Seminar

Chronic hepatitis B virus infection

Wai-Kay Seto, Ying-Ru Lo, Jean-Michel Pawlotsky, Man-Fung Yuen

Chronic hepatitis B virus infection is a global public health threat that causes considerable liver-related morbidity and Lancet 2018; 392: 2313–24
mortality. It is acquired at birth or later via person-to-person transmission. Vaccination effectively prevents infection Department of Medicine,
and chronic hepatitis B virus carriage. In chronically infected patients, an elevated serum hepatitis B virus DNA The University of Hong Kong
Queen Mary Hospital,
concentration is the main risk factor for disease progression, although there are other clinical and viral parameters
Hong Kong Special
that influence disease outcomes. In addition to liver biochemistry, virological markers, and abdominal ultrasonography, Administrative Region, China
non-invasive assessment of liver fibrosis is emerging as an important assessment modality. Long-term nucleos(t)ide- (W-K Seto MD,
analogue therapy is safe and well tolerated, achieves potent viral suppression, and reduces the incidence of liver- Prof M-F Yuen DSc);
Department of Medicine,
related complications. However, a need to optimise management remains. Promising novel therapies are at the
The University of Hong Kong-
developmental stage. With current vaccines, therapies, and an emphasis on improving linkage to care, WHO’s goal of Shenzhen Hospital, Shenzhen,
eliminating hepatitis B virus as a global health threat by 2030 is achievable. Guangdong, China (W-K Seto,
Prof M-F Yuen); State Key
Laboratory for Liver Research,
Introduction virus (mostly people infected through use of injectable The University of Hong Kong,
Approximately three decades ago, one of the biggest drugs) and 5% with hepatitis D virus. Hepatitis D virus Hong Kong Special
breakthroughs in the management of chronic hepatitis B requires HBV infection to be present, and the prevalence Administrative Region, China
virus (HBV) infection was the approval of the hepatitis B of hepatitis D virus infection in chronic HBV carriers (W-K Seto, Prof M-F Yuen);
WHO Representative Office in
vaccine. Since then, dramatic progress has been made in varies widely with geographical region. Malaysia, Brunei Darussalam,
understanding of the natural history of chronic HBV and Singapore, Cyberjaya,
infection, as well as advances in antiviral treatment and Vaccination Malaysia (Y-R Lo MD); National
accessibility of clinical care for hepatitis. In 2016, WHO’s Vaccination against HBV at birth remains the main Reference Centre for Viral
Hepatitis B, C, and Delta,
Global Strategy for Viral Hepatitis endorsed the goal of strategy for the elimination of hepatitis B and the Department of Virology,
elimination of viral hepatitis, including hepatitis B, as a reduction of liver cancer incidence. In 1981, the first Henri Mondor Hospital,
public health threat by 2030.1 This Seminar describes plasma-derived hepatitis B vaccine was licensed in University of Paris-Est, Créteil,
the epidemiology of HBV infection, vaccination, patho­ the USA. It was replaced in 1986 and 1989 by recombinant France (Prof J-M Pawlotsky PhD);
and Department of Molecular
physiology, risk factors and management of chronic hepatitis B vaccines.6 The complete hepatitis B vaccine Virology and Immunology,
HBV infection, and existing controversies, as well as series (birth dose plus two additional booster doses) Inserm U955, Créteil, France
providing a discussion of future prospects. induces protective amounts of anti-HBs antibodies in (Prof J-M Pawlotsky)
more than 95% of vaccinated infants.4 Correspondence to:
Epidemiology WHO recommends that all infants receive the first dose Prof Man-Fung Yuen,
Department of Medicine,
Globally, viral hepatitis accounted for 1·34 million deaths of a monovalent hepatitis B vaccine as soon as possible The University of Hong Kong
in 2015, a toll as high as that of tuberculosis (1·37 million) after birth, preferably within 24 h, to prevent perinatal Queen Mary Hospital,
and higher than those of HIV infection (1·06 million) and HBV transmission. Indeed, observational data also Hong Kong Special
malaria (0·44 million). 96% of those deaths were due to suggest that HBV vaccination is most effective if given Administrative Region, China
mfyuen@hkucc.hku.hk
complications of chronic hepatitis, with the majority (66%) within 24 h after birth, but remains effective, albeit to a
caused by HBV.2 The worldwide estimated prev­alence of lesser extent, if given after this time.7 The first dose should
chronic HBV infection in 2016 was 3·5% with 257 million be followed by at least two subsequent booster doses,
people living with chronic infection.3 The WHO western either as two doses of monovalent hepatitis B vaccines or
Pacific region (which includes 37 countries) bears the as hepatitis B-containing combination childhood vaccines.
highest disease burden (6·2%), followed by the African
region (6·1%).2
The serological marker of chronic HBV infectivity, Search strategy and selection criteria
HBsAg, is used to elucidate the endemicity of HBV in We searched MEDLINE, Embase, and the Cochrane database
the general population in a defined geographical area for articles published between January, 2000,
(appendix). Most of the HBV disease burden is a result of and June, 2018, with the terms “hepatitis B”, HBV”, “HBsAg”, See Online for appendix
infections acquired through perinatal transmission or “HBeAg”, “nucleoside analogue”, “interferon”, “HBV DNA”,
during early childhood exposure to HBV (appendix), as “HCC”, “fibrosis”, and “transient elastography”.
well as immigration from high-endemicity areas.4 The We prioritised selection of publications from the past
earlier HBV infection is acquired, the higher the likelihood 4 years, but also selected highly referenced older
of it becoming chronic.5 Horizontal trans­mission occurs publications. We also searched the reference list of articles
among individuals engaging in high-risk sexual behaviour, identified by this search strategy and selected those judged
such as unprotected anal and vaginal sex, and individuals to be relevant, and supplemented the search with additional
who share contaminated injecting devices are at increased references from the personal databases of all coauthors. All
risk of HBV infection. About 10–15% of people with selected articles were published in or translated into English.
chronic HBV infection are co-infected with hepatitis C

