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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

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Seminar

hepatocytes and transmission to progeny cells (figure 1).11


HBV virion The HBV genome has four overlapping frame-shifted
cccDNA† NTCP receptor
open reading frames that serve for the pregenomic RNA
(the template for reverse transcription into rcDNA within
Protein-free Entry
mRNA rcDNA
the nucleocapsid),10 synthesis of the core protein and
transcription rcDNA Uncoating HBV polymerase, and mRNAs producing HBeAg, large,
middle, and small HBsAg, and X protein. Nucleocapsids
HBV DNA Recycling of containing newly formed rcDNAs are released from the
integration* nucleocapsid Viral secretion
hepatocyte as new virions (figure 1) or recycled to the
Reverse nucleus to replenish the cccDNA pool.
transcription
Other genomic forms of DNA exist. Integration of HBV
Viral protein secretion
DNA sequences is a major source of HBsAg production
Encapsidation Negative Positive during HBeAg-negative disease and contri­butes to viral
strand strand
synthesis synthesis
persistence. Mutated viral proteins are also generated and
Translation
HBV RNA virion-like can participate in hepatocarcinogenesis.12 Spliced viral
particle secretion proteins are also described, although their role in the
Figure 1: Life cycle of HBV
HBV life cycle remains poorly understood.13
cccDNA=covalently closed circular DNA. HBV=hepatitis B virus. NTCP=sodium taurocholate cotransporting There are ten different HBV genotypes (A to J), classified
polypeptide. rcDNA=relaxed circular DNA. *Integrated HBV DNA sequences can produce HBsAg and generate according to at least 8% difference in the full-length
mutant viral proteins that have a role in hepatocarcinogenesis. †cccDNA is the stable form of intrahepatic HBV genome sequence.14 These genotypes have different geo­
DNA responsible for the persistence of HBV.
graphical distributions related to the history of HBV
transmission over the centuries. Whether different geno­
The impact of immunisation programmes at the pop­ types are associated with different disease courses remains
ulation level has been shown in the WHO western Pacific debated, and this association might be related to their
region, which was among the first to introduce HBV different epidemiologies rather than biological differences.
vaccination programmes with time-bound targets.8 Such In addition, HBV genetic variability is constrained by the
programmes were first introduced in the 1980s and 1990s overlapping nature of the four open reading frames in its
in several countries and, by 2005, all countries and areas genome, which makes many of the occurring mutations
of the western Pacific region had started vaccinating lethal. Thus, only a few substitutions with clinical
infants.9 Mathematical modelling estimated that hepatitis significance have been identified.15 The 1896G→A precore
B vaccination prevented more than 37 million cases of mutation and the 1762A→T or 1764G→A basal core
chronic HBV infection among children born between promoter mutations are associated with abolished or
1990 and 2014 in this region, thereby averting more than reduced production of the HBe protein, respectively.
7 million deaths related to HBV. In 2014, with an average During the natural course of infection, precore or basal
HBV three-dose vaccination coverage of 92·2% and HBV core promoter mutant viruses are selected as the dominant
birth-dose coverage of 81·5%, approximately 3 million viral population at the time of HBeAg loss or HBe sero­
chronic infections and 570 566 deaths were prevented.9 conversion.16 Mutations have also been described in the
As of 2015, the global HBsAg prevalence has decreased pre-S and S regions of the genome, including HBsAg
as a result of worldwide vaccination programmes mutations associated with HBV vacc­ ine or hepatitis B
from 4·7% to 1·3% in children under 5 years of age; immunoglobulin treatment escape (eg, Gly145Arg).17
however, the prevalence remains high in non-vaccinated Nucleos(t)ide analogue treatment pressure can select
people.2 HBV vaccination of infants had been imple­ pre-existing resistant viral populations, which reduce
mented nationwide in 186 countries and coverage with susceptibility to the antiviral effect of the drugs.18 Early-
three doses of HBV vaccine was estimated to be 84% by generation nucleos(t)ide analogues, such as lamivudine,
the end of 2016 (appendix). adefovir, and telbivudine, have a low barrier to resistance.
By contrast, entecavir and tenofovir have a high barrier
HBV virology to resistance and should therefore be exclusively used
Life cycle and genetic variability to treat chronic hepatitis B.19 Three mutations must be
Human HBV is a member of the Hepadnaviridae family. present for entecavir resistance to occur, including
The infectious virion contains a partially double- rtLeu180Met, rtMet204Val, and one of rtThr184Gly/Ser,
stranded, relaxed circular DNA (rcDNA) genome of rtSer202Ile/Gly, or rtMet250Val—an unlikely situation
approximately 3200 bp, covalently linked to the HBV responsible for only a 1·2% cumulative 5-year incidence
polymerase.10 After viral entry, the rcDNA is delivered of treatment failure related to resistance after long-term
into the nucleus and converted into fully double-stranded entecavir treatment.20 No mutations have been reported
DNA, which is itself converted by ligation into covalently to confer tenofovir resistance in vivo, a result in keeping
closed circular DNA (cccDNA), the stable form of HBV with the 0% cumulative incidence of tenofovir resistance
DNA that is respon­sible for its persistence in infected after 8 years of therapy.19

