PRIMER

Hepatitis B virus infection

Man-Fung Yuen1,2*, Ding-Shinn Chen3,4, Geoffrey M. Dusheiko5, Harry L. A. Janssen6,
Daryl T. Y. Lau7, Stephen A. Locarnini8, Marion G. Peters9 and Ching-Lung Lai1,2
Abstract | Hepatitis B virus (HBV) is a hepatotropic virus that can establish a persistent and chronic
infection in humans through immune anergy. Currently, 3.5% of the global population is chronically
infected with HBV, although the incidence of HBV infections is decreasing owing to vaccination and,
to a lesser extent, the use of antiviral therapy to reduce the viral load of chronically infected
individuals. The course of chronic HBV infection typically comprises different clinical phases, each of
which potentially lasts for decades. Well-defined and verified serum and liver biopsy diagnostic
markers enable the assessment of disease severity, viral replication status, patient risk stratification
and treatment decisions. Current therapy includes antiviral agents that directly act on viral
replication and immunomodulators, such as interferon therapy. Antiviral agents for HBV include
reverse transcriptase inhibitors, which are nucleoside or nucleotide analogues that can profoundly
suppress HBV replication but require long-term maintenance therapy. Novel compounds are being
actively investigated to achieve the goal of HBV surface antigen seroclearance (functional cure),
a serological state that is associated with a higher remission rate (thus, no viral rebound) after
treatment cessation and a lower rate of cirrhosis and hepatocellular carcinoma. This Primer addresses
several aspects of HBV infection, including epidemiology, immune pathophysiology, diagnosis,
prevention and management.

*e-mail:
mfyuen@hkucc.hku.hk
Article number: 18035
doi:10.1038/nrdp.2018.35
Published online 7 Jun 2018
Hepatitis B virus (HBV), a partially double-stranded
hepatotropic DNA virus, is the aetiological agent (BOX 1;
FIG.  1) of acute and chronic hepatitis B in humans.
In countries where HBV prevalence is high, infection
usually occurs early in life, leading to lifelong chronic
infection and carriage of the virus, whereas infection later
in life usually leads to an acute, self-resolving illness fol-
lowed by viral clearance or, in rare fulminant cases, liver
failure. Chronic hepatitis B infection is defined as the
detection of serum hepatitis B surface antigen (HBsAg;
the viral glycoprotein) after 6 months of infection. The
transmission route of HBV is primarily through blood
and bodily fluids and includes perinatal and early infant
transmission (mother to child t­ ransmission (MTCT))
as well as sexual and parenteral modes.
Chronic HBV infection is a major public health prob-
lem. In chronic HBV infection, there may be ongoing
low-grade liver inflammation, with episodes of transient
high-grade liver inflammation and activation of fibro-
genic processes, leading to liver fibrosis and cirrhosis,
which may culminate in decompensated (symptomatic)
liver disease and/or the development of hepatocellular
carcinoma (HCC) in 25–40% of HBV carriers1. In addi-
tion, HBV infection has further oncogenic potential
after HBV integration into the host genome, which is an
­additional pathway contributing to HCC.
HBV infection is managed with reverse transcriptase
inhibitors, which are nucleoside or nucleotide analogues
(NUCs), and, less commonly interferon (IFN) therapy.
The total elimination of HBV from patients (HBV cure)
remains a remote treatment goal, but a more practi-
cal goal is the achievement of HBsAg seroclearance
(functional cure) as early as possible after infection.
Although HBsAg seroclearance occurs in only a small
proportion of patients who have undergone treatment
with NUCs, it is associated with a low rate of clinical
complications and a high chance of disease remission
after treatment cessation.
Vaccination remains the most effective tool to pre-
vent HBV infection. HBsAg produced in yeast has
been engineered as an effective recombinant vaccine
for HBV and was licensed for use in the United States
in 1986. An updated generation of HBV vaccines has
been developed that consists of genetically engineered
viral proteins, which can achieve a primary neutral-
izing antibody response after vaccination in >95% of
individuals2. In this Primer, we cover the mechanisms
and pathophysio­logy of HBV infection. Furthermore,
we consider the epidemiology, diagnosis, prevention
and management of infection from a global perspective.
Finally, we discuss promising future research directions
and new drug development.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18035 | 1

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

Author addresses to low prevalence countries9,10. Moreover, mass immigra-

1
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
2
State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary
Hospital, Hong Kong.
3
Hepatitis Research Center, National Taiwan University Hospital, Department of Internal
Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
4
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
5
University College London Medical School and Kings College Hospital, London, UK.
6
Toronto Center for Liver Diseases, Toronto General Hospital, University Health Network,
University of Toronto, Toronto, Ontario, Canada.
7
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, MA, USA.
8
Victorian Infectious Diseases Reference Laboratory, Melbourne, Victoria, Australia.
9
Department of Gastroenterology, University of California, San Francisco, CA, USA.
Epidemiology
Global prevalence
The distribution of chronic HBV infection varies substan-
tially in the world (FIG. 2). The prevalence of chronic HBV
infection is highest in the Western Pacific (6.2% or 115
million individuals have a chronic HBV infection) and
African regions (6.1% or 60 million individuals). The
Eastern Mediterranean region has fairly high prevalence
(3.3% or 21 million individuals); prevalence is lower in
the South–East Asian (2.0% or 39 million individ­uals) and
European regions (1.6% or 15 million i­ ndividuals) and is
lowest in the North and South American regions (0.7%
or 7 million individuals)3. These prevalence data are
instrumental in estimating the disease burden of HBV
and in guiding regional health policies. The prevalence
of chronic HBV infection has been recently meticulously
reviewed and estimated4. According to the most recent
European report 5, prevalence of chronic HBV infection
varies between different parts of Europe with the follow-
ing figures: <1.5% in Northern Europe, <2% in Southern
Europe, <1% in Western Europe and <5% in Eastern
Europe (except for Uzbekistan: 8%). There has been a
steady decline of prevalence of chronic HBV infection in
European countries overall in the past 30 years.
The epidemiology of HBV infection has evolved sub-
stantially since the 1980s owing to the widely used hep-
atitis B vaccine and demographic changes as a result of
population migration6,7. However, despite the advent of
effective vaccines, as well as other disease control meas-
ures, including antiviral therapy, HBV infection is still
a serious global health problem. The WHO estimated
in 2015 that 257 million individuals (3.5% of the global
population) are chronically infected with HBV3, most
of whom were born before the widespread use of the
vaccine3,6,7. Numbers of infected children have declined
since the introduction of the expanded vaccination pro-
gramme promoted by the WHO; in 2015, only ~1.3%
of children <5 years of age developed chronic infection
worldwide3 (FIG. 2b). The WHO African region still has a
high prevalence of chronic hepatitis B infection in chil-
dren, owing to the low coverage of HBV vaccination and
the high viral load (and, therefore, increased ­infectivity)
in pregnant mothers (discussed below)8.
The prevalence of infection in different regions has
also been affected by immigration, owing to the trend of
individuals from HBV-endemic countries immigrating
tion has been a constant feature in recent history, owing
to the globalization of the economy, increasing air and
sea travel, and persistent military or political conflicts
in different parts of the world. After immigration to a
new country, many patients with chronic HBV infection
remain in minority groups with suboptimal health care,
which can hinder the control of HBV infection. Thus,
in countries with high levels of immigration, a hepati-
tis B control programme needs to address the related
cultural, social and logistical hurdles to case f­ inding
and referral9–11.
HBV genotype distribution
There are ten different genotypes of HBV (A–J), and
the geographical distribution of each HBV genotype is
distinct 12,13 (FIG. 2). Infection with different genotypes of
HBV is associated with different outcomes in chroni­
city after infection, disease progression and responses
to IFNα treatment; however, the approved HBV vaccines
are effective against all genotypes12,13. The characteriza-
tion of different HBV genotypes in given populations
may have epidemiological importance, as HBV genotype
generally reflects its country of origin and, therefore,
may be used to track patterns of transmission; as such,
an immigrant’s HBV genotype is generally consistent
with their country of origin14.
Long-term complications and mortality
On average, ~25% of untreated individuals with chronic
HBV infection will die of cirrhosis complications and/or
HCC; this number increases to 50% if only men are
taken into account 15. However, there is a lack of recent
studies on the natural history of untreated HBV infec-
tion, as it is unethical to deny treatment for the virus.
The incidence of long-term sequelae of hepatitis B,
which are cirrhosis and HCC, generally parallels the
occurrence of chronic HBV infection16. The incidence
of the cirrhosis and HCC can be difficult to assess owing
to the slow evolution of disease from chronic hepatitis to
cirrhosis and HCC. Furthermore, cirrhosis and HCC
are asymptomatic in the early stage17,18 and currently
lack good non­invasive biomarkers, making diagnosis
difficult. Moreover, the aetiology of cirrhosis and HCC
is heterogeneous worldwide19,20, adding further diffi-
culties to the estimation of the incidence of liver dis-
ease caused by a given specific aetiology. Nevertheless,
as cirrhosis and HCC will ultimately mani­fest with
decompensated liver disease or death, the frequency
of HBV complications can be extrapolated from mor-
bidity and mortality data. According to the WHO3,
mortality due to viral hepatitis is increasing. In 2000,
1.1 million individuals died of viral hepatitis globally;
this number increased by 22% to 1.3 million individuals
in 2015. In 2015, approximately 0.8 million deaths were
­attributed to HBV infection.
In a large systematic analysis for the Global Burden
of Disease Study 2010 (REF.21), deaths at all ages associ-
ated with acute HBV were 68,600 in 1990 and 132,200
in 2010. For cirrhosis, deaths at all ages attributable to
HBV were 241,700 in 1990 and 312,400 in 2010, and

2 | ARTICLE NUMBER 18035 | VOLUME 4 www.nature.com/nrdp

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

for HCC, deaths attributed to HBV were 210,200 in
1990 and 341,400 in 2010. In 2010, HBV, therefore,
caused a total of 786,000 deaths as a result of acute
HBV infection, cirrhosis and HCC. In the systematic
analysis for the Global Burden of Disease Study 2016
(REF.22), deaths at all ages caused by acute HBV infection
were 100,300 in 2016. By contrast, for HBV-associated
HCC, deaths at all ages were 349,500 in 2016, and cir-
rhosis due to HBV was associated with 365,600 deaths
at all ages. These data emphasize the key burden of
disease due to hepatitis B worldwide and the need for
appropriate interventions.
Mechanisms/pathophysiology
HBV is an enveloped, DNA virus that belongs to the
Hepadnaviridae family 23. The envelope surrounds an
icosahedral nucleocapsid, which encloses a partially
double-­stranded, relaxed circular DNA (rcDNA) genome
of ~3.2 kilobases. Four partially overlapping open read-
ing frames (ORFs), termed P (poly­merase), S (surface),
C (core) and X (HBx protein), define the coding capac-
ity of the HBV genome (FIG. 3). Phylogenetic analyses
of HBV strains isolated from various regions of the
world have identified ten major genotypes (A–J) that
differ at the nucleotide level across full-length genomes
by >8%24.
HBV infection and replication
HBV infects and replicates largely in hepatocytes (FIG. 4).
Initiation of infection is a multistep process and involves
the binding of a highly conformational determinant
region (a) of the HBsAg glycoprotein to heparan sulfate
proteoglycans on the cell surface25; this is a low-affinity
binding reaction that is reversible. Subsequently, HBV
interacts with its specific major receptor, the hepatic bile
acid transporter sodium taurocholate co‑transporting
polypeptide (NTCP)26, with high affinity via the large
HBsAg (L) protein (encoded by pre‑S1) of the virus,
Box 1 | Discovery of HBV
Hepatitis was initially described inappropriately as catarrhal jaundice in 1865, a
description that was later corrected by redefinition as hepatic inflammation in 1930s184.
However, it was not until 1965 that geneticist Baruch Blumberg discovered evidence of
hepatitis B virus (HBV); he observed that an immunoprecipitant formed after mixing the
serum of a patient with haemophilia with that of an individual of aboriginal origin185.
He was later awarded a Nobel Prize for this discovery in 1976. The initially named
Australia antigen marked the beginning of the journey of discovery of HBV. Another
researcher, Alfred M. Prince, linked Australia antigen with serum hepatitis and published
his findings 3 years later186. Later, Australia antigen was commonly found in individuals
living in institutions187, suggesting that crowded conditions facilitated virus acquisition.
Results from subsequent studies on Australia antigen in patients with abnormal serum
aminotransferases confirmed the link between the antigen and hepatitis.
In 1967, Krugman and colleagues188 identified two types of hepatitis, which were
termed MS‑1 and MS‑2. MS‑1 was typically acquired through the oral route after a
short incubation period, whereas MS‑2 was ostensibly transmitted parenterally with
a long incubation period. MS‑1 and MS‑2 hepatitis were subsequently classified as
hepatitis A and B, respectively. Serial chimpanzee and human experiments confirmed
that Australia antigen was responsible for hepatitis B; hence, it was renamed as HBV.
In 1970, Dane and colleagues189 used electron microscopy to visualize diverse subviral
particles (hepatitis B surface antigen existing in circular and filamentous forms (FIG. 1))
in addition to the complete enveloped virions, which were termed Dane particles.
triggering viral internalization. The regions of inter­
action between the NTCP and pre‑S1 proteins have been
mapped26,27, permitting future rational drug design for
blocking viral entry.
Following entry, the rcDNA genome is transported
into the nucleus and converted into covalently closed
circular DNA (cccDNA) using the host cell DNA repair
response28. HBV cccDNA molecules associate with his-
tones H3 and H4 and non-histone proteins, forming a
typical viral minichromosome29; the acetylation status
of histones H3 and H4 directly drives transcriptional
activity from HBV cccDNA30, whereas methylation
of H4 represses cccDNA transcription31. Pregenomic
RNA (pgRNA) is exported from the nucleus and forms
the template for reverse transcription from which the
two strands of HBV DNA are formed. The pgRNA also
serves as the translational template for the core protein
and polymerase. Replication complexes of core parti-
cles containing pgRNA and HBV polymerase assemble
in the cytosol following the binding of polymerase to
the 5ʹ stem–loop structure (ε) in pgRNA. The binding
event induces a packaging reaction, which results in the
formation of immature nucleocapsids in which reverse
transcription of the pgRNA occurs; the circular double-­
stranded rcDNA genome is generated after a complex
multistep process of priming and template shifts within
the nucleocapsid32 (FIG. 4). To egress from cells, HBV
genome-containing capsid binds to HBV surface pro-
teins in the endoplasmic reticulum (ER) and is trans­
located in the ER before exiting the hepatocytes through
the secretory pathway.
A minority of nucleocapsids (~10%) enclose a
double-­stranded linear genome. Double-stranded linear
HBV genomes are efficient precursors for HBV DNA
integration into the host cell genome33. The produc-
tion of double-stranded linear DNA increases with the
progression of liver disease, including in the develop-
ment of HCC34, which corresponds to viral integration
being a tumorigenic event. As HBV DNA integration
typically leaves only the whole HBsAg ORF intact, this
has implications for achieving therapeutic HBsAg loss
(see below).
A characteristic feature of HBV replication is the
secretion into the blood of a vast excess of subviral par-
ticles of HBsAg, predominantly in the form of 17–25 nm
enveloped spherical vesicles. In addition, the translation
of the precore ORF can result in the presence of a secre-
tory protein required for the establishment of chronicity,
hepatitis B e antigen (HBeAg; produced by processing of
precore protein), in the serum during certain infection
phases (FIG. 4).
Immunopathogenesis
Chronic HBV infection can be considered a disease
that is characterized by the failure to mount an effective
and coordinated adaptive immune response, resulting
in viral persistence, which may be a consequence of
the ability of HBV to manipulate key innate immune
responses. Coordinated innate and adaptive immune
responses are important for clearance of HBV from the
liver. Importantly, under most circumstances, HBV is