www.thelancet.com Vol 392 November 24, 2018 2313

 Seminar
HBV virion
cccDNA† NTCP receptor
Protein-free Entry
mRNA rcDNA
transcription rcDNA Uncoating
HBV DNA Recycling of
integration* nucleocapsid Viral secretion
Reverse
transcription
Viral protein secretion
Encapsidation Negative Positive
strand strand
synthesis synthesis
Translation
HBV RNA virion-like
particle secretion
Figure 1: Life cycle of HBV
cccDNA=covalently closed circular DNA. HBV=hepatitis B virus. NTCP=sodium taurocholate cotransporting
polypeptide. rcDNA=relaxed circular DNA. *Integrated HBV DNA sequences can produce HBsAg and generate
mutant viral proteins that have a role in hepatocarcinogenesis. †cccDNA is the stable form of intrahepatic HBV
DNA responsible for the persistence of HBV.
The impact of immunisation programmes at the pop­
ulation level has been shown in the WHO western Pacific
region, which was among the first to introduce HBV
vaccination programmes with time-bound targets.8 Such
programmes were first introduced in the 1980s and 1990s
in several countries and, by 2005, all countries and areas
of the western Pacific region had started vaccinating
infants.9 Mathematical modelling estimated that hepatitis
B vaccination prevented more than 37 million cases of
chronic HBV infection among children born between
1990 and 2014 in this region, thereby averting more than
7 million deaths related to HBV. In 2014, with an average
HBV three-dose vaccination coverage of 92·2% and HBV
birth-dose coverage of 81·5%, approximately 3 million
chronic infections and 570 566 deaths were prevented.9
As of 2015, the global HBsAg prevalence has decreased
as a result of worldwide vaccination programmes
from 4·7% to 1·3% in children under 5 years of age;
however, the prevalence remains high in non-vaccinated
people.2 HBV vaccination of infants had been imple­
mented nationwide in 186 countries and coverage with
three doses of HBV vaccine was estimated to be 84% by
the end of 2016 (appendix).
HBV virology
Life cycle and genetic variability
Human HBV is a member of the Hepadnaviridae family.
The infectious virion contains a partially double-
stranded, relaxed circular DNA (rcDNA) genome of
approximately 3200 bp, covalently linked to the HBV
polymerase.10 After viral entry, the rcDNA is delivered
into the nucleus and converted into fully double-stranded
DNA, which is itself converted by ligation into covalently
closed circular DNA (cccDNA), the stable form of HBV
DNA that is respon­sible for its persistence in infected
2314 www.thelancet.com Vol 392 November 24, 2018
hepatocytes and transmission to progeny cells (figure 1).11
The HBV genome has four overlapping frame-shifted
open reading frames that serve for the pregenomic RNA
(the template for reverse transcription into rcDNA within
the nucleocapsid),10 synthesis of the core protein and
HBV polymerase, and mRNAs producing HBeAg, large,
middle, and small HBsAg, and X protein. Nucleocapsids
containing newly formed rcDNAs are released from the
hepatocyte as new virions (figure 1) or recycled to the
nucleus to replenish the cccDNA pool.
Other genomic forms of DNA exist. Integration of HBV
DNA sequences is a major source of HBsAg production
during HBeAg-negative disease and contri­butes to viral
persistence. Mutated viral proteins are also generated and
can participate in hepatocarcinogenesis.12 Spliced viral
proteins are also described, although their role in the
HBV life cycle remains poorly understood.13
There are ten different HBV genotypes (A to J), classified
according to at least 8% difference in the full-length
genome sequence.14 These genotypes have different geo­
graphical distributions related to the history of HBV
transmission over the centuries. Whether different geno­
types are associated with different disease courses remains
debated, and this association might be related to their
different epidemiologies rather than biological differences.
In addition, HBV genetic variability is constrained by the
overlapping nature of the four open reading frames in its
genome, which makes many of the occurring mutations
lethal. Thus, only a few substitutions with clinical
significance have been identified.15 The 1896G→A precore
mutation and the 1762A→T or 1764G→A basal core
promoter mutations are associated with abolished or
reduced production of the HBe protein, respectively.
During the natural course of infection, precore or basal
core promoter mutant viruses are selected as the dominant
viral population at the time of HBeAg loss or HBe sero­
conversion.16 Mutations have also been described in the
pre-S and S regions of the genome, including HBsAg
mutations associated with HBV vacc­ ine or hepatitis B
immunoglobulin treatment escape (eg, Gly145Arg).17
Nucleos(t)ide analogue treatment pressure can select
pre-existing resistant viral populations, which reduce
susceptibility to the antiviral effect of the drugs.18 Early-
generation nucleos(t)ide analogues, such as lamivudine,
adefovir, and telbivudine, have a low barrier to resistance.
By contrast, entecavir and tenofovir have a high barrier
to resistance and should therefore be exclusively used
to treat chronic hepatitis B.19 Three mutations must be
present for entecavir resistance to occur, including
rtLeu180Met, rtMet204Val, and one of rtThr184Gly/Ser,
rtSer202Ile/Gly, or rtMet250Val—an unlikely situation
responsible for only a 1·2% cumulative 5-year incidence
of treatment failure related to resistance after long-term
entecavir treatment.20 No mutations have been reported
to confer tenofovir resistance in vivo, a result in keeping
with the 0% cumulative incidence of tenofovir resistance
after 8 years of therapy.19