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Mechanism of HBV persistence Serum


The likelihood of HBV persistence strongly depends on HBV DNA
age at acquisition. Perinatal infection leads to chronicity Intrahepatic HBV DNA
in most cases, whereas most infection can be controlled still present
in adults. This difference is probably because of the
differing immune maturity between adults and young Current HBeAg-positive HBeAg-positive HBeAg-negative HBeAg-negative HBsAg-negative
terminology chronic infection chronic hepatitis chronic infection chronic hepatitis phase
children.21 The state of the mother’s infection could
also be important, with maternal production of HBeAg Previous Immune tolerant Immune clearance
Inactive carrier phase -
possibly promoting HBV persistence after birth.22 terminology phase phase
Upon hepatocyte infection, the presence of HBV appears Serum HBsAg
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
Serum ALT
replication intermediates from the cellular machinery
and contributes to viral persistence.
The functionality of antiviral effector cells, such as Figure 2: Different phases of chronic HBV infection in relation to the kinetics of serum HBV DNA, HBsAg,
dendritic cells, Kupffer cells, or cytolytic cells (eg, natural and ALT
killer cells), is impaired in patients who develop chronic ALT=alanine aminotransferase. HBV=hepatitis B virus.

HBV infection. These alterations include changes


in the ability of these cells to produce various cyto­ character­ised by immune-mediated liver necroinflam­
kines (including interferon α, interferon γ, interleukin mation, fibrosis, and fluctuating serum ALT concentra­
[IL]6, and IL1), thereby altering the degree of local tion. HBeAg loss and the appearance of anti-HBe
inflammation and inducing a tolerogenic liver environ­ antibodies occur at the end of this second phase. The
ment.23 In addition, CD4-positive and CD8-posi­ tive timing of HBeAg seroconversion is influenced by several
T cell responses are qualitatively and quantitatively factors, including age at acquisition and HBV genotype.14
altered in chronic HBV infection.21,23 CD4-positive T cell Patients in whom seroconversion occurs after age
responses are predominantly of the T-helper-1 type.21,23 40 years have a higher risk of developing cirrhosis and
CD8-positive T cells bear both cytolytic and non-cytolytic hepatocellular carcinoma compared with patients with
effector func­ tions. These responses are con­ comitant earlier sero­conversion.25
with the peak of serum aminotransferase activity that In the HBeAg-negative chronic infection phase, formerly
precedes HBV control. The roles of regulatory T cells, known as the inactive carrier state,19 ALT con­centrations
B cells, and neutralising antibodies in the control of are within the normal range, with HBV DNA falling to less
HBV remain obscure. than 2000 IU/mL, and sometimes becoming undetec­
table.26 Disease progression can occur in a proportion of
Disease course and predictors patients who develop HBeAg-negative chronic hepatitis,
The natural history and disease course of chronic HBV which is characterised by intermittent fluctuations in
infection involve a dynamic interaction between the serum HBV DNA and ALT concen­trations.19 A minority
virus and the host immune responses and can there­ of patients with HBeAg-negative chronic infection can
fore be widely variable. A substantial proportion of spontaneously achieve HBsAg seroclearance (also known
patients develop cirrhosis, complications of cirrhosis, as functional cure of HBV infection), the best possible
and hepatocellular carcinoma, whereas others have outcome,27 although intra­ hepatic HBV persists at low
lifelong quiescent disease activity not requiring antiviral replicative and transcriptional levels.28
