Seminar

582 www.thelancet.com Vol 373 February 14, 2009

Hepatitis B virus infection
Yun-Fan Liaw, Chia-Ming Chu
Since the introduction of the hepatitis B vaccine and other preventive measures, the worldwide prevalence of
hepatitis B infection has fallen. However, chronic infection remains a challenging global health problem, with more
than 350 million people chronically infected and at risk of hepatic decompensation, cirrhosis, and hepatocellular
carcinoma. An improved understanding of hepatitis B virology, immunology, and the natural course of chronic
infection, has identied hepatitis B virus replication as the key driver of immune-mediated liver injury and disease
progression. The approval of potent oral antiviral agents has revolutionised hepatitis B treatment since 1998.
Conventional and pegylated interferon alfa and nucleoside and nucleotide analogues are widely authorised treatments,
and monotherapy with these drugs greatly suppresses virus replication, reduces hepatitis activity, and halts disease
progression. However, hepatitis B virus is rarely eliminated, and drug resistance is a major drawback during long
term therapy. The development of new drugs and strategies is needed to improve treatment outcomes.
Introduction
Hepatitis B virus is one of the most serious and prevalent
health problems, aecting more than 2 billion people
worldwide. Although highly eective vaccines against
hepatitis B virus have been available since 1982, there are
still more than 350 million chronic carriers, 75% of
whom reside in the Asia Pacic region. People with
hepatitis B are at increased risk of developing hepatic
decompensation, cirrhosis, and hepatocellular carcinoma.
The estimated worldwide mortality is 05 to 12 million
deaths a year.
1
Substantial improvement in the understanding of
hepatitis B virology and immunology during past decades,
combined with the advent of highly sensitive assays, has
led to new insights into the natural history of such
infection. Furthermore, the approval of oral antiviral
agents has revolutionised hepatitis B treatment since 1998,
and enabled eective clinical management of the disease.
Viral epidemiology
Hepatitis B virus is a double-stranded DNA virus of the
hepadnaviridae family. The virus is enveloped, and
contains a viral DNA genome of about 3200 bps within its
core. After the virus enters a hepatocyte, the viral genome
is delivered to the nucleus, and the relaxed circular DNA
is converted to covalently-closed-circular DNA (cccDNA).
The cccDNA serves as a template for the transcription of
the viral RNA. The hepatitis B virus replication cycle
includes reverse transcription of RNA intermediates to
prime DNA synthesis and translation of the hepatitis B
proteins, including hepatitis B surface antigen (HBsAg)
and e antigen (HBeAg).
2
Thus, cccDNA plays a key part in
the maintenance of chronic hepatitis B infection. The
virus has at least eight major genotypes (A to H), based
on an intergroup divergence of more than 8% in the
complete nucleotide sequence. Apart from
genotypes E and G, the genotypes have sub-genotypes
with a sequence dierence of at least 4%.
3
Hepatitis B virus is transmitted parenterally via
apparent or inapparent percutaneous or permucosal
exposure to infected blood or other body uids. Risk
factors for infection include transfusion of unscreened
blood, sexual promiscuity, sharing or re-using of syringes
between injection drug users, tattooing, working or
residing in a health-care setting, living in a correctional
facility, renal dialysis, and long-term household or
intimate non-sexual contact with an HBsAg-positive
individual.
1,4
In low-prevalence areas, hepatitis B is
typically a disease of young adults who acquire the
infection through risky behavioursuch as unprotected
sexual contact or sharing syringes with HBsAg-positive
peopleand through exposure to contaminated
equipment used for therapeutic injections and
procedures. In high-prevalence regions, most infection
occurs perinatally or during early childhood.
About 90% of HBeAg-seropositive mothers (with high
viral load) transmit hepatitis B virus to their ospring,
compared with 1020% of HBeAg-seronegative carrier
mothers.
5
The prevalence of HBeAg is higher in Asian
than in African HBsAg carrier mothers (40 vs 15%), so
perinatal transmission is greater in Asians, but mainly
horizontal in Africans.
6,7

The prevalence of chronic hepatitis B infection is
about 5% worldwide, but diers between regions.
Infection rates are low (0120%) in the USA and
western Europe, intermediate (2080%) in
Mediterranean countries and Japan, and high
(80200%) in southeast Asia and sub-Saharan regions.
1