Mechanism of HBV persistence
The likelihood of HBV persistence strongly depends on
age at acquisition. Perinatal infection leads to chronicity
in most cases, whereas most infection can be controlled
in adults. This difference is probably because of the
differing immune maturity between adults and young
children.21 The state of the mother’s infection could
also be important, with maternal production of HBeAg
possibly promoting HBV persistence after birth.22
Upon hepatocyte infection, the presence of HBV appears
to be recognised by several sensors, resulting in weak
interferon and interferon-stimulated gene responses.21
In addition, the use of cccDNA as a template hides
replication intermediates from the cellular machinery
and contributes to viral persistence.
The functionality of antiviral effector cells, such as
dendritic cells, Kupffer cells, or cytolytic cells (eg, natural
killer cells), is impaired in patients who develop chronic
HBV infection. These alterations include changes
in the ability of these cells to produce various cyto­
kines (including interferon α, interferon γ, interleukin
[IL]6, and IL1), thereby altering the degree of local
inflammation and inducing a tolerogenic liver environ­
ment.23 In addition, CD4-positive and CD8-posi­ tive
T cell responses are qualitatively and quantitatively
altered in chronic HBV infection.21,23 CD4-positive T cell
responses are predominantly of the T-helper-1 type.21,23
CD8-positive T cells bear both cytolytic and non-cytolytic
effector func­ tions. These responses are con­ comitant
with the peak of serum aminotransferase activity that
precedes HBV control. The roles of regulatory T cells,
B cells, and neutralising antibodies in the control of
HBV remain obscure.
Disease course and predictors
The natural history and disease course of chronic HBV
infection involve a dynamic interaction between the
virus and the host immune responses and can there­
fore be widely variable. A substantial proportion of
patients develop cirrhosis, complications of cirrhosis,
and hepatocellular carcinoma, whereas others have
lifelong quiescent disease activity not requiring antiviral
therapy. Different phases of chronic HBV infection have
been described, with changing denominations over
time and differing biochemical and virological profiles
(figure 2).19 The different disease phases are not
necessarily sequential and can sometimes be reversed
(eg, HBeAg or HBsAg seroreversion). Extrahepatic
immune-mediated manifes­tations, including glomerulo­
nephritis, skin changes, polyarteritis nodosa, and mixed
cryoglobulinemia, can also develop.24
The first phase, known as the immune tolerant phase
and renamed HBeAg-positive chronic infection,19 is
characterised by high serum HBV DNA but normal
serum alanine aminotransferase (ALT) and near-
normal liver histology. The second, immune clearance
phase, termed HBeAg-positive chronic hepatitis,19 is
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Seminar
Serum
HBV DNA
Intrahepatic HBV DNA
still present
Current HBeAg-positive HBeAg-positive HBeAg-negative HBeAg-negative HBsAg-negative
terminology chronic infection chronic hepatitis chronic infection chronic hepatitis phase
Previous Immune tolerant Immune clearance
Inactive carrier phase -
terminology phase phase
Serum HBsAg
Serum ALT
Figure 2: Different phases of chronic HBV infection in relation to the kinetics of serum HBV DNA, HBsAg,
and ALT
ALT=alanine aminotransferase. HBV=hepatitis B virus.
character­ised by immune-mediated liver necroinflam­
mation, fibrosis, and fluctuating serum ALT concentra­
tion. HBeAg loss and the appearance of anti-HBe
antibodies occur at the end of this second phase. The
timing of HBeAg seroconversion is influenced by several
factors, including age at acquisition and HBV genotype.14
Patients in whom seroconversion occurs after age
40 years have a higher risk of developing cirrhosis and
hepatocellular carcinoma compared with patients with
earlier sero­conversion.25
In the HBeAg-negative chronic infection phase, formerly
known as the inactive carrier state,19 ALT con­centrations
are within the normal range, with HBV DNA falling to less
than 2000 IU/mL, and sometimes becoming undetec­
table.26 Disease progression can occur in a proportion of
patients who develop HBeAg-negative chronic hepatitis,
which is characterised by intermittent fluctuations in
serum HBV DNA and ALT concen­trations.19 A minority
of patients with HBeAg-negative chronic infection can
spontaneously achieve HBsAg seroclearance (also known
as functional cure of HBV infection), the best possible
outcome,27 although intra­ hepatic HBV persists at low
replicative and transcriptional levels.28
The frequency of complications varies greatly among
different regions. In areas of low HBV prevalence, the
incidence of liver-related complications in untreated,
asymptomatic patients can be as low as 1·2% after
16 years.29 By contrast, the frequency of complications is
increased in highly endemic regions, where the 5-year
cumulative incidence of cirrhosis in patients with
HBeAg-positive hepatitis ranges from 13% to 38%, with
the 5-year cumulative incidence of liver decompensation
among patients with cirrhosis reaching 15%. The 5-year
cumulative incidence of hepatocellular carcinoma is also
substantially higher in highly endemic regions, ranging
from 3% in patients without cirrhosis to 17% in those
with cirrhosis.30 This higher incidence of liver-related
complications in high-endemicity areas, where the
 Seminar
Panel: Serum HBV virological markers
HBsAg
• Hallmark of infection; positivity for 6 months or more
indicates chronicity
• Infection persists even after seroclearance
(HBsAg-negative phase)
• Quantitated levels can prognosticate disease with respect
to seroclearance
HBeAg
• Positive in early disease phases
• Serostatus reflection of natural history of disease course
HBV DNA
• Cardinal predictor of disease activity
• Important for treatment indication, monitoring,
and post-treatment follow-up
Anti-HBc
• Indicates exposure to HBV
• HBV reactivation after potent immunosuppression is
possible in HBsAg-negative phase of disease
Hepatitis B core-related antigen (HBcrAg) and HBV RNA
• Emerging markers, clinical relevance still unclear
• Might be used as endpoints for clinical trials of novel
HBV drugs
majority of patients were infected during their early
years, might result from longer durations of infection.31
Serum HBV DNA concentration is the cardinal
predictor of disease activity in HBeAg-negative patients.
The REVEAL-HBV study32,33 in Taiwan included more
than 3500 HBsAg-positive participants, 85% of whom
were HBeAg-negative, followed up for 11 years on
average. Compared with patients with HBV DNA of
2000 IU/mL or less, the relative risk of cirrhosis was
2·5 (95% CI 1·6–3·8) and of hepatocellular carcinoma
was 2·7 (1·3–5·6) in patients with serum HBV DNA
of more than 2000 IU/mL. The risks of cirrhosis
and hepatocellular carcinoma further increased with
incremental augmentations of serum HBV DNA
concentration.32,33 In patients with HBV DNA of less than
2000 IU/mL, quantitative measurement of serum HBsAg
predicted liver disease progression. HBsAg concen­
tration of 1000 IU/mL or more, compared with less
than 1000 IU/mL, increased the risk of hepatitis
(relative risk 1·5 [1·2–1·9]) and hepatocellular carcinoma
(13·7 [4·8–39·9]).34,35 For HBeAg-positive disease, high
HBV DNA concentrations were generally not predictive
of complications; instead, moderately high HBV DNA
(above 20 000 IU/mL) together with advanced age was
more predictive of increased risk of hepatocellular
carcinoma.36 Other virological and clinical risk factors of
disease progression are presented in the appendix.37–48
Disease progression can occur even with normal or
slightly elevated ALT concentration. An observational
2316 www.thelancet.com Vol 392 November 24, 2018
cohort of 3233 Chinese patients with chronic HBV
infection found a substantial risk of developing liver-related
complications in patients with normal ALT concentration.49
In a systematic analysis, 20·7% (16·2–26·0) of patients
with normal ALT (up to 40 U/L) showed evidence of
advanced liver fibrosis.50 Among those with slightly
elevated ALT (from the upper limit of normal to two-times
the upper limit of normal), the risk of advanced fibrosis
increased to 48% (36–61).51
Spontaneous HBsAg seroclearance occurs at an
annual rate of 0·7–2·3%,52,53 with cumulative sero­
clearance rates reaching 33% in certain patient
populations.54 Although cccDNA persists in the liver and
low-level intrahepatic replication can be present, HBsAg
sero­clearance is associated with a negligible risk of
cirrhosis in non-cirrhotic patients28 and a substantially
decreased risk of hepatocellular carcinoma, including in
patients with cirrhosis (relative risk 0·34 [0·20–0·56]).55
After HBsAg seroclearance, the lifetime cumulative
incidence of hepatocellular carcinoma falls from 14·2%
to 4·0%.56 Among patients who clear HBsAg, the age at
sero­clearance is the best predictor of hepatocellular
carcinoma, with a relative risk of 4·31 (1·72–10·84) in
patients older than 50 years of age compared with
younger patients.57 The kinetics of HBV viral markers
can predict HBsAg seroclearance and other favourable
clinical outcomes (appendix).53,58–60
Initial evaluation of chronic HBV infection
Virological markers
HBV infection is diagnosed by the detection of HBsAg in
serum or plasma by means of enzyme immunoassay.
Chronic infection is defined by HBsAg positivity for
6 months or more. HBsAg quantification in serum or
plasma is optional and can offer value in disease
prognostication with respect to subsequent HBsAg
seroclearance (appendix).
HBV DNA detection and quantification by PCR assay
can be used to confirm diagnosis, to decide when to
treat, and for treatment monitoring and post-treatment
follow-up. Additional serological markers, including
anti-HBs antibodies, HBeAg and anti-HBe antibodies,
anti-HBc and anti-HBc IgM, are useful to classify HBV-
infected patients into the different phases of the disease,
guide treatment decisions, and characterise the response
to therapy.19 Hepatitis B core-related antigen (HBcrAg)
and HBV RNA are novel serological markers that reflect
different HBV life-cycle intermediates, and might be
used increasingly in future clinical trials investigating
novel HBV drugs. Descriptions of both established
and emerging HBV virological markers are described
in the panel.
Liver assessment
Non-invasive methods are replacing liver biopsy for
assessment of fibrosis. Among these methods, transient
elastography has been the best validated in patients
 Seminar