therapy. Different phases of chronic HBV infection have The frequency of complications varies greatly among
been described, with changing denominations over different regions. In areas of low HBV prevalence, the
time and differing biochemical and virological profiles incidence of liver-related complications in untreated,
(figure 2).19 The different disease phases are not asymptomatic patients can be as low as 1·2% after
necessarily sequential and can sometimes be reversed 16 years.29 By contrast, the frequency of complications is
(eg, HBeAg or HBsAg seroreversion). Extrahepatic increased in highly endemic regions, where the 5-year
immune-mediated manifes­tations, including glomerulo­ cumulative incidence of cirrhosis in patients with
nephritis, skin changes, polyarteritis nodosa, and mixed HBeAg-positive hepatitis ranges from 13% to 38%, with
cryoglobulinemia, can also develop.24 the 5-year cumulative incidence of liver decompensation
The first phase, known as the immune tolerant phase among patients with cirrhosis reaching 15%. The 5-year
and renamed HBeAg-positive chronic infection,19 is cumulative incidence of hepatocellular carcinoma is also
characterised by high serum HBV DNA but normal substantially higher in highly endemic regions, ranging
serum alanine aminotransferase (ALT) and near- from 3% in patients without cirrhosis to 17% in those
normal liver histology. The second, immune clearance with cirrhosis.30 This higher incidence of liver-related
phase, termed HBeAg-positive chronic hepatitis,19 is complications in high-endemicity areas, where the

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Seminar

cohort of 3233 Chinese patients with chronic HBV


Panel: Serum HBV virological markers infection found a substantial risk of developing liver-related
HBsAg complications in patients with normal ALT concentration.49
• Hallmark of infection; positivity for 6 months or more In a systematic analysis, 20·7% (16·2–26·0) of patients
indicates chronicity with normal ALT (up to 40 U/L) showed evidence of
• Infection persists even after seroclearance advanced liver fibrosis.50 Among those with slightly
(HBsAg-negative phase) elevated ALT (from the upper limit of normal to two-times
• Quantitated levels can prognosticate disease with respect the upper limit of normal), the risk of advanced fibrosis
to seroclearance increased to 48% (36–61).51
Spontaneous HBsAg seroclearance occurs at an
HBeAg annual rate of 0·7–2·3%,52,53 with cumulative sero­
• Positive in early disease phases clearance rates reaching 33% in certain patient
• Serostatus reflection of natural history of disease course populations.54 Although cccDNA persists in the liver and
HBV DNA low-level intrahepatic replication can be present, HBsAg
• Cardinal predictor of disease activity sero­clearance is associated with a negligible risk of
• Important for treatment indication, monitoring, cirrhosis in non-cirrhotic patients28 and a substantially
and post-treatment follow-up decreased risk of hepatocellular carcinoma, including in
patients with cirrhosis (relative risk 0·34 [0·20–0·56]).55
Anti-HBc After HBsAg seroclearance, the lifetime cumulative
• Indicates exposure to HBV incidence of hepatocellular carcinoma falls from 14·2%
• HBV reactivation after potent immunosuppression is to 4·0%.56 Among patients who clear HBsAg, the age at
possible in HBsAg-negative phase of disease sero­clearance is the best predictor of hepatocellular
Hepatitis B core-related antigen (HBcrAg) and HBV RNA carcinoma, with a relative risk of 4·31 (1·72–10·84) in
• Emerging markers, clinical relevance still unclear patients older than 50 years of age compared with
• Might be used as endpoints for clinical trials of novel younger patients.57 The kinetics of HBV viral markers
HBV drugs can predict HBsAg seroclearance and other favourable
clinical outcomes (appendix).53,58–60