Additionally, hepatitis B virus genotypes have a distinct
Lancet 2009; 373: 58292
Liver Research Unit, Chang
Gung Memorial Hospital,
Chang Gung University College
of Medicine, Taipei, Taiwan
(Prof Y-F Liaw MD,
Prof C-M Chu MD)
Correspondence to:
Prof Yun-Fan Liaw, Liver
Research Unit, Chang Gung
University and Memorial
Hospital, 199 Tung Hwa North
Road, Taipei, Taiwan
livery@so-net.net.tw
Search strategy and selection criteria
Medline and PubMed were searched from 2000 to 2008 using
the terms hepatitis B virus, HBV, viral hepatitis, and
chronic hepatitis as search terms for hepatitis B virology,
immunology, epidemiology, and clinical liver disease status.
Reference lists of the identied articles and review articles
from the past 3 years were also searched. Publications from
the past 35 years were selected. Earlier publications were not
excluded, however, if they were highly cited or if there were no
recent appropriate publications. Review articles covering
earlier studies on important issues were selected and cited
rather than the earlier original articles.
Seminar
www.thelancet.com Vol 373 February 14, 2009 583
geographical distribution: genotype A is prevalent in
northwestern Europe and the USA; genotypes B and C in
Asia; genotype D in the Mediterranean basin, Middle East,
and India; genotype E in west Africa; genotype F in South
and Central America; genotype G in the USA and France;
and genotype H in Mexico and South America.
3
Hepatitis B virus pre-core mutations occur most
frequently in genotype D, followed by genotypes C and B,
and are seen least frequently in genotype A.
8
Accordingly,
HBeAg-negative chronic hepatitis B is most common in
genotype D dominant regions. The percentage of patients
with chronic hepatitis B who are HBeAg negative
is 8090% in Mediterranean areas, 3050% in southeast
Asia, and less than 10% in the USA and northwestern
Europe.
9
Prevention
Through understanding the routes and modes of
hepatitis B transmission, infection can be prevented by
avoidance or interruption of transmission. Since
the 1970s, serological screening of donor blood has
become progressively routine, resulting in substantial
reduction of transfusion-associated hepatitis B.
1

Syringe-exchange programmes are run in the USA and
other high-income countries, and provide free sterile
syringes in exchange for used syringes, reducing
transmission of blood-borne pathogensincluding
hepatitis Bin injection drug users. Operating at xed
sites and on mobile van routes, the syringe-exchange
programmes can make contact with otherwise
hard-to-reach populations to deliver social and medical
services, such as testing for hepatitis B, counselling, and
vaccination.
10
An eective hepatitis B vaccine has been available since
the early 1980s, and in the early 1990s WHO recommended
the addition of the hepatitis B vaccination to all national
immunisation programmes. Universal vaccination
programmes for newborn babies have been implemented
in more than 160 countries, and international nancial
support and a reduced cost are facilitating introduction
of the vaccine into more low-income countries.
11
Some
high-income countries with low or very low endemicity
of hepatitis B infection, such as northern European
countries, apply a strategy of selective vaccination for
individuals at high risk of infection, because the low
burden of disease does not warrant the added cost of
universal vaccination.
11,12
Hepatitis B vaccination is the
most eective preventive measure in adult populations
with risk factors.
1,4,10,11
Since the introduction of hepatitis B vaccination, the
worldwide rates of infection have fallen. For example,
the HBsAg carrier rate in Taiwanese children decreased
from 10% in 1984 to less than 1% in 2004, with a
68% reduction of fulminant hepatitis in infants
(01 year), and a 75% decline in hepatocellular carcinoma
in children (aged 614 years).
13,14
In the USA the incidence
of reported acute hepatitis B fell by 81% between
1990 and 2006, from 85 to 16 cases per
100 000 population, and few cases occurred in blood
recipients, dialysis patients, and health-care workers.
4

However, the rate of infection among injection drug
users, people with sexual risk factors, and immigrants
from high-prevalence areas such as Asia has raised the
burden of chronic hepatitis B infection in high-income
countries, reinforcing the need to improve preventive
eorts aimed at high-risk groups.
4,14
Post-exposure
prophylaxis with hepatitis B immunoglobulin is eective
and indicated for newborn infants of HBsAg-positive
mothers, after percutaneous or mucosal exposure to
HBsAg positive blood in health-care settings.
Immunoglobulin is further indicated for prophylaxis
after exposure to body uids (sexual exposure) and for
the prevention of hepatitis B recurrence after liver
transplantation.
11
Pathophysiology
Hepatitis B virus is not cytopathogenic. In acute infection,
clinical hepatitis B becomes apparent after an incubation
period of 45180 days. The elimination of hepatitis B
virus by non-cytopathic mechanisms begins several
weeks before the disease onset. Hepatitis B virus DNA
clearance is mediated largely (up to 90%) by antiviral
cytokines that are produced by cells of the innate and
adaptive immune responsesincluding tumour necrosis
factor , interferon alfa, or interferon beta.
1517
After viral
DNA declines, a cytolytic immune response with
hepatocyte apoptosis and necrosis ensues, coincident
with the onset of clinical hepatitis and a rise in serum
alanine aminotransferase (ALT). The recognition of
infected hepatocytes by virus-specic CD8 cytotoxic
T cells, via class I human lymphocyte antigen
(HLA-I)-presenting hepatitis B virus peptides, is
presumed to be the main mechanism causing both liver
damage and virus control. Cytotoxic T cells further recruit
various antigen-non-specic inammatory cells into the
liver by secreting cytokines, initiating a cascade of
immunological events leading to necro inammation.
1820

