Hepatitis B virus infection
Yun-Fan Liaw, Chia-Ming Chu
Lancet 2009; 373: 582–92 Since the introduction of the hepatitis B vaccine and other preventive measures, the worldwide prevalence of
Liver Research Unit, Chang hepatitis B infection has fallen. However, chronic infection remains a challenging global health problem, with more
Gung Memorial Hospital, than 350 million people chronically infected and at risk of hepatic decompensation, cirrhosis, and hepatocellular
Chang Gung University College
carcinoma. An improved understanding of hepatitis B virology, immunology, and the natural course of chronic
of Medicine, Taipei, Taiwan
(Prof Y-F Liaw MD, infection, has identiﬁed hepatitis B virus replication as the key driver of immune-mediated liver injury and disease
Prof C-M Chu MD) progression. The approval of potent oral antiviral agents has revolutionised hepatitis B treatment since 1998.
Correspondence to: Conventional and pegylated interferon alfa and nucleoside and nucleotide analogues are widely authorised treatments,
Prof Yun-Fan Liaw, Liver and monotherapy with these drugs greatly suppresses virus replication, reduces hepatitis activity, and halts disease
Research Unit, Chang Gung
progression. However, hepatitis B virus is rarely eliminated, and drug resistance is a major drawback during long
University and Memorial
Hospital, 199 Tung Hwa North term therapy. The development of new drugs and strategies is needed to improve treatment outcomes.
Road, Taipei, Taiwan
liveryﬂ@so-net.net.tw Introduction the viral RNA. The hepatitis B virus replication cycle
Hepatitis B virus is one of the most serious and prevalent includes reverse transcription of RNA intermediates to
health problems, aﬀecting more than 2 billion people prime DNA synthesis and translation of the hepatitis B
worldwide. Although highly eﬀective vaccines against proteins, including hepatitis B surface antigen (HBsAg)
hepatitis B virus have been available since 1982, there are and e antigen (HBeAg).2 Thus, cccDNA plays a key part in
still more than 350 million chronic carriers, 75% of the maintenance of chronic hepatitis B infection. The
whom reside in the Asia Paciﬁc region. People with virus has at least eight major genotypes (A to H), based
hepatitis B are at increased risk of developing hepatic on an intergroup divergence of more than 8% in the
decompensation, cirrhosis, and hepatocellular carcinoma. complete nucleotide sequence. Apart from
The estimated worldwide mortality is 0·5 to 1·2 million genotypes E and G, the genotypes have sub-genotypes
deaths a year.1 with a sequence diﬀerence of at least 4%.3
Substantial improvement in the understanding of Hepatitis B virus is transmitted parenterally via
hepatitis B virology and immunology during past decades, apparent or inapparent percutaneous or permucosal
combined with the advent of highly sensitive assays, has exposure to infected blood or other body ﬂuids. Risk
led to new insights into the natural history of such factors for infection include transfusion of unscreened
infection. Furthermore, the approval of oral antiviral blood, sexual promiscuity, sharing or re-using of syringes
agents has revolutionised hepatitis B treatment since 1998, between injection drug users, tattooing, working or
and enabled eﬀective clinical management of the disease. residing in a health-care setting, living in a correctional
facility, renal dialysis, and long-term household or
Viral epidemiology intimate non-sexual contact with an HBsAg-positive
Hepatitis B virus is a double-stranded DNA virus of the individual.1,4 In low-prevalence areas, hepatitis B is
hepadnaviridae family. The virus is enveloped, and typically a disease of young adults who acquire the
contains a viral DNA genome of about 3200 bps within its infection through risky behaviour—such as unprotected
core. After the virus enters a hepatocyte, the viral genome sexual contact or sharing syringes with HBsAg-positive
is delivered to the nucleus, and the relaxed circular DNA people—and through exposure to contaminated
is converted to covalently-closed-circular DNA (cccDNA). equipment used for therapeutic injections and
The cccDNA serves as a template for the transcription of procedures. In high-prevalence regions, most infection
occurs perinatally or during early childhood.