majority of patients were infected during their early Initial evaluation of chronic HBV infection
years, might result from longer durations of infection.31 Virological markers
Serum HBV DNA concentration is the cardinal HBV infection is diagnosed by the detection of HBsAg in
predictor of disease activity in HBeAg-negative patients. serum or plasma by means of enzyme immunoassay.
The REVEAL-HBV study32,33 in Taiwan included more Chronic infection is defined by HBsAg positivity for
than 3500 HBsAg-positive participants, 85% of whom 6 months or more. HBsAg quantification in serum or
were HBeAg-negative, followed up for 11 years on plasma is optional and can offer value in disease
average. Compared with patients with HBV DNA of prognostication with respect to subsequent HBsAg
2000 IU/mL or less, the relative risk of cirrhosis was seroclearance (appendix).
2·5 (95% CI 1·6–3·8) and of hepatocellular carcinoma HBV DNA detection and quantification by PCR assay
was 2·7 (1·3–5·6) in patients with serum HBV DNA can be used to confirm diagnosis, to decide when to
of more than 2000 IU/mL. The risks of cirrhosis treat, and for treatment monitoring and post-treatment
and hepatocellular carcinoma further increased with follow-up. Additional serological markers, including
incremental augmentations of serum HBV DNA anti-HBs antibodies, HBeAg and anti-HBe antibodies,
concentration.32,33 In patients with HBV DNA of less than anti-HBc and anti-HBc IgM, are useful to classify HBV-
2000 IU/mL, quantitative measurement of serum HBsAg infected patients into the different phases of the disease,
predicted liver disease progression. HBsAg concen­ guide treatment decisions, and characterise the response
tration of 1000 IU/mL or more, compared with less to therapy.19 Hepatitis B core-related antigen (HBcrAg)
than 1000 IU/mL, increased the risk of hepatitis and HBV RNA are novel serological markers that reflect
(relative risk 1·5 [1·2–1·9]) and hepatocellular carcinoma different HBV life-cycle intermediates, and might be
(13·7 [4·8–39·9]).34,35 For HBeAg-positive disease, high used increasingly in future clinical trials investigating
HBV DNA concentrations were generally not predictive novel HBV drugs. Descriptions of both established
of complications; instead, moderately high HBV DNA and emerging HBV virological markers are described
(above 20 000 IU/mL) together with advanced age was in the panel.
more predictive of increased risk of hepatocellular
carcinoma.36 Other virological and clinical risk factors of Liver assessment
disease progression are presented in the appendix.37–48 Non-invasive methods are replacing liver biopsy for
Disease progression can occur even with normal or assessment of fibrosis. Among these methods, transient
slightly elevated ALT concentration. An observational elastography has been the best validated in patients