A vigorous, multispecic CD4 and CD8 response is
associated with viral clearance.
21
In individuals with
chronic hepatitis B infection, the hepatitis B virus-specic
CD4 and CD8 response is insu cient;
21
and can cause a
persistent inammatory response that is ineective for
hepatitis B virus clearance.
22
Timely conventional liver biochemical tests are
essential for diagnosis of hepatitisincluding
measurement of ALT for the degree of hepatocellular
damages, bilirubin for conjugation and excretion
function, and albumin values and prothrombin time for
liver synthesis function. Liver biopsy is important for the
grading of necroinammation and staging of brosis.
Ultrasonography and other imagining methods are
non-invasive ways to detect cirrhosis and hepatocellular
carcinoma
23
the judicious use of these methods and
assays is crucial to dierentiate the nature and severity of
Seminar
584 www.thelancet.com Vol 373 February 14, 2009
disease. Testing for hepatitis B virus markers is mandatory
for the detection and diagnosis of hepatitis B. Serological
markers of hepatitis B are HBsAg and its
antibody (antiHBs), HBeAg and its antibody (antiHBe),
and immunoglobulins G and M antibody to hepatitis B
virus core antigen (IgG antiHBc and IgM antiHBc).
HBsAg seropositivity indicates infection, and HBeAg is a
surrogate marker of viral replication with high hepatitis B
virus DNA. HBsAg assays should be done in those at risk
for hepatitis B infection, people with ALT elevation or
evidence of liver disease, and anyone about to receive
immunosuppressive treatment or chemotherapy.
The rst serological marker to appear in acute
hepatitis B infection is HBsAg, usually 16 weeks before
the manifestation of clinical symptoms. IgM antiHBc
appears 12 weeks after HBsAg, and persists for up to
6 months after HBsAg is cleared.
23
Previously
undiagnosed chronic HBsAg carriers with acute
exacerbation of hepatitis B or superinfection with other
hepatitis virus(es) presenting as clinical acute hepatitis,
are seronegative for IgM antiHBc.
24
Serum IgM antiHBc
assay is, therefore, mandatory for the serodiagnosis of
acute hepatitis B. HBeAg and hepatitis B virus DNA are
present early during acute infection. Both markers
usually disappear when serum ALT peaks, or soon
thereafter, and before HBsAg seroclearance, which
occurs within 12 months, and are followed by the
appearance of antiHBs several weeks later (gure 1).
Previous infection is diagnosed by the detection of
antiHBc and antiHBs.
23
Presence of HBeAg for more than 10 weeks indicates a
high likelihood of transition to persistent infection.
Persistence of serum HBsAg for more than 6 months
implies progression to chronic infection. People with
HBeAg-positive chronic infection usually have high
levels of hepatitis B virus DNA, whereas serum
concentrations are lower in patients with HBeAg-negative
infection. Serial testing showing a hepatitis B virus DNA
concentration of less than 210 IU/mL and normal ALT
values is needed to verify an inactive carrier state.
25,26
Serum hepatitis B virus DNA assay is a direct measure
of viral load. It is particularly useful for assessment of
risk of disease progression and candidacy for antiviral
therapy, monitoring treatment response, and to
distinguish active hepatitis B from the inactive carrier
state with other causes of high ALT. PCR-based assays,
with high sensitivity and a wide dynamic range
(1010 IU/mL), are the mainstay for measurement of
hepatitis B viral load. WHO has established an
international standard for hepatitis B virus quantication
units, in which 1 IU is equal to about ve genome
equivalents.
27
Assays for hepatitis B virus genotypes and
mutations are available and becoming increasingly
important in the clinical eld.
Natural history
The spectrum of acute hepatitis B infection ranges from
asymptomatic infection to self-limited hepatitis, to
fulminant hepatitis and it depends on various viral and
host factors. Symptomatic hepatitis is rare in neonates
(less than 1%) and occurs in about 10% of children
15 years old.
1,22
Fulminant hepatitis is very rare in
paediatric patients, with most reported cases being in
infants born to HBeAg-negative, HBsAg-carrier
mothers.
28
One proposed explanation is that the absence
of HBeAg in maternal blood fails to induce immunological
tolerance,
29
thus allowing vigorous immune clearance of
hepatitis B virus from the infant liver. A third of acute
infections in adults are symptomatic,
22
and fulminant
hepatitis occurs in less than 1% of cases, with a mortality
of about 70%. Fulminant hepatitis B is related to an
enhanced immune response with rapid viral clearance,
which means serum HBsAg and hepatitis B virus DNA
might be undetectable at the time of clinical presentation,
and the diagnosis is made only by the presence of serum
IgM antiHBc.
2
Resolution of hepatitis B with HBsAg seroclearance
occurs in more than 95% of adult patients. However,
small amounts of hepatitis B virus DNA can still be
detected by PCR in serum and peripheral mononuclear
cells years after recovery from hepatitis, indicating a
state of occult infection.
30
Hepatitis B can be transmitted
via organ transplantation, and hepatitis B reactivation
might occur under immunosuppressive treatmentor
by chemotherapy in such cases.
31
The risk of chronicity
is correlated closely with the patients age at the time of
infection. Infection persists in about 90% of infants
infected at birth, 2030% of children infected between
the ages of 1 and 5 years, 6% of infection in children
Months after hepatitis B virus infection
0 1
C
o
n
c
e
n
t
r
a
t
i
o
n
2 3 4 5 6 12 24 36
IgG-antiHBc IgM-antiHBc
HBV-DNA
HBeAg
HBsAg
AntiHBs
ALT in acute infection
ALT in chronic infection
Acute hepatitis B
Transition from acute to
chronic hepatitis B
Clinical symptoms
appear
Figure 1: Serological and clinical changes after acute hepatitis B virus (HBV) infection
Shaded bars indicate the duration of seropositivity in self-limited acute hepatitis B infection. Pointed bars indicate
that HBV-DNA and HbeAg can become seronegative during chronic infection. Only IgG antiHBc is detectable after
resolution of acute hepatitis or during chronic infection. Y axis is schematic concentration of ALT and antiHBs.
Seminar
www.thelancet.com Vol 373 February 14, 2009 585
aged 515 years and only 15% of patients infected as
adults.
1
One possible explanation for the high chronicity
in infants is that the fetus develops tolerance to the virus
in utero after the transplacental passage of viral
proteins.
32
The natural course of chronic hepatitis B infection
consists of distinct phases resulting from the interaction
between the virus, hepatocytes and host immune
response. Typically, chronic infection acquired perinatally
or during infancy has three phases: immune tolerant,
immune clearance, and inactive residual.
33
Hepatitis B
re-activation can occur in some patients with inactive
disease and trigger immune-mediated liver injury.
34,35

