver, icteric sclera and skin. Splenomegaly is uncommon.
HBsAg is the rst marker to appear in the blood. HBeAg
may appear early but is cleared rapidly. HBsAg is cleared
and its antibody (anti-HBs) appears within 6 months of dis-
ease onset in most occasions.
The outcome of acute hepatitis B is usually good with
complete recovery from the liver damage and seroconver-
sion to anti-HBs, which represents a long-term protection
for HBV infection.
Chronic HBV infection
Chronic HBV infection is dened as persistence of HBsAg for
more than 6 months. Three phases have been observed in
the natural course of chronic HBV infection according to
the serum HBeAg and HBV DNA status: initial HBeAg sero-
positive (HBV highly replicative) phase with normal alanine
aminotransferase (ALT) levels, HBe seroconversion (HBV
clearance) phase with elevated ALT levels and post-HBe
seroconversion (HBV low or non-replicative) phase.
Children who carry HBsAg are mostly HBeAg seropositive
with normal ALT levels. The HBeAg seropositive rate is 80e
85% in HBsAg carrier children below 15 years of age. With
age, they gradually clear the HBV DNA and HBeAg and enter
the HBe seroconversion phase. They nally loose HBeAg and
become anti-HBe seropositive. The process of HBeAg sero-
conversion may occur during childhood, or later when
they enter adulthood.
Initial HBeAg seropositve (HBV highly replicative) phase
During this HBV highly replicative and HBeAg seropositive
phase, the host is in an immune-tolerant state to HBV and is
usually asymptomatic. The aminotransferase levels are
usually normal, at borderline, or mildly elevated. The
serum HBV DNA levels are usually high.
The HBV clearance (HBe seroconversion) phase
When children enter the HBe seroconversion stage, most of
them still remain asymptomatic, or have mild non-specic
symptoms such as general malaise, poor appetite, etc. The
ALT levels become elevated and the peak ALT levels may
uctuate from below 100 IU/l to more than 1000 IU/l,
Table 2 Maternal serum HBV status and the outcome of HBV infection in infants
Mother Infant
No vaccination With immunoprophylaxis
HBeAg(), HBsAg() >90% chronic Vaccine HBIG/10e15% chronic infection
HBeAg(), HBsAg() <5% chronic, with risk of FH, AH <1% chronic infection and risk of FH, AH reduced
HBeAg(), HBsAg() Not infected Not infected
FH, fulminant hepatitis; AH, acute hepatitis; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBIG, hepatitis B
immunoglobulin.
162 M.-H. Chang
depending on the liver damage developed during this virus-
host interaction process. Severe and permanent liver dam-
age that progresses into liver cirrhosis occurs rarely during
childhood. Liver cirrhosis was reported in 3.4% of 292 long-
term follow-up Italian HBsAg carrier children with elevated
aminotransferase activity.
17
Although 166 of the remaining
children had chronic active hepatitis, none progressed to
liver cirrhosis during a mean follow-up period of 4 years.
The course of HBV infection in children varies in different
individuals. The HBeAg seroconversion rate is affected by
age and maternal HBsAg status.
18
Before 3 years of age, the
annual HBe seroconversion rate is very low (less than 2% per
year in a Taiwanese cohort). After the age of 3, the annual
HBe seroconversion rate increases gradually to around 5%.
Children with HBeAg positive mothers have a lower HBeAg
seroconversion rate than those whose mothers were not
HBeAg carriers, who tend to clear HBeAg earlier.
Post HBeAg seroconversion (low or non-replicative)
phase
After HBeAg seroconversion, aminotransferase levels grad-
ually return to normal. The livers histological change in
anti-HBe positive HBsAg carrier children is usually mild or
non-specic if studied beyond 6 months after HBeAg sero-
conversion. HBV DNA was detectable in only 1% of the
anti-HBe-positive sera using the hybridisation method. How-
ever, by using the polymerase chain reaction (PCR), HBV
DNA can be demonstrated to persist in the serum of children
with chronic hepatitis B in the long term after HBeAg sero-
conversion. Bortolotti et al. studied 39 children after hepa-
titis B e seroconversion:
19
87% had HBV DNA detectable by
PCR at the 5 year follow-up and at 10 years after serocon-
version in 58% of cases. ALT levels were persistently normal
in 92%, whereas 8% had slightly elevated ALT levels.