with chronic HBV infection. Transient elastography has a

short procedural time and can be done easily in outpatient Transient elastography
settings. However, it lacks accuracy in differentiating
intermediate stages of fibrosis. Because inflammation can
influence the result of transient elastography,61 an ALT-
<6 kPa 6–9 kPa 9–12 kPa >12 kPa
based algorithm has been established to diagnose or
exclude severe liver fibrosis (figure 3).62 Serum indices Normal or Normal or Normal or
elevated ALT elevated ALT elevated ALT
of fibrosis (eg, Enhanced Liver Fibrosis test63 or
Elevated ALT Normal ALT
Mac-2-binding protein glycan isomer64) are available with
validated data specific to HBV. The aspartate amino­
transferase to platelet ratio index, which relies on simple, No severe fibrosis Grey area Severe fibrosis or cirrhosis
readily available blood tests, can be considered, especially
in low-resource settings.65 With the emergence of non-
Consider follow-up assessment Consider liver biopsy if it will Consider treatment and screening
invasive alternatives, the role of liver biopsy, particularly in influence management, for varices and hepatocellular
stable and asymptomatic patients, is diminishing. including treatment decisions carcinoma
Liver ultrasonography is essential to detect hepato­
cellular carcinoma at an early stage. Twice-yearly ultra­ Figure 3: Algorithm for the diagnosis and exclusion of severe fibrosis in chronic hepatitis B virus infection
sonographic assessment has been shown to reduce based on ALT and transient elastography results
Algorithm is based on recommendations by the European Association for the Study of the Liver.62 Elevated ALT is
HBV-related hepatocellular carcinoma mortality by 37%,66 limited to concentration less than five-times the upper limit of normal, based on an upper limit of normal of 40 U/L.
and the efficacy is significantly reduced if surveil­lance Other indices of fibrosis (eg, aspartate aminotransferase to platelet ratio index) can also be considered, especially in
is only annual.67 Thus, patients with risk factors for resource-limited settings. ALT=alanine aminotransferase.
hepatocellular carcinoma development, including men
aged 40 years and older, women aged 50 years and
Prior exposure to High risk for renal Pregnancy Decompensated
older, individuals with a family history of hepatocellular lamivudine or or bone toxicity disease
carcinoma, or patients with cirrhosis, should undergo telbivudine
ultrasonographic surveillance twice a year.68 Entecavir Not suitable Suitable Not suitable Suitable
Tenofovir disoproxil Suitable Not suitable Suitable Suitable
Treatment of chronic HBV infection fumarate
Available antiviral therapies Tenofovir alafenamide Suitable Suitable No data No data
Oral nucleos(t)ide analogue therapy is the main form of
Table 1: Factors affecting the choice between the three recommended nucleos(t)ide analogues
anti-HBV treatment worldwide. Recommended first-line
choices include entecavir and two prodrugs of tenofovir:
tenofovir disoproxil fumarate and tenofovir alafenamide. older-generation nucleos(t)ide ana­ logues, including
The three drugs achieve high virological suppression in a lamivudine, adefovir, and telbivudine.
high proportion of patients (more than 95% of patients Although generally safe, long-term administration of
achieve undetectable serum HBV DNA), with favourable tenofovir disoproxil fumarate has been associated with
safety and tolerability profiles and an extremely low chronic renal tubular damage, Fanconi syndrome, and a
incidence of virological breakthroughs owing to their high decrease of bone mineral density.75 Using sensitive
barrier to resistance.20,69,70 Although entecavir is not rec­ biomarkers of renal function and bone turnover, tenofovir
ommended for patients pretreated with lamivudine or alafenamide, a more liver-targeted prodrug of tenofovir
telbivudine, tenofovir disoproxil fumarate and tenofovir that ensures lower peripheral blood concentrations than
alafenamide are effective in patients with lamivudine- those with tenofovir disoproxil fumarate, has been
resistant or telbivudine-resistant HBV. Tenofovir disoproxil associated with better renal and bone safety, with
fumarate is the drug of choice in pregnant women. comparable rates of viral suppression,69 but long-term
Long-term treatment (more than 5 years) is associated data are unavailable. Several factors affect the optimal
with a reduction of the intrahepatic amount of cccDNA.71 choice of drug (table 1).
Long-term viral suppression by nucleos(t)ide analogue Subcutaneous injection of pegylated interferon alfa
therapy also leads to significant histological improvement, for a finite duration of 1 year remains possible as first-
including regression of cirrhosis in 71% of patients.70 The line therapy in patients with chronic HBV infection.
complications of cirrhosis (relative risk 0·51 [0·31–0·99]) However, its unfavourable side-effect profile and the low
and hepato­cellular carcinoma (0·37 [0·34–0·39]) are also likelihood of sustained viral suppression after treatment
reduced in incidence.72,73 Nucleos(t)ide analogues improve dis­continuation compared with long-term nucleos(t)ide
liver function in patients with decompensated disease, analogue therapy makes it an unpopular choice of
with a substantial proportion of those with an indication treatment. Pegylated interferon therapy is associated
for liver transplantation being delisted.74 The effectiveness with low off-treatment viral control, with only 23% of
of entecavir, tenofovir disoproxil fumarate, and tenofovir patients achieving a serum HBV DNA concentration of
alafenamide has now rendered obsolete the use of 80 IU/mL or less in the long term.76 This therapy is also

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 Seminar

Chronic HBV infection

No cirrhosis Cirrhosis

No treatment indication • ALT normal or more • ALT more than

than ULN two-times ULN
• HBV DNA >2000 IU/mL • HBV DNA >20 000
• Moderate fibrosis* IU/mL

HBeAg-positive HBeAg-negative

HBV DNA <2000 IU/mL HBV DNA≥2000 IU/mL

Monitoring interval
• ALT: 3 months
• HBV DNA: 6–12 months
• Fibrosis*: 12 months
Monitoring interval
• ALT: 6–12 months
• HBV DNA: 2–3 years
• Fibrosis*: 2–3 years
• Consider quantitative
HBsAg testing
Monitoring interval Start treatment Start treatment when
• ALT: 3–6 months HBV DNA detectable,
• HBV DNA: 12 months regardless of ALT
• Fibrosis*: 12 months concentration