Such patients, therefore, enter a variant phase of immune
clearance (gure 2).
23,36
Adult-acquired chronic infection
has a similar clinical course, except that there is no
obvious initial immune tolerant phase.
37
The mechanisms of immune tolerance during the rst
phase are not well understood. Work in mice suggests
that a transplacental transfer of maternal HBeAg could
induce a specic unresponsiveness of helper T cells to
HBeAg, and result in an ineective cytotoxic T-cell
response to nucleocapsid antigens in neonates.
32
Patients in the immune-tolerant phase are usually
young, asymptomatic, and HBeAg seropositive, with
high viral loads (more than 210 to 210 IU/mL) but
normal serum ALT levels and near-normal liver
histology. There is usually no, or only minimum,
disease progression while serum ALT concentrations
remain normal.
38
The mechanisms triggering loss of immune tolerance
are mostly unknown, but a high viral load seems
necessary to maintain the tolerant state.
39
The
immune-clearance phase is associated with falling
serum hepatitis B virus DNA concentrations, but their
causal relation remains unclear. Other ndings that
characterise the transition from the immune tolerant to
the immune clearance phase include a shift of
hepatocyte expression of hepatitis B virus-core
antigen (HBcAg) from nucleus to cytoplasm,
40
and a
gradual accumulation of pre-core or core-promoter
mutations.
41,42
During the immune-clearance phase, hepatitis activity
and intermittent acute ALT increase can are to over
ve times the upper limit of normal, usually without
apparent symptoms. This activity of ares can be
complicated by hepatic decompensation. The rises in
ALT and ares are attributable to the hosts immune
response against hepatitis B virus with resultant
apoptosis and necrosis, thus, higher ALT concentrations
usually indicate a more vigorous immune response
against hepatitis B virus and more extensive hepatocyte
damage.
43
The occurrence of hepatitis are varies in
patient cohorts, but has reached 25% of patients per
year during the rst 35 years of follow-up in
hospital-based studies
4345
The overall occurrence of
hepatic failure in patients was estimated to be 05%.
24

Hepatitis ares can lead to cirrhosis but will eventually
be followed by HBeAg seroconversion to antiHBe. The
estimated yearly proportion of spontaneous HBeAg
seroconversion is 215%, depending on factors such as
age, ALT concentrations, and hepatitis B virus
genotype.
4146
In Asia, HBeAg seroconversion occurs at a
mean age of 3035 years, with most cases
(90%) occurring before age 40.
4548
Patients infected with
genotype B seroconvert earlier and more frequently
than do those with genotype C.
3,47,4951
In native Alaskans
with chronic hepatitis B infection, the median age of
HBeAg seroclearance is younger than 20 years in
patients with genotypes A, B, D, and F, but over 40 years
in patients with genotype C.
52
HBeAg seroconversion is usually followed by clinical
remission and a life-long inactive state with an excellent
outcome, although a few patients may develop
hepatocellular carcinoma.
34,35,5356
Spontaneous HBsAg
seroclearance can occur, reported at a rate of less than
1% per year in early studies.
5357
A study with 1965 patients
showed that HBsAg seroclearance occurred at a rate of
12% per year, and rose to 18% per year in individuals
over age 50; to a 45% cumulative incidence after 25 years
of follow-up.
58
Patients with virus genotype A and B
infection have a higher likelihood of HBsAg
seroclearance than do patients with other genotypes.
59,60

