Seminars in Fetal & Neonatal Medicine (2007) 12, 160e167

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s i n y

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 Summary Hepatitis B virus (HBV) infection is a worldwide health problem and may cause
Hepatitis B virus; acute, fulminant, chronic hepatitis, liver cirrhosis, or hepatocelullar carcinoma (HCC). Infec-
Mother-to-infant tion with HBV in infancy or early childhood may lead to a high rate of persistent infection (25e
transmission; 90%), while the rates are lower if infection occurs during adulthood (5e10%). In most endemic
Chronic hepatitis B; areas, infection occurs mainly during early childhood and mother-to-infant transmission
Hepatitis B e antigen; accounts for approximately 50% of the chronic infection cases.
Hepatitis B Hepatitis B during pregnancy does not increase maternal mortality or morbidity or the risk of
immunoglogulin; fetal complications. Approximately 90% of the infants of HBsAg carrier mothers with positive
Hepatitis B vaccine hepatitis B e-antigen (HBeAg) will become carriers if no immunoprophylaxis is given. Transpla-
cental HBeAg may induce a specific 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 efficacy. The first 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 where the prevalence of hepatitis B surface antigen (HBsAg)
problem and may lead to acute, fulminant or chronic carriers in the general population ranges from 2e20%. HBV
hepatitis, liver cirrhosis and liver carcinoma.1 It is most prev- infection occurs mainly during infancy and early childhood
alent in Asia, Africa, Southern Europe and Latin America, in hyperendemic areas, where the effect of chronic HBV
infection usually begins early in life. An example of such a
* Tel.: 886 2 2312 3456x5131; fax: 886 2 2393 8871. hyperendemic area is Taiwan, where the HBsAg carrier
E-mail address: [email protected] rate in the population is 10e20%. Before the universal HBV

1744-165X/$ - see front matter 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2007.01.013
Hepatitis B virus infection 161

vaccination programme, the HBsAg seropositive (chronic Hepatitis B during pregnancy

infection) rate in Taipei city was around 5% in infancy. It
reached 10% at 2 years of age and remained stationary Acute hepatitis B or exacerbation of chronic HBV disease
thereafter, while the total infection rate increased with may occur during pregnancy. Although the early literature
age and reached 50% by age 15.2 This suggests that most reported an increased risk of mortality or morbidity of the
HBsAg carriers in the population were infected before fetus, later data denied this.8 Pregnancy neither increased
2 years of age. Another example is the rural community of maternal mortality or morbidity from hepatitis B nor the
Senegal where the total HBV infection rate was 25% by risk of fetal complications, such as fetal death, abortion,
2 years of age. At 15 years of age, 80% of the population or congenital anomalies. However, pre-term labour was re-
was infected.3 ported to be increased in mothers with acute hepatitis B
North America, Northern Europe and the Oceanic areas during pregnancy. Although infection is rarely symptomatic,
are low prevalence areas (prevalence rate of around 0.1% in 70e90% of babies infected from their mothers will remain
the general population) for HBV infection. HBV infection in chronically infected into adult life, if immunoprophylaxis
those areas occurs mainly in adolescents and adults. is not given.
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,
Mother-to-infant transmission
remain a problem to be solved.
The age at which HBV infection occurs is an important
factor affecting the outcome (Table 1). The earlier the in-
Biology of HBV fection occurs, the higher is the risk for chronicity. With
no immunoprophylaxis, more than 90% of infants who
HBV is a 3.2 kilobase (kb), circular, partially double- were infected by their HBeAg/HBsAg positive mothers will
stranded deoxyribonucleic acid (DNA) virus. HBV contains develop chronic HBV infection during follow-up (Table 2).6
four open reading frames, which encode major structural This may be explained by the very high virus amount trans-
and non-structural proteins for HBV. These are the poly- mitted to the neonate with a physiologically immature
merase gene region for polymerase, surface gene region immune system. The chronicity rate after HBV infection
for three surface proteins (large, middle and major decreases to approximately one quarter (23%) in children
surface proteins), precore and core gene regions for infected at preschool age9 and to 2.7% in young adults.10
hepatitis B core antigen (HBcAg) and hepatitis B e antigen Perinatal transmission decreased to <5% if the mother
(HBeAg), as well as the X gene region for hepatitis B X was HBsAg positive but HBeAg negative.
protein.4,5 Intrauterine infection occurs rarely in <5% of the infants
During active replication, viral particles appear in large born to HBeAg and HBsAg positive mothers. In our study in
quantities in the serum in two forms: one is the complete Taiwan, over a 10 year period, 2.4% of the 665 infants of
virion of 42 nm diameter, the other is a 22 nm empty viral HBeAg and HBsAg positive mothers were sero-positive for
envelope, which contains only the HBsAg. A soluble anti- HBsAg at birth, suggesting intrauterine infection.11 They re-
gen, HBeAg, which is closely related to the non-secretory mained HBsAg positive at 12 months of age. Transplacental
capsid antigen HBcAg, also appears in the serum during leakage of HBeAg-positive maternal blood, which is induced
the highly replicative phase of HBV infection. HBeAg is a by uterine contractions during pregnancy and the disrup-
serum marker that is used to identify highly infectious tion of placental barriers, is the most likely route for caus-
mothers and also those subjects with active viral replica- ing HBV intrauterine infection.12
tion for antiviral therapy.
Perinatal transmission of HBV and immune
tolerance
Route of transmission
HBeAg is a secretary small antigen produced by HBV. It can
HBV can be transmitted either perinatally or horizontally to cross the placental barrier from the mother to the infant.
the child. Perinatal transmission from highly infectious Transplacental HBeAg from the mother induces a specific
mothers to their neonates is an important route for HBV unresponsiveness of helper T cells to HBeAg and HBcAg in
infection in Asian countries and endemic areas.6 It accounts neonates born to HBeAg-positive HBsAg carrier mothers.13
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
Table 1 Effect of infection age on the chronicity rate of
generation to the next.
the infected subjects
In Africa, where HBV infection is also hyperendemic,
horizontal infection during early childhood is the main Chronicity rate
route of transmission. The two most important sources of Perinatal infectiona >90%b
horizontal infection in children are highly infectious family Preschool age: 23%b
members, particularly siblings, and infection through non- Adolescents/adults: 2.7e10%b
sterile syringes or needles.7 Other sources include close a
From HBeAg positive HBsAg carrier mothers.
contact among institutionalised children, skin piercing b
Source: Beasley et al. (1983).10
and multiple blood transfusions.
162 M.-H. Chang