About 90% of HBeAg-seropositive mothers (with high
Search strategy and selection criteria viral load) transmit hepatitis B virus to their oﬀspring,
Medline and PubMed were searched from 2000 to 2008 using compared with 10–20% of HBeAg-seronegative carrier
the terms “hepatitis B virus”, “HBV”, “viral hepatitis”, and mothers.5 The prevalence of HBeAg is higher in Asian
“chronic hepatitis” as search terms for hepatitis B virology, than in African HBsAg carrier mothers (40 vs 15%), so
immunology, epidemiology, and clinical liver disease status. perinatal transmission is greater in Asians, but mainly
Reference lists of the identiﬁed articles and review articles horizontal in Africans.6,7
from the past 3 years were also searched. Publications from The prevalence of chronic hepatitis B infection is
the past 3–5 years were selected. Earlier publications were not about 5% worldwide, but diﬀers between regions.
excluded, however, if they were highly cited or if there were no Infection rates are low (0·1–2·0%) in the USA and
recent appropriate publications. Review articles covering western Europe, intermediate (2·0–8·0%) in
earlier studies on important issues were selected and cited Mediterranean countries and Japan, and high
rather than the earlier original articles. (8·0–20·0%) in southeast Asia and sub-Saharan regions.1
Additionally, hepatitis B virus genotypes have a distinct
582 www.thelancet.com Vol 373 February 14, 2009
geographical distribution: genotype A is prevalent in 1990 and 2006, from 8·5 to 1·6 cases per
northwestern Europe and the USA; genotypes B and C in 100 000 population, and few cases occurred in blood
Asia; genotype D in the Mediterranean basin, Middle East, recipients, dialysis patients, and health-care workers.4
and India; genotype E in west Africa; genotype F in South However, the rate of infection among injection drug
and Central America; genotype G in the USA and France; users, people with sexual risk factors, and immigrants
and genotype H in Mexico and South America.3 from high-prevalence areas such as Asia has raised the
Hepatitis B virus pre-core mutations occur most burden of chronic hepatitis B infection in high-income
frequently in genotype D, followed by genotypes C and B, countries, reinforcing the need to improve preventive
and are seen least frequently in genotype A.8 Accordingly, eﬀorts aimed at high-risk groups.4,14 Post-exposure
HBeAg-negative chronic hepatitis B is most common in prophylaxis with hepatitis B immunoglobulin is eﬀective
genotype D dominant regions. The percentage of patients and indicated for newborn infants of HBsAg-positive
with chronic hepatitis B who are HBeAg negative mothers, after percutaneous or mucosal exposure to
is 80–90% in Mediterranean areas, 30–50% in southeast HBsAg positive blood in health-care settings.
Asia, and less than 10% in the USA and northwestern Immunoglobulin is further indicated for prophylaxis
Europe.9 after exposure to body ﬂuids (sexual exposure) and for
the prevention of hepatitis B recurrence after liver
Through understanding the routes and modes of
hepatitis B transmission, infection can be prevented by Pathophysiology
avoidance or interruption of transmission. Since Hepatitis B virus is not cytopathogenic. In acute infection,
the 1970s, serological screening of donor blood has clinical hepatitis B becomes apparent after an incubation
become progressively routine, resulting in substantial period of 45–180 days. The elimination of hepatitis B
reduction of transfusion-associated hepatitis B.1 virus by non-cytopathic mechanisms begins several
Syringe-exchange programmes are run in the USA and weeks before the disease onset. Hepatitis B virus DNA
other high-income countries, and provide free sterile clearance is mediated largely (up to 90%) by antiviral
syringes in exchange for used syringes, reducing cytokines that are produced by cells of the innate and
transmission of blood-borne pathogens—including adaptive immune responses—including tumour necrosis
hepatitis B—in injection drug users. Operating at ﬁxed factor α, interferon alfa, or interferon beta.15–17 After viral
sites and on mobile van routes, the syringe-exchange DNA declines, a cytolytic immune response with
programmes can make contact with otherwise hepatocyte apoptosis and necrosis ensues, coincident
hard-to-reach populations to deliver social and medical with the onset of clinical hepatitis and a rise in serum
services, such as testing for hepatitis B, counselling, and alanine aminotransferase (ALT). The recognition of
vaccination.10 infected hepatocytes by virus-speciﬁc CD8 cytotoxic
An eﬀective hepatitis B vaccine has been available since T cells, via class I human lymphocyte antigen
the early 1980s, and in the early 1990s WHO recommended (HLA-I)-presenting hepatitis B virus peptides, is
the addition of the hepatitis B vaccination to all national presumed to be the main mechanism causing both liver
immunisation programmes. Universal vaccination damage and virus control. Cytotoxic T cells further recruit
programmes for newborn babies have been implemented various antigen-non-speciﬁc inﬂammatory cells into the
in more than 160 countries, and international ﬁnancial liver by secreting cytokines, initiating a cascade of
support and a reduced cost are facilitating introduction immunological events leading to necroinﬂammation.18–20
of the vaccine into more low-income countries.11 Some A vigorous, multispeciﬁc CD4 and CD8 response is
high-income countries with low or very low endemicity associated with viral clearance.21 In individuals with
of hepatitis B infection, such as northern European chronic hepatitis B infection, the hepatitis B virus-speciﬁc
countries, apply a strategy of selective vaccination for CD4 and CD8 response is insuﬃcient;21 and can cause a
individuals at high risk of infection, because the low persistent inﬂammatory response that is ineﬀective for
burden of disease does not warrant the added cost of hepatitis B virus clearance.22
universal vaccination.11,12 Hepatitis B vaccination is the Timely conventional liver biochemical tests are
most eﬀective preventive measure in adult populations essential for diagnosis of hepatitis—including
with risk factors.1,4,10,11 measurement of ALT for the degree of hepatocellular
Since the introduction of hepatitis B vaccination, the damages, bilirubin for conjugation and excretion
worldwide rates of infection have fallen. For example, function, and albumin values and prothrombin time for
the HBsAg carrier rate in Taiwanese children decreased liver synthesis function. Liver biopsy is important for the
from 10% in 1984 to less than 1% in 2004, with a grading of necroinﬂammation and staging of ﬁbrosis.