Acute exacerbation of inammation with reactivation of
HBV replication and a rise in aminotransferase levels is not
common in children after hepatitis B e seroconversion.
18,20
Permanent liver damage may, however, develop and inte-
gration of the genome of HBV may occur insidiously and
gradually, despite clearance of HBeAg. The subsequent de-
velopment of cirrhosis or hepatocellular carcinoma is occa-
sionally observed during childhood, mostly in the anti-HBe
positive state. A long-term follow-up study revealed that
the overall prognosis for chronic hepatitis B in horizontally
infected Caucasian children was favourable; however, 2%
progressed to hepatocellular carcinoma (HCC) and 6% had
HBeAg-negative hepatitis.
21
It is generally believed that a therapeutic agent, which
can achieve HBeAg seroconversion as early as possible is
benecial to the HBsAg carriers. In a small proportion of
children, HBeAg seroconversion occurs in early life (less
than 3 years of age). In one study, 10 (14%) of the 72 children
who were followed since infancy had HBeAg seroconverted
before the age of 3. However, early HBe seroconversion
may not necessarily indicate a good prognosis, since severe
and permanent liver damage may develop during the pro-
cess of HBeAg seroconversion.
22
Two of the 10 children
who had seroconverted before 3 years of age developed
HCC at 10e15 years of age.
23
Their ALT levels were elevated
to >500 IU/l during infancy or the second year of life and
returned to normal after 2 years of age. The ALT levels
remained normal during the later part of the follow up pe-
riod before the development of liver cancer.
Hepatocellular carcinoma
In areas of endemic HBV infection, HCC in children is
closely associated with HBV infection. In contrast to
hepatoblastoma, which occurs mostly in children younger
than 6 years old, HCC occurs mainly in children older than
6 years of age. In areas of endemic HBV infection in Taiwan,
where maternal transmission of HBV is the main route of
transmission of HBV, more than 95% of HCC children were
found to be HBsAg seropositive.
24
The prognosis for child-
hood HCC is grave unless complete tumour resection is per-
formed. However, because of the late diagnosis in most
cases, resectability is very low.
Genotypes of HBV
Eight genotypes of HBV have been dened (forms A to H).
Different genotypes are distributed in different geograph-
ical areas. Infection with different genotypes may have
different clinical courses and outcomes. For example,
genotypes B and C are prevalent in Asia, while genotypes
A and D are more common in Europe, the Middle East and
India. Children with HBV genotype C have a slower HBeAg
seroconversion rate than those with genotype B.
25
Prevention of HBV infection by Immunisation
Methods of immunoprophylaxis
Three main methods of immunoprophylaxis are used world-
wide, depending on the prevalence of HBV infection and
the resources of the countries (Table 3).
Passive and active immunisation
In addition to active immunisation with HBV vaccines,
passive immunisation with hepatitis B immunoglobulin
(HBIG) can neutralise HBV transmitted from the mother
during perinatal period. Prophylaxis must be given within
24 h of birth. The worlds rst universal hepatitis B vaccina-
tion programme was launched in July 1984 in Taiwan.
26
Pregnant women were screened for serum HBsAg and
HBeAg. All infants received 4 doses (at 0, 1, 2 and 12 months
of age) of plasma-derived HBV vaccine (before July 1992), or
3 doses (at 0, 1 and 6 months of age) of recombinant HBV
vaccine (after July 1992). In addition, infants of high-risk
mothers with positive HBeAg and HBsAg received 0.5 ml
HBIG within 24 h of birth. All of the vaccines and HBIG given
to the infants were paid for by the government. The vacci-
nation programme was gradually extended to preschool
and school children and adults.