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

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

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high-risk immunosuppressive therapies, including phase of disease because of the very high HBV DNA
anti-CD20 monoclonal antibodies such as rituximab86 concentration at the start of therapy.99
and haemopoietic stem cell transplantation.87 In such Emerging evidence shows that an active HBV-specific
patients, when reactivation is defined as detectable serum T-cell immune response and clonal hepatocyte expansion,
HBV DNA, 2-year reactivation rates of more than risk factors for hepatocarcinogenesis, are already present
40% have been reported. The presence of anti-HBc at this early disease phase.100 Furthermore, advanced
antibodies in the absence of HBsAg indicates previous liver fibrosis might already be present, especially in
HBV exposure, thereby exposing the patient to the risk of older patients.101 Current recommendations indicate that
reactivation, but it can also be a false-positive result. patients at this early stage of disease can be considered for
A finite duration of prophylactic therapy with a therapy if there is evidence of advanced fibrosis or if they
nucleos(t)ide analogue, irrespective of serum HBV DNA are older than 30–40 years.19,68 An additional factor that can
concentration, has effectively reduced the incid­ ence influence the decision to treat early is a family history of
of HBV reactivation during immunosup­ pression hepatocellular carcinoma, which is associated with an
(appendix).88,89 Except in patients receiving low-risk increased cumulative risk of hepato­ cellular carcinoma
immuno­ suppressive therapies, such as azathioprine, in HBsAg-positive individuals (15·8% vs 7·5%),102 and
mercaptopurine, or methotrexate mono­ therapy,90 nuc­ the need for transmission prevention (eg, health-care
leos(t)ide analogue prophylaxis should be initiated workers or to reduce sexual transmission).19
and continued for at least 6 months after cessation Treatment at early stages of the disease is likely to raise
of immunosuppression, and for 12–18 months after issues regarding long-term drug compliance and
cessation of anti-CD20 monoclonal antibodies.19,68 additional financial burdens to health-care systems,
After liver transplantation in chronic HBsAg carriers, emphas­ ising the need for clinical studies assessing
prophylactic nucleos(t)ide analogue therapy should be whether earlier treatment leads to improved disease
continued indefinitely, as these drugs have been proven outcomes.103
to be effective in preventing HBV recurrence,91 even
without concomitant administration of hepatitis B Acute-on-chronic liver failure
immunoglobulins, for up to 8 years.92 Acute-on-chronic liver failure (ACLF) is defined as an
Maternal risk factors for post-birth HBV vaccine acute liver failure (manifesting as any or all of jaundice,
failure include HBV DNA concentration more than coagulopathy, ascites, and encephalopathy) in patients
200 000 IU/mL, HBeAg-positivity, and HBsAg concen­ with underlying chronic liver disease. Acute exacerbation
tration more than 10  000 IU/mL.93,94 Concerning its of chronic HBV infection, which presents as a sudden
prevention, a systematic analysis showed that antiviral rise in the serum HBV DNA followed by an ALT flare, can
therapy reduced the risk of vaccine failure (relative manifest as ACLF, especially in previously undiagnosed
risk 0·3, 95% CI 0·2–0·5).93 A randomised controlled patients.104 HBV-related ACLF suboptimally responds
trial in China showed that prophylactic tenofovir to nucleos(t)ide analogue therapy. Although disease
disoproxil fumarate in HBsAg-positive women with outcomes have improved, the 3-month transplant-free
HBV DNA concentration more than 200 000 IU/mL survival rates remain at less than 60% for this condition.105
significantly reduced the risk of transmission.95 Prophy­ Several different additional interventions, including
lactic tenofovir disoproxil fumarate therapy was also cost- N-acetylcysteine,106 granulocyte colony-stimulating fac­
effective.96 Nonetheless, the effectiveness of prophylaxis tor,107 and mesenchymal stem cell transplantation,108 have
might depend on the local frequency of vaccine failure. been suggested to improve survival, but no double-blind
In a randomised trial done in Thailand, where the randomised controlled trials have tested their efficacy.
incidence of vaccine failure in at-risk cohorts was New therapies would be particularly impactful in regions
only 2%, efficacy of tenofovir disoproxil fumarate with suboptimal accessibility to liver transplantation.
prophylaxis was not shown.97
Other forms of prophylactic therapy are listed in the Nucleos(t)ide analogue discontinuation
appendix.5,19,68,90,98 The question has been raised as to whether interrupting
nucleos(t)ide analogue administration after years of
Controversies and uncertainties successful virological suppression could yield a sus­
Expanding treatment indications tained virological response (off-treatment HBV DNA
Antiviral therapy is generally not recommended in concen­tration that remains less than 2000 IU/mL, with
patients in the immune tolerant phase of chronic HBV a reduced risk of long-term complications) and increase
infection (HBeAg-positive chronic HBV infection; the HBsAg seroclearance rate. The feasibility of this
figure 2),19 a phase of the disease characterised by high approach was shown by a prospective study of
HBV DNA concentration, normal ALT concentration, 33 European patients with HBeAg-negative chronic
and no immune-mediated liver damage. A randomised hepatitis B who discontinued long-term adefovir
controlled trial showed suboptimal viral suppression treatment: 55% of these patients remained in virological
with nucleos(t)ide analogue therapy during this early remission, whereas 33% lost HBsAg during follow-up.109