68% reduction of fulminant hepatitis in infants Ultrasonography and other imagining methods are
(0–1 year), and a 75% decline in hepatocellular carcinoma non-invasive ways to detect cirrhosis and hepatocellular
in children (aged 6–14 years).13,14 In the USA the incidence carcinoma23—the judicious use of these methods and
of reported acute hepatitis B fell by 81% between assays is crucial to diﬀerentiate the nature and severity of
www.thelancet.com Vol 373 February 14, 2009 583
Persistence of serum HBsAg for more than 6 months
ALT in acute infection implies progression to chronic infection. People with
ALT in chronic infection
Clinical symptoms Acute hepatitis B HBeAg-positive chronic infection usually have high
appear Transition from acute to levels of hepatitis B virus DNA, whereas serum
chronic hepatitis B
concentrations are lower in patients with HBeAg-negative
infection. Serial testing showing a hepatitis B virus DNA
concentration of less than 2×10³ 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
HBsAg risk of disease progression and candidacy for antiviral
therapy, monitoring treatment response, and to
HBeAg distinguish active hepatitis B from the inactive carrier
state with other causes of high ALT. PCR-based assays,
IgM-antiHBc IgG-antiHBc with high sensitivity and a wide dynamic range
(10¹–10⁹ IU/mL), are the mainstay for measurement of
HBV-DNA hepatitis B viral load. WHO has established an
international standard for hepatitis B virus quantiﬁcation
0 1 2 3 4 5 6 12 24 36 units, in which 1 IU is equal to about ﬁve genome
Months after hepatitis B virus infection equivalents.27 Assays for hepatitis B virus genotypes and
mutations are available and becoming increasingly
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
important in the clinical ﬁeld.
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. Natural history
The spectrum of acute hepatitis B infection ranges from
disease. Testing for hepatitis B virus markers is mandatory asymptomatic infection to self-limited hepatitis, to
for the detection and diagnosis of hepatitis B. Serological fulminant hepatitis and it depends on various viral and
markers of hepatitis B are HBsAg and its host factors. Symptomatic hepatitis is rare in neonates
antibody (antiHBs), HBeAg and its antibody (antiHBe), (less than 1%) and occurs in about 10% of children
and immunoglobulins G and M antibody to hepatitis B 1–5 years old.1,22 Fulminant hepatitis is very rare in
virus core antigen (IgG antiHBc and IgM antiHBc). paediatric patients, with most reported cases being in
HBsAg seropositivity indicates infection, and HBeAg is a infants born to HBeAg-negative, HBsAg-carrier
surrogate marker of viral replication with high hepatitis B mothers.28 One proposed explanation is that the absence
virus DNA. HBsAg assays should be done in those at risk of HBeAg in maternal blood fails to induce immunological
for hepatitis B infection, people with ALT elevation or tolerance,29 thus allowing vigorous immune clearance of
evidence of liver disease, and anyone about to receive hepatitis B virus from the infant liver. A third of acute
immunosuppressive treatment or chemotherapy. infections in adults are symptomatic,22 and fulminant
The ﬁrst serological marker to appear in acute hepatitis occurs in less than 1% of cases, with a mortality
hepatitis B infection is HBsAg, usually 1–6 weeks before of about 70%. Fulminant hepatitis B is related to an
the manifestation of clinical symptoms. IgM antiHBc enhanced immune response with rapid viral clearance,
appears 1–2 weeks after HBsAg, and persists for up to which means serum HBsAg and hepatitis B virus DNA
6 months after HBsAg is cleared.23 Previously might be undetectable at the time of clinical presentation,
undiagnosed chronic HBsAg carriers with acute and the diagnosis is made only by the presence of serum
exacerbation of hepatitis B or superinfection with other IgM antiHBc.2
hepatitis virus(es) presenting as clinical acute hepatitis, Resolution of hepatitis B with HBsAg seroclearance
are seronegative for IgM antiHBc.24 Serum IgM antiHBc occurs in more than 95% of adult patients. However,
assay is, therefore, mandatory for the serodiagnosis of small amounts of hepatitis B virus DNA can still be