Figure 4: Recommended treatment and management algorithm for chronic HBV infection
Adapted from the European Association for the Study of the Liver guidelines. ALT=alanine aminotransferase. HBV=hepatitis B virus. ULN=upper limit of normal.
*Assessed by non-invasive methods of fibrosis testing or by liver biopsy. The American Association for the Study of the Liver guidelines additionally indicates elevated
ALT and HBV DNA 2000–20 000 IU/mL in HBeAg-positive patients can represent seroconversion, and recommends monitoring every 1–3 months, and treatment if
ALT elevation persists for 6 months. The following patients not fulfilling treatment indications can be considered for treatment: HBeAg-positive and older than
30 years of age, family history of hepatocellular carcinoma, and extrahepatic manifestations.

contra­indicated in patients with decompensated cirr­
hosis. HBsAg seroclearance is more frequent with
pegylated interferon than with nucleos(t)ide analogues,
but is mainly observed in patients infected with HBV
genotype A (58%, vs 11% in non-genotype A patients),77
and seldom seen in Asians.78 Pegylated interferon as an
add-on therapy to nucleos(t)ide analogues did not
significantly improve the virological and serological
outcomes in both HBeAg-positive79 and HBeAg-negative
patients.80 Pegylated inter­feron should therefore be
reserved for certain patient subgroups, including those
with cirrhosis and infected with genotype A,81 or patients
with concomitant hepatitis D virus infection,82 as well as
young patients who are reluctant to engage in lifelong
treatment with nucleos(t)ide analogues.
Treatment indications
The recommended indications for treatment (figure 4)
are based on three parameters: serum HBV DNA
concentration, serum ALT concentration, and severity
of liver disease as assessed by either non-invasive
methods or liver biopsy.
International clinical practice guidelines differ on the
cutoffs for treatment initiation: serum HBV DNA of
20 000 IU/mL or above, or 2000 IU/mL or above; and
serum ALT above the upper limit of normal, or more than
two-times the upper limit of normal.19,68 The definition of
the upper limit of normal for ALT also differs, ranging
from 33 U/L for men and 25 U/L for women68 to 40 U/L
for both men and women.19 Nonetheless, all guidelines
agree that patients with cirrhosis, including compensated
or decompensated, should be treated when serum HBV
DNA is detectable, regardless of the ALT concentration.
Treatment should also be considered when there is a
moderate degree of liver fibrosis, even when serum ALT
concentration is normal (figure 4).
The suggested endpoint of antiviral treatment is HBsAg
seroclearance, which has good off-treatment durability
and is associated with improved disease outcomes.83 In
HBeAg-positive patients, treatment cessation can be
considered after HBeAg seroconversion and an additional
treatment consolidation period of at least 12 months;
however, relapse is common after treatment cessation,84
and thus HBsAg seroclearance is regarded as a safer
treatment endpoint.19,68 Because on-treatment HBsAg
seroclearance is uncommon,83 nucleos(t)ide analogue
treatment will be lifelong for most patients.
Prophylactic therapy
HBV reactivation is a potentially fatal complication
of immunosuppressive therapy. A systematic review
showed that reactivation during different regimens or
after cessation of immunosuppressive regimens in
HBsAg-positive individuals occurred in 4–68% of cases.85
HBV reactivation is also possible in HBsAg-negative
anti-HBc antibody-positive individuals receiving certain