In the USA, pregnant women are screened for HBsAg but
not HBeAg. Every infant is recommended to receive 3 doses
of HBV vaccines. In addition, all infants of HBsAg positive
mothers, regardless of their HBeAg status, receive HBIG
within 24 h of birth.
27
This strategy saves the cost of mater-
nal HBeAg screening, but increases the cost of HBIG, which
is much more expensive than vaccine.
Hepatitis B virus infection 163
Active immunisation without HBIG
In order to save the cost of screening and HBIG, some
countries with intermediate/low prevalence of chronic
HBV infection or inadequate resources, do not screen the
pregnant woman and all infants receive 3 doses of HBV
vaccines without HBIG.
28
Effect of the HBV vaccination programme
HBV vaccination can prevent acute and chronic HBV
infection
According to the report of the Expanded Program on
Immunization (EPI) of the World Health Organisation
(WHO) Department of Vaccines and Biologicals, post-
exposure immunisation, beginning at birth with either
hepatitis B vaccine alone or with hepatitis B vaccine and
HBIG, can prevent the spread of more than 90% of HBV
infections from mother to baby.
29
In Taiwan, the chronic
infection rate (HBsAg carrier rate) decreased signicantly
from around 10% before to <1% in Taipei after the vaccina-
tion programme was initiated in children.
30,31
The total in-
fection rate (i.e. both acute and chronic infection) was
also decreased, even in those individuals not vaccinated
during infancy (anti-HBc seropositivity declined from 38%
to 16% and then even further down to 4.6% in children tested
15 years after the programme). The vaccination programme
has indeed reduced both the perinatal and horizontal trans-
mission of HBV.
32
The incidence of hepatoma in children
is reduced by HBV immunisation
A decline in the incidence of HCC in children was success-
fully achieved in Taiwan. The average annual incidence of
HCC in children aged 6e14 years declined from 0.52e0.54
per 100,000 children born before 1984, to 0.13e0.20 per
100,000 children born after 1984.
32,33
A further decline in
the incidence of HCC in adults is to be expected.
The mortality rate of fulminant hepatitis B
is reduced in infancy
The mortality rate of fulminant hepatitis per 100,000
infants was reduced from 5.1 in those who were born
before the vaccination programme to 1.71 in those born
after the vaccination program in Taiwan.
34
HBsAg gene mutants in HBsAg carriers born
after the vaccination programme
The rate of HBV surface gene mutations was 7.8%, 17.8%,
28.1% and 23.8%,respectively, before and 5 years, 10 years
and 15 years after the launch of the HBV vaccination
programme.
35,36
Management of chronic hepatitis B
in pregnancy
Women with chronic hepatitis B (CHB) who become preg-
nant while on therapy can continue treatment, but the
stage of the mothers liver disease and the potential benet
of treatment must be weighed against the small risk to the
fetus.
37
Using data from rabbit work, lamivudine has been
classied as a category C drug in terms of safety for use in
pregnancy by the Food and Drug Administration (FDA). It is
generally not recommended for use against HBV in the rst
trimester of pregnancy. However, potential benets may
justify the potential risk. Lamivudine crosses the placenta
freely and can be found in colostrum and breast milk at
concentrations equivalent to those in maternal serum.