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.

This may be one explanation for the fact that 90% of the in- cases, the prodromal symptoms include general malaise,
fants of HBeAg positive carrier mothers became chronic anorexia, nausea, vomiting and fever, which may last for
carriers, while only approximately <5% of the infants of several days to weeks. Right upper quadrant discomfort or
HBeAg negative HBsAg carrier mothers become chronic car- flu-like symptoms may also present. The patient may then
riers. The immune tolerance state persists for years to have jaundice (icteric hepatitis), or be jaundice free
decades after neonatal infection. (unicteric hepatitis). The stool colour may become light
yellowish when jaundice deepens. Physical examination
Perinatal transmission of HBV and usually reveals hepatomegaly and mild tenderness over the
fulminant or acute hepatitis B liver, icteric sclera and skin. Splenomegaly is uncommon.
HBsAg is the first marker to appear in the blood. HBeAg
Acute or fulminant hepatitis B can occur in infancy. Mother- may appear early but is cleared rapidly. HBsAg is cleared
to-infant transmission, mainly from HBeAg negative, HBsAg and its antibody (anti-HBs) appears within 6 months of dis-
positive mothers, is the most important route of trans- ease onset in most occasions.
mission for acute or fulminant hepatitis in infancy.14,15 The The outcome of acute hepatitis B is usually good with
incidence of fulminant hepatitis B is higher in infancy than complete recovery from the liver damage and seroconver-
in other age periods.15 An incubation period of 6 weeks sion to anti-HBs, which represents a long-term protection
to 6 months usually precedes the presentation of acute or for HBV infection.
fulminant hepatitis B. HBV is not considered to be an aetio-
logical agent of neonatal viral hepatitis, which has its symp- Chronic HBV infection
tom onset before 1e2 months of age and is caused mostly
by cytomegalovirus, herpes virus, rubella, etc. Chronic HBV infection is defined as persistence of HBsAg for
Fulminant hepatitis B should be considered if signs of liver more than 6 months. Three phases have been observed in
failure, including coagulopathy, increasing bilirubin levels the natural course of chronic HBV infection according to
with declining aminotransferase levels, a decreasing liver the serum HBeAg and HBV DNA status: initial HBeAg sero-
size and hepatic encephalopathy, develop within 8 weeks of positive (HBV highly replicative) phase with normal alanine
the onset of symptoms of acute hepatitis B without previous aminotransferase (ALT) levels, HBe seroconversion (HBV
history of chronic liver disease. Hepatitis B core IgM antibody clearance) phase with elevated ALT levels and post-HBe
(IgM anti-HBc) is a helpful marker for the diagnosis of acute seroconversion (HBV low or non-replicative) phase.
or fulminant hepatitis B. Serum HBsAg is often positive at Children who carry HBsAg are mostly HBeAg seropositive
presentation. However, absence of this marker does not ex- with normal ALT levels. The HBeAg seropositive rate is 80e
clude the possibility of fulminant hepatitis B since serocon- 85% in HBsAg carrier children below 15 years of age. With
version of HBsAg to anti-HBs may occur rapidly. age, they gradually clear the HBV DNA and HBeAg and enter
The mortality rate of fulminant hepatitis B is very high the HBe seroconversion phase. They finally loose HBeAg and
(around 67%),16 yet it is lower than that in adults (around 90%). become anti-HBe seropositive. The process of HBeAg sero-
Liver transplantation is indicated if recovery is not possible. conversion may occur during childhood, or later when
they enter adulthood.