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18035 | 3

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

noncytopathic (does not directly kill hepatocytes); thus,
the liver inflammation and fibrosis that complicate long-
term chronic infection are predominantly ­mediated by
the host immune response.
Initial events after HBV infection. Following HBV infec-
tion, there is a lag period of 4–7 weeks before HBV DNA
and HBsAg become detectable in serum or the liver
(incubation period). Gene array studies during the
incubation period have not revealed a strong interferon-­
stimulated gene response, leading to the proposition
that HBV might be a stealth virus capable of evading
initial innate immune responses35,36. In addition, virus-
driven suppressive responses have been demonstrated,
including: blocking recruitment of natural killer (NK)
cells, NK T cells and macrophages37; decreasing cytokine
secretion (interferon-γ (IFNγ), tumour necrosis fac-
tor (TNF), IL‑6, IL‑8 and IL‑1β) from Kupffer cells38;
and blocking retinoic-­acid inducible gene I protein
(RIG‑I; also known as DDX58) and Toll-like receptor
(TLR)-signalling, within the hepatocyte39,40.
In acute infection in adults, once viraemia becomes
detectable, the HBV DNA level increases exponentially
in serum to peak levels of 108–109 viral copies per ml
but then typically declines, preceding the onset of clin­
ical hepatitis41. Peripheral HBV-specific CD4+ and CD8+
T cell-mediated responses become detectable with the
exponential increase in HBV replication. In the liver,
there is a lack of any detectable cellular infiltration of
immune cells, suggesting a process of noncytolytic
(no direct killing of infected hepatocytes) clearance of
HBV, which mainly involves cytokine-mediated inhib­
ition of HBV replication via IFNγ and TNF, which are
secreted from virus-specific CD8+ T cells42. The clear-
ance of infected hepatocytes and prevention of further
Subviral particle
Dane particle
Figure 1 | Hepatitis B virions and subviral particles under electron
Nature microscopy.
Reviews | Disease Primers
Electromicrograph of hepatitis B virus (HBV) showing complete double-shelled virions
(Dane particles) and excess subviral particles (containing hepatitis B surface antigen
(HBsAg)) in tubular and small spherical form. Dane particles measure approximately 45 nm
in diameter. The subviral particles do not contain the HBV genome. Taken from the US
Centers for Disease Control and Prevention’s (CDC) Public Health Image Library (PHIL),
identification number #5631.
intra­hepatic spread probably require a combination of
cytolytic and noncytolytic mechanisms43 (FIG. 5). Thus,
during acute resolving hepatitis B, there is a robust,
coordin­ated adaptive immune response with virus-­
specific CD8+ T cells mediating clearance of infected
cells, B cells secreting neutralizing antibodies against
HBsAg (anti-HBs) that block further infection and CD4+
T cells supporting effective viral clearance44. Importantly,
acute hepatitis B with full clinical recovery does not usu-
ally occur when the infection occurs perinatally and in
very early childhood because of the immaturity of the
immune system, which can lead to chronic infection.
Mechanisms leading to HBV chronicity. Persistent
chronic HBV infection occurs mainly in infections
acquired at birth or during the first 2 years of life.
Virological factors that can influence persistence include
the continuous production of HBsAg in concentrations
at least 1,000‑fold higher than that of infectious virions45.
Excessive quantities of subviral particles containing
HBsAg may act as a decoy for HBV-specific humoral
immunity and have been shown to promote a state of
virus-specific T cell anergy (exhaustion triggered by
constant triggering of antigen-specific T cell receptor
signalling pathways) and deletion. Subviral particles
can also negatively modulate innate immune signalling
pathways, including nuclear factor-κB (NF‑κB) and
mitogen-activated protein kinase (MAPK), suppress-
ing inflammatory cytokines and interferon-stimulated
gene transcription normally upregulated by TLR signal-
ling 45–48. Furthermore, the multifunctional HBx protein
can inhibit proteasome-based degradation of viral pro-
teins, thereby reducing HBV antigen presentation49 and
decreasing the host antiviral response. HBx also blocks
key host viral restriction factors, such as SMC 5/6 (two
of the six proteins in sister chromatid cohesion), which
silence HBV cccDNA. Both mechanisms possibly con-
tribute to establishment and/or maintenance of viral per-
sistence49, whereas expression of the HBV polymerase
protein suppresses the production of the myeloid dif-
ferentiation primary response protein MYD88, which
is crucial for TLR signalling 50. The precore or HBeAg
proteins can generate viral tolerance51 by downregulat-
ing TLR2 expression on hepatocytes, Kupffer cells and
peripheral monocytes of patients during HBeAg-positive
disease52 and by downregulating the co‑stimulatory mol-
ecules CD28 on HBV-specific cytotoxic T lymphocytes
(CTLs)53 and CD86 on peripheral blood monocytes and
Kupffer cells in the liver 52 (FIG. 5). Interestingly, a recent
study reported that the expression of co-stimulatory
molecule OX40 ligand (OX40L) in innate immune cells
is important for the clearance of HBV from a mouse
model of infection54. The age-dependent expression of
OX40L may partly explain the high chronicity rate
of infection in children.
Most immunological studies of chronic HBV infec-
tion have been performed on the peripheral blood com-
partment; however, the cellular composition of the liver
is different from that of blood. Intrahepatic immune
responses are described in BOX 2. On the adaptive arm
of the immune response, HBV-specific CD4+ and CD8+

4 | ARTICLE NUMBER 18035 | VOLUME 4 www.nature.com/nrdp

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

a c 120
D

A 100

D
B and C
H E

Number of persons (in millions)

80
A, B, C and D A
F B, C and D
A and D 60

b
40

20

ric io c

on

ed gi n

ro eg an

on

gi th
Af reg cifi

M re Asia

Eu r rane
gi

gi
an n

ite on

an n

s
re ou
on
pe io
Pa

re

re

an S
st
rn

ic nd
Ea
te

er h a
h–
es

Am rt
ut
W

No
So

n
er
Rate of chronic hepatitis B virus infection

st
Ea
Low (<2%) Moderate (2–8%) High (≥8%) WHO region
Figure 2 | Global distribution of chronic hepatitis B infection and viral genotypes. Regions with different population
prevalence of chronic hepatitis B infection, categorized as high (>8%), moderate (2–8%) and low Reviews
Nature (<2%), are| Disease
depicted in
Primers
part a. High prevalence of chronic hepatitis B infection is found in the Western Pacific and Africa. Prevailing genotypes
(letters) in different countries are also depicted in part a. Part b illustrates the global prevalence of chronic hepatitis B
infection in children <5 years old. There has been a substantial reduction of prevalence of chronic hepatitis B infection
in children as a result of a successful vaccination programme, for example, in Asian countries. Part c shows the exact
population size of chronic hepatitis B carriers in different WHO regions.

T cell responses are substantially decreased and barely
functional relative to individuals with resolved acute
infection. Notably, in chronic HBV infection, the fre-
quency and function of both intrahepatic and periph-
eral HBV-specific T cells are inversely proportional
to the level of circulating HBV DNA55. Furthermore,
these blunted T cell responses are coupled to the sus-
tained presence of high levels of virus and viral anti-
gens, therefore, leading to progressive exhaustion and
dysfunction of HBV-specific T cells56,57. The upregu-
lation of mol­ecules responsible for suppressing CTL
function, such as the programmed cell death protein 1
(PD1) receptor, has been demonstrated on HBV-specific
CTLs in patients with chronic HBV infection58,59, with
a corresponding increased expression of PD1 ligand 1
(PDL1) on the surface of dendritic cells60. Moreover, the
inhibitory co‑stimulatory marker cytotoxic T lympho-
cyte antigen 4 (CTLA4) is also upregulated on CD8+
T cells61, and the positive co‑stimulatory ligand CD40
is downregulated on CD4+ T cells62. In addition, in
chronic HBV infection, hepatic macrophages expressing
the C‑type lectin pattern recognition receptor CD206
have been found to produce amphiregulin, which pro-
motes the immunosuppressive activity of intrahepatic
regulatory T cells63. Collectively, these changes result in
the suppression of signalling molecules associated with
T cell proliferation64 and result in increased production
of ­immunosuppressive IL‑10 (REF.62).
Finally, humoral immunity may also play an impor-
tant but incompletely understood part in chronic HBV
infection. This is evidenced by the treatment of individ-
uals with resolved chronic HBV with specific anti‑B cell
therapy (for example, rituximab or ofatumumab) to treat
unrelated diseases; these patients have a substantial risk
(30–60%) of viral reactivation. This risk persists even in
patients who have achieved HBsAg sero­clearance and
seroconversion to anti-HBs. The rate of reactivation after
rituximab is higher than for similarly matched patients
treated with T cell immunosuppressive agents65,66, hint-
ing at the importance of the B cell response for the
­control of HBV.
Natural history of HBV infection
New terminology has been suggested for the phases
of chronic HBV infection. The previously used terms of
immune tolerance, immune active and/or clearance
and immune control and/or residual phases have been
replaced by HBeAg-positive chronic infection, HBeAg-
positive chronic hepatitis and HBeAg-negative chronic
infection, respectively 67 (FIG. 6).

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18035 | 5

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

may contribute to the development of HCC by trans-

PreS2
S1 activating human oncogenes. Detectable HBV-specific
Pre T cell immunity could reflect immune tolerance (which
determines virus persistence and chronicity) if immune
Po tolerance to HBV is defined operationally as the dele-
– lym
er tion or silencing of a sufficient number of HBV-specific
+ a
T cell clones69.

S
se
Immune clearance phase — HBeAg-positive chronic
hepatitis. The second phase, historically termed
immune clearance or immune active phase, most com-
monly occurs in the third or fourth decade of life in
patients who were infected with HBV at an early age.
In this phase, the triggering of immune T cell-mediated
responses against infected hepatocytes leads to the cyto­
lytic release of alanine transaminases (ALT) and reduc-
tion of HBV DNA levels. However, the intensity of the
immune response fluctuates over time, resulting in fluc-
tuating levels of ALT (hepatitis flares, which are defined
C

3' differently in different studies; for example, twofold ele-

5'
3' vation from the baseline ALT levels70,71) and HBV DNA.
5' The liver damage caused by hepatitis flares may lead to
P different degrees of fibrosis and cirrhosis. This phase
Pre can be of varying duration and ends with a reduction of
C HBV DNA concentrations and HBeAg seroconversion
to anti‑HBe positivity (antibodies specific for HBeAg).

X Immune control phase — HBeAg-negative chronic

Figure 3 | Genomic structure of HBV. The hepatitis B virus (HBV)
Nature genome
Reviews is organized
| Disease in
Primers
a circular form with the positive-strand DNA (with variable base length) forming the inner
circle and the negative-strand DNA (completely circular) forming the outer circle. The
four overlapping genes are P for translating polymerase, PreS1/PreS/S for hepatitis B
surface antigen (HBsAg), PreC/C for core protein and X for HBx protein. The P protein has
reverse transcriptase activity. The C and S open reading frames (ORFs) have extensions at
their 5ʹ ends termed pre‑C and pre‑S. The pre‑S region is divided into pre‑S1 and pre‑S2
domains, and translation of the S ORF leads to the production of the large (L), medium
(M) and small (S) HBsAg. Translation of the pre‑C ORF results in a secretory protein,
hepatitis B e antigen (HBeAg), which is an accessory protein required establishing
chronicity, whereas the C ORF results in the capsid protein. HBx is required for
establishment of infection and maintenance of active replication by inhibiting the host
nuclear restriction factor, sister chromatid cohesion 5/6 (SMC 5/6)202. Overexpression of
HBx has been shown to result in cellular transformation via promiscuous transactivation.
Immune tolerance phase — HBeAg-positive chronic
infection. The natural history and immunopatho­genesis
of HBV infection are still being defined. Chronic HBV
infection can be divided into several phases (FIG. 6).
The first immune tolerance phase (also termed the
high replicative, low inflammatory phase or HBeAg-
positive chronic infection) typically occurs during
childhood chronic infection. This phase is character-
ized by high viral load (with HBV DNA levels often
>107 international units (IU) per ml), near normal liver
histology owing to a minimal host immune-mediated
reaction and serum positivity for HBeAg. The concept
of immunological tolerance in young patients who are
HBeAg positive has been criticized as recent studies
have indicated that adolescents may have detectable
HBV-specific functionally active T cells. Studies of this
phase of the disease have also revealed clonal expansion
of hepatocytes and discernible HBV integrants68, which
infection. A proportion of patients (annual rate of ~15%)
will spontaneously seroconvert from HBeAg to anti-
HBe; these patients (previously referred to as inactive
carriers) typically show near normal serum aminotrans-
ferases and HBV DNA concentrations of <2,000 IU per
ml. A more rapid seroconversion to anti-HBe (occur-
ring before the accumulation of marked hepatitis fibro-
sis) with continued low levels of replication and hepatic
inflammation confers good prognosis. However, in gen-
eral, HBeAg-negative patients are older, and if patients
still have moderate or high levels of viral replication,
they would have more-progressive histological disease,
and progression to cirrhosis can be more-rapid.
Notably, in a substantial proportion of patients in
Asian and Mediterranean countries, HBeAg seroconver-
sion is associated with the occurrence of precore and/or
core promoter mutations72,73. In these patients, HBeAg
is absent as a result of the selection of HBV virions that
do not express HBeAg (precore mutant HBV).
Finally, patients may have spontaneous HBsAg sero-
clearance during the natural course of disease. Various
studies have shown that patients with spontaneous
HBsAg seroclearance at an earlier age have a better
outcome than those without HBsAg sero­clearance. In a
cohort of 298 Chinese patients, the cumulative risk of
HCC was higher in patients with HBsAg sero­clearance
at ages ≥50 years compared with those with HBsAg sero­
clearance at ages <50 years. Moreover, fibrosis measured
by liver stiffness assessment was also substantially higher
in the former group (29.5% and 7.9%, respectively).
Intrahepatic total HBV DNA and cccDNA (occult
infection; BOX 3) were detected in 100% and 79.3% of
patients, respectively 74.