Prevention of HBV vaccine failure
Although a high rate of successful protection with a combi-
nation of active and passive immunoprophylaxis (HBIG plus
HBV vaccine) has been achieved, failure of immunoprophy-
laxis does occur in mothers with a high viral load. The
prevention of such HBV vaccine failure due to intrauterine
HBV infection by the use of an antiviral agent in the third
trimester of pregnancy in those mothers with a high viral
load is still under investigation. A pilot study has been
conducted using the nuceloside analogue lamivudine during
pregnancy to prevent perinatal transmission of HBV infec-
tion. Eight highly viraemic (HBV-DNA 1.2 10
9
copies/ml)
mothers were treated with 150 mg of lamivudine per day
during the last month (from34 weeks) of pregnancy. Another
24 children, born to untreated highly viraemic mothers,
served as historical controls. All children received passive-
active immunisation at birth and were followed-up for
12 months. In the lamivudine group, 1/8 (12.5%) children
were still HBsAg and HBV-DNA positive at the age of
Table 3 Different strategies for HBV immunisation, their costs and efcacy
Maternal
screening
Infant Cost Efcacy Example
Vaccine HBIG
1. Active Only No Yes No Lower Modest Thailand
2. Active Passive
Type I HBsAg and Yes Infants of HBeAg(), Higher High Taiwan
HBeAg HBsAg() mothers
Type II HBsAg Yes Infants of HBsAg() Highest High USA
only mothers
Active immunization Zhepatitis B vaccines. Passive immunization Zhepatitis B immunoglobulin (HBIG). HBV, hepatitis B virus; HBeAg,
hepatitis B e antigen; HBsAg, hepatitis B surface antigen.
164 M.-H. Chang
12 months. In the untreated historical control group, perina-
tal transmission occurred in 7/25 (28%) children.
38
Another clinical trial, which was placebo controlled, used
the following entry criteria for mothers: age >16 years, with
estimated gestational period of 26e30 weeks at screening,
HBsAg positive and serumHBV-DNA >1000 MEq/ml at screen-
ing. Maternal ALT was <10 times the upper limit of normal,
withno history or evidenceof hepatic decompensation. Lam-
ivudine100 mg per day was givenfrom34 weeks gestationto
4 weeks after delivery. Standard immunisation with HBIG
within 24 h of birth and 3 doses of HBV vaccine in the rst
week, at 1 month and at 6 months after birth were given to
the infants.
39
At week 52, 18% of the 56 infants in the lamivudine
treatment group and 39% of the placebo group were HBsAg
seropostive (p Z0.014). Unfortunately, 13% of the lamivu-
dine group and 39% of the placebo group were lost to
follow-up at week 52. The adverse reactions were similar
in both treated and placebo groups.
39
Lamivudine during late pregnancy in mothers with a high
viral load may reduce, but did not prevent, all of the
mother-to-infant transmission of HBV and appeared safe.
However, the considerable number of infants, particularly
in the placebo group, not tested for HBsAg at week 52,
limited the interpretation of the primary analysis. Further-
more, in addition to the high cost and the screening of viral
load before enrolment, the problems of discontinuation of
lamivudine in postpartum mothers needs to be addressed.
Further studies to clarify the benet and efcacy of the
nucleoside analogue in the prevention of intrauterine
infection are needed.
Treatment of HBV infection in children
Currently no effective treatment exists for children who
are chronically infected by HBV and have normal ALT levels.
For children with an ALT elevation >2 times the upper limit
of normal, interferon-a or nucleoside analogue therapy can
be used.
Interferon therapy
The advantages of interferon therapy are a clear treatment
duration and no problems with the development of re-
sistant strains. The disadvantages of interferon are pain on
injection and side effects such as fever, general malaise,
leukopaenia and depression, particularly during the rst
month of treatment.
40
Transient growth suppression in
some young children may occur during therapy. In patients
with elevated aminotrans-ferase levels, the results of inter-
feron treatment are similar to those in adults, with the rate
of HBe seroconversion and normalisation of aminotransfer-
ase levels being 20e40% higher in the treatment group than
in the control group.
41e46
A systematic meta-analysis of the
literature has shown a signicant benet of interferon ther-
apy for chronic HBV infection in children.
47
Factors that are
predictive for a positive response to interferon include high
pretreatment levels of aminotrans-ferase, low pretreat-
ment HBV-DNA levels, late acquisition of HBV infection
and hepatocellular inammation. The recommended dose
of interferon for children with hepatitis B is 0.1 MU/kg or
3e6 MU/m
2
three times a week for 4e6 months. Long
term effects in 107 treated children compared with 59 con-
trol children revealed a similar HBeAg clearance rate of 60%
in treated patients versus 65% in controls. However, the
rate of HBsAg loss rate was 25% of IFN responders versus
0% of controls.