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In a subsequent systematic analysis, 38·2% of prevent vertical transmission.7 In countries with low
HBsAg-positive patients achieved a sustained viro­ endemicity, vaccine effectiveness might be impaired if
logical response after nucleos(t)ide analogue discon­ there is immigration from highly endemic regions.
tinuation.110 In another randomised controlled trial, Long-term data from such countries will be needed.
62% of HBsAg-positive patients could stop tenofovir
disoproxil fumarate therapy; however, the strength of Challenges and prospects
the study was limited by the small number of patients Screening and linkage to care
recruited (n=42).111 Incidence of off-treatment virological From a public health perspective, enhancing clinical
relapse in Asian patients was higher than in the afore­ service engagement and patient retention is integral to
mentioned studies,110,111 varying from 57·9% to 91·4%, maximising the benefits of HBV-specific interventions.
probably because of differences in inclusion criteria and Nonetheless, many individuals worldwide are not aware of
study endpoints.112–114 Moreover, despite regular post- their HBV serological status, and clinical service coverage
treatment cessation monitoring and early retreatment, might be rudimentary in low-income and middle-income
severe hepatitis flares, with ALT more than 1000 U/L, countries where the disease burden is the highest.120 Even
have been reported.112 Quantification of serum HBsAg in high-income countries, such as the USA, more than a
has been suggested to predict off-treatment virological third of HIV-infected patients had missed opportunities
relapse,113 but the accuracy of this parameter greatly for initiating HBV vaccination.121 It is estimated that only
varies.112 A probable prerequisite of treatment cessation 16·7% of infected indivi­duals worldwide received antiviral
would be a marked reduction of cccDNA as a result of therapy in 2016.3 Thus, screening for HBV infection and
prolonged nucleos(t)ide analogue therapy.71 Nonetheless, linkage to care requires substantial improvement.
cccDNA quantification is accessible only from a liver Collaborative community-based programmes and out­
biopsy, there are no reliable serum bio­ markers of reach networks targeting specific at-risk populations (eg,
intrahepatic cccDNA, and no predictive cutoffs have immigrants from endemic regions) can dramatically
been established. improve patient uptake.122 Public health interventions,
Altogether, these results suggest that nucleos(t)ide such as educational promotions by lay health workers,
analogue treatment cessation is possible in a minority can increase HBV testing rates (relative risk 2·68,
of HBsAg-positive patients, provided that careful mon­ 95% CI 1·82–3·93),120 with the goal of providing access to
itoring and retreatment rules are put in place. This antiviral therapy to infected individuals and vaccination
approach remains an option for only non-cirrhotic to unprotected people. The use of rapid diagnostic tests
pa­tients, with data on its long-term efficacy still required. that do not require laboratory infrastructure and can use
various matrices (eg, whole-blood collected by finger-
Interaction of metabolic disorders with HBV prick testing)123 might increase screening and diagnosis
Metabolic disorders, including obesity,41 diabetes,42,43 rates. For effective implementation, strategies will need
and metabolic syndrome,44 worsen HBV-related disease to be tailored to different populations, and further
outcomes. Severe hepatic steatosis, the hallmark of non- research is needed to evaluate and optimise different
alcoholic fatty liver disease (NAFLD), is associated with HBV service programmes worldwide.
increased liver fibrosis in treatment-naive patients and
in patients receiving antiviral treatment.115 However, Emerging novel therapies
para­doxically, another study suggested that HBV was The main disadvantage of nucleos(t)ide analogues is the
protective against NAFLD,116 and concomitant NAFLD is need for lifelong therapy given a low likelihood of HBsAg
associated with lower serum HBV DNA concen­trations seroclearance. Novel therapies aiming at achieving HBsAg
than those in patients without NAFLD.117 The proportion seroclearance (ie, a functional cure of HBV infection), are
of treated patients is increasing worldwide.73 Thus, the at preclinical or early clinical (phase 1 and 2) developmental
responsibility of metabolic factors in the course of the stages (appendix). These therapies in­clude, in particular,
disease is likely to become predominant. HBV-specific immunomodulators, such as immune
stimulators (eg, the RIG-I and NOD2 agonist inarigivir
Timing of universal HBV vaccination [SB 9200]124 and the anti-programmed cell death protein 1
As of 2017, although universal infant vaccination has antibody nivolumab),125 and thera­ peutic vaccines
been introduced nationwide in 186 countries, many (eg, GS-4774 and TG-1050).126,127 These approaches have
countries do not implement a vaccine dose within 24 h been reported to reduce HBsAg concentration to various
of birth.5 The UK, for example, provides vaccination extents and, in a few instances, to induce HBsAg
at 8, 12, and 16 weeks after birth.118 Starting vaccination seroclearance.
a few weeks after birth allows easy administration by Antiviral drugs targeting different steps of the HBV life
health-care facilities and improves compliance by vaccine cycle are also in development. These include small
recipients,119 and might remain effective in countries interfering RNAs that inhibit HBV mRNA transcription
where horizontal transmission is the main method of (eg, ARC-520,128 GLS4JHS,129 and ARB-1467130), inhibitors
infection. However, such a vaccination schedule does not of nucleocapsid assembly (eg, NVR 3-778131, ABI-H0731,132