6 | ARTICLE NUMBER 18035 | VOLUME 4 www.nature.com/nrdp

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

Diagnosis, screening and prevention
Diagnosis
The key serological marker of acute and chronic hepati-
tis B is the detection of HBsAg in serum. However, sev-
eral other HBV serological markers are clinically useful
in HBV infection. For example, in patients with clinical
recovery of HBV infection, antibodies to HBsAg (anti-
HBs) and hepatitis B core antigen (HBcAg; anti-HBc)
may be detectable. Anti-HBc antibodies may remain
detectable in patients with chronic HBV infection, and
other serum markers can assess the viro­logical status of
the disease (FIG. 4). In addition to serum tests, an assess-
ment of the fibrosis and cirrhosis status in patients with
chronic HBV infection is also important for disease
prognostication, treatment indication and manage-
ment. An accurate but invasive test of liver disease is
liver biopsy, whereas noninvasive tests include tran-
sient elastography (to measure liver stiffness) or vari­ous
serum biomarkers. With the availability of the latter two
methodo­logies, most patients and clinicians are reluctant
to go through with liver biopsy because of its invasive
nature. Algorithms for the use of serum biomarkers and
liver stiffness measurements (if transient elastography is
available) can be used in clin­ical practice to adjudge the
degree of fibrosis in chronic hepatitis B75.
Detection of HBsAg and HBsAg-specific antibodies.
Detection of HBsAg in serum is the standard serolog-
ical test to confirm HBV infection and is also used for
screening in population-based epidemiological studies
to establish the prevalence of chronic HBV infection76.
Conventionally, a chronic HBV infection is diagnosed
by a repeat positive test for HBsAg, 6 months after the
initial positive test. By contrast, after recovery from
acute HBV infection, the levels of HBsAg become
undetectable. HBsAg concentrations differ during the
varying longi­tudinal phases of disease and are generally
higher in individuals with detectable HBeAg (discussed
below) 77. Importantly, HBsAg remains measurable
when serum HBV DNA falls to undetectable levels by

Hepatocyte Bloodstream
HBV
Cytoplasm HBV DNA HBsAg

rcDNA
pgRNA
Nucleus Complete virons Subviral
with rcDNA particles
A(n)
cccDNA A(n)
A(n) HBcAg HBsAg
HBeAg HBV RNA

ATG ATG
PreC HBV core gene
C-terminal
Core protein domain
Translation HBcAg
HBcAg
HBcrAg HBeAg
Precore protein
p22cr
Incomplete Protein processing
protein
processing HBeAg
p22cr

Figure 4 | The HBV replication cycle and key viral markers. After viral entry into hepatocytes
Naturevia the high
Reviews affinity Primers
| Disease
receptor sodium taurocholate co‑transporting polypeptide (left upper diagram), hepatitis B virus (HBV) relaxed circular
DNA (rcDNA) enters the nucleus and is converted into covalently closed circular DNA (cccDNA) in the form of a
minichromosome — the major transcriptional template of the virus. The transcription products are exported from the
nucleus, with the larger pregenomic RNA (pgRNA) incorporated into replication complexes in the cytoplasm comprising
the viral polymerase and core protein. Within these replication complexes, pgRNA is reverse-transcribed into HBV DNA,
which can replenish cccDNA or undergo further packaging. The HBV DNA-containing capsid binds to the HBV surface
proteins on the endoplasmic reticulum, is translocated into the lumen before exiting the hepatocytes through the
secretory pathway and is then released as mature virus particles. mRNAs transcribed from cccDNA also produce various
viral antigens. Except for cccDNA, all the other viral products (HBV rcDNA, HBV RNA, hepatitis B e antigen (HBeAg),
hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBcAg) and 22 kDa precore protein (p22cr)) are easily
measurable in the blood (right diagram). The lower left part of the diagram illustrates the three antigens, HBcAg, HBeAg
and p22cr (collectively known as hepatitis B core-related antigen (HBcrAg)), produced from translation of different starting
codons of the preC core gene and differential protein processing afterwards. A(n), polyadenosine at the end of mRNAs.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18035 | 7

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

sensitive PCR. Moreover, quantitative measurement
of HBsAg has prognostic importance and has been
incorporated into risk scores to predict the risk of
HCC, and may also indicate the risk of viral rebound
after stopping NUCs78. A positive test result for anti-
HBs in patients who tested negative for HBsAg can be
associated with a response to HBV vaccination, recov-
ery from acute hepatitis or HBsAg seroconversion in
chronic HBV infection. HBsAg seroclearance occurs
in 0.1–2% of patients with chronic HBV infection per
year. Thus, the c­ umulative rate can be substantial in
long‑term follow‑up.

Innate immune response Adaptive immune response

Kupffer B cell
Monocyte
cell
Antibodies
TNF TLR2 TH2 CD4+
IL-6 T cell
IL-8
IL-1β HBeAg+ CD4+
T cell
TCR
APC
Cell HBV
death MHC II
TH1 CD4+ Treg cell
MHC I T cell (FOXP3 CD4+
Hepatocyte
CD25+)
TRAIL
TNF
IL-10 CD8+
T cell Cytolytic
PD1 hepatocyte
NO PDL1
Perforins
Granzyme
FAS

NK cell NK T cell Macrophage FASL

Noncytolytic
hepatocyte

HBV-specific IFNγ
HBV CD8+ T cell
Subviral particles
Nature Reviews | Disease Primers
Figure 5 | HBV-specific immune responses. Successful clearance of hepatitis B virus (HBV) from infected hepatocytes
requires the coordinated effort of both the innate and adaptive arms of the immune response. During infection, HBV
­pathogen-associated molecular patterns are sensed by cells of the innate response, including Kupffer cells and monocytes
(top left-hand side of figure), resulting in the release of antiviral cytokines, including tumour necrosis factor (TNF) and
interferon-γ (IFNγ). The virus counters this initial response with the expression of its own proteome, particularly
hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg). The HBeAg downregulates Toll-like receptor 2
(TLR2) signalling on Kupffer cells, and monocytes and hepatocytes promote viral persistence. Excess production of HBsAg
subviral particles (FIG. 4) also substantially blunts the responses of natural killer (NK) cells, NK T cells and macrophages with
the overproduction of the immunosuppressive cytokine IL‑10 (bottom left-hand side of figure). Viral clearance and disease
pathogenesis are linked to the appearance of a vigorous T cell response to the entire HBV proteome. By contrast, viral
persistence is associated with a markedly diminished HBV-specific T cell response. The HBV-specific CD8+ T cell is
regarded as the main immune effector cell clearing HBV infection (lower right-hand side of figure), but other mechanisms
of control and clearance, including antibody-dependent cell cytotoxicity and intracellular neutralization, could also
contribute (top right-hand side of figure). The onset of viral clearance in acute hepatitis B is strongly linked to the
appearance of virus-specific T cells as well as CD3, CD8 and IFNγ‑mRNA in the liver. Whether this temporal relationship
also holds true during the steps towards functional cure needs to be established because exhaustion markers, such as
programmed cell death protein 1 (PD1), are found at much higher frequencies in chronic hepatitis B (central part of figure).
Thus, the host immune response directed against HBV requires the coordinated action of both the innate immunity and
cellular and humoral adaptive immunity to affect both noncytolytic and cytolytic clearance and control. The coordinating
cell that bridges the innate and adaptive response is the antigen-presenting cell (APC) (central part of figure), and
virus-specific blocking of antigen presentation is an effective mechanism of persistence. FAS, tumour necrosis factor
receptor superfamily member 6; FASL, tumour necrosis factor ligand superfamily member 6 (also known as FASLG);
FOXP3, forkhead box protein P3; MHC, major histocompatibility complex; NO, nitric oxide; PDL1, programmed cell death
protein 1 ligand 1; TCR, T cell receptor; TH1, T helper 1; TH2, T helper 2; TRAIL, TNF-related apoptosis-inducing ligand
(also known as TNFSF10); Treg, regulatory T cell. Adapted with permission from REF.203, Baishideng Publishing Group.

8 | ARTICLE NUMBER 18035 | VOLUME 4 www.nature.com/nrdp

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

Box 2 | Intrahepatic immune responses in chronic HBV
Studies of the immune response that focus on the peripheral blood compartment
rather than intrahepatic events have resulted in concepts and paradigms that are not
universally accepted. Furthermore, studies using liver-derived material from untreated
patients have established a pivotal role for innate immunity in the immunopathology of
hepatitis B virus (HBV) infection and challenge earlier concepts, including the concept
that HBV is a stealth virus that evades innate immunity. The discovery that HBV is
recognized in hepatocytes by nucleic acid sensors, such as the Toll-like receptors and
the retinoic acid-inducible gene protein I (RIG‑I) systems, and that other cell
populations have important roles within the liver microenvironment have all
contributed to these new insights. For example, evidence suggests that HBV is a weak
inducer and active repressor of innate proinflammatory cytokines, such as interferon-γ
(IFNγ), in hepatocytes190 rather than having evasive properties. Furthermore, it is
recognized that natural killer (NK) cell numbers are increased several-fold in the liver
compartment compared with the periphery191 and that other innate lymphoid cell
subsets, such as myeloid-derived suppressor cells and mucosal-associated invariant
T cells, play a key part in HBV immunopathogenesis. A landmark study performed
biopsies on >100 patients with untreated chronic HBV infection and demonstrated a
strong downregulation of the major innate immune response pathways, including
interferon-­stimulated gene, Toll-like and pathogen recognition receptor pathways,
and antiviral sensors40. Thus, this work identified a strong impairment of innate immune
responses in the livers of patients with chronic HBV. The investigators also
demonstrated an association of low quantifiable levels of hepatitis B surface antigen
(HBsAg) with decreased innate immune gene repression compared with patients with
higher HBsAg levels, in whom some innate genes were substantially more suppressed.
Detection of HBeAg. HBeAg serological testing, usu-
ally performed after establishing HBsAg positivity
for >6 months (chronic HBV-infected patients), dis-
tinguishes two forms of hepatitis B: HBeAg-positive
and HBeAg-negative chronic HBV infection. HBeAg-
negative, anti-HBe-positive chronic HBV infection is
characterized by the absence of HBeAg in serum. HBeAg
seroconversion marks the transition from the immune
clearance phase or HBeAg-positive chronic hepatitis to
the immune control phase or HBeAg-negative chronic
infection or hepatitis (FIG. 6).
Detection of anti-HBc. Total anti-HBc measured by
immunoassay is a marker of acute, chronic and resolved
HBV infection, or occult hepatitis B (BOX 3). In addition,
the presence of anti-HBc can predict reactivation of
HBV associated with rituximab or immunosuppressive
therapy. Immunoglobulin M (IgM) anti-HBc is detected
during acute HBV infection and is also detected during
exacerbations of chronic HBV, and importantly, it may
be the only serological marker detectable in fulminant
acute hepatitis B. Thus, measurement of anti-HBc is usu-
ally recommended for diagnosis in patients suspected
to have an acute exacerbation of chronic HBV infection
or to decide if patients who are planning to undergo
immunosuppressive therapy will require prophylactic
antiviral therapy.
Detection of HBV DNA. HBV DNA tests should be per-
formed on a regular basis (for example, every 6 months)
in all patients with chronic HBV. Tests for HBV DNA in
serum directly assess viral replication. The concentra-
tions of HBV DNA provide an indication for therapy
within current guidelines67,79–81 and for monitoring treat-
ment efficacy. Indications for treatment are based on the
association between HBV DNA concentrations and the
risk of HCC82. A decline in HBV DNA concentrations
can predict the efficacy of treatment, and an increase in
HBV DNA in serum is observed with the development
of resistance to NUCs18 (discussed below).
Prevention
Vaccination. The age of HBV infection is of vital impor-
tance in determining the risk of chronicity. The risk is
>90% for infants and children <1 years of age, 30% for
children 1–5 years of age and 0–2% for adults83–85. Thus,
most chronic HBV infections are acquired through
MTCT at the time of birth or during infancy and child-
hood. In addition, transmission to children can occur
from other close relatives who are HBV positive86.
MTCT is particularly important in the South-East
Asian and Western Pacific regions, where HBV preva-
lence is still high and the young female population has
a high HBV load, and Africa, where coverage of uni-
versal vaccination for HBV is still suboptimal. In par-
ticular, HBeAg-positive infection increases the risk of
MTCT owing to high viral load. Additionally, horizontal
household and community transmission are problem-
atic in endemic regions87. Effective and safe vaccines are
available that prevent HBV infection and are the key
preventive measure88,89. The introduction of childhood
vaccination has pivotally led to a decline in the preva-
lence of hepatitis B in children3,6,90 (FIG. 2). The world-
wide health threat from chronic hepatitis B has led to the
drafting of aspirational targets to eliminate HBV infec-
tion. The WHO elimination goals include 90% complete
coverage of HBV vaccination, a reduction in the preva-
lence of HBsAg in children <5 years of age to 0.1% and,
finally, an i­ mprovement in the rates of treatment to 80%
by 2030 (REF.91).
The WHO recommends universal vaccination for
HBV and that all infants should receive the first dose
of vaccine soon after birth, preferably within 24 hours.
The birth dose, or vaccination within the expanded
programme on immunization (EPI) dose, is followed
by an additional two to three doses, depending upon
national policies and prevalence. In 2016, 186 of the 194
WHO member countries included the HBV vaccine
in their EPI. However, many births in Global Alliance
for Vaccines and Immunization (GAVI)-supported
countries still occur outside of hospitals and, hence,
these infants do not receive the standard vaccination.
Moreover, only monovalent HBV vaccine can be used
at birth, and the monovalent vaccine is not funded by
GAVI. As such, in 2014, <38% of babies born world-
wide received HBV birth-dose vaccine within 24 hours
of birth92.
In addition to the high infection risk faced by neo-
nates and infants, HBV transmission is also more
common in some groups of people and, therefore, vacci-
nation is more important in these specific groups. These
include health-care providers, laboratory technicians
who handle bodily fluid samples, immunocompromised
patients, institutionalized individuals (for example, pris-
oners) and patients on regular fluid exchange procedures
(for example, dialysis).