48
Nucleoside analogues
Lamivudine is a nucleoside analogue that is administered
orally. The recommended dose for children is 3 mg/kg/day
up to a maximal dose of 100 mg/day. The efcacy of
52 weeks of lamivudine therapy was evaluated in 286 chil-
dren in a multicentred placebo-controlled study. Complete
virological response (with HBeAg clearance and negative
HBV-DNA) at the end of treatment was achieved in 23% of
the treatment group (191 children) and 13% of the placebo
group (95 children). The anti-HBe seroconversion rate was
22% versus 13%, in the treatment and control groups, re-
spectively. ALT normalisation was noted in 55% of the treat-
ment group and 12% of the placebo group. The HBsAg loss
rate was minimal (2% in the treatment group and 0% in
the placebo group).
49
Higher ALT levels and liver histologi-
cal inammation scores and lower HBV-DNA levels before
treatment predict a better treatment response.
At 24 months of follow-up after the end of 1 year of lam-
ivudine therapy, the durability of persistent normal ALT
levels was observed in 71% and a virological response in
87% of the 49 children who had seroconverted to anti-HBe
positive during the previous 1-year lamivudine trial, while
92% of a further 14 children who had previously received
placebo had normal ALT levels and virological responses.
50
In addition, 24 months of lamivudine therapy was given to
210 children. Twenty-one percent of 133 children who had
been treated for 1-year with lamivudine (but did not have
HBeAg seroconversion) and 30% of 77 children who had pre-
viously received placebo achieved a virological response
(HBV-DNA negative and HBeAg loss) at the end of the
24 months. The incidence of YMDD mutation at month 24
was 64% in children previously treated with lamivudine
and 49% in those children previously treated with placebo.
50
The advantage of lamivudine therapy is its convenient
application without pain or prominent side effects. The
main disadvantage is the emergence of resistant strains
(e.g. YMDD mutants) and uncertainty regarding the dura-
tion of treatment.
51
Hepatic decompensation may occur
after the emergence of YMDD mutation.
Adefovir dipifoxil, entecavir and telbivudine are ap-
proved for use in treating hepatitis B in adults, but not
yet in children. Other new agents, such as telbivudine,
tenofovir and clevudine are still undergoing clinical trials.
Future prospects
Prevention is the most cost effective method for success-
fully controlling HBV infection and its complications. In
1997, the World Health Organisation recommended that
universal hepatitis B immunisation should be introduced in
all countries. According to a later WHO report, immunisa-
tion for HBV had been integrated into the Expanded
Program of Immunization (EPI) in children in 155 countries
Hepatitis B virus infection 165
by 2005, while 131 countries have a coverage rate for 3
doses of HBV vaccine of 80%. The average coverage rate is
about 50% of the global infant population. It is particularly
urgent in areas where HBV infection and HCC are prevalent.
With the integration of the hepatitis B vaccination pro-
gramme into EPI in most countries of the world, chronic
HBV infection and its complications will be further con-
trolled in this century. For those who fail to be protected by
the HBV immunisation or who do not receive HBV vaccina-
tion and become chronically infected by HBV, better
antiviral therapies are needed.
References
1. Ganem D, Prince AM. Hepatitis B virus infection natural his-
tory and clinical consequences. N Engl J Med 2004;350:
1118e29.
2. Hsu HY, Chang MH, Chen DS, Lee CY, Sung JL. Baseline seroepi-
demiology of hepatitis B virus infection in children in Taipei,
1984: a study just before mass hepatitis B vaccination program
in Taiwan. J Med Virol 1986;18:301e7.
3. Feret E, Larouze B, Dip B, Sow M, London WT, Blumberg BS.
Epidemiology of hepatitis B virus infection in the rural commu-
nity of Tip, Senegal. Am J Epidemiol 1987;125:140e9.
4. Tiollais P, Pourcel C, Dejean A. The hepatitis B virus. Nature
1985;37:489e95.
5. Lau JYN, Wright TL. Molecular virology and pathogenesis of
hepatitis B. Lancet 1993;342:1335e44.