HBsAg seroclearance usually confers an excellent
long-term outcome if there is no pre-existing cirrhosis
or viral superinfection.
61,62
However, a small amount of
hepatitis B virus DNA may persist in a state of occult
infection.
31
Age (years)
20 35 60 35
Absent Nucleus/cytoplasm
HBsAg loss
Mutant>wild Wild>mutant Wild type Mutant
HBeAg
reversion
HBeAg-
negative
hepatitis
Nucleus/cytoplasm Nucleus Hepatocyte expression
of liver HBcAg
Minimum Liver histology
ALT
Pre C/BCP
2x10
4
2x10
9
IU/mL
Immune tolerant
phase
Immune clearance
phase
Inactive residual
phase
Active hepatitis Minimum inactive Active hepatitis
HBV DNA
HBeAg-positive AntiHBe-positive
HCC
HCC
Cirrhosis
Cirrhosis
Reactivation
Figure 2: Natural course of chronic hepatitis B virus (HBV) infection acquired perinatally and during infancy
The reactivion phase is similar in every aspect to the immune-clearance-phase, except for HBeAg status.
Adult-acquired infection usually presents in the immune-clearance or reactivation phase (inset). The events during
the immune-clearance and reactivation phases could lead to cirrhosis and hepatocellular carcinoma (HCC) (adapted
from Liaw
21
with permission). HBeAg=hepatitis B e antigen; antiHBe=hepatitis B e antigen antibody; pre C=pre core;
BCP=basal core promoter; ALT=serum alanine aminotransferase.
Seminar
586 www.thelancet.com Vol 373 February 14, 2009
After HBeAg seroconversion, 14% patients have HBeAg
seropositive hepatitis again (HBeAg reversion), whereas a
greater proportion of patients develop HBeAg-negative
chronic hepatitis B because of reactivation of the hepatitis B
virus with pre-core or core promoter mutations that
abolish or downregulate HBeAg production.
34,35,42,63
Results
from Taiwanese studies showed relapse in 23% of patients
per year,
34,45
with a cumulative rate of 2025% after 15 years
of follow-up.
64
The proportion of relapse was very low in
patients who HBeAg-seroconverted before age 30,
55,64
but
was raised in men, patients with genotype C, those who
HBeAg-seroconverted after age 40,
65
and in patients with
serum hepatitis B virus DNA concentrations greater than
10 000 copies per mL.
66
These age-related ndings show
that early HBeAg seroconversion, or a short HBeAg-positive
phase, are associated with an improved chance of sustained
remission.
48
Cirrhosis or hepatocellular carcinoma, or both, can
develop during the natural course of chronic hepatitis B
infection. Results of large population-based studies with
mostly (85%) HBeAg-negative, HBsAg-positive people
older than 30 years at recruitment have shown that the
risk of cirrhosis, hepatocellular carcinoma, and mortality
increases proportionally with increasing viral DNA
concentrations, starting with at least 110
4
copies per mL.
6769

The study ndings suggest hepatitis B virus replication,
with subsequent immune-mediated liver injuries, is the
main driver of disease progression
70
(gure 3). Further risk
factors for the development of cirrhosis include: male sex;
increasing age;
6769,71,72
HBeAg positivity;
72
virus genotype C
(vs B);
47,49,7376
HBeAg reversion or virus reactivation;
34,47

persistent seropositivity for HBeAg
77
or viral DNA;
78

persistent raised ALT;
79
viral superinfections;
80
as well as
the severity (hepatic decompensation), extent (bridging
hepatic necrosis), and frequency of hepatitis are, and the
duration of hepatic lobular alterations.
71
At least a third of patients with cirrhosis are seropositive
for HBeAg or hepatitis B virus DNA at presentation,
81
and
disease progression can continue after cirrhosis
development.
82
The 5-year probability of hepatic
decompensation is 1520%, and is four-fold higher in
patients with active viral replication than in patients
without.
83
The yearly rate of hepatocellular carcinoma
occurrence is 36%.
81,82
The estimated 5-year survival rate
of patients with compensated cirrhosis is 8085% and
3050% in patients with decompensated cirrhosis.
81
Hepatocellular carcinoma mostly develops in patients
with cirrhosis, therefore, hepatocellular carcinoma and
cirrhosis share the same risk factors, with a raised risk in
patients with a family history of hepatocellular carcinoma.
84