Natural course of HBV infection Initial HBeAg seropositve (HBV highly replicative) phase
During this HBV highly replicative and HBeAg seropositive
HBV infection may run an acute course with complete phase, the host is in an immune-tolerant state to HBV and is
recovery, or a fulminant course due to hepatic failure with usually asymptomatic. The aminotransferase levels are
a high mortality rate. Alternatively it may last for more usually normal, at borderline, or mildly elevated. The
than 6 months and become a chronic infection. serum HBV DNA levels are usually high.

Acute HBV infection The HBV clearance (HBe seroconversion) phase

When children enter the HBe seroconversion stage, most of
Acute infection can be symptomatic or asymptomatic. In them still remain asymptomatic, or have mild non-specific
asymptomatic cases, biochemical abnormalities such as the symptoms such as general malaise, poor appetite, etc. The
elevation of aminotransferase levels are usually undetected ALT levels become elevated and the peak ALT levels may
unless a routine check-up is performed. In symptomatic fluctuate from below 100 IU/l to more than 1000 IU/l,
Hepatitis B virus infection 163

depending on the liver damage developed during this virus- remained normal during the later part of the follow up pe-
host interaction process. Severe and permanent liver dam- riod before the development of liver cancer.
age that progresses into liver cirrhosis occurs rarely during
childhood. Liver cirrhosis was reported in 3.4% of 292 long- Hepatocellular carcinoma
term follow-up Italian HBsAg carrier children with elevated
aminotransferase activity.17 Although 166 of the remaining In areas of endemic HBV infection, HCC in children is
children had chronic active hepatitis, none progressed to closely associated with HBV infection. In contrast to
liver cirrhosis during a mean follow-up period of 4 years. hepatoblastoma, which occurs mostly in children younger
The course of HBV infection in children varies in different than 6 years old, HCC occurs mainly in children older than
individuals. The HBeAg seroconversion rate is affected by 6 years of age. In areas of endemic HBV infection in Taiwan,
age and maternal HBsAg status.18 Before 3 years of age, the where maternal transmission of HBV is the main route of
annual HBe seroconversion rate is very low (less than 2% per transmission of HBV, more than 95% of HCC children were
year in a Taiwanese cohort). After the age of 3, the annual found to be HBsAg seropositive.24 The prognosis for child-
HBe seroconversion rate increases gradually to around 5%. hood HCC is grave unless complete tumour resection is per-
Children with HBeAg positive mothers have a lower HBeAg formed. However, because of the late diagnosis in most
seroconversion rate than those whose mothers were not cases, resectability is very low.
HBeAg carriers, who tend to clear HBeAg earlier.