2318 www.thelancet.com Vol 392 November 24, 2018


high-risk immunosuppressive therapies, including
anti-CD20 monoclonal antibodies such as rituximab86
and haemopoietic stem cell transplantation.87 In such
patients, when reactivation is defined as detectable serum
HBV DNA, 2-year reactivation rates of more than
40% have been reported. The presence of anti-HBc
antibodies in the absence of HBsAg indicates previous
HBV exposure, thereby exposing the patient to the risk of
reactivation, but it can also be a false-positive result.
A finite duration of prophylactic therapy with a
nucleos(t)ide analogue, irrespective of serum HBV DNA
concentration, has effectively reduced the incid­ ence
of HBV reactivation during immunosup­ pression
(appendix).88,89 Except in patients receiving low-risk
immuno­ suppressive therapies, such as azathioprine,
mercaptopurine, or methotrexate mono­ therapy,90 nuc­
leos(t)ide analogue prophylaxis should be initiated
and continued for at least 6 months after cessation
of immunosuppression, and for 12–18 months after
cessation of anti-CD20 monoclonal antibodies.19,68
After liver transplantation in chronic HBsAg carriers,
prophylactic nucleos(t)ide analogue therapy should be
continued indefinitely, as these drugs have been proven
to be effective in preventing HBV recurrence,91 even
without concomitant administration of hepatitis B
immunoglobulins, for up to 8 years.92
Maternal risk factors for post-birth HBV vaccine
failure include HBV DNA concentration more than
200 000 IU/mL, HBeAg-positivity, and HBsAg concen­
tration more than 10  000 IU/mL.93,94 Concerning its
prevention, a systematic analysis showed that antiviral
therapy reduced the risk of vaccine failure (relative
risk 0·3, 95% CI 0·2–0·5).93 A randomised controlled
trial in China showed that prophylactic tenofovir
disoproxil fumarate in HBsAg-positive women with
HBV DNA concentration more than 200 000 IU/mL
significantly reduced the risk of transmission.95 Prophy­
lactic tenofovir disoproxil fumarate therapy was also cost-
effective.96 Nonetheless, the effectiveness of prophylaxis
might depend on the local frequency of vaccine failure.
In a randomised trial done in Thailand, where the
incidence of vaccine failure in at-risk cohorts was
only 2%, efficacy of tenofovir disoproxil fumarate
prophylaxis was not shown.97
Other forms of prophylactic therapy are listed in the
appendix.5,19,68,90,98
Controversies and uncertainties
Expanding treatment indications
Antiviral therapy is generally not recommended in
patients in the immune tolerant phase of chronic HBV
infection (HBeAg-positive chronic HBV infection;
figure 2),19 a phase of the disease characterised by high
HBV DNA concentration, normal ALT concentration,
and no immune-mediated liver damage. A randomised
controlled trial showed suboptimal viral suppression
with nucleos(t)ide analogue therapy during this early
www.thelancet.com Vol 392 November 24, 2018 2319
Seminar
phase of disease because of the very high HBV DNA
concentration at the start of therapy.99
Emerging evidence shows that an active HBV-specific
T-cell immune response and clonal hepatocyte expansion,
risk factors for hepatocarcinogenesis, are already present
at this early disease phase.100 Furthermore, advanced
liver fibrosis might already be present, especially in
older patients.101 Current recommendations indicate that
patients at this early stage of disease can be considered for
therapy if there is evidence of advanced fibrosis or if they
are older than 30–40 years.19,68 An additional factor that can
influence the decision to treat early is a family history of
hepatocellular carcinoma, which is associated with an
increased cumulative risk of hepato­ cellular carcinoma
in HBsAg-positive individuals (15·8% vs 7·5%),102 and
the need for transmission prevention (eg, health-care
workers or to reduce sexual transmission).19
Treatment at early stages of the disease is likely to raise
issues regarding long-term drug compliance and
additional financial burdens to health-care systems,
emphas­ ising the need for clinical studies assessing
whether earlier treatment leads to improved disease
outcomes.103
Acute-on-chronic liver failure
Acute-on-chronic liver failure (ACLF) is defined as an
acute liver failure (manifesting as any or all of jaundice,
coagulopathy, ascites, and encephalopathy) in patients
with underlying chronic liver disease. Acute exacerbation
of chronic HBV infection, which presents as a sudden
rise in the serum HBV DNA followed by an ALT flare, can
manifest as ACLF, especially in previously undiagnosed
patients.104 HBV-related ACLF suboptimally responds
to nucleos(t)ide analogue therapy. Although disease
outcomes have improved, the 3-month transplant-free
survival rates remain at less than 60% for this condition.105
Several different additional interventions, including
N-acetylcysteine,106 granulocyte colony-stimulating fac­
tor,107 and mesenchymal stem cell transplantation,108 have
been suggested to improve survival, but no double-blind
randomised controlled trials have tested their efficacy.
New therapies would be particularly impactful in regions
with suboptimal accessibility to liver transplantation.
Nucleos(t)ide analogue discontinuation
The question has been raised as to whether interrupting
nucleos(t)ide analogue administration after years of
successful virological suppression could yield a sus­
tained virological response (off-treatment HBV DNA
concen­tration that remains less than 2000 IU/mL, with
a reduced risk of long-term complications) and increase
the HBsAg seroclearance rate. The feasibility of this
approach was shown by a prospective study of
33 European patients with HBeAg-negative chronic
hepatitis B who discontinued long-term adefovir
treatment: 55% of these patients remained in virological
remission, whereas 33% lost HBsAg during follow-up.109
 Seminar