acute hepatitis B. HBeAg and hepatitis B virus DNA are detected by PCR in serum and peripheral mononuclear
present early during acute infection. Both markers cells years after recovery from hepatitis, indicating a
usually disappear when serum ALT peaks, or soon state of occult infection.30 Hepatitis B can be transmitted
thereafter, and before HBsAg seroclearance, which via organ transplantation, and hepatitis B reactivation
occurs within 1–2 months, and are followed by the might occur under immunosuppressive treatment—or
appearance of antiHBs several weeks later (ﬁgure 1). by chemotherapy in such cases.31 The risk of chronicity
Previous infection is diagnosed by the detection of is correlated closely with the patient’s age at the time of
antiHBc and antiHBs.23 infection. Infection persists in about 90% of infants
Presence of HBeAg for more than 10 weeks indicates a infected at birth, 20–30% of children infected between
high likelihood of transition to persistent infection. the ages of 1 and 5 years, 6% of infection in children
584 www.thelancet.com Vol 373 February 14, 2009
aged 5–15 years and only 1–5% of patients infected as Hepatitis ﬂares can lead to cirrhosis but will eventually
adults.1 One possible explanation for the high chronicity be followed by HBeAg seroconversion to antiHBe. The
in infants is that the fetus develops tolerance to the virus estimated yearly proportion of spontaneous HBeAg
in utero after the transplacental passage of viral seroconversion is 2–15%, depending on factors such as
proteins.32 age, ALT concentrations, and hepatitis B virus
The natural course of chronic hepatitis B infection genotype.41–46 In Asia, HBeAg seroconversion occurs at a
consists of distinct phases resulting from the interaction mean age of 30–35 years, with most cases
between the virus, hepatocytes and host immune (90%) occurring before age 40.45–48 Patients infected with
response. Typically, chronic infection acquired perinatally genotype B seroconvert earlier and more frequently
or during infancy has three phases: immune tolerant, than do those with genotype C.3,47,49–51 In native Alaskans
immune clearance, and inactive residual.33 Hepatitis B with chronic hepatitis B infection, the median age of
re-activation can occur in some patients with inactive HBeAg seroclearance is younger than 20 years in
disease and trigger immune-mediated liver injury.34,35 patients with genotypes A, B, D, and F, but over 40 years
Such patients, therefore, enter a variant phase of immune in patients with genotype C.52
clearance (ﬁgure 2).23,36 Adult-acquired chronic infection HBeAg seroconversion is usually followed by clinical
has a similar clinical course, except that there is no remission and a life-long inactive state with an excellent
obvious initial immune tolerant phase.37 outcome, although a few patients may develop
The mechanisms of immune tolerance during the ﬁrst hepatocellular carcinoma.34,35,53–56 Spontaneous HBsAg
phase are not well understood. Work in mice suggests seroclearance can occur, reported at a rate of less than
that a transplacental transfer of maternal HBeAg could 1% per year in early studies.53–57 A study with 1965 patients
induce a speciﬁc unresponsiveness of helper T cells to showed that HBsAg seroclearance occurred at a rate of
HBeAg, and result in an ineﬀective cytotoxic T-cell 1·2% per year, and rose to 1·8% per year in individuals
response to nucleocapsid antigens in neonates.32 over age 50; to a 45% cumulative incidence after 25 years
Patients in the immune-tolerant phase are usually of follow-up.58 Patients with virus genotype A and B
young, asymptomatic, and HBeAg seropositive, with infection have a higher likelihood of HBsAg
high viral loads (more than 2×10⁶ to 2×10⁷ IU/mL) but seroclearance than do patients with other genotypes.59,60
normal serum ALT levels and near-normal liver HBsAg seroclearance usually confers an excellent
histology. There is usually no, or only minimum, long-term outcome if there is no pre-existing cirrhosis
disease progression while serum ALT concentrations or viral superinfection.61,62 However, a small amount of
remain normal.38 hepatitis B virus DNA may persist in a state of occult
The mechanisms triggering loss of immune tolerance infection.31