Genotypes of HBV
Post HBeAg seroconversion (low or non-replicative)
phase Eight genotypes of HBV have been defined (forms A to H).
After HBeAg seroconversion, aminotransferase levels grad- Different genotypes are distributed in different geograph-
ually return to normal. The livers histological change in ical areas. Infection with different genotypes may have
anti-HBe positive HBsAg carrier children is usually mild or different clinical courses and outcomes. For example,
non-specific if studied beyond 6 months after HBeAg sero- genotypes B and C are prevalent in Asia, while genotypes
conversion. HBV DNA was detectable in only 1% of the A and D are more common in Europe, the Middle East and
anti-HBe-positive sera using the hybridisation method. How- India. Children with HBV genotype C have a slower HBeAg
ever, by using the polymerase chain reaction (PCR), HBV seroconversion rate than those with genotype B.25
DNA can be demonstrated to persist in the serum of children
with chronic hepatitis B in the long term after HBeAg sero- Prevention of HBV infection by Immunisation
conversion. Bortolotti et al. studied 39 children after hepa-
titis B e seroconversion:19 87% had HBV DNA detectable by
Methods of immunoprophylaxis
PCR at the 5 year follow-up and at 10 years after serocon-
version in 58% of cases. ALT levels were persistently normal
Three main methods of immunoprophylaxis are used world-
in 92%, whereas 8% had slightly elevated ALT levels.
wide, depending on the prevalence of HBV infection and
Acute exacerbation of inflammation with reactivation of
the resources of the countries (Table 3).
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- Passive and active immunisation
gration of the genome of HBV may occur insidiously and In addition to active immunisation with HBV vaccines,
gradually, despite clearance of HBeAg. The subsequent de- passive immunisation with hepatitis B immunoglobulin
velopment of cirrhosis or hepatocellular carcinoma is occa- (HBIG) can neutralise HBV transmitted from the mother
sionally observed during childhood, mostly in the anti-HBe during perinatal period. Prophylaxis must be given within
positive state. A long-term follow-up study revealed that 24 h of birth. The worlds first universal hepatitis B vaccina-
the overall prognosis for chronic hepatitis B in horizontally tion programme was launched in July 1984 in Taiwan.26
infected Caucasian children was favourable; however, 2% Pregnant women were screened for serum HBsAg and
progressed to hepatocellular carcinoma (HCC) and 6% had HBeAg. All infants received 4 doses (at 0, 1, 2 and 12 months
HBeAg-negative hepatitis.21 of age) of plasma-derived HBV vaccine (before July 1992), or
It is generally believed that a therapeutic agent, which 3 doses (at 0, 1 and 6 months of age) of recombinant HBV
can achieve HBeAg seroconversion as early as possible is vaccine (after July 1992). In addition, infants of high-risk
beneficial to the HBsAg carriers. In a small proportion of mothers with positive HBeAg and HBsAg received 0.5 ml
children, HBeAg seroconversion occurs in early life (less HBIG within 24 h of birth. All of the vaccines and HBIG given
than 3 years of age). In one study, 10 (14%) of the 72 children to the infants were paid for by the government. The vacci-
who were followed since infancy had HBeAg seroconverted nation programme was gradually extended to preschool
before the age of 3. However, early HBe seroconversion and school children and adults.
may not necessarily indicate a good prognosis, since severe In the USA, pregnant women are screened for HBsAg but
and permanent liver damage may develop during the pro- not HBeAg. Every infant is recommended to receive 3 doses
cess of HBeAg seroconversion.22 Two of the 10 children of HBV vaccines. In addition, all infants of HBsAg positive
who had seroconverted before 3 years of age developed mothers, regardless of their HBeAg status, receive HBIG
HCC at 10e15 years of age.23 Their ALT levels were elevated within 24 h of birth.27 This strategy saves the cost of mater-
to >500 IU/l during infancy or the second year of life and nal HBeAg screening, but increases the cost of HBIG, which
returned to normal after 2 years of age. The ALT levels is much more expensive than vaccine.
164 M.-H. Chang

Table 3 Different strategies for HBV immunisation, their costs and efficacy
Maternal Infant Cost Efficacy Example
screening 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 Z hepatitis B vaccines. Passive immunization Z hepatitis B immunoglobulin (HBIG). HBV, hepatitis B virus; HBeAg,
hepatitis B e antigen; HBsAg, hepatitis B surface antigen.