6. Stevens CE, Beasley RP, Tsui J, Lee WC. Vertical transmission of
hepatitis B antigen in Taiwan. N Engl J Med 1975;292:771e4.
7. Hsu SC, Chang MH, Ni YH, Hsu HY, Lee CY. Horizontal transmis-
sion of HBV in children. J Pediatr Gastroenterol Nutr 1993;16:
66e9.
8. Hieber JP, Dalton D, Shorey J, Combes B. Hepatitis and preg-
nancy. J Pediatr 1977;91:545e9.
9. Beasley RP, Hwang LY, Lin CC, Leu ML, Steven CE, Szmuness W,
et al. Incidence of hepatitis B virus infection in preschool chil-
dren in Taiwan. J Infect Dis 1982;146:198e204.
10. Beasley RP, Hwang LY, Lin CC, Ko YC, Twn SJ. Incidence of hep-
atitis among students at a university in Taiwan. Am J Epidemiol
1983;117:213e22.
11. Tang JR, Hsu HY, Lin HH, Ni YH, Chang MH. Hepatitis B surface
antigenemia at birth: a long-term follow-up study. J Pediatr
1998;133:374e7.
12. Lin HH, Lee TY, Chen DS, Suns JL, Ohto H, Etoh T, et al. Trans-
placental leakage of HbeAg-positive maternal blood as the
most likely route in causing intrauterine infection with hepati-
tis B virus. J Pediatr 1987;111:877e81.
13. Hsu HY, Chang MH, Hsieh KH, Lee CY, Li HH, Hwang LH, et al.
Cellular immune response to hepatitis B core antigen in mater-
nal infant transmission of hepatitis B virus. Hepatology 1992;
15:770e6.
14. Shiraki K, Yoshihara N, Sakurai M, Eto T, Kawana T. Acute hep-
atitis B in infants born to carrier mothers with the antibody to
hepatitis B e antigen. J Pediatr 1980;97:768e70.
15. Chen HL, Chang CJ, Kong MS, Huang FC, Lee HC, Lin CC, et al.
Fulminant hepatic failure in children in endemic area of hepa-
titis B virus infection: 15 years after universal hepatitis B vac-
cination. Hepatology 2004;39:58e63.
16. Chang MH, Lee CY, Chen DS, Hsu HC, Lai MY. Fulminant hepa-
titis in children in Taiwan: the important role of hepatitis B
virus. J Pediatr 1987;111:34e9.
17. Bortolotti F, Cadrobbi P, Crivellaro C, Guido M, Rugge M,
Noventa F, et al. Long-term outcome of chronic type B hepati-
tis in patients who acquire hepatitis B virus in infection in
childhood. Gastroenterology 1990;99:805e10.
18. Chang MH, Sung JL, Lee CY, Chen JS, Hsu HY, Lee PI, et al.
Factors affecting clearance of hepatitis B e antigen in hepatitis
B surface antigen carrier children. J Pediatr 1989;115:385e90.
19. Bortolotti F, Wirth S, Crivellaro C, Alberti A, Martine U, de
Moliner L. Long-term persistence of hepatitis B virus DNA in
the serum of children with chronic hepatitis B after hepatitis
B e antigen to antibody seroconversion. J Pediatr Gastroen-
terol Nutr 1996;22:270e4.
20. Bortolotti F, Cadrobbi M, Crivellaro C, Guido M, Rugge M,
Noventa F, et al. Long-term outcome of chronic type B hepati-
tis in patients who acquire hepatitis B virus infection in child-
hood. Gastroenterology 1990;99:805e10.
21. Bortolotti F, Cuido M, Bartolacci S, Cadrobbi P, Crivellaro C,
Noventa F, et al. Chronic hepatitis B in children after e antigen
seroclearance: nal report of a 29-year longitudinal study.
Hepatology 2006;43:556e62.