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 Immune tolerant Immune clearance Inactive residual Reactivation
phase phase phase
causal relation remains unclear. Other ﬁndings that IU/mL
characterise the transition from the immune tolerant to 2x109
HBV DNA HBeAg negative
the immune clearance phase include a shift of reversion hepatitis
hepatocyte expression of hepatitis B virus-core 2x104
antigen (HBcAg) from nucleus to cytoplasm,40 and a
Pre C/BCP Wild type Wild>mutant Mutant>wild Mutant
gradual accumulation of pre-core or core-promoter HBsAg loss
During the immune-clearance phase, hepatitis activity
and intermittent acute ALT increase can ﬂare to over Cirrhosis HCC
ﬁve times the upper limit of normal, usually without
apparent symptoms. This activity of ﬂares can be
complicated by hepatic decompensation. The rises in
Liver histology Minimum Active hepatitis Minimum inactive Active hepatitis
ALT and ﬂares are attributable to the host’s immune
Hepatocyte expression Nucleus Nucleus/cytoplasm Absent Nucleus/cytoplasm
response against hepatitis B virus with resultant of liver HBcAg
apoptosis and necrosis, thus, higher ALT concentrations
20 35 60 35
usually indicate a more vigorous immune response Age (years)
against hepatitis B virus and more extensive hepatocyte
damage.43 The occurrence of hepatitis ﬂare varies in Figure 2: Natural course of chronic hepatitis B virus (HBV) infection acquired perinatally and during infancy
patient cohorts, but has reached 25% of patients per 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
year during the ﬁrst 3–5 years of follow-up in the immune-clearance and reactivation phases could lead to cirrhosis and hepatocellular carcinoma (HCC) (adapted
hospital-based studies43–45 The overall occurrence of from Liaw21 with permission). HBeAg=hepatitis B e antigen; antiHBe=hepatitis B e antigen antibody; pre C=pre core;
hepatic failure in patients was estimated to be 0·5%.24 BCP=basal core promoter; ALT=serum alanine aminotransferase.
www.thelancet.com Vol 373 February 14, 2009 585
persistent seropositivity for HBeAg77 or viral DNA;78
Chronic HBV infection persistent raised ALT;79 viral superinfections;80 as well as
the severity (hepatic decompensation), extent (bridging
HBeAg(+) hepatitis hepatic necrosis), and frequency of hepatitis ﬂare, and the
HBV-DNA >2×106-7 IU/mL duration of hepatic lobular alterations.71
~5% At least a third of patients with cirrhosis are seropositive
2–15%/year for HBeAg or hepatitis B virus DNA at presentation,81 and
HBeAg(+) hepatitis 5% HBeAg 90~95% disease progression can continue after cirrhosis
HBV-DNA >2×104-5 IU/mL seroconversion development.82 The 5-year probability of hepatic
~4%/year decompensation is 15–20%, and is four-fold higher in
~3%/year HBeAg(–) hepatitis Remission patients with active viral replication than in patients
HBV-DNA >2×103-4 IU/mL
~0·5%/year ~10% without.83 The yearly rate of hepatocellular carcinoma
occurrence is 3–6%.81,82 The estimated 5-year survival rate
Liver cirrhosis HBsAg loss of patients with compensated cirrhosis is 80–85% and
~4%/year ~6%/year 30–50% in patients with decompensated cirrhosis.81
Hepatocellular carcinoma mostly develops in patients
<0·1%/year with cirrhosis, therefore, hepatocellular carcinoma and
cirrhosis share the same risk factors, with a raised risk in
~15%/year patients with a family history of hepatocellular carcinoma.84
Death/transplantation Curative therapy Viral factors also contribute to hepatocellular carcinoma
development, including hepatitis B virus DNA level,
Figure 3: Hepatitis B virus (HBV) replication and the outcomes of chronic Hepatitis B infection
genotypes, and naturally occurring mutations such as
Note that Hepatitis B e antigen (HBeAg) seroconversion is followed by remission in most people but that hepatitis B virus pre-S and basal core promoter A1762T/
HBeAg-negative (–) hepatitis (HBV-DNA ≥ 2x10³–2x10⁴ IU/mL) may develop. Patients who remain HBeAg G1764A double mutations.68,85–89 Other contributing factors
seropositive or develop HBeAg-negative hepatitis have a high occurrence of cirrhosis (~4 and ~3% per year). Most are habitual alcohol consumption, cigarette smoking, and
hepatocellular carcinoma (HCC) develops in patients who have cirrhosis.