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18035 | 9

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

HBV DNA HBsAg

ALT HBeAg
Anti-HBe

HBV DNA levels

ALT levels
HBeAg-positive HBeAg-positive HBeAg-negative HBeAg-negative
New terminology
chronic infection chronic hepatitis chronic infection chronic hepatitis
Immune tolerance Immune active Immune control Residual phase
Old terminology
phase and/or clearance phase and/or residual phase and/or disease flares

Treatment indicated Treatment indicated

Figure 6 | Hepatitis B disease phases and treatment indications. Diagram showing the relationship between hepatitis B
Nature Reviews | Disease Primers
virus (HBV) DNA and alanine transaminase (ALT) levels and the relation of these levels to different phases of chronic HBV
infection using new and old terminology. Some patients (solid lines) experience intermittent flares in HBV DNA and ALT
levels before achieving HBeAg seroconversion, whereas other patients (dashed line) may have a less frequent flares.
Treatment is indicated when the HBV DNA levels are >2,000 or >20,000 international units (IU) per litre and ALT levels are
higher than one or two times the upper limit of normal according to different regional guidelines. anti-HBe, antibodies
against HBeAG; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.

Antiviral prophylaxis. Vaccine protection may fail in
infants born to highly viraemic mothers, typically deline­
ated as maternal HBV DNA concentrations of 2 × 105 IU
per ml. Thus, despite prophylaxis, MTCT is more likely
to be observed in HBeAg-positive women93, occurring
in 8–32% of infants94. The rationale and effectiveness
of NUC prophylaxis in highly viraemic ­mothers have
been recognized, and clinical trials have shown reduced
MTCT with telbivudine, lamivudine or tenofovir dis-
oproxil fumarate (TDF) prophylaxis93,95–97. In a recent
study, despite vaccination at birth, 7% of infants became
HBsAg positive; however, this was reduced to 0% of
infants whose mothers received TDF from 30–32 weeks
of gestation95. At present, the American Association
for the Study of Liver Diseases (AASLD) recommends
the administration of antiviral prophylaxis to HBsAg-
positive mothers whose serum HBV DNA concentra-
tions exceed 2 × 105 IU per ml in the third trimester of
pregnancy. TDF is the recommended NUC for prophy-
laxis in pregnancy, as the drug is safe in pregnancy, with
birth defect rates similar to those of the general popula-
tion. TDF can be stopped 3 months after delivery if the
only indication is to prevent MTCT.
Antiviral prevention of HBV MTCT requires screen-
ing to identify HBV-infected mothers with high levels
of viraemia using HBV DNA testing. However, in many
countries where universal vaccination is administered,
HBV DNA concentrations are not tested in pregnancy.
Implementation of this preventive strategy would require
additional testing, which remains largely unattainable in
resource-limited countries.
Management
Indications for treatment
The relationship between different phases of chronic
HBV and indications for therapy is depicted in FIG. 6.
Indications for treatment in chronic HBV infection are
based on the levels of serum HBV DNA, ALT and severity
of liver disease. Treatment indications are generally sim-
ilar for HBeAg-positive and HBeAg-negative diseases.
Treatment is generally indicated for those with HBV
DNA levels >2,000 IU per ml, or depending on regional
guidelines, at a higher level, for example, 20,000 IU per
ml for HBeAg-positive disease67,80,81 (TABLE 1). Treatment
is also generally indicated for elevated ALT levels, which
are defined, depending on the regional guidelines, as ALT
levels greater than the upper limit of normal (ULN) or
greater than twice the ULN. The presence of moderate
fibrosis by liver biopsy or noninvasive testing may also be
taken into consideration in some conditions, for example,
in elderly patients with relatively normal ALT levels. For
patients with HBV DNA >20,000 IU per ml and ALT
levels greater than twice the ULN, no assessment of fibro-
sis is needed for treatment initiation67. In the presence
of cirrhosis, treatment is often recommended in cases of
detectable HBV DNA levels regardless of the ALT levels.
Other factors to take into account for the indication
of treatment include the patient’s age (older age should
be a factor to consider when starting treatment), a fam-
ily history of liver cancer, comorbidities (for example,
obesity or the presence of alcoholic liver disease), risk of
HBV transmission and extrahepatic manifestations of
hepatitis B. Another situation in which treatment would
be indicated is for the rapid control of viral replication
in patients with severe HBV flares from chronic HBV
infection, the parameters of which include ALT levels
>10-times the ULN with or without clinical symptoms,
including malaise, loss of appetite and tea-coloured
urine. By contrast, treatment for acute HBV infection
is primarily supportive, and antiviral treatment is not
indicated under normal circumstances unless patients
have fulminant liver failure.

10 | ARTICLE NUMBER 18035 | VOLUME 4 www.nature.com/nrdp

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

Disease progression patient monitoring and for informing treatment deci-

In patients who acquire HBV infection during early child-
hood, the majority sequelae of cirrhosis and HCC occur
after HBeAg seroconversion. In a study of 3,233 Chinese
patients, the median age of HBeAg seroconversion was
35 years, whereas the median age for the development
of complications was 57.2 years, and of those with com-
plications, 73.5% were positive for anti-HBe98. However,
serum HBV DNA level is an independent and important
factor for the development of disease ­complications and
is a surrogate marker for HBV replication.
Multiple studies have shown a direct proportionality
between HBV DNA levels and the risk of development
of cirrhosis and HCC; the most rigorous are the two
REVEAL studies from Taiwan82,99. In these two studies,
81.6% and 80.1% of patients were HBeAg negative with
normal ALT levels. For patients with HBV DNA levels
>106 copies per ml (~200,000 IU per ml), the incidence
of cirrhosis and HCC were 2,498 and 1,152 per 100,000
person-years, respectively. However, for patients with
HBV DNA levels <300 copies per ml (~60 IU per ml),
the incidence of complications per 100,000 person-years
was still moderately high at 338.8 for cirrhosis and 108
for HCC. This finding implies that antiviral treatment
should aim to maintain sustained suppression of HBV
DNA to very low, preferably undetectable, levels100.
Other risk factors for HCC include male sex, increasing
age and the presence of core promoter mutations and
pre‑S deletions in HBV101,102. The carcinogenic effects
of HBV are potentiated in patients with several risk
factors concomitantly 103.
Several risk calculators that use common clinical and
laboratory parameters have been derived to predict the
risk of HCC in patients with chronic HBV. These include
GAG (guide with age, gender, HBV DNA, core promoter
mutations and cirrhosis)–HCC score101, CU (Chinese
University)–HCC score104, REACH–B (risk estimation
for HCC in chronic hepatitis B) score105 and the PAGE–B
(platelet, age, gender) score106. These scores are useful
for the strategic planning for disease complications and
Box 3 | Occult HBV infection
Occult hepatitis B is defined as the detection of hepatitis B virus (HBV) DNA in the livers
(with or without detectable HBV DNA in the serum) of individuals negative for HBV
surface antigen (HBsAg)192. The incidence tends to depend on the endemicity of the
hepatitis B infection. These individuals are positive for antibodies specific for hepatitis
B core antigen (anti-HBc) and/or anti-HBs, indicating previous exposure to HBV.
HIV co-infection may be associated with occult HBV infection193,194.
Studies performed in France demonstrated that a large proportion of patients with
alcohol-related hepatocellular carcinoma (HCC) had HBV DNA integrated into the
genome of the neoplastic liver cells195. A second study of cryptogenic HCC in Chinese
individuals also found that 73% had HBV in non-tumour and/or tumour liver tissues196.
Both studies imply that occult HBV infection may be an important cause of HCC in
HBsAg-negative patients.
There is a resurgence of interest in occult hepatitis B because of the widespread use
of potent B cell-depleting monoclonal antibodies against CD20, such as rituximab
(and anti-CD52). These agents are associated with severe, sometimes fatal HBV
reactivation in patients with occult HBV infection up to 12 months after cessation of
rituximab therapy. It is, therefore, important to monitor the HBV DNA levels in these
patients and initiate antiviral therapy once HBV DNA levels become detectable.
Prophylactic antiviral therapy can also be considered in these patients197.
sions; for example, patients calculated to have a rela-
tively high risk of developing HCC should be strongly
­recommended to receive long-term antiviral treatment.
End points of treatment
HBV treatment is typically aimed to achieve profound
virological suppression, which in turn will lead to bio-
chemical remission (return of ALT values to the ­normal
range), histological improvement and prevention of
the complications of liver disease, such as cirrhosis,
liver failure and HCC. A more advanced functional
cure is HBsAg seroclearance, as spontaneous or treat-
ment-associated HBsAg seroclearance substantially
decreases the risk of HCC development, provided the
patient is <50 years of age and has not developed cir-
rhosis74,107,108. However, HBsAg seroclearance is rarely
achieved with the currently available anti-HBV agents
(TABLE 2). A more realistic end point is, therefore, the
induction of sustained or maintained virological remis-
sion, as indicated by undetectable HBV DNA levels and
HBeAg seroconversion.
Current potent NUCs have a profound effect on viro-
logical suppression with continued therapy. For NUCs:
a virological response is defined as undetectable serum
HBV DNA (10–60 IU per ml); a serological response
as HBeAg and/or HBsAg seroconversion; a biochemi-
cal response as normalization of serum ALT level; and a
histological response as a decrease in necroinflam­mation
of the liver 67,80,81. Worldwide, pegylated ­interferon-α
(PEG-IFNα) therapy is given for a finite duration to a
small subset of patients (discussed below) with the aim
of achieving sustained off-treatment immune control.
The response is assessed 6 months post-treatment,
with criteria similar to those of NUCs, except for the
viro­logical response, which is defined as HBV DNA
<2,000 IU per ml.
Long-term follow‑up studies of sustained treatment
with NUCs demonstrate that a profound reduction in
development of cirrhosis can be achieved with the early
initiation of treatment. Consequently, this has resulted
in an almost complete elimination of liver failure in the
setting of treated patients with chronic HBV infection.
In addition, there is a clear reduction, but not complete
prevention, of the development of HCC109,110.
Treatment agents
Treatment agents approved by the US FDA, European
Medicines Agency and many countries in Asia are
broadly classified into immunomodulatory agents
and antiviral agents. The former includes conven-
tional IFNα‑2b and PEG-IFNα‑2a. The latter includes
NUCs, namely, lamivudine, adefovir dipivoxil, ente-
cavir, telbivudine, TDF and tenofovir alafenamide
(TAF). The mainstay of treatment in most countries are
NUCs (FIG. 7).
NUCs. Of the six NUCs licensed by the FDA (FIG. 7),
entecavir, TDF and TAF are the advocated first-line
agents because of their potency and low resistance
rates (TABLE 2). Entecavir has negligible adverse effects

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18035 | 11

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

and is an excellent agent for treatment-naive patients.
However, patients previously treated with lamivudine
who have developed lamivudine resistance will already
have two of the three mutations required for the develop­
ment of entecavir resistance; 51% of these individ­uals
will develop entecavir resistance within 5  years111.
In lamivudine-­resistant patients, TDF and TAF are
the best treatment options. Compared with TDF, TAF
can achieve a higher intrahepatic level of tenofovir;
thus, a lower dose of TAF can be used to exert the same
degree of viral suppression. As such, the off-target effects
of TAF are decreased112. According to one study, TAF
has comparable viral suppression to TDF with improved
rates of ALT normalization, substantially fewer declines
in hip and spine bone mineral density (an adverse effect
of TDF) and smaller decreases in estimated glomerular
filtration rate, indicating TAF has less of an off-target
effect on renal function113. However, in general, clin­
ical adverse effects are considered to be minimal during
long-term NUC therapy.
Short and medium term (1–5 years) treatment with
NUCs can achieve sustained suppression of HBV DNA
to very low, often undetectable levels in all patients100.
Normal ALT levels (30 U per litre for men; 19 U per
litre for women) can be achieved in the majority of
patients. Importantly, long-term treatment with NUCs
has been shown to reverse cirrhosis of the liver 114,115 and
decrease the risk of HCC109. These improvements are not
­dependent on the genotype of HBV.
HBsAg seroclearance occurs in 3–11% of patients
receiving NUCs (TABLE  2). According to one study,
HBsAg seroclearance is unlikely to occur with NUCs
treatment 116. This is corroborated by another study in
42 patients on long-term NUCs (median duration of
treatment of 126 months) with three liver biopsies per-
formed over the course of the study 117. In this study,
long-term treatment with NUCs for >5 years caused
a reduction of intrahepatic HBV DNA and cccDNA
by >99%, whereas HBsAg titres were reduced by only
71.5%; notably, there was no correlation between HBsAg
levels and intrahepatic HBV DNA and cccDNA levels at
the time of the third biopsy. Both studies postulate that
after potent suppression of HBV replication (resulting
in undetectable HBV DNA), HBsAg continues to be
produced by other sources, most likely from integrated
viral sequences117. Currently, no large systematic analy-
ses exist for HBsAg seroclearance rates on NUC therapy.
For the majority of patients, NUCs should be taken on
a long-term, probably lifelong, basis. NUCs can be
stopped after HBsAg seroclearance, but monitoring for
the development of HCC should be continued, especially
for patients with HBsAg seroclearance who are >50 years
of age or who have cirrhosis.
The cost-effectiveness of using NUCs for chronic
HBV infection is also the subject of research. A recent
study carried out community-based screening using
an HBsAg rapid test followed by antiviral treatment in
individuals who were HBsAg positive in a highly HBV
prevalent area, The Gambia118. The study showed an
incremental cost-effective ratio of US$540 per disabil-
ity adjusted life-year and $640 quality-adjusted life-year
saved compared with no intervention.
Interferon-based therapy. PEG-IFNα has both immune
modulatory and antiviral properties and is administered
subcutaneously once per week in subsets of patients who
are indicated for treatment (see below). One year of
PEG-IFNα treatment leads to a sustained off-treatment
response in ~30% of treated patients119,120; treatment
response is defined as serum HBV DNA <2,000 IU per ml
together with ALT levels within the normal range and in
HBeAg-positive patients, HBeAg loss or seroconversion.
HBsAg loss (functional cure) is the desired outcome,
but this occurs in only 10% of treated patients. A longer
duration of therapy could lead to higher response rates
but is difficult to tolerate for many patients121. Adverse
events can be prominent, and patients undergoing
PEG-IFNα therapy require careful monitoring for, for
example, clinical symptoms of malaise, fever, thyrotoxic
features, depression and lab­oratory tests of blood cell
count, liver biochemistry and thyroid function. In addi-
tion, PEG-IFNα is ­contraindicated in patients with
decompensated cirrhosis.
As the response rate is modest and there are con-
siderable adverse effects, PEG-IFNα therapy should be
individualized and given to only a subset of patients who
are predicted to have the highest response rates to PEG-
IFNα therapy. In HBeAg-positive patients, PEG-IFNα
is a reasonable choice as first-line therapy for patients
infected with HBV genotype A or B (which are more
responsive to IFN therapy) who are young, lack major
comorbidities and have lower serum HBV DNA levels
and ALT levels greater than twice the ULN122. In patients
who are HBeAg negative, pretreatment factors that

Table 1 | Indications for initiating treatment in chronic HBV infection

Guideline Individuals who are HBeAg positivea Individuals who are HBeAg negativea
HBV DNA IU/ml ALT U/l HBV DNA IU/ml ALT U/l
EASL67 2017 ≥2,000 >ULN and/or at least moderate liver ≥2,000 >ULN and/or at least moderate liver
necroinflammation or fibrosis necroinflammation or fibrosis
≥20,000 >2× ULN irrespective of fibrosis ≥20,000 >2× ULN irrespective of fibrosis
AASLD80 2016 >20,000 >2× ULN or significant histological disease >2,000 >2× ULN or significant histological disease
APASL 2015
81
≥20,000 >2× ULN or significant histological disease ≥2,000 >2× ULN or significant histological disease
AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; APASL, Asian Pacific Association for the Study of Liver; EASL,
European Association for the Study of the Liver; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IU, international units; ULN, upper limit of normal. aPatients
with cirrhosis with detectable HBV DNA should be treated irrespective of the HBV DNA and ALT levels.