22. Chang MH, Hsu HY, Hsu HC, Ni YH, Chen JS, Chen DS. The sig-
nicance of spontaneous HBeAg seroconversion in childhood:
with special emphasis on the clearance of HBeAg before three
years of age. Hepatology 1995;22:1387e92.
23. Wen WH, Chang MH, Hsu HY, Ni YH, Chen HL. The development
of hepatocellular carcinoma among 426 prospectively followed
children with chronic hepatitis B virus infection. J Pediatr
2004;144:397e9.
24. Chang MH, Chen DS, Hsu HC, Hsu HY, Lee CY. Maternal trans-
mission of hepatitis B virus in childhood hepatocellular carci-
noma. Cancer 1989;64:2377e80.
25. Ni YH, Chang MH, Wang KJ, Hsu HY, Chen HL, Kao JH, et al.
Clinical relevance of hepatitis B virus genotype in children
with chronic hepatitis B and hepatocellular carcinoma. Gastro-
enterology 2004;127:1733e8.
26. Hsu NHM, Chen DS, Chuang CH, Lu JC, Jwo DM, Lee CC, et al.
Efcacy of a mass hepatitis B vaccination program in Taiwan:
studies on 3464 infants of hepatitis B surface antigen-carrier
mothers. J Am Med Assoc 1988;260:2231e5.
Practice points
The main route of chronic hepatitis B virus (HBV)
infection is through mother-to-infant transmission
from HBsAg and HBeAg carrier mothers, while ful-
minant hepatitis in infancy is mainly transmitted
from HBeAg negative HBsAg carrier mothers.
Prevention by hepatitis B immunisation is the best
way to control HBV infection and its related
complications.
Research agenda
Studies are needed to see if giving an antiviral
agent during the third trimester of pregnancy
can safely and effectively reduce intrauterine in-
fection or not.
Is a new hepatitis B vaccine containing hepatitis B
virus (HBV) surface gene mutants needed for
future immunisation programmes?
166 M.-H. Chang
27. Shepard CW, Simard EP, Finelli L, Fiore AF, Bell BP. Hepatitis B
virus infection: epidemiology and vaccination. Epidemiol Rev
2006;28:112e25.
28. PoovorawanY, Theamboonlers A, Vimolket T, SinlaparatsameeS,
Chaiear K, Siraprapasiri T, et al. Impact of hepatitis B immuniza-
tion as part of the EPI. Vaccine 2000;19:943e9.
29. WHO. Report on the Expanded Program on Immunization (EPI)
of the World Health Organisation (WHO) Department of Vac-
cines and Biologicals. (Post-exposure immunization for hepati-
tis B). Geneva: WHO; www.who.immunization/.
30. Chen HL, Chang MH, Ni YH, Hsu HY, Lee PI, Chen DS, et al.
Seroepidemiology of hepatitis B virus infection in children e
ten years of mass vaccination in Taiwan. J Am Med Assoc
1996;276:906e8.
31. Ni YH, Chang MH, Huang LM, Chen HL, Hsu HY, Chiu TY, et al.
Hepatitis B virus infection in children and adolescents in a hy-
perendemic area: 15 years after mass hepatitis B vaccination.
Ann Intern Med 2001;135:796e800.
32. Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, et al.
Universal hepatitis B vaccination in Taiwan and the incidence
of hepatocellular carcinoma in children. N Engl J Med 1997;
336:1855e9.
33. Chang MH, Chen J, Hsu HM, Wu TC, Kong MS, Liang DC, et al.
Prevention of hepatocellular carcinoma by universal vaccina-
tion against hepatitis B virus: the effect and problems. Clin
Cancer Res 2005;11:7953e7.
34. Kao JH, Hsu HM, Shau WY, Chang MH, Chen DS. Universal hepati-
tis B vaccination and the decreased mortality from fulminant
hepatitis in infants in Taiwan. J Pediatr 2001;139:349e52.
35. Hsu HY, Chang MH, Ni YH, Chen HL. Survey of hepatitis B sur-
face variant infection in children 15 years after nationwide
vaccination program in Taiwan. Gut 2004;53:1499e503.