After HBeAg seroconversion, 1–4% patients have HBeAg
seropositive hepatitis again (HBeAg reversion), whereas a Management
greater proportion of patients develop HBeAg-negative Acute hepatitis B in adults is selﬂimiting in more
chronic hepatitis B because of reactivation of the hepatitis B than 95% of cases, therefore, antiviral therapy is indicated
virus with pre-core or core promoter mutations that only for patients with protracted severe acute hepatitis or
abolish or downregulate HBeAg production.34,35,42,63 Results fulminant hepatitis B.25 Management of patients with
from Taiwanese studies showed relapse in 2–3% of patients chronic hepatitis B infection should include thorough
per year,34,45 with a cumulative rate of 20–25% after 15 years patient assessment and counselling. Although patients
of follow-up.64 The proportion of relapse was very low in are usually asymptomatic, they can be anxious and
patients who HBeAg-seroconverted before age 30,55,64 but attribute a wide range of negative psychological, social,
was raised in men, patients with genotype C, those who and physical symptoms to their condition.91 Counselling
HBeAg-seroconverted after age 40,65 and in patients with should include dietary and lifestyle advice, including
serum hepatitis B virus DNA concentrations greater than guidance to increase physical activity and control alcohol
10 000 copies per mL.66 These age-related ﬁndings show use. Further, health-care providers and patients should
that early HBeAg seroconversion, or a short HBeAg-positive discuss the behaviours that lead to superinfection,
phase, are associated with an improved chance of sustained prevention of such infection and preventive measures
remission.48 against transmission of hepatitis B to intimate contacts.
Cirrhosis or hepatocellular carcinoma, or both, can The importance of the long term hepatocellular
develop during the natural course of chronic hepatitis B carcinoma surveillance, with ultrasonography
infection. Results of large population-based studies with supplemented with α-fetoprotein assay, should be
mostly (85%) HBeAg-negative, HBsAg-positive people emphasised to patients older than 40 years, with advanced
older than 30 years at recruitment have shown that the ﬁbrosis or cirrhosis, and with a family history of
risk of cirrhosis, hepatocellular carcinoma, and mortality hepatocellular carcinoma.25,36,81
increases proportionally with increasing viral DNA Hepatitis B virus replication is key to liver injury and
concentrations, starting with at least 1×104 copies per mL.67–69 disease progression,70 and, therefore, the main aims of
The study ﬁndings suggest hepatitis B virus replication, treatment are to suppress the virus to achieve HBeAg
with subsequent immune-mediated liver injuries, is the seroconversion or undetectable viral-DNA levels, or both;
main driver of disease progression70 (ﬁgure 3). Further risk stop or reduce hepatic necroinﬂammation; and prevent
factors for the development of cirrhosis include: male sex; the development of hepatic decompensation. Long term
increasing age;67–69,71,72 HBeAg positivity;72 virus genotype C goals are to reduce cirrhosis and hepatocellular carcinoma
(vs B);47,49,73–76 HBeAg reversion or virus reactivation;34,47 development, and ultimately extend survival. Viraemic
586 www.thelancet.com Vol 373 February 14, 2009
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/ 10 mg/ 10 mg/ 10 mg/ 0–5 mg/ 0–5 mg/ 600 mg/ 600 mg/ 300 mg/ 300 mg/ 180 μg/week 180 μg/week
day orally day orally day orally day orally day orally day orally day orally day orally day orally day orally subcutaneous subcutaneous
Cost (US$/year per person)* 2482 2482 6647 6647 8694 8694 5924 5924 5811 5811 18 480 18 480
Log reduction at year 1† 5·4 4·5 3·6 (1·0) 3·7 (1·4) 6·9 5·0 5·7 4·4 6·5 4·5 4·5 4·1
Undetectable at year 1† 40% 72% 21% (0%) 61% (0%) 67% 90% 60% 88% 76% 93% 25% 63%
HBeAg seroconversion at 20% – 12% (6%) – 21% – 23% – 21% – 32% –
Year 1 11–14% 6–27% 0% 0% 0% 0% 5% 2% 0 0 0 0
Year 2 40% 26–54% ·· 3% 0% 0% 25% 11% 0 0 – –
Year 3 56% 57% ·· 11% ~1% ~1% ·· ·· ·· ·· – –
Year 5 69% 65% 20% 29% 1·2% 1·2% ·· ·· ·· ·· – –
Other side-eﬀects Negligible Negligible Creatinine Creatinine Negligible Negligible Increase Increase Negligible Negligible Various, Various,
increase increase in CK in CK unpleasant 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
patients with an ALT concentration of twice the upper 32% when assessed 24 weeks after completion of
limit of normal or more, or substantial liver disease, are therapy.95–97 Patients with genotype A (vs D) or B (vs C)
candidates for drug therapy. Of note, ALT ﬂare may infection tend to have a better response to interferon or
precede spontaneous HBeAg seroconversion.43 Obser- pegylated interferon.3,95–97 HBeAg seroconversion response
vation for 3 months before considering drug therapy is is sustained in more than 80% of people, and can be
acceptable.25,36 Liver biopsy is recommended to assess the followed by HBsAg loss,77,98,99 which is the desired end
necroinﬂammation grade and ﬁbrosis stage, because point.