12 | ARTICLE NUMBER 18035 | VOLUME 4 www.nature.com/nrdp

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

Table 2 | Resistance rates and HBsAg seroclearance rates of anti-HBV drugs
Drug Resistance HBsAg seroclearance Refs
Entecavir 1.2% (7 years follow-up) 2.5% (7 years follow-up)
TDF 0% (9 years follow-up) 11.8% for HBeAg+ and 1.3% for
HBeAg– (7 years follow-up)
TAF 0% (96 weeks follow-up)a NA
−
, negative; +, positive; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV,
hepatitis B virus; NA, not yet available; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil
fumarate. aBecause TAF is newly licensed, only 96‑week data are available.
predict response at 24 weeks after treatment included
younger age, female sex, high baseline ALT levels and
low HBV DNA; i­ nterferon treatment would be indicated
in these patients123.
On‑treatment termination rules have been established
for patients who do not respond to PEG-IFNα treatment,
which will prevent unneeded costs for continuation of
treatment in the context of a very low chance of response
and adverse effects. In HBeAg-positive patients, no
decline in levels of HBsAg at week 12 of PEG-IFNα ther-
apy is a strong indication of non-­response in genotypes A
and D, whereas HBsAg >20,000 IU per ml is an indica-
tion for halting therapy in patients infected with geno-
types B and C. At week 24 of treatment, all patients with
a serum HBsAg >20,000 IU per ml are classified as having
a very high chance of treatment failure, irrespective of
HBV genotype124. In these patients, PEG-IFNα treatment
should be discontinued or treatment with NUCs initiated.
HBeAg-negative patients who have no decline in HBsAg
and <2 log decline in HBV DNA at week 12 of treatment
have a very low chance of achieving a treatment response,
and therapy should be similarly discontinued125.
Combined therapy. Studies using combination ther-
apy aim to determine whether drug combinations can
increase the rate of HBsAg seroclearance. According
to one study with 740 treatment-naive patients, a com-
bination of PEG-IFNα with TDF resulted in a higher
rate of HBsAg seroclearance: 9.1% (TDF and 48‑week
PEG-IFNα), 2.8% (TDF and 16‑week PEG-IFNα), 0%
(120‑week TDF) and 2.8% (48‑week PEG-IFNα). Thus,
the combination therapy is superior to both TDF mono-
therapy and PEG-IFNα monotherapy126. Notably, most of
the patients who had HBsAg seroclearance were infected
with HBV genotype A or B. In another study in NUC-
treated patients who were HBeAg negative with undetect-
able HBV DNA, the addition of 48 weeks of PEG-IFNα
was not associated with a significant increase in HBsAg
seroclearance rate (7.8% with PEG-IFNα versus 3.2%
without PEG-IFNα, P = 0.15)127. It is important to note
that these two studies had discrepant results. It might
be that combination therapy using NUCs and PEG-IFNα
works better in treatment-naive patients who are infected
with genotype A or B. In general, combination therapy is
not routinely advocated at the present time.
Antiviral therapy for decompensated liver disease.
It is estimated that ~15–30% of patients with chronic
HBV infection progress to cirrhosis and decompen-
sated liver disease128,129. The availability of potent NUC
therapy has substantially improved the management of
HBV-associated decompensated liver disease. Prolonged
suppression of HBV DNA with NUCs can lead to sub-
204
stantial improvements in hepatic fibrosis and hepatic
205 synthetic function and reduced HCC risks; if patients
with decompensated disease are stabilized, it can obviate
206 the need for liver transplantation130–133. Treating patients
with decompensated cirrhosis in a timely manner is
critical. There is evidence that higher pretreatment bil-
irubin, creatinine and HBV DNA levels are associated
with the highest risk of mortality, despite the initiation
of NUC therapy 134,135.
Ethical considerations mean it is not possible to per-
form large randomized clinical trials of NUC treatment
in decompensated disease, as NUCs are the standard of
care. However, one study compared the clinical outcomes
of 70 decompensated patients who received enteca-
vir with 144 compensated patients who received ente-
cavir daily as first-line therapy for 1 year 135. At the end
of therapy, both groups had similar degrees of viral sup-
pression and rates of undetectable HBV DNA levels and
HBeAg seroconversion. However, among the decom-
pensated patients, six patients died of liver failure and
three had liver transplantation within the first 6 months
of therapy. At baseline, all nine of these patients had high
Child–Pugh–Turcotte (CPT) scores (>10, grade C: the
most advanced grade). Transplantation, therefore, should
not be postponed for patients with grade C CPT score
or a model of end-stage liver disease (MELD) score >15,
as these patients may be at a high risk of liver failure.
A prospective randomized study compared the effi-
cacy of TDF versus TAF plus emtricitabine (another
NUC similar to lamivudine with anti-HBV effect) ver-
sus entecavir in 112 treatment-experienced and treat-
ment-naive patients with decompensated liver disease
for 48 weeks136. Although the primary end point of this
study was safety, secondary outcomes were virological
markers and CTP scores. The rates of HBV DNA sup-
pression were similar in all groups, and improvements
in CPT (≥2 points) were observed in 26–48% of patients.
Overall survival was >90% in all treatment arms. The
rates of adverse events, including nephrotoxicity, were
similar at 1 year of therapy in all groups. The study sug-
gests that, in general, NUCs are effective at suppress-
ing HBV, with an acceptable 1‑year survival in patients
with decompensated liver disease. Although TAF has
lower risks of bone and renal toxic effects, its efficacy
in patients with advanced liver disease still needs to
be evaluated.
Regular HCC surveillance is essential for patients
with advanced baseline hepatic fibrosis, even if they
show a favourable virological response after treatment.
A study examined the efficacy of long-term entecavir
therapy in reducing the risk of HCC in a large cohort
of HBV-related cirrhotic patients137. The suppression of
HBV DNA to <20 IU per ml with entecavir in the first
year of treatment was associated with a 38% reduction in
HCC. However, the annual HCC rate remained signifi­
cant at 2.4%. Older age, male sex, HBeAg positivity and
baseline α-fetoprotein ≥7 ng per ml were predictors
of HCC.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18035 | 13

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

IFNα-2b Lamivudine Adefovir Telbivudine TDF the introduction of TDF and ETV, optimal suppression
of HBV DNA before transplant can be achieved. Thus,
post-transplant prophylaxis with TDF or ETV alone may
be adequate to prevent infection reoccurrence, but not
1990 1998 2002 2005 2006 2008 2016 enough data currently exist to recommend this strat-
egy. TAF likely will replace TDF for all post-transplant
prophylaxis owing to its improved safety profile.
Interferon therapy Entecavir

NUCs therapy Special hepatitis B populations

PEG-IFNα TAF
Immunosuppressed individuals. There is a high rate
Figure 7 | Approved treatment agents for chronic HBVNature Reviews
infection. | Disease
A timeline thatPrimers
shows of HBV reactivation in patients who have previously
the year of US FDA approval for individual hepatitis B virus (HBV) treatment agents. All the achieved HBV suppression after treatment but then
treatment agents have also been approved by the European Medicines Agency and in become immunosuppressed146,147. This may occur dur-
various Asian countries. The boxes in green refer to nucleoside or nucleotide analogues ing chemotherapy, in patients with HIV after immune
(NUCs), and the pale yellow boxes refer to interferon-based therapy. In 2018, the reconstitution (after highly active antiretroviral ther-
recommended first-line agents are pegylated interferon α-2a (PEG-IFNα), entecavir,
apy), after organ transplant and haematopoietic stem cell
tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF).
transplant, or with B cell-depleting agents such as rituxi-
mab (anti‑CD20) or with biological response modifiers
Liver transplantation such as TNF inhibitors. HBV reactivation can also occur
Since 2000, HCC has become the primary indication in immunocompetent patients treated with steroids and
for liver transplantation in patients with chronic HBV biological response modifiers.
infection. However, the rate for liver transplantation for Rituximab is the most potent reactivator of HBV.
decompensated cirrhosis has decreased and is likely the Chemotherapy-induced HBV reactivation can result in
result of the excellent efficacy of antiviral therapy 138. the abrupt reappearance or increase in HBV replication
The use of prophylactic therapy has a major impact with liver damage occurring during and/or following
in preventing the risk of recurrent HBV infection post-­ immune reconstitution. Clinically, this may range from
transplant 139. In many transplant centres, the standard subclinical to severe or even fatal hepatitis (with con-
prophylactic combination therapy is hepatitis B immuno­ current rises in virological and biochemical markers)
globulin (HBIg) given intramuscularly, with dosing and may progress to liver failure and death. The rate of
aimed at maintaining a protective serum anti-HBs level, HBV reactivation after chemotherapy for solid tumours
and NUC therapy. With such an approach, the efficacy is varies148. Of concern, HBV DNA may be undetect­able
>90% in preventing recurrent HBV infection after liver at the time of the ALT peak, and HBV reactivation
transplantation139. With the availability of NUCs with a should always be considered in immunosuppressed
low risk of HBV resistance developing, such as entecavir patients who are HBV positive. A lack of pre-emptive
and TDF, protection can be achieved with lower dose and antiviral therapy can lead to liver damage, resulting in
shorter duration of HBIg 140. In fact, some post-transplant chemotherapy treatment interruptions and premature
centre protocols recommend HBIg use only during the termination of chemotherapy 148. All patients who are
perioperative period (time period immediately after sur- to receive immuno­suppressive therapy should be tested
gery). Researchers in Hong Kong pioneered HBIg-free for HBsAg, anti-HBs and anti-HBc, and the initiation of
prophylaxis, which uses continuous entecavir mono- antiviral therapy before immunosuppression is recom-
therapy from the day of transplant 141,142. This approach mended if HBsAg is positive. If anti-HBc is positive but
provided encouraging results with progressive rates of HBsAg is negative, anti-HBV therapy should be admin-
HBsAg seroclearance from 85% in year 1 to 92% by year istered pre-emptively in the case of rituximab treatment
8 shown in 265 patients. or haematopoietic stem cell transplant, or HBV DNA
The selection of HBV prophylaxis needs to be indi- should be monitored monthly, as the risk of seroreversion
vidualized. Before the era of prophylaxis, patients with (to HBsAg positive status) is at least 10%146. For other
HBV and hepatitis D virus (HDV) co-infection (BOX 4) forms of chemotherapy, close monitoring of HBV DNA
had improved outcomes after liver transplantation as should be considered146,149. In patients who are HBsAg
they have lower HBV DNA levels before transplant 143. negative, anti-HBs positivity seems to be associated with
However, recurrent HDV infection can occur if HBsAg a decreased risk of HBV reactivation150. Reactivation
levels rebound, as the HDV replicative cycle requires may also occur in patients with rheumatoid arthritis
HBsAg. For patients with HDV co-infection, it would who are treated with methotrexate or biological response
be advisable to use a combination of HBIg and NUCs to ­modifiers, including anti-TNF agents151.
ensure long-term suppression of HBsAg post-­transplant,
therefore, preventing graft loss by recurrent infec- HIV co-infection. Co-infection with HBV occurs in ~10%
tion139,144. Liver transplantation has been successfully of HIV-infected patients owing to similar modes of trans-
performed for patients with HIV and HBV co-­infection mission. Globally, HBV is generally acquired in child-
in the United States and Europe since 2001. The combin­ hood, whereas HIV infection occurs later in life owing
ation of HBIg and NUCs was previously used in these to sexual transmission; however, both viruses can be
co-infected patients, especially those with detectable acquired sexually, via MTCT or via intravenous drug use.
HBV DNA levels before transplant 145. However, with Adults with HIV infection who are exposed to HBV have

14 | ARTICLE NUMBER 18035 | VOLUME 4 www.nature.com/nrdp

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

a higher risk (~20%) of developing chronic HBV infec-
tion152. HBV serology may be atypical in HIV patients:
HIV and HBV co-infected patients may have a negative
HBsAg with positive anti-HBc. Isolated anti-HBc (in the
absence of any other serum viral marker) occurs in 7–19%
of HIV-infected patients and is more likely in patients
with underlying hepatitis C virus (HCV) co-infection153.
With the immunosuppression that can accompany HIV
infection, seroreversion may occur from HBsAg negative
to positive. The US Department of Health and Human
Service guidelines state that all HIV patients who are
HBsAg positive should be treated with antiretroviral
therapy that include two drugs effective against HBV,
regardless of HBV DNA level and ALT level. TDF-based
or TAF-based therapy plus lamivudine or TDF or TAF
plus emtricitabine is preferred as initial therapy; HIV–
HBV treatment should be indefinite, as interruption may
lead to severe HBV flares and death154. Anti-HBV drugs
should not be used alone in HIV patients, as most HBV
drugs also have anti-HIV activity, and using them alone
may result in HIV drug resistance155.
HCV co-infection. HCV co-infection in HBV-infected
patients is uncommon156 as is triple infection with
HBV, HCV and HIV157. Co-infected patients have more
extensive hepatic fibrosis and an increased risk of
end-stage liver disease, HCC and death than in HBV
monoinfected patients. HCV treatment is as safe and
effective in co-infected patients as it is in monoinfected
patients and should be considered following the same
rules as HCV monoinfected patients. However, HBV
reactivation can occur in patients with HBV and HCV
co‑infection who are treated with direct-acting anti­
virals (DAAs)158,159. HCV patients co‑infected with HBV
should be treated for HBV before initiating DAA therapy.
Furthermore, HBsAg-negative patients with serological
evidence of prior HBV should be monitored closely for
HBV DNA and ALT levels during and after receiving
DAA therapy for HBV reactivation.
Extrahepatic manifestations
Extrahepatic manifestations of HBV are uncommon and
include rheumatological, neurological, renal and vascu-
litic complications, and all are associated with immune
complexes160. Both membranous glomerulonephritis
and membranoproliferative glomerulonephritis are seen
in chronic HBV patients. Notably, 20–30% of patients
with polyarteritis nodosa have chronic HBV. Antiviral
therapy for HBV can improve both renal and vasculitic
manifestations of disease.