In a subsequent systematic analysis, 38·2% of
HBsAg-positive patients achieved a sustained viro­
logical response after nucleos(t)ide analogue discon­
tinuation.110 In another randomised controlled trial,
62% of HBsAg-positive patients could stop tenofovir
disoproxil fumarate therapy; however, the strength of
the study was limited by the small number of patients
recruited (n=42).111 Incidence of off-treatment virological
relapse in Asian patients was higher than in the afore­
mentioned studies,110,111 varying from 57·9% to 91·4%,
probably because of differences in inclusion criteria and
study endpoints.112–114 Moreover, despite regular post-
treatment cessation monitoring and early retreatment,
severe hepatitis flares, with ALT more than 1000 U/L,
have been reported.112 Quantification of serum HBsAg
has been suggested to predict off-treatment virological
relapse,113 but the accuracy of this parameter greatly
varies.112 A probable prerequisite of treatment cessation
would be a marked reduction of cccDNA as a result of
prolonged nucleos(t)ide analogue therapy.71 Nonetheless,
cccDNA quantification is accessible only from a liver
biopsy, there are no reliable serum bio­ markers of
intrahepatic cccDNA, and no predictive cutoffs have
been established.
Altogether, these results suggest that nucleos(t)ide
analogue treatment cessation is possible in a minority
of HBsAg-positive patients, provided that careful mon­
itoring and retreatment rules are put in place. This
approach remains an option for only non-cirrhotic
pa­tients, with data on its long-term efficacy still required.
Interaction of metabolic disorders with HBV
Metabolic disorders, including obesity,41 diabetes,42,43
and metabolic syndrome,44 worsen HBV-related disease
outcomes. Severe hepatic steatosis, the hallmark of non-
alcoholic fatty liver disease (NAFLD), is associated with
increased liver fibrosis in treatment-naive patients and
in patients receiving antiviral treatment.115 However,
para­doxically, another study suggested that HBV was
protective against NAFLD,116 and concomitant NAFLD is
associated with lower serum HBV DNA concen­trations
than those in patients without NAFLD.117 The proportion
of treated patients is increasing worldwide.73 Thus, the
responsibility of metabolic factors in the course of the
disease is likely to become predominant.
Timing of universal HBV vaccination
As of 2017, although universal infant vaccination has
been introduced nationwide in 186 countries, many
countries do not implement a vaccine dose within 24 h
of birth.5 The UK, for example, provides vaccination
at 8, 12, and 16 weeks after birth.118 Starting vaccination
a few weeks after birth allows easy administration by
health-care facilities and improves compliance by vaccine
recipients,119 and might remain effective in countries
where horizontal transmission is the main method of
infection. However, such a vaccination schedule does not
2320 www.thelancet.com Vol 392 November 24, 2018
prevent vertical transmission.7 In countries with low
endemicity, vaccine effectiveness might be impaired if
there is immigration from highly endemic regions.
Long-term data from such countries will be needed.
Challenges and prospects
Screening and linkage to care
From a public health perspective, enhancing clinical
service engagement and patient retention is integral to
maximising the benefits of HBV-specific interventions.
Nonetheless, many individuals worldwide are not aware of
their HBV serological status, and clinical service coverage
might be rudimentary in low-income and middle-income
countries where the disease burden is the highest.120 Even
in high-income countries, such as the USA, more than a
third of HIV-infected patients had missed opportunities
for initiating HBV vaccination.121 It is estimated that only
16·7% of infected indivi­duals worldwide received antiviral
therapy in 2016.3 Thus, screening for HBV infection and
linkage to care requires substantial improvement.
Collaborative community-based programmes and out­
reach networks targeting specific at-risk populations (eg,
immigrants from endemic regions) can dramatically
improve patient uptake.122 Public health interventions,
such as educational promotions by lay health workers,
can increase HBV testing rates (relative risk 2·68,
95% CI 1·82–3·93),120 with the goal of providing access to
antiviral therapy to infected individuals and vaccination
to unprotected people. The use of rapid diagnostic tests
that do not require laboratory infrastructure and can use
various matrices (eg, whole-blood collected by finger-
prick testing)123 might increase screening and diagnosis
rates. For effective implementation, strategies will need
to be tailored to different populations, and further
research is needed to evaluate and optimise different
HBV service programmes worldwide.
Emerging novel therapies
The main disadvantage of nucleos(t)ide analogues is the
need for lifelong therapy given a low likelihood of HBsAg
seroclearance. Novel therapies aiming at achieving HBsAg
seroclearance (ie, a functional cure of HBV infection), are
at preclinical or early clinical (phase 1 and 2) developmental
stages (appendix). These therapies in­clude, in particular,
HBV-specific immunomodulators, such as immune
stimulators (eg, the RIG-I and NOD2 agonist inarigivir
[SB 9200]124 and the anti-programmed cell death protein 1
antibody nivolumab),125 and thera­ peutic vaccines
(eg, GS-4774 and TG-1050).126,127 These approaches have
been reported to reduce HBsAg concentration to various
extents and, in a few instances, to induce HBsAg
seroclearance.
Antiviral drugs targeting different steps of the HBV life
cycle are also in development. These include small
interfering RNAs that inhibit HBV mRNA transcription
(eg, ARC-520,128 GLS4JHS,129 and ARB-1467130), inhibitors
of nucleocapsid assembly (eg, NVR 3-778131, ABI-H0731,132