signiﬁcant ﬁbrosis could have developed in patients with Patients with HBeAg-negative chronic hepatitis B
normal ALT, except during the immunotolerant phase.92 respond to interferon alfa therapy but often relapse after
Before drug therapy is initiated, the eﬃcacy, advantages treatment completion.78,100 The combined response to
and disadvantages, and cost of available therapies should pegylated interferon therapy (normal ALT+hepatitis B
be discussed with the patient.36 virus DNA concentration less than 2×10⁴ copies per mL)
Approved and widely used agents are conventional in HBeAg-negative patients is 36% at 6 months post
interferon alfa and pegylated interferon-alfa-2a; the treatment.101,102 Improved response rates are achieved in
nucleoside analogues lamivudine, entecavir, and patients with low serum viral DNA, raised ALT and low
telbivudine; and the nucleotide analogue adefovir HBeAg concentrations at baseline, and low HBeAg after
dipivoxil. Tenofovir, another nucleotide analogue 24 weeks’ treatment.102–104 HBsAg seroconversion occurs in
approved for the treatment of HIV infection, was more 3% of the pegylated interferon treated patients,96,97,101 and
eﬀective than adefovir in hepatitis B,93 it has been the rate increases to 10% at 4 years after therapy.105 These
approved in European countries and USA, and will response ﬁgures are better than those of lamivudine
probably be approved worldwide. Drug therapy should be monotherapy. Results from follow-up studies suggest
selected according to the patient’s condition, the drug’s that interferon alfa therapy has long term beneﬁts by
mechanism, rapidity of action, potency, convenience of promoting cumulative HBeAg seroconversion,
administration, adverse eﬀect proﬁle, and cost (see increasing HBsAg loss, reducing development of
table). cirrhosis and hepatocellular carcinoma, and extending
survival—especially in responders.70,77,98–100 Further
Interferon-based therapy advantages of interferon-based therapy are the ﬁnite
Interferon alfa and pegylated interferon have treatment duration and that patients do not develop drug
immunomodulating activity. Theoretically, interferons resistance. Eventually, pegylated interferon treatment will
are the ideal treatment for patients with chronic replace interferon alfa because of its improved
hepatitis B, but the response rate after 4–6 months of eﬀectiveness and convenient once a week
interferon alfa is only 30–40% in HBeAg-positive administration.36,95 Interferon-based therapy is associated
patients, with a risk diﬀerence of 23–25% against with many adverse events; including inﬂuenza-like
untreated controls.94 48 weeks of pegylated interferon symptoms, fatigue, anorexia, weight loss, hair loss,
therapy yields a sustained HBeAg seroconversion rate of thyroid dysfunction, emotional instability, and bone
www.thelancet.com Vol 373 February 14, 2009 587
marrow suppression. Patients might need symptomatic upper limit of normal, but in only 5% of patients with
treatment, and some require dose modiﬁcation or ALT values less than twice the upper limit of normal.111,112
discontinuation of therapy.95 Most patients are able to Thus, patients with a stronger endogenous immune
complete 48 weeks of pegylated interferon treatment response to the hepatitis B virus might have an improved
despite the side-eﬀects.96,97,101 chance of reducing cccDNA and HBeAg translation.111
Additionally, patients with ALT values more than ﬁve
Nucleoside or nucleotide analogues times the upper limit of normal could be developing
Oral antiviral agents have fast and potent inhibitory severe hepatitis or hepatic decompensation, especially if
eﬀects on hepatitis B virus polymerase and reverse they have advanced ﬁbrosis.43 These patients should be
transcriptase activity, and are safe and eﬀective for monitored every week or every two weeks so that
hepatitis B virus DNA suppression, ALT normalisation, fast-acting antiviral drugs can be started to arrest the
and histological improvement. Results from cross-trial development, or deterioration, of hepatic de-
1 year treatment data suggest entecavir is the most potent compensation.113 Similarly, nucleoside and nucleotide
of the drugs, followed by tenofovir, telbivudine, analogues might rescue patients with decompensated
lamivudine, and adefovir. However, the antiviral potency cirrhosis by increasing serum albumin concentrations,
of these drugs does not result in an increase in HBeAg and stabilising bilirubin values and prothrombin time,
seroconversion—which was seen at a rate of around removing the need for transplantation and prolonging
20% after 1 year of treatment (see table)—and HBsAg survival.114,115
loss is very rare.106–110 After 1 year of lamivudine treatment 20–50% of patients who have HBeAg seroconversion