Box 4 | HDV infection
Virology
Hepatitis D virus (HDV) is a defective RNA virus that contains a circular single-stranded
negative-sense RNA genome. The viroid-like 1.7 kb genome encodes two isoforms
(large or small) of the hepatitis D antigen (HDAg). The viral life cycle requires
concomitant hepatitis B virus (HBV) infection for HDV to assemble and propagate within
the host, as the HDV ribonucleoprotein complex requires an envelope of the three HBV
(small, middle and large hepatitis B surface antigen (HBsAg)) envelope proteins.
Epidemiology
Globally, 6–8% of chronic HBV-infected carriers are also infected with HDV. There are
several different HDV genotypes: genotype 1 is prevalent worldwide; genotypes 2 and
4 are prevalent in Japan and Taiwan; genotype 3 is prevalent in the Amazon basin;
and genotypes 5–8 are prevalent in individuals of African origin.
Disease course
Infection occurs either as co-infection (simultaneous HBV–HDV infection) or as a
superinfection in a patient with chronic HBV infection. Fulminant hepatitis can occur
in 3–4% of co-infected individuals. Chronic HDV and HBV superinfection lead to a high
rate of chronic disease and to severe and progressive chronic viral hepatitis with a
high rate of cirrhosis.
Management
HDV infection is managed with pegylated interferon-α (PEG-IFNα) given weekly for
12–18 months. Serum HDV RNA remains undetectable after 6 months of therapy in
~25% of patients198.
Novel treatment on trial
Lonafarnib is an orally ingested tricyclic derivative of carboxamide that inhibits
prenylation of the large HDAg by inhibiting farnesyltransferase199. Myrcludex B
(a 47‑mer myristoylated pre‑S1 lipopeptide) is a subcutaneously delivered allosteric
inhibitor of sodium taurocholate co‑transporting polypeptide200. Nucleic acid polymers
(NAPS) (phosphorothioated oligonucleotides) interfere with viral entry via heparin
sulfate proteoglycans201. All these therapies for HDV are currently in clinical trials.
Outlook
The clearance of HDV RNA depends on the clearance of HBsAg. Other potential
antiviral strategies, including silencing RNAs or immunomodulatory therapies, may be
required for the effective treatment of HDV.
Quality of life
Convincing evidence exists that advanced chronic
liver disease, especially with the presence of ascites and
encephalopathy, is associated with significantly impaired
health-related quality of life (HRQOL) scores161. By con-
trast, patients with mild disease can present with subtle,
nonspecific symptoms. Fatigue is the mostly commonly
recorded symptom among patients with viral hepatitis.
However, malaise and lethargy are generally common,
with prevalence of these symptoms being as high as 25%
in the general population162. A validated fatigue score is,
therefore, necessary to systematically evaluate patients
with chronic HBV infection.
The NIH Patient-Reported Outcomes Management
Information System (PROMIS) is highly reliable in
measuring physical, mental and social functioning. The
PROMIS Fatigue Short Form was applied in addition to
the Medical Outcomes Study 36‑item Short Form Mental
Health Functioning subscale to evaluate a large cohort of
patients with chronic HBV in North America under the
NIH-sponsored Hepatitis B Research Network163. This
cohort included 948 participants who were predominantly
of Asian descent (71%), and only 2% had advanced hepatic
fibrosis with aspartate-to‑platelet ratio index (APRI;
an index of liver fibrosis) scores >1.5. The frequency of
fatigue in this cohort was lower than that reported in the
general population. The mean fatigue scores were simi-
lar among Asian, black and white individ­uals. The study
confirmed that patients with more advanced fibrosis and
those with comorbid conditions, such as diabetes melli-
tus and low mental health functioning, tend to experience
more fatigue. The findings underscore the importance of
being alerted to the possibility of advanced liver disease
or concurrent mental and medical conditions if patients
expressed fatigue during clinic visits.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18035 | 15

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

In another population of patients with chronic HBV
infection in the United States, differences in disease and
treatment perceptions were reported between different
racial groups, with non-Asian patients experiencing
more symptoms164. Interestingly, patients with a history
of interferon-based therapy reported greater symptom-
atology compared with patients treated with only oral
antiviral therapy.
Future studies of HRQOL among patients with
chronic HBV infection should take into account the
health attitudes of the different racial groups, the influ-
ence of the various comorbid ethnic and the effects of
therapy in both mild and severe disease states.
Outlook
Disease control
As of 2016, a universal hepatitis B vaccination pro-
gramme has been implemented in 186 countries
worldwide3. Global coverage with three doses of HBV
vaccine is estimated to be 84% (>90% in the Western
Pacific, regions of the Americas and the South–East Asia
region). In addition, strategic planning is emerging for
antiviral prophylaxis in pregnant HBV-infected women,
which effectively decreases MTCT. As a result of these
efforts, the global prevalence of HBV infection and also
the incidence of HBV-associated liver decompensation
and HCC are expected to decline. However, it may take
at least 30 years for this favourable outcome to emerge.
Until then, we should improve awareness of the dis-
ease, case finding, surveillance strategies and treatment
optimization for the existing 257 million HBV chron-
ically infected people. These challenging steps should
be implemented without delay in all countries to reach
the goal set in May 2016 by the WHO: the elimination
of viral hepatitis as a public threat, with 90% reduction of
new hepatitis infections and 65% reduction in mortality
by 2030. Although health-care workers, health-related
statutory personnel, paramedics and patient groups are
actively involved in the first three aspects, HBV disease
clinicians and researchers are the key persons to improve
the treatment for HBV disease.
New HBV markers. Improved and supplementary HBV
markers, in addition to pre-existing markers, are con-
tinuously being sought for better disease prognostica-
tion and treatment management. The two most recently
developed markers are hepatitis B core-related antigen
(HBcrAg; FIG. 4) and HBV RNA. HBcrAg consists of
three related proteins sharing an identical 149 amino
acid sequence: HBcAg, HBeAg and a truncated 22 kDa
precore protein (p22Cr) (FIG. 4). Monoclonal antibodies
can be used to detect all three proteins, and there is a
good correlation between HBcrAg, serum HBV DNA
and cccDNA165,166. Detectable HBcrAg may demonstrate
the persistence of intrahepatic cccDNA. HBcrAg detec-
tion can differentiate HBeAg-negative from HBeAg-
positive disease and may be used to predict HBeAg
seroconversion, sustained response to NUCs treatment,
the presence of necroinflammatory disease, the risk of
reactivation of hepatitis B with immunosuppression and
the risk of HCC development 166–172.
With HBV RNA testing, it has become apparent that
RNA-containing virus like particles are secreted from
the hepatocytes during HBV replication (FIG. 4). Recent
reports have demonstrated the detection of HBV RNA in
serum samples of HBV-infected patients. The nature of
the HBV RNA in the serum is uncertain but could repre-
sent pgRNA. However, there are technical difficulties in
discriminating HBV RNA from a large excess of rcDNA.
Serum HBV RNA is being assessed as a surrogate to
monitor cccDNA, to assess suppression of DNA synthe-
sis, to determine treatment efficacy using new agents
such as capsid inhibitors and to define end points173–177.
Novel treatment
The ideal treatment goal is the total eradication of HBV
from carriers, that is, the elimination of cccDNA and
integrated HBV DNA from the liver. A definition exists
for such a goal: the sterilizing cure of HBV. To achieve
this, very preliminary research in cell culture and murine
experiments is using targeted endonucleases (CRISPR)
that specifically cleave highly selected HBV DNA
sequences. However, it is anticipated important safety
considerations need to be e­ valuated before these agents
can be tested in humans.
In the near future, we may have several novel
thera­peutic approaches to enhance the rate of HBsAg
seroclearance, hence achieving the functional cure.
These include agents acting through different target­
able steps in the viral life cycle (FIG. 4). One promising
approach entering clinical trials is through viral tran-
scription silencing using short interfering RNAs. In
selected patient popu­lations, a profound reduction of
HBsAg, HBcAg and HBeAg has been observed178,179.
Amelioration of these immune-exhausting viral pro-
teins will hopefully restore innate and specific HBV
immune responses, leading to higher rates of HBsAg
sero­clearance. HBsAg seroclearance is a disease state
in which there is minimal chance of viral rebound on
treatment cessation and is associated with the lowest
risk of developing disease c­ omplications and death if
achieved early in life.
Another group of promising novel antiviral com-
pounds is the capsid protein assembly modifiers or
inhibitors. Disrupting core proteins may affect mul-
tiple vital functions for viral replication, including
viral RNA packaging, immune modulating func-
tions, replenishment of cccDNA and expression of
cccDNA180. In addition, viral protein release inhibitors
and viral entry inhibitors are also being actively inves-
tigated with preliminary promising effects. All these
DAAs are developed with the aim of the restoration of
immune control181,182.
Direct immune-modulating agents, for example,
therapeutic vaccines and TLR agonists, have promising
effects in animal models but have yet to show major
positive effects when tested in humans. However, there
is an interesting upcoming group of compounds acting
through activation of viral sensor proteins, for example,
RIG‑I, to stimulate type I and III interferon production
and boost antiviral immunity. An initial phase I study
has shown promising results183.

16 | ARTICLE NUMBER 18035 | VOLUME 4 www.nature.com/nrdp

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

The agents discussed above are now under active
early clinical phase I and phase II studies. Once their
efficacies and safety profiles are established, the remain-
ing challenge is to determine the best combination and
sequence of agents to achieve the practical goal of HBsAg
seroclearance. Another challenge will be the time required
to achieve this goal. The ideal goal is to have therapy
leading to HBsAg seroclearance at a younger age, which
may result in a considerable reduction of ­development of
­cirrhosis and HCC in HBV-infected persons.