36. Hsu HY, Chang MH, Liaw SH, Ni YH, Chen HL. Changes of hep-
atitis B surface variants in carrier children before and after
universal vaccination in Taiwan. Hepatology 1999;30:1312e7.
37. Liaw YF, Leung N, Guan R, Lau GKK, Merican I, McCaughan G,
et al. Asian-Pacic consensus statement on the management
of chronic hepatitis B: a 2005 update. Liver Int 2005;25:
472e89.
38. Van Zonneveld M, van Nunen AB, Niesters HGM, de Man RA,
Schalm SW, Janssen HLA. Lamivudine treatment during preg-
nancy to prevent perinatal transmission of hepatitis B virus
infection. J Viral Hepatitis 2003;10:294e7.
39. Xu WM, Cui YT, Wang L, Yang H, Liang ZQ, Li XM, et al. Efcacy
and safety of lamivudine in late pregnancy for the prevention
of mother-child transmission of hepatitis B: a multicentre, ran-
domized, double-blind, placebo-controlled study. Hepatology
2004;40:272A [abstract 246].
40. Torre D, Tambini R. Interferon alfa-2a therapy for chronic hep-
atitis B in children: a meta-analysis. Clin Infect Dis 1996;23:
131e7.
41. Lai CL, Lok ASF, Lin HJ, Wu PC, Yeoh EK, Yeung CY. Placebo-
controlled trial of recombinant a2-interferon in Chinese
HBsAg-carrier children. Lancet 1987;17:877e80.
42. Barbera C, Bortolotti F, Crivellaro C, Coscia A, Zancan L,
Cadrobbi P, et al. Recombinant interferon-2a hastens the
rate of HBeAg clearance in children with chronic hepatitis B.
Hepatology 1994;20:287e90.
43. Ruiz-Moreno M, Camps T, Jimenez J, Lopez R, Castillo I,
Bartolome J, et al. Factors predictive of response to interferon
therapy in children with chronic hepatitis B. J Hepatol 1995;
22:540e4.
44. Gregorio GV, Jara P, Hierro L, Diaz C, Vega A de la, Vegnente A,
et al. Lymphoblastoid interferon alfa with or without steroid
pretreatment in children with chronic hepatitis B: a multicenter
controlled trial. Hepatology 1996;23:700e7.
45. Vajro P, Tedesco M, Fontanella A, De Vincenzo A, Raffaella V,
Ammendola R, et al. Prolonged and high dose recombinant in-
terferon alpha-2b alone or after prednisone priming acceler-
ates termination of active viral replication in children with
chronic hepatitis B infection. Pediatr Infect Dis J 1996;15:
223e31.
46. Sokal EM, Conjeevaram HS, Roberts EA, Alvarez F, Bern EM,
Goyens P, et al. Interferon alpha therapy for chronic hepatitis
B in children: a multinational randomized controlled trial. Gas-
troenterology 1998;114:988e95.
47. Torre D, Tambini R. Interferon-a therapy for chronic hepatitis B
in children: a meta-analysis. Clin Infect Dis 1996;23:131e7.
48. Bortolotti F, Jara P, Barbera C, Ramos J, Perney P, Laurent C,
et al. Long term effect of alpha interferon in children with
chronic hepatitis B. Gut 2000;46:715e8.
49. Jonas M, Kelly Pa, Mizerski J, Badia IB, Areias JA, Schwarz KB,
et al. Clinical trial of lamivudine in children with chronic hep-
atitis B. N Engl J Med 2002;346:1706e13.
50. Sokal EM, Kelly DA, Badia IB, Badia IB, Areias JA, Schwarz KB,
et al. Long-term lamivudine therapy for children with HBeAg-
positive chronic hepatitis B. Hepatology 2006;43:225e32.
51. Zoulin F, Trepo C. Drug therapy for chronic hepatitis B: antivi-
ral efcacy and inuence of hepatitis B virus polymerase muta-
tions on the outcome of therapy. J Hepatol 1998;29:151e68.
Hepatitis B virus infection 167