and JNJ-56136379133), the viral entry inhibitor
myrcludex B,134 and the HBsAg release inhibitor REP
2139.135 These compounds can reduce serum concen­
trations of different HBV markers, including HBV DNA,
HBV RNA, and HBsAg. Their effects might be enhanced
by the con­ comitant administration of a nucleos(t)ide
analogue.136
Achieving a functional cure of HBV infection will
probably require the combination of different modalities,
including nucleos(t)ide analogue therapy to suppress
viral replication, immune modulation, and another anti­
viral approach. Nonetheless, a complete cure of HBV
remains elusive without the possibility to eradicate
intrahepatic cccDNA. Altogether, our improved under­
standing on the natural history of HBV-related disease,
the accessibility of vaccination worldwide, and the
exciting prospects in emerging therapies will lay the
foundation for WHO’s mission to eliminate viral
hepatitis as a public health threat by 2030.
Contributors
W-KS, Y-RL, J-MP and M-FY participated in the literature search,
writing, and revision of the manuscript, and approved the final version.
Declaration of interests
W-KS is an advisory board member of Gilead Sciences and Bristol-
Myers Squibb, and has received speaker’s fees from AbbVie, Gilead
Sciences, and Bristol-Myers Squibb. Y-RL is a staff member of World
Health Organization; the author alone is responsible for the views
expressed in this publication and they do not necessarily represent the
decisions or policies of the World Health Organization. She declares no
other competing interests. J-MP has received research grants from and
has acted as an adviser for Abbott and Gilead Sciences. M-FY is advisory
board member and has received speaker’s fees from AbbVie, Janssen,
Biocartis NV, Bristol-Myers Squibb, Fujirebio Incorporation, Gilead
Sciences, Merck Sharp and Dohme, and Sysmex Corporation, and has
also received research funding from Bristol-Myers Squibb and
Gilead Sciences.
Acknowledgments
We acknowledge the assistance of Spencer Ng in the generation of
graphics for this Seminar.
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