1. Marynard, J., Kare, M. A. & Alter, M. in Viral Hepatitis
and Liver Disease (ed. Zukerman, A.) 967–969
(Alan R. Liss, New York, 1988).
2. Keating, G. M. & Noble, S. Recombinant hepatitis B
vaccine (Engerix‑B): a review of its immunogenicity
and protective efficacy against hepatitis B. Drugs 63,
1021–1051 (2003).
3. World Health Organization. Global Hepatitis Report,
2017 (WHO, Geneva, 2017).
4. Schweitzer, A., Horn, J., Mikolajczyk, R. T., Krause, G.
& Ott, J. J. Estimations of worldwide prevalence of
chronic hepatitis B virus infection: a systematic review
of data published between 1965 and 2013. Lancet
386, 1546–1555 (2015).
5. European Association for the Study of the Liver. EASL-
HEPAHEALTH Project Report: Risk Factors and the
Burden of Liver Disease in Europe and Selected
Central Asian Countries (EASL, Geneva, 2018).
6. Ott, J. J., Stevens, G. A., Groeger, J. & Wiersma, S. T.
Global epidemiology of hepatitis B virus infection: new
estimates of age-specific HBsAg seroprevalence and
endemicity. Vaccine 30, 2212–2219 (2012).
7. Ni, Y.‑H. et al. Continuing decrease in hepatitis B virus
infection 30 years after initiation of infant vaccination
program in Taiwan. Clin. Gastroenterol. Hepatol. 14,
1324–1330 (2016).
This study describes the positive long-term effects
of universal vaccination on the reduction of
hepatitis B prevalence.
8. Tamandjou, C. R., Maponga, T. G., Chotun, N.,
Preiser, W. & Andersson, M. I. Is hepatitis B birth dose
vaccine needed in Africa? Pan Afr. Med. J. 27, 18
(2017).
9. Sharma, S., Carballo, M., Feld, J. J.
& Janssen, H. L. A. Immigration and viral hepatitis.
J. Hepatol. 63, 515–522 (2015).
10. Ward, J. W. & Byrd, K. K. Hepatitis B in the United
States: a major health disparity affecting many
foreign-born populations. Hepatology 56, 419–421
(2012).
11. Kao, J.‑H. & Chen, D.‑S. Universal hepatitis B
vaccination: killing 2 birds with 1 stone. Am. J. Med.
121, 1029–1031 (2008).
12. Kao, J.‑H. & Chen, D.‑S. HBV genotypes: epidemiology
and implications regarding natural history.
Curr. Hepat. Rep. 5, 5–13 (2006).
13. Sunbul, M. Hepatitis B virus genotypes: global
distribution and clinical importance.
World J. Gastroenterol. 20, 5427 (2014).
14. Mixson-Hayden, T. et al. Hepatitis B virus and
hepatitis C virus infections in United States-bound
refugees from Asia and Africa. Am. J. Trop. Med. Hyg.
90, 1014–1020 (2014).
15. Beasley, R. P. Hepatitis B virus as the etiologic agent
in hepatocellular carcinoma — epidemiologic
considerations. Hepatology 2, 21S–26S (1982).
16. Shafritz, D., Sherman, M. & Tur-Kaspa, R. in
Hepatology: A Textbook of Liver Disease 945–958
(WB Saunders, Philadelphia, 1990).
17. Chen, D. From hepatitis to hepatoma: lessons from
type B viral hepatitis. Science 262, 369–370 (1993).
18. Yuen, M.‑F. et al. Chronic hepatitis B virus infection:
disease revisit and management recommendations.
J. Clin. Gastroenterol. 50, 286–294 (2016).
19. Mokdad, A. A. et al. Liver cirrhosis mortality in 187
countries between 1980 and 2010: a systematic
analysis. BMC Med. 12, 145 (2014).
20. El‑Serag, H. B. Hepatocellular carcinoma. N. Engl.
J. Med. 365, 1118–1127 (2011).
21. Lozano, R. et al. Global and regional mortality from
235 causes of death for 20 age groups in 1990 and
2010: a systematic analysis for the Global Burden of
Disease Study 2010. Lancet 380, 2095–2128
(2012).
22. GBD 2016 Causes of Death Collaborators. Global,
regional, and national age-sex specific mortality for
264 causes of death, 1980‑2016: a systematic
analysis for the Global Burden of Disease Study 2016.
Lancet 390, 1151–1210 (2017).
23. Seitz, S., Urban, S., Antoni, C. & Böttcher, B.
Cryo‑electron microscopy of hepatitis B virions reveals
variability in envelope capsid interactions. EMBO J.
26, 4160–4167 (2007).
24. Okamoto, H. et al. Typing hepatitis B virus by
homology in nucleotide sequence: comparison
of surface antigen subtypes. J. Gen. Virol. 69,
2575–2583 (1988).
25. Sureau, C. & Salisse, J. A conformational heparan
sulfate binding site essential to infectivity overlaps
with the conserved hepatitis B virus A‑determinant.
Hepatology 57, 985–994 (2013).
26. Yan, H. et al. Sodium taurocholate cotransporting
polypeptide is a functional receptor for human
hepatitis B and D virus. eLife 1, e00049 (2012).
27. Ni, Y. et al. Hepatitis B and D viruses exploit sodium
taurocholate co‑transporting polypeptide for species-
specific entry into hepatocytes. Gastroenterology
146, 1070–1083 (2014).
28. Schreiner, S. & Nassal, M. A. Role for the host DNA
damage response in hepatitis B virus cccDNA
formation — and beyond? Viruses 9, 125 (2017).
29. Newbold, J. E. et al. The covalently closed duplex form
of the hepadnavirus genome exists in situ as a
heterogeneous population of viral minichromosomes.
J. Virol. 69, 3350–3357 (1995).
30. Levrero, M. et al. Control of cccDNA function in
hepatitis B virus infection. J. Hepatol. 51, 581–592
(2009).
31. Zhang, W. et al. PRMT5 restricts hepatitis B virus
replication through epigenetic repression of covalently
closed circular DNA transcription and interference
with pregenomic RNA encapsidation. Hepatology 66,
398–415 (2017).
32. Bremer, C. & Glebe, D. The molecular virology of
hepatitis B virus. Semin. Liver Dis. 33, 103–112
(2013).
33. Tu, T., Budzinska, M., Shackel, N. & Urban, S. HBV
DNA integration: molecular mechanisms and clinical
implications. Viruses 9, 75 (2017).
34. Zhao, X.‑L. et al. Serum viral duplex-linear DNA
proportion increases with the progression of liver
disease in patients infected with HBV. Gut 65,
502–511 (2015).
35. Wieland, S. F., Spangenberg, H. C., Thimme, R.,
Purcell, R. H. & Chisari, F. V. Expansion and
contraction of the hepatitis B virus transcriptional
template in infected chimpanzees. Proc. Natl Acad.
Sci. USA 101, 2129–2134 (2004).
36. Wieland, S., Thimme, R., Purcell, R. H. & Chisari, F. V.
Genomic analysis of the host response to hepatitis B
virus infection. Proc. Natl Acad. Sci. USA 101,
6669–6674 (2004).
37. Fisicaro, P. et al. Early kinetics of innate and adaptive
immune responses during hepatitis B virus infection.
Gut 58, 974–982 (2009).
38. Hösel, M. et al. Not interferon, but interleukin‑6
controls early gene expression in hepatitis B virus
infection. Hepatology 50, 1773–1782 (2009).
39. Revill, P. & Yuan, Z. New insights into how HBV
manipulates the innate immune response to establish
acute and persistent infection. Antivir. Ther. 18, 1–15
(2013).
40. Lebossé, F. et al. Intrahepatic innate immune response
pathways are downregulated in untreated chronic
hepatitis B. J. Hepatol. 66, 897–909 (2017).
41. Webster, G. Incubation phase of acute hepatitis B
in man: dynamic of cellular immune mechanisms.
Hepatology 32, 1117–1124 (2000).
42. Xia, Y. et al. Interferon‑γ and tumor necrosis factor‑α
produced by T cells reduce the HBV persistence form,
cccDNA, without cytolysis. Gastroenterology 150,
194–205 (2016).
43. Xia, Y. & Protzer, U. Control of hepatitis B virus by
cytokines. Viruses 9, 18 (2017).
44. Shin, E.‑C., Sung, P. S. & Park, S.‑H. Immune
responses and immunopathology in acute and chronic
viral hepatitis. Nat. Rev. Immunol. 16, 509–523
(2016).
45. Shi, B. et al. HBsAg inhibits IFN‑α production in
plasmacytoid dendritic cells through TNF‑α and IL‑10
induction in monocytes. PLoS ONE 7, e44900
(2012).
46. Wu, J. et al. Hepatitis B virus suppresses toll-like
receptor-mediated innate immune responses in
murine parenchymal and nonparenchymal liver cells.
Hepatology 49, 1132–1140 (2008).
47. Jiang, M. et al. Toll-like receptor-mediated immune
responses are attenuated in the presence of high
levels of hepatitis B virus surface antigen. J. Viral
Hepat. 21, 860–872 (2014).
48. Wang, S. et al. Hepatitis B virus surface antigen
selectively inhibits TLR2 ligand-induced IL‑12
production in monocytes/macrophages by interfering
with JNK activation. J. Immunol. 190, 5142–5151
(2013).
49. Seeger, C. & Mason, W. S. Hepatitis B virus biology.
Microbiol. Mol. Biol. Rev. 64, 51–68 (2000).
50. Wu, M. et al. Hepatitis B virus polymerase inhibits the
interferon-inducible MyD88 promoter by blocking
nuclear translocation of Stat1. J. Gen. Virol. 88,
3260–3269 (2007).
51. Milich, D. Exploring the biological basis of hepatitis B
e antigen in hepatitis B virus infection. Hepatology
38, 1075–1086 (2003).
52. Visvanathan, K. et al. Regulation of Toll-like receptor‑2
expression in chronic hepatitis B by the precore
protein. Hepatology 45, 102–110 (2006).
53. Li, X. et al. Changes of costimulatory molecule CD28
on circulating CD8+T cells correlate with disease
pathogenesis of chronic hepatitis B. Biomed. Res. Int.
2014, 423181 (2014).
54. Publicover, J. et al. An OX40/OX40L interaction
directs successful immunity to hepatitis B virus. Sci.
Transl Med. 10, eaah5766 (2018).
55. Webster, G. J. M. et al. Longitudinal analysis of CD8+
T cells specific for structural and nonstructural
hepatitis B virus proteins in patients with chronic
hepatitis B: implications for immunotherapy. J. Virol.
78, 5707–5719 (2004).
56. Wherry, E. J., Blattman, J. N., Murali-Krishna, K.,
van der Most, R. & Ahmed, R. Viral persistence alters
CD8 T‑cell immunodominance and tissue distribution
and results in distinct stages of functional impairment.
J. Virol. 77, 4911–4927 (2003).
57. Zhou, S., Ou, R., Huang, L., Price, G. E.
& Moskophidis, D. Differential tissue-specific
regulation of antiviral CD8+ T‑cell immune
responses during chronic viral infection. J. Virol. 78,
3578–3600 (2004).
58. Boni, C. et al. Characterization of hepatitis B virus
(HBV)-specific T‑cell dysfunction in chronic HBV
infection. J. Virol. 81, 4215–4225 (2007).
59. Fisicaro, P. et al. Combined blockade of programmed
death‑1 and activation of CD137 increase responses
of human liver T cells against HBV, but not HCV.
Gastroenterology 143, 1576–1585.e4 (2012).
60. Chen, L. et al. B7‑H1 up‑regulation on myeloid
dendritic cells significantly suppresses T cell immune
function in patients with chronic hepatitis B.
J. Immunol. 178, 6634–6641 (2007).
61. Schurich, A. et al. Role of the coinhibitory receptor
cytotoxic T lymphocyte antigen‑4 on apoptosis-Prone
CD8 T cells in persistent hepatitis B virus infection.
Hepatology 53, 1494–1503 (2011).
62. Barboza, L. et al. Altered T cell costimulation during
chronic hepatitis B infection. Cell. Immunol. 257,
61–68 (2009).
63. Dai, K., Huang, L., Sun, X., Yang, L. & Gong, Z. Hepatic
CD206‑positive macrophages express amphiregulin
to promote the immunosuppressive activity of
regulatory T cells in HBV infection. J. Leukoc. Biol. 98,
1071–1080 (2015).
64. Chen, C.‑F. et al. Regulation of T cell proliferation
by JMJD6 and PDGF‑BB during chronic hepatitis B
infection. Sci. Rep. 4, 6359 (2014).
65. Shibolet, O. & Shouval, D. Immunosuppression and
HBV Reactivation. Semin. Liver Dis. 33, 167–177
(2013).
66. Seto, W.‑K. et al. Hepatitis B reactivation in patients
with previous hepatitis B virus exposure undergoing
rituximab-containing chemotherapy for lymphoma:
a prospective study. J. Clin. Oncol. 32, 3736–3743
(2014).