Viral factors also contribute to hepatocellular carcinoma
development, including hepatitis B virus DNA level,
genotypes, and naturally occurring mutations such as
hepatitis B virus pre-S and basal core promoter A1762T/
G1764A double mutations.
68,8589
Other con tributing factors
are habitual alcohol consumption, cigarette smoking, and
aatoxin exposure.
90
Management
Acute hepatitis B in adults is selimiting in more
than 95% of cases, therefore, antiviral therapy is indicated
only for patients with protracted severe acute hepatitis or
fulminant hepatitis B.
25
Management of patients with
chronic hepatitis B infection should include thorough
patient assessment and counselling. Although patients
are usually asymptomatic, they can be anxious and
attribute a wide range of negative psychological, social,
and physical symptoms to their condition.
91
Counselling
should include dietary and lifestyle advice, including
guidance to increase physical activity and control alcohol
use. Further, health-care providers and patients should
discuss the behaviours that lead to superinfection,
prevention of such infection and preventive measures
against transmission of hepatitis B to intimate contacts.
The importance of the long term hepatocellular
carcinoma surveillance, with ultrasonography
supplemented with -fetoprotein assay, should be
emphasised to patients older than 40 years, with advanced
brosis or cirrhosis, and with a family history of
hepatocellular carcinoma.
25,36,81
Hepatitis B virus replication is key to liver injury and
disease progression,
70
and, therefore, the main aims of
treatment are to suppress the virus to achieve HBeAg
seroconversion or undetectable viral-DNA levels, or both;
stop or reduce hepatic necroinammation; and prevent
the development of hepatic decompensation. Long term
goals are to reduce cirrhosis and hepatocellular carcinoma
development, and ultimately extend survival. Viraemic
Chronic HBV infection
215%/year
~5%
~05%/year
~15%/year
~4%/year ~6%/year
~10%
~12%/year
<01%/year
~4%/year
5% 90~95%
~3%/year
~15%/year
~08%/year
Liver cirrhosis HBsAg loss
HCC
Death/transplantation
Decompensation
HBeAg(+) hepatitis
HBV-DNA >210
6-7
IU/mL
HBeAg(+) hepatitis
HBV-DNA >210
4-5
IU/mL
HBeAg() hepatitis
HBV-DNA >210
3-4
IU/mL
HBeAg
seroconversion
Remission
Inactive carrier
Curative therapy
~15%/year
Figure 3: Hepatitis B virus (HBV) replication and the outcomes of chronic Hepatitis B infection
Note that Hepatitis B e antigen (HBeAg) seroconversion is followed by remission in most people but that
HBeAg-negative () hepatitis (HBV-DNA 2x102x10 IU/mL) may develop. Patients who remain HBeAg
seropositive or develop HBeAg-negative hepatitis have a high occurrence of cirrhosis (~4 and ~3% per year). Most
hepatocellular carcinoma (HCC) develops in patients who have cirrhosis.
Seminar
www.thelancet.com Vol 373 February 14, 2009 587
patients with an ALT concentration of twice the upper
limit of normal or more, or substantial liver disease, are
candidates for drug therapy. Of note, ALT are may
precede spontaneous HBeAg seroconversion.
43
Obser-
vation for 3 months before considering drug therapy is
acceptable.
25,36
Liver biopsy is recommended to assess the
necroinammation grade and brosis stage, because
signicant brosis could have developed in patients with
normal ALT, except during the immunotolerant phase.
92