Active immunisation without HBIG HBsAg gene mutants in HBsAg carriers born
In order to save the cost of screening and HBIG, some after the vaccination programme
countries with intermediate/low prevalence of chronic
HBV infection or inadequate resources, do not screen the The rate of HBV surface gene mutations was 7.8%, 17.8%,
pregnant woman and all infants receive 3 doses of HBV 28.1% and 23.8%,respectively, before and 5 years, 10 years
vaccines without HBIG.28 and 15 years after the launch of the HBV vaccination
programme.35,36
Effect of the HBV vaccination programme

HBV vaccination can prevent acute and chronic HBV Management of chronic hepatitis B
infection in pregnancy
According to the report of the Expanded Program on
Immunization (EPI) of the World Health Organisation Women with chronic hepatitis B (CHB) who become preg-
(WHO) Department of Vaccines and Biologicals, post- nant while on therapy can continue treatment, but the
exposure immunisation, beginning at birth with either stage of the mothers liver disease and the potential benefit
hepatitis B vaccine alone or with hepatitis B vaccine and of treatment must be weighed against the small risk to the
HBIG, can prevent the spread of more than 90% of HBV fetus.37
infections from mother to baby.29 In Taiwan, the chronic Using data from rabbit work, lamivudine has been
infection rate (HBsAg carrier rate) decreased significantly classified as a category C drug in terms of safety for use in
from around 10% before to <1% in Taipei after the vaccina- pregnancy by the Food and Drug Administration (FDA). It is
tion programme was initiated in children.30,31 The total in- generally not recommended for use against HBV in the first
fection rate (i.e. both acute and chronic infection) was trimester of pregnancy. However, potential benefits may
also decreased, even in those individuals not vaccinated justify the potential risk. Lamivudine crosses the placenta
during infancy (anti-HBc seropositivity declined from 38% freely and can be found in colostrum and breast milk at
to 16% and then even further down to 4.6% in children tested concentrations equivalent to those in maternal serum.
15 years after the programme). The vaccination programme
has indeed reduced both the perinatal and horizontal trans-
Prevention of HBV vaccine failure
mission of HBV.32
Although a high rate of successful protection with a combi-
The incidence of hepatoma in children
nation of active and passive immunoprophylaxis (HBIG plus
is reduced by HBV immunisation HBV vaccine) has been achieved, failure of immunoprophy-
laxis does occur in mothers with a high viral load. The
A decline in the incidence of HCC in children was success- prevention of such HBV vaccine failure due to intrauterine
fully achieved in Taiwan. The average annual incidence of HBV infection by the use of an antiviral agent in the third
HCC in children aged 6e14 years declined from 0.52e0.54 trimester of pregnancy in those mothers with a high viral
per 100,000 children born before 1984, to 0.13e0.20 per load is still under investigation. A pilot study has been
100,000 children born after 1984.32,33 A further decline in conducted using the nuceloside analogue lamivudine during
the incidence of HCC in adults is to be expected. pregnancy to prevent perinatal transmission of HBV infec-
tion. Eight highly viraemic (HBV-DNA 1.2  109 copies/ml)
The mortality rate of fulminant hepatitis B mothers were treated with 150 mg of lamivudine per day
is reduced in infancy during the last month (from 34 weeks) of pregnancy. Another
24 children, born to untreated highly viraemic mothers,
The mortality rate of fulminant hepatitis per 100,000 served as historical controls. All children received passive-
infants was reduced from 5.1 in those who were born active immunisation at birth and were followed-up for
before the vaccination programme to 1.71 in those born 12 months. In the lamivudine group, 1/8 (12.5%) children
after the vaccination program in Taiwan.34 were still HBsAg and HBV-DNA positive at the age of
Hepatitis B virus infection 165