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19 European Association for the Study of the Liver. EASL 2017 clinical
foundation for WHO’s mission to eliminate viral practice guidelines on the management of hepatitis B virus
hepatitis as a public health threat by 2030. infection. J Hepatol 2017; 67: 370–98.
20 Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up to
Contributors 5 years in patients with hepatitis B e antigen-positive chronic
W-KS, Y-RL, J-MP and M-FY participated in the literature search, hepatitis B. Hepatology 2010; 51: 422–30.
writing, and revision of the manuscript, and approved the final version. 21 Tsai KN, Kuo CF, Ou JJ. Mechanisms of hepatitis B virus
Declaration of interests persistence. Trends Microbiol 2018; 26: 33–42.
W-KS is an advisory board member of Gilead Sciences and Bristol- 22 Tian Y, Kuo CF, Akbari O, Ou JH. Maternal-derived hepatitis B virus
Myers Squibb, and has received speaker’s fees from AbbVie, Gilead e antigen alters macrophage function in offspring to drive viral
Sciences, and Bristol-Myers Squibb. Y-RL is a staff member of World persistence after vertical transmission. Immunity 2016; 44: 1204–14.
Health Organization; the author alone is responsible for the views 23 Boeijen LL, Hoogeveen RC, Boonstra A, Lauer GM. Hepatitis B
expressed in this publication and they do not necessarily represent the virus infection and the immune response: the big questions.
Best Pract Res Clin Gastroenterol 2017; 31: 265–72.
decisions or policies of the World Health Organization. She declares no
other competing interests. J-MP has received research grants from and 24 Han SH. Extrahepatic manifestations of chronic hepatitis B.
Clin Liver Dis 2004; 8: 403–18.
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, 25 Chen YC, Chu CM, Liaw YF. Age-specific prognosis following
spontaneous hepatitis B e antigen seroconversion in chronic
Biocartis NV, Bristol-Myers Squibb, Fujirebio Incorporation, Gilead
hepatitis B. Hepatology 2010; 51: 435–44.
Sciences, Merck Sharp and Dohme, and Sysmex Corporation, and has
26 Papatheodoridis GV, Manolakopoulos S, Liaw YF, Lok A.
also received research funding from Bristol-Myers Squibb and
Follow-up and indications for liver biopsy in HBeAg-negative
Gilead Sciences. chronic hepatitis B virus infection with persistently normal ALT:
Acknowledgments a systematic review. J Hepatol 2012; 57: 196–202.
We acknowledge the assistance of Spencer Ng in the generation of 27 Zeisel MB, Lucifora J, Mason WS, et al. Towards an HBV cure:
graphics for this Seminar. state-of-the-art and unresolved questions—report of the ANRS
workshop on HBV cure. Gut 2015; 64: 1314–26.
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