Before drug therapy is initiated, the e cacy, advantages
and disadvantages, and cost of available therapies should
be discussed with the patient.
36
Approved and widely used agents are conventional
interferon alfa and pegylated interferon-alfa-2a; the
nucleoside analogues lamivudine, entecavir, and
telbivudine; and the nucleotide analogue adefovir
dipivoxil. Tenofovir, another nucleotide analogue
approved for the treatment of HIV infection, was more
eective than adefovir in hepatitis B,
93
it has been
approved in European countries and USA, and will
probably be approved worldwide. Drug therapy should be
selected according to the patients condition, the drugs
mechanism, rapidity of action, potency, convenience of
administration, adverse eect prole, and cost (see
table).
Interferon-based therapy
Interferon alfa and pegylated interferon have
immunomodulating activity. Theoretically, interferons
are the ideal treatment for patients with chronic
hepatitis B, but the response rate after 46 months of
interferon alfa is only 3040% in HBeAg-positive
patients, with a risk dierence of 2325% against
untreated controls.
94
48 weeks of pegylated interferon
therapy yields a sustained HBeAg seroconversion rate of
32% when assessed 24 weeks after completion of
therapy.
9597
Patients with genotype A (vs D) or B (vs C)
infection tend to have a better response to interferon or
pegylated interferon.
3,9597
HBeAg seroconversion response
is sustained in more than 80% of people, and can be
followed by HBsAg loss,
77,98,99
which is the desired end
point.
Patients with HBeAg-negative chronic hepatitis B
respond to interferon alfa therapy but often relapse after
treatment completion.
78,100
The combined response to
pegylated interferon therapy (normal ALT+hepatitis B
virus DNA concentration less than 210 copies per mL)
in HBeAg-negative patients is 36% at 6 months post
treatment.
101,102
Improved response rates are achieved in
patients with low serum viral DNA, raised ALT and low
HBeAg concentrations at baseline, and low HBeAg after
24 weeks treatment.
102104
HBsAg seroconversion occurs in
3% of the pegylated interferon treated patients,
96,97,101
and
the rate increases to 10% at 4 years after therapy.
105
These
response gures are better than those of lamivudine
monotherapy. Results from follow-up studies suggest
that interferon alfa therapy has long term benets by
promoting cumulative HBeAg seroconversion,
increasing HBsAg loss, reducing development of
cirrhosis and hepatocellular carcinoma, and extending
survivalespecially in responders.
70,77,98100
Further
advantages of interferon-based therapy are the nite
treatment duration and that patients do not develop drug
resistance. Eventually, pegylated interferon treatment will
replace interferon alfa because of its improved
eectiveness and convenient once a week
administration.
36,95
Interferon-based therapy is associated
with many adverse events; including inuenza-like
symptoms, fatigue, anorexia, weight loss, hair loss,
thyroid dysfunction, emotional instability, and bone
Lamivudine Adefovir Entecavir Telbivudine Tenofovir Pegylated interferon alfa-2a
e+ e e+ e e+ e e+ e e+ e e+ e
Dose/route 10 mg/
day orally
10 mg/
day orally
10 mg/
day orally
10 mg/
day orally
05 mg/
day orally
05 mg/
day orally
600 mg/
day orally
600 mg/
day orally
300 mg/
day orally
300 mg/
day orally
180 g/week
subcutaneous
180 g/week
subcutaneous
Cost (US$/year per person)* 2482 2482 6647 6647 8694 8694 5924 5924 5811 5811 18 480 18 480
HBV-DNA (PCR)
Log reduction at year 1 54 45 36 (10) 37 (14) 69 50 57 44 65 45 45 41
Undetectable at year 1 40% 72% 21% (0%) 61% (0%) 67% 90% 60% 88% 76% 93% 25% 63%
HBeAg seroconversion at
year 1
20% 12% (6%) 21% 23% 21% 32%
Drug resistance
Year 1 1114% 627% 0% 0% 0% 0% 5% 2% 0 0 0 0
Year 2 40% 2654% 3% 0% 0% 25% 11% 0 0
Year 3 56% 57% 11% ~1% ~1%
Year 5 69% 65% 20% 29% 12% 12%
Other side-eects Negligible Negligible Creatinine
increase
Creatinine
increase
Negligible Negligible Increase
in CK
Increase
in CK
Negligible Negligible Various,
unpleasant
Various,
unpleasant
CK=creatine kinase. e=hepatitis B e antigen. =not applicable. *From Hoofnagle and colleagues.
130
Data in brackets refer to untreated controls.
Table: Comparison of the drugs used in treatment-naive patients with chronic hepatitis B
Seminar
588 www.thelancet.com Vol 373 February 14, 2009
marrow suppression. Patients might need symptomatic
treatment, and some require dose modication or
discontinuation of therapy.
95
Most patients are able to
complete 48 weeks of pegylated interferon treatment
despite the side-eects.
96,97,101
Nucleoside or nucleotide analogues
Oral antiviral agents have fast and potent inhibitory
eects on hepatitis B virus polymerase and reverse
transcriptase activity, and are safe and eective for
hepatitis B virus DNA suppression, ALT normalisation,
and histological improvement. Results from cross-trial
1 year treatment data suggest entecavir is the most potent
of the drugs, followed by tenofovir, telbivudine,
lamivudine, and adefovir. However, the antiviral potency
of these drugs does not result in an increase in HBeAg
seroconversionwhich was seen at a rate of around
20% after 1 year of treatment (see table)and HBsAg
loss is very rare.
106110
After 1 year of lamivudine treatment
an HBeAg seroconversion was achieved in more than
half of patients with ALT values more than ve times the
upper limit of normal, but in only 5% of patients with
ALT values less than twice the upper limit of normal.
111,112

Thus, patients with a stronger endogenous immune
response to the hepatitis B virus might have an improved
chance of reducing cccDNA and HBeAg translation.
111

Additionally, patients with ALT values more than ve
times the upper limit of normal could be developing
severe hepatitis or hepatic decompensation, especially if
they have advanced brosis.
43
These patients should be
monitored every week or every two weeks so that
fast-acting antiviral drugs can be started to arrest the
development, or deterioration, of hepatic de-
compensation.
113
Similarly, nucleoside and nucleotide
analogues might rescue patients with decompensated
cirrhosis by increasing serum albumin concentrations,
and stabilising bilirubin values and prothrombin time,
removing the need for transplantation and prolonging
survival.
114,115
2050% of patients who have HBeAg seroconversion
will relapse with HBeAg reversion within 612 months
o therapy, and more patients may relapse if the
duration of consolidation therapy after HBeAg
seroconversion is less than 6 months.
25,36
In
HBeAg-negative patients, there is no end point such as
HBeAg seroconversion, so treatment duration is
indenite, and stopping drug therapy after 1 year is
associated with a 90% relapse rate.
116
Relapses are
characterised by increasing hepatitis B virus DNA level
followed by rising ALT or a hepatitis are which could
be life threatening.
117
Therefore, continuing long-term
drug therapy is usually necessary to maintain a
virological response. Results of a large randomised
controlled trial in patients with advanced brosis or
cirrhosis showed the benets of long-term therapy after
3 years of lamivudine therapy were reduced dis-
ease progression and hepatocellular carcinoma
development.
118
The emergence of drug-resistant genotypic mutations
of hepatitis B virus in long term therapy is a major
problem. Clinically, emergence of drug resistance is
indicated by viral breakthroughan increase of serum
hepatitis B virus DNA to more than ten-fold increase
in HBV concentrations from the nadir of initial
responsewith subsequent biochemical breakthrough
or raised ALT values in more than 90% of patients.
119