12 months. In the untreated historical control group, perina- 3e6 MU/m2 three times a week for 4e6 months. Long
tal transmission occurred in 7/25 (28%) children.38 term effects in 107 treated children compared with 59 con-
Another clinical trial, which was placebo controlled, used trol children revealed a similar HBeAg clearance rate of 60%
the following entry criteria for mothers: age >16 years, with in treated patients versus 65% in controls. However, the
estimated gestational period of 26e30 weeks at screening, rate of HBsAg loss rate was 25% of IFN responders versus
HBsAg positive and serum HBV-DNA >1000 MEq/ml at screen- 0% of controls.48
ing. Maternal ALT was <10 times the upper limit of normal,
with no history or evidence of hepatic decompensation. Lam- Nucleoside analogues
ivudine 100 mg per day was given from 34 weeks gestation to
4 weeks after delivery. Standard immunisation with HBIG
Lamivudine is a nucleoside analogue that is administered
within 24 h of birth and 3 doses of HBV vaccine in the first
orally. The recommended dose for children is 3 mg/kg/day
week, at 1 month and at 6 months after birth were given to
up to a maximal dose of 100 mg/day. The efficacy of
the infants.39
52 weeks of lamivudine therapy was evaluated in 286 chil-
At week 52, 18% of the 56 infants in the lamivudine
dren in a multicentred placebo-controlled study. Complete
treatment group and 39% of the placebo group were HBsAg
virological response (with HBeAg clearance and negative
seropostive (p Z 0.014). Unfortunately, 13% of the lamivu-
HBV-DNA) at the end of treatment was achieved in 23% of
dine group and 39% of the placebo group were lost to
the treatment group (191 children) and 13% of the placebo
follow-up at week 52. The adverse reactions were similar
group (95 children). The anti-HBe seroconversion rate was
in both treated and placebo groups.39
22% versus 13%, in the treatment and control groups, re-
Lamivudine during late pregnancy in mothers with a high
spectively. ALT normalisation was noted in 55% of the treat-
viral load may reduce, but did not prevent, all of the
ment group and 12% of the placebo group. The HBsAg loss
mother-to-infant transmission of HBV and appeared safe.
rate was minimal (2% in the treatment group and 0% in
However, the considerable number of infants, particularly
the placebo group).49 Higher ALT levels and liver histologi-
in the placebo group, not tested for HBsAg at week 52,
cal inflammation scores and lower HBV-DNA levels before
limited the interpretation of the primary analysis. Further-
treatment predict a better treatment response.
more, in addition to the high cost and the screening of viral
At 24 months of follow-up after the end of 1 year of lam-
load before enrolment, the problems of discontinuation of
ivudine therapy, the durability of persistent normal ALT
lamivudine in postpartum mothers needs to be addressed.
levels was observed in 71% and a virological response in
Further studies to clarify the benefit and efficacy of the
87% of the 49 children who had seroconverted to anti-HBe
nucleoside analogue in the prevention of intrauterine
positive during the previous 1-year lamivudine trial, while
infection are needed.
92% of a further 14 children who had previously received
placebo had normal ALT levels and virological responses.50
Treatment of HBV infection in children In addition, 24 months of lamivudine therapy was given to
210 children. Twenty-one percent of 133 children who had
Currently no effective treatment exists for children who been treated for 1-year with lamivudine (but did not have
are chronically infected by HBV and have normal ALT levels. HBeAg seroconversion) and 30% of 77 children who had pre-
For children with an ALT elevation >2 times the upper limit viously received placebo achieved a virological response
of normal, interferon-a or nucleoside analogue therapy can (HBV-DNA negative and HBeAg loss) at the end of the
be used. 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
Interferon therapy
The advantage of lamivudine therapy is its convenient
application without pain or prominent side effects. The
The advantages of interferon therapy are a clear treatment main disadvantage is the emergence of resistant strains
duration and no problems with the development of re- (e.g. YMDD mutants) and uncertainty regarding the dura-
sistant strains. The disadvantages of interferon are pain on tion of treatment.51 Hepatic decompensation may occur
injection and side effects such as fever, general malaise, after the emergence of YMDD mutation.
leukopaenia and depression, particularly during the first Adefovir dipifoxil, entecavir and telbivudine are ap-
month of treatment.40 Transient growth suppression in proved for use in treating hepatitis B in adults, but not
some young children may occur during therapy. In patients yet in children. Other new agents, such as telbivudine,
with elevated aminotrans-ferase levels, the results of inter- tenofovir and clevudine are still undergoing clinical trials.
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 Future prospects
in the control group.41e46 A systematic meta-analysis of the
literature has shown a significant benefit of interferon ther- Prevention is the most cost effective method for success-
apy for chronic HBV infection in children.47 Factors that are fully controlling HBV infection and its complications. In
predictive for a positive response to interferon include high 1997, the World Health Organisation recommended that
pretreatment levels of aminotrans-ferase, low pretreat- universal hepatitis B immunisation should be introduced in
ment HBV-DNA levels, late acquisition of HBV infection all countries. According to a later WHO report, immunisa-
and hepatocellular inflammation. The recommended dose tion for HBV had been integrated into the Expanded
of interferon for children with hepatitis B is 0.1 MU/kg or Program of Immunization (EPI) in children in 155 countries
166 M.-H. Chang

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10. Beasley RP, Hwang LY, Lin CC, Ko YC, Twn SJ. Incidence of hep-
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HBV infection and its complications will be further con- 1983;117:213e22.
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placental leakage of HbeAg-positive maternal blood as the
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