an HBeAg seroconversion was achieved in more than will relapse with HBeAg reversion within 6–12 months
half of patients with ALT values more than ﬁve times the oﬀ therapy, and more patients may relapse if the
duration of consolidation therapy after HBeAg
seroconversion is less than 6 months.25,36 In
Chronic HBV infection
HBeAg-negative patients, there is no end point such as
HBeAg seroconversion, so treatment duration is
HBeAg(+) HBeAg(–) indeﬁnite, 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
HBV-DNA >2×104 IU/mL HBV-DNA >2×103 IU/mL HBV-DNA <2×103 IU/mL
followed by rising ALT or a hepatitis ﬂare which could
be life threatening.117 Therefore, continuing long-term
ALT<ULN ALT>ULN ALT<ULN ALT<ULN ALT>ULN
drug therapy is usually necessary to maintain a
virological response. Results of a large randomised
controlled trial in patients with advanced ﬁbrosis or
cirrhosis showed the beneﬁts of long-term therapy after
3-month 3-month 6-month 6-month
3 years of lamivudine therapy were reduced dis-
follow-up follow-up follow-up follow-up follow-up ease progression and hepatocellular carcinoma
The emergence of drug-resistant genotypic mutations
>40 years Concern of <2× ULN >40 years >40 years of hepatitis B virus in long term therapy is a major
decompensation problem. Clinically, emergence of drug resistance is
indicated by viral breakthrough—an increase of serum
Biopsy/therapy + Yes No Biopsy/therapy + HCC surveillence
hepatitis B virus DNA to more than ten-fold increase
HCC surveillence HCC surveillence in HBV concentrations from the nadir of initial
response—with subsequent biochemical breakthrough
3–6 months or raised ALT values in more than 90% of patients.119
Hepatitis ﬂares develop frequently, sometimes
NA IFN or NA associated with hepatic decompensation during
continued antiviral therapy,120 and, the initial clinical
and histological beneﬁts of antiviral therapy
Response Non-response diminish.118,121,122
The occurrence of drug resistance rises with
increasing therapy duration, although the generation of
Stop/monitor Consider other
strategies nucleoside and nucleotide analogues has improved
potency and raised the genetic barrier to resistant
Figure 4: Management of patients with chronic hepatitis B virus (HBV) infection
mutations (see table). Drug resistance occurs most
HBeAg=hepatitis B e antigen. ULN=upper limit of normal. NA=nucleoside or nucleotide analogues. frequently with lamivudine, followed by telbivudine,
IFN=interferon-based therapy. HCC=hepatocellular carcinoma. adefovir and tenofovir, and is very low with entecavir.106–110
588 www.thelancet.com Vol 373 February 14, 2009
Studies have shown that suppression of the hepatitis B Hepatitis B virus re-activation is a serious complication
virus to undetectable level at 24 weeks of telbivudine in patients undergoing transplantation, immuno-
and lamivudine therapy is associated with low incidence suppression, or chemotherapy. Patients should be
of drug resistance at week 48.110 Rescue therapy for drug screened for HBsAg and, if positive, prophylactic therapy
resistance is now available and, therefore, monitoring with a direct antiviral agent should be started before the
hepatitis B virus DNA levels during drug treatment to beginning of and at least 12 weeks after the end of the
detect drug resistance early enough to start rescue immunosuppressive treatment or chemotherapy.36,131 For
therapy before serum hepatitis B virus DNA increases all patients with hepatitis B virus-associated liver failure
over 1×10⁶ copies per mL123,124 is very important. In who are listed for transplantation, nucleoside or nucleotide
patients with drug resistance, add-on therapy without analogues should be started and continued after
cross-resistance (adefovir and tenofovir vs lamivudine, transplantation as prophylaxis against re-infection of the
telbivudine and entecavir) should be instituted.123,125 allograft.25,36
Switching to interferon-based therapy can be a further Conﬂict of interest statement
option.126 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 conﬂict of interest.
Drug treatment strategies
In view of the array of drugs available, physician and Acknowledgments
We thank Chang-Gung Medical Research Fund and the Prosperous
patient should decide which drug should be used, and Foundation, Taipei, Taiwan, for long term grant support;
when to start and stop treatment. Oral antiviral agents Ellen Donaldson and Eric Matluck for English editing; and
with fast and potent hepatitis B virus-suppressive eﬀects Su-Chiung Chu for secretarial assistance.
are preferred for patients with ensuing or overt hepatic References
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