Hepatitis ares develop frequently, sometimes
associated with hepatic decompensation during
continued antiviral therapy,
120
and, the initial clinical
and histological benets of antiviral therapy
diminish.
118,121,122
The occurrence of drug resistance rises with
increasing therapy duration, although the generation of
nucleoside and nucleotide analogues has improved
potency and raised the genetic barrier to resistant
mutations (see table). Drug resistance occurs most
frequently with lamivudine, followed by telbivudine,
adefovir and tenofovir, and is very low with entecavir.
106110

Chronic HBV infection
HBV-DNA >210
3
IU/mL HBV-DNA >210
4
IU/mL
HBeAg(+)
ALT<ULN ALT>ULN ALT<ULN ALT<ULN ALT>ULN
Other causes?
3-month
follow-up
3-month
follow-up
13-month
follow-up
6-month
follow-up
6-month
follow-up
HBeAg()
Concern of
decompensation
HBV-DNA <210
3
IU/mL
HCC surveillence Biopsy/therapy +
HCC surveillence
Biopsy/therapy +
HCC surveillence
<2 ULN
<2 ULN >40 years >40 years >40 years
>2
Yes No
NA IFN or NA
Response Non-response
Stop/monitor Consider other
strategies
36 months
Figure 4: Management of patients with chronic hepatitis B virus (HBV) infection
HBeAg=hepatitis B e antigen. ULN=upper limit of normal. NA=nucleoside or nucleotide analogues.
IFN=interferon-based therapy. HCC=hepatocellular carcinoma.
Seminar
www.thelancet.com Vol 373 February 14, 2009 589
Studies have shown that suppression of the hepatitis B
virus to undetectable level at 24 weeks of telbivudine
and lamivudine therapy is associated with low incidence
of drug resistance at week 48.
110
Rescue therapy for drug
resistance is now available and, therefore, monitoring
hepatitis B virus DNA levels during drug treatment to
detect drug resistance early enough to start rescue
therapy before serum hepatitis B virus DNA increases
over 110 copies per mL
123,124
is very important. In
patients with drug resistance, add-on therapy without
cross-resistance (adefovir and tenofovir vs lamivudine,
telbivudine and entecavir) should be instituted.
123,125

Switching to interferon-based therapy can be a further
option.
126
Drug treatment strategies
In view of the array of drugs available, physician and
patient should decide which drug should be used, and
when to start and stop treatment. Oral antiviral agents
with fast and potent hepatitis B virus-suppressive eects
are preferred for patients with ensuing or overt hepatic
decompensation. Interferon-based therapy is preferred
in patients with compensated liver diseaseparticularly
in young patients, women of childbearing age, and
those with low ALT valuesbecause of the nite
duration of treatment, sustained response, and long
term benets including prevention of hepatocellular
carcinoma.
36,127
For oral antiviral agents, the benet of
long-term therapy should be weighed against possible
drug resistance and durability of treatment response. If
long term therapy is anticipated, the drug with the
lowest rate of resistance is preferable, although cost
may aect choice. A combination of two or more
antiviral drugs, as in HIV therapy, reduces drug
resistance but does not enhance e cacy.
96,101,128,129
Figure 4
shows an algorithm for the management of patients
with chronic hepatitis B, designed on the basis of
published guidelines.
25,26
Drug therapy is not usually recommended for children
and women of childbearing ageunless there is an
absolute indication such as ensuing or overt hepatic
decompensationbecause of potential problems
associated with long-term therapy.
36
When treatment is
absolutely indicated, interferon-based therapy is
preferred for non-pregnant women, and pregnancy is
discouraged during treatment. Women who become
pregnant while receiving oral antiviral agents can
continue treatment with telbivudine or tenofovir, which
are category B agents.
36,130
In patients with concurrent hepatitis C or D virus
infection, the dominant virus should be determined and
treated accordingly. In patients with HIV coinfection,
adefovir or interferon (if CD4 is greater than 500) is
preferred if HIV infection does not need treatment. If
HIV treatment is required, tenofovir or combination
lamivudine and tenofovir should be included in the active
antiretroviral therapy.
25,36
Hepatitis B virus re-activation is a serious complication
in patients undergoing transplantation, immuno-
suppression, or chemotherapy. Patients should be
screened for HBsAg and, if positive, prophylactic therapy
with a direct antiviral agent should be started before the
beginning of and at least 12 weeks after the end of the
immunosuppressive treatment or chemotherapy.
36,131
For
all patients with hepatitis B virus-associated liver failure
who are listed for transplantation, nucleoside or nucleotide
analogues should be started and continued after
transplantation as prophylaxis against re-infection of the
allograft.
25,36
Conict of interest statement
Yun-Fan Liaw has been involved in clinical trials or served as a global
advisory board member of Roche, BMS, GSK, Novartis, Gilead Sciences.
Chia-Ming Chu declares that he has no conict of interest.
Acknowledgments
We thank Chang-Gung Medical Research Fund and the Prosperous
Foundation, Taipei, Taiwan, for long term grant support;
Ellen Donaldson and Eric Matluck for English editing; and
Su-Chiung Chu for secretarial assistance.
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