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18035 | 17

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

67. European Association for the Study of the Liver. EASL
2017 Clinical Practice Guidelines on the management
of hepatitis B virus infection. J. Hepatol. 67, 370–398
(2017).
68. Mason, W. S. et al. HBV DNA integration and clonal
hepatocyte expansion in chronic hepatitis B patients
considered immune tolerant. Gastroenterology 151,
986–998.e4 (2016).
This study reports that HBV DNA integration
occurs even in the early phase of chronic
hepatitis B infection.
69. Milich, D. R. The concept of immune tolerance in
chronic hepatitis B virus infection is alive and well.
Gastroenterology 151, 801–804 (2016).
70. Yuen, M. et al. Prognostic factors in severe
exacerbation of chronic hepatitis B. Clin. Infect. Dis.
36, 979–984 (2003).
71. Yuen, M.‑F. et al. Role of hepatitis B virus genotypes in
chronic hepatitis B exacerbation. Clin. Infect. Dis. 37,
593–597 (2003).
72. Yuan, H.‑J. et al. Precore and core promoter mutations
at the time of HBeAg seroclearance in Chinese
patients with chronic hepatitis B. J. Infect. 54,
497–503 (2007).
73. Laras, A., Koskinas, J., Avgidis, K. & Hadziyannis, S. J.
Incidence and clinical significance of hepatitis B virus
precore gene translation initiation mutations in e
antigen-negative patients. J. Viral Hepat. 5, 241–248
(1998).
74. Yuen, M. et al. HBsAg seroclearance in chronic
hepatitis B in Asian patients: replicative level and risk
of hepatocellular carcinoma. Gastroenterology 135,
1192–1199 (2008).
This is the first study to report the persistent risk
of development of HCC in patients with HBsAg
seroclearance >50 years of age.
75. European Association for Study of Liver & Asociacion
Latinoamericana para el Estudio del Higado. EASL-
ALEH Clinical Practice Guidelines: Non-invasive tests
for evaluation of liver disease severity and prognosis.
J. Hepatol. 63, 237–264 (2015).
76. Botha, J. F., Dusheiko, G. M., Ritchie, M. J. J.,
Mouton, H. W. K. & Kew, M. C. Hepatitis B virus
carrier state in black children in ovamboland: role
of perinatal and horizontal infection. Lancet 323,
1210–1212 (1984).
77. Seto, W.‑K. et al. Linearized hepatitis B surface
antigen and hepatitis B core-related antigen in the
natural history of chronic hepatitis B. Clin. Microbiol.
Infect. 20, 1173–1180 (2014).
This study reports the profile of HBsAg levels in
different phases of chronic hepatitis B disease.
78. Cornberg, M. et al. The role of quantitative hepatitis B
surface antigen revisited. J. Hepatol. 66, 398–411
(2017).
79. World Health Organization. Guidelines for the
Prevention, Care and Treatment of Persons With
Chronic Hepatitis B Infection (WHO, Geneva, 2015).
80. Terrault, N. A. et al. AASLD guidelines for treatment
of chronic hepatitis B. Hepatology 63, 261–283
(2015).
81. Sarin, S. K. et al. Asian-Pacific clinical practice
guidelines on the management of hepatitis B: a 2015
update. Hepatol. Int. 10, 1–98 (2016).
82. Chen, C.‑J. Risk of hepatocellular carcinoma across
a biological gradient of serum hepatitis B virus DNA
level. JAMA 295, 65 (2006).
This study reports the direct proportional
relationship between HBV DNA level and the risk of
development of HCC and cirrhosis.
83. Seeff, L. B. et al. A serologic follow‑up of the 1942
epidemic of post-vaccination hepatitis in the United
States Army. N. Engl. J. Med. 316, 965–970 (1987).
84. Ozasa, A. et al. Influence of genotypes and precore
mutations on fulminant or chronic outcome of acute
hepatitis B virus infection. Hepatology 44, 326–334
(2006).
85. Stevens, C. E., Beasley, R. P., Tsui, J. & Lee, W.‑C.
Vertical transmission of hepatitis B antigen in Taiwan.
N. Engl. J. Med. 292, 771–774 (1975).
86. Lin, H. J. et al. Evidence for intrafamilial transmission
of hepatitis B virus from sequence analysis of mutant
HBV DNAs in two Chinese families. Lancet 336,
208–212 (1990).
87. Li, Z., Hou, X. & Cao, G. Is mother-to‑infant
transmission the most important factor for persistent
HBV infection? Emerg. Microbes Infect. 4, e30 (2015).
88. Thio, C. L., Guo, N., Xie, C., Nelson, K. E.
& Ehrhardt, S. Global elimination of mother-to‑child
transmission of hepatitis B: revisiting the current
strategy. Lancet Infect. Dis. 15, 981–985 (2015).
89. World Health Organization. Immunization, vaccines
and biologicals: Hepatitis B. WHO http://www.who.int/
immunization/monitoring_surveillance/burden/vpd/
surveillance_type/passive/hepatitis/en/ (2017).
90. Liang, X. et al. Epidemiological serosurvey of hepatitis
B in China — declining HBV prevalence due to hepatitis
B vaccination. Vaccine 27, 6550–6557 (2009).
91. World Health Organization. Global Health Sector
Strategy On Viral Hepatitis 2016–2021
(WHO, Geneva, 2017).
92. World Health Organization. Data, Statistics and
Graphics (WHO, Geneva, 2018).
93. Patton, H. & Tran, T. T. Management of hepatitis B
during pregnancy. Nat. Rev. Gastroenterol. Hepatol.
11, 402–409 (2014).
94. Lin, X. et al. Immunoprophylaxis failure against
vertical transmission of hepatitis B virus in the Chinese
population. Pediatr. Infect. Dis. J. 33, 897–903
(2014).
95. Pan, C. Q. et al. Tenofovir to prevent hepatitis B
transmission in mothers with high viral load. N. Engl.
J. Med. 374, 2324–2334 (2016).
This study demonstrates the efficacy of nucleotide
analogue therapy on reducing the rate of MTCT of
HBV.
96. Zhang, H. et al. Telbivudine or lamivudine use in late
pregnancy safely reduces perinatal transmission of
hepatitis B virus in real-life practice. Hepatology 60,
468–476 (2014).
97. Brown, R. S. et al. Antiviral therapy in chronic hepatitis
B viral infection during pregnancy: a systematic review
and meta-analysis. Hepatology 63, 319–333 (2015).
98. Yuen, M.‑F. Prognostic determinants for chronic
hepatitis B in Asians: therapeutic implications. Gut 54,
1610–1614 (2005).
99. Iloeje, U. H. et al. Predicting cirrhosis risk based
on the level of circulating hepatitis B viral load.
Gastroenterology 130, 678–686 (2006).
100. Lai, C.‑L. & Yuen, M.‑F. Chronic hepatitis B — new
goals, new treatment. N. Engl. J. Med. 359,
2488–2491 (2008).
101. Yuen, M.‑F. et al. Independent risk factors and
predictive score for the development of hepatocellular
carcinoma in chronic hepatitis B. J. Hepatol. 50,
80–88 (2009).
102. Zhang, A.‑Y. et al. Deep sequencing analysis of
quasispecies in the HBV pre‑S region and its
association with hepatocellular carcinoma.
J. Gastroenterol. 52, 1064–1074 (2017).
103. Yuen, M.‑F. et al. Risk for hepatocellular carcinoma
with respect to hepatitis B virus genotypes B/C,
specific mutations of enhancer II/core promoter/
precore regions and HBV DNA levels. Gut 57, 98–102
(2007).
This study reports the synergistic effects of
different risk factors on the development of HCC.
104. Wong, V. W.‑S. et al. Clinical scoring system to predict
hepatocellular carcinoma in chronic hepatitis B
carriers. J. Clin. Oncol. 28, 1660–1665 (2010).
105. Yang, H.‑I. et al. Risk estimation for hepatocellular
carcinoma in chronic hepatitis B (REACH‑B):
development and validation of a predictive score.
Lancet Oncol. 12, 568–574 (2011).
106. Papatheodoridis, G. et al. PAGE‑B predicts the risk of
developing hepatocellular carcinoma in Caucasians
with chronic hepatitis B on 5‑year antiviral therapy.
J. Hepatol. 64, 800–806 (2016).
107. Kim, G.‑A. et al. Incidence of hepatocellular carcinoma
after HBsAg seroclearance in chronic hepatitis B
patients: a need for surveillance. J. Hepatol. 62,
1092–1099 (2015).
108. Kim, G.‑A. et al. HBsAg seroclearance after nucleoside
analogue therapy in patients with chronic hepatitis B:
clinical outcomes and durability. Gut 63, 1325–1332
(2013).
This study reports the sustained clinical benefits in
patients with HBsAg seroclearance after cessation
of therapy.
109. Lai, C.‑L. & Yuen, M.‑F. Prevention of hepatitis B
virus-related hepatocellular carcinoma with antiviral
therapy. Hepatology 57, 399–408 (2013).
110. Hosaka, T. et al. Long-term entecavir treatment
reduces hepatocellular carcinoma incidence in patients
with hepatitis B virus infection. Hepatology 58,
98–107 (2013).
111. Tenney, D. J. et al. Long-term monitoring shows
hepatitis B virus resistance to entecavir in nucleoside-
naïve patients is rare through 5 years of therapy.
Hepatology 49, 1503–1514 (2009).
112. Murakami, E. et al. Implications of efficient hepatic
delivery by tenofovir alafenamide (GS‑7340) for
hepatitis B virus therapy. Antimicrob. Agents
Chemother. 59, 3563–3569 (2015).
113. Buti, M. et al. Tenofovir alafenamide versus tenofovir
disoproxil fumarate for the treatment of patients with
HBeAg-negative chronic hepatitis B virus infection:
a randomised, double-blind, phase 3, non-inferiority
trial. Lancet Gastroenterol. Hepatol. 1, 196–206
(2016).
114. Marcellin, P. et al. Regression of cirrhosis during
treatment with tenofovir disoproxil fumarate for
chronic hepatitis B: a 5‑year open-label follow‑up
study. Lancet 381, 468–475 (2013).
115. Chang, T.‑T. et al. Long-term entecavir therapy results
in the reversal of fibrosis/cirrhosis and continued
histological improvement in patients with chronic
hepatitis B. Hepatology 52, 886–893 (2010).
116. Chevaliez, S., Hézode, C., Bahrami, S., Grare, M.
& Pawlotsky, J.‑M. Long-term hepatitis B surface
antigen (HBsAg) kinetics during nucleoside/nucleotide
analogue therapy: Finite treatment duration unlikely.
J. Hepatol. 58, 676–683 (2013).
117. Lai, C.‑L. et al. Reduction of covalently closed circular
DNA with long-term nucleos(t)ide analogue treatment
in chronic hepatitis B. J. Hepatol. 66, 275–281
(2017).
This study reports the virological status in the liver
after long-term nucleos(t)ide analogue treatment.
118. Nayagam, S. et al. Cost-effectiveness of community-
based screening and treatment for chronic hepatitis B
in The Gambia: an economic modelling analysis.
Lancet Glob. Health 4, e568–e578 (2016).
119. Janssen, H. L. A. et al. Pegylated interferon alfa‑2b
alone or in combination with lamivudine for HBeAg-
positive chronic hepatitis B: a randomised trial. Lancet
365, 123–129 (2005).
120. Marcellin, P. et al. Peginterferon alfa‑2a alone,
lamivudine alone, and the two in combination in
patients with HBeAg-negative chronic hepatitis B.
N. Engl. J. Med. 351, 1206–1217 (2004).
121. Lampertico, P. et al. Randomised study comparing 48
and 96 weeks peginterferon α-2a therapy in genotype
D HBeAg-negative chronic hepatitis B. Gut 62,
290–298 (2012).
122. Buster, E. H. C. J. et al. Factors that predict response
of patients with hepatitis B e antigen–positive chronic
hepatitis B to peginterferon-alfa. Gastroenterology
137, 2002–2009 (2009).
123. Bonino, F. et al. Predicting response to
peginterferon‑2a, lamivudine and the two combined
for HBeAg-negative chronic hepatitis B. Gut 56,
699–705 (2007).
124. Sonneveld, M. J. et al. Response-guided peginterferon
therapy in hepatitis B e antigen-positive chronic
hepatitis B using serum hepatitis B surface antigen
levels. Hepatology 58, 872–880 (2013).
125. Rijckborst, V. et al. Early on‑treatment prediction of
response to peginterferon alfa‑2a for HBeAg-negative
chronic hepatitis B using HBsAg and HBV DNA levels.
Hepatology 52, 454–461 (2010).
126. Marcellin, P. et al. Combination of tenofovir disoproxil
fumarate and peginterferon α-2a increases loss of
hepatitis B surface antigen in patients with chronic
hepatitis B. Gastroenterology 150, 134–144.e10
(2016).
127. Bourlière, M. et al. Effect on HBs antigen clearance of
addition of pegylated interferon alfa‑2a to nucleos(t)
ide analogue therapy versus nucleos(t)ide analogue
therapy alone in patients with HBe antigen-negative
chronic hepatitis B and sustained undetectable plasma
hepatitis. Lancet Gastroenterol. Hepatol. 2, 177–188
(2017).
128. Fattovich, G., Bortolotti, F. & Donato, F. Natural
history of chronic hepatitis B: Special emphasis on
disease progression and prognostic factors. J. Hepatol.
48, 335–352 (2008).
129. Chen, C.‑J. & Yang, H.‑I. Natural history of chronic
hepatitis B REVEALed. J. Gastroenterol. Hepatol. 26,
628–638 (2011).
130. Buti, M. et al. Long-term clinical outcomes in cirrhotic
chronic hepatitis B patients treated with tenofovir
disoproxil fumarate for up to 5 years. Hepatol. Int. 9,
243–250 (2015).
131. Papatheodoridis, G. V., Chan, H. L.‑Y., Hansen, B. E.,
Janssen, H. L. A. & Lampertico, P. Risk of
hepatocellular carcinoma in chronic hepatitis B:
assessment and modification with current antiviral
therapy. J. Hepatol. 62, 956–967 (2015).
132. Ahn, J. et al. Lower observed hepatocellular carcinoma
incidence in chronic hepatitis B patients treated with
entecavir: results of the ENUMERATE study.
Am. J. Gastroenterol. 111, 1297–1304 (2016).

18 | ARTICLE NUMBER 18035 | VOLUME 4 www.nature.com/nrdp

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

133. Yao, F. Lamivudine treatment is beneficial in patients
with severely decompensated cirrhosis and actively
replicating hepatitis B infection awaiting liver
transplantation: a comparative study using a matched,
untreated cohort. Hepatology 34, 411–416 (2001).
134. Fontana, R. J. et al. Determinants of early mortality in
patients with decompensated chronic hepatitis B
treated with antiviral therapy. Gastroenterology 123,
719–727 (2002).
135. Shim, J. H. et al. Efficacy of entecavir in treatment-
naïve patients with hepatitis B virus-related
decompensated cirrhosis. J. Hepatol. 52, 176–182
(2010).
136. Liaw, Y.‑F. et al. Tenofovir disoproxil fumarate (TDF),
emtricitabine/TDF, and entecavir in patients with
decompensated chronic hepatitis B liver disease.
Hepatology 53, 62–72 (2010).
137. Su, T.‑H. et al. Four-year entecavir therapy reduces
hepatocellular carcinoma, cirrhotic events and
mortality in chronic hepatitis B patients. Liver Int. 36,
1755–1764 (2016).
138. Flemming, J. A., Kim, W. R., Brosgart, C. L.
& Terrault, N. A. Reduction in liver transplant wait-
listing in the era of direct-acting antiviral therapy.
Hepatology 65, 804–812 (2016).
139. Zhou, K. & Terrault, N. Management of hepatitis B
in special populations. Best Pract. Res. Clin.
Gastroenterol. 31, 311–320 (2017).
140. Cholongitas, E. & Papatheodoridis, G. V. High genetic
barrier nucleos(t)ide analogue(s) for prophylaxis from
hepatitis B virus recurrence after liver transplantation:
a systematic review. Am. J. Transplant. 13, 353–362
(2012).
141. Fung, J. et al. Entecavir monotherapy is effective
in suppressing hepatitis B virus after liver
transplantation. Gastroenterology 141, 1212–1219
(2011).
142. Fung, J. et al. Long-term outcomes of entecavir
monotherapy for chronic hepatitis B after liver
transplantation: results up to 8 years. Hepatology 66,
1036–1044 (2017).
This study reports a high rate of HBsAg negativity
using long-term entecavir monotherapy after liver
transplantation.
143. Samuel, D. et al. Liver transplantation in European
patients with the hepatitis B surface antigen. N. Engl.
J. Med. 329, 1842–1847 (1993).
144. Adil, B. et al. Hepatitis B virus and hepatitis D virus
recurrence in patients undergoing liver transplantation
for hepatitis B virus and hepatitis B virus plus
hepatitis D virus. Transplant. Proc. 48, 2119–2123
(2016).
145. Coffin, C. S. et al. Virologic and clinical outcomes
of hepatitis B virus infection in HIV-HBV coinfected
transplant recipients. Am. J. Transplant. 10,
1268–1275 (2010).
146. Loomba, R. & Liang, T. J. Hepatitis B reactivation
associated with immune suppressive and biological
modifier therapies: current concepts, management
strategies, and future directions. Gastroenterology
152, 1297–1309 (2017).
147. Dong, H.‑J. et al. Risk of hepatitis B virus (HBV)
reactivation in non-Hodgkin lymphoma patients
receiving rituximab-chemotherapy: a meta-analysis.
J. Clin. Virol. 57, 209–214 (2013).
 172. Mak, L.‑Y. et al. Review article: hepatitis B core-related
148. Voican, C. S. et al. Hepatitis B virus reactivation in
patients with solid tumors receiving systemic
anticancer treatment. Ann. Oncol. 27, 2172–2184
(2016).
149. Coluccio, C. et al. Hepatitis B in patients with
hematological diseases: an update. World J. Hepatol.
9, 1043 (2017).
150. Paul, S. et al. Role of surface antibody in hepatitis B
reactivation in patients with resolved infection and
hematologic malignancy: a meta-analysis. Hepatology
66, 379–388 (2017).
151. Cheung, K.‑S., Seto, W.‑K., Lai, C.‑L. & Yuen, M.‑F.
Prevention and management of hepatitis B virus
reactivation in cancer patients. Hepatol. Int. 10,
407–414 (2016).
152. Koziel, M. J. & Peters, M. G. Viral hepatitis in HIV
infection. N. Engl. J. Med. 356, 1445–1454 (2007).
153. Bhattacharya, D. et al. Isolated hepatitis B core
antibody is associated with advanced hepatic fibrosis
in HIV/HCV infection but not in HIV infection alone.
J. Acquir. Immune Def. Syndr. 72, e14–e17 (2016).
154. Panel on Antiretroviral Guidelines for Adults and
Adolescents. Guidelines for the Use of Antiretroviral
Agents in Adults and Adolescents Living with HIV.
AIDSinfo https://aidsinfo.nih.gov/contentfiles/
lvguidelines/adultandadolescentgl.pdf (2018)
155. McMahon, M. A. et al. The HBV drug entecavir —
effects on HIV‑1 replication and resistance. N. Engl.
J. Med. 356, 2614–2621 (2007).
156. Pol, S. et al. The negative impact of HBV/HCV
coinfection on cirrhosis and its consequences.
Aliment. Pharmacol. Ther. 46, 1054–1060 (2017).
157. Bonacini, M., Louie, S., Bzowej, N. & Wohl, A. R.
Survival in patients with HIV infection and viral
hepatitis B or C. AIDS 18, 2039–2045 (2004).
158. Bersoff-Matcha, S. J. et al. Hepatitis B Virus
reactivation associated with direct-acting antiviral
therapy for chronic hepatitis C virus: a review of cases
reported to the U. S. Food and Drug Administration
Adverse Event Reporting System. Ann. Intern. Med.
166, 792 (2017).
159. Chen, G. et al. Hepatitis B reactivation in hepatitis B
and C coinfected patients treated with antiviral
agents: a systematic review and meta-analysis.
Hepatology 66, 13–26 (2017).
160. Han, S. H. Extrahepatic manifestations of chronic
hepatitis B. Clin. Liver Dis. 8, 403–418 (2004).
161. Orr, J. G. et al. Health related quality of life in people
with advanced chronic liver disease. J. Hepatol. 61,
1158–1165 (2014).
162. Cullen, W., Kearney, Y. & Bury, G. Prevalence of fatigue
in general practice. Ir. J. Med. Sci. 171, 10–12
(2002).
163. Evon, D. M. et al. Fatigue in patients with chronic
hepatitis B living in North America: results from the
Hepatitis B Research Network (HBRN). Dig. Dis. Sci.
61, 1186–1196 (2016).
164. Hann, H.‑W. et al. Symptomatology and health
attitudes of chronic hepatitis B patients in the USA.
J. Viral Hepat. 15, 42–51 (2008).
165. Chen, E.‑Q. et al. Serum hepatitis B core-related
antigen is a satisfactory surrogate marker of
intrahepatic covalently closed circular DNA in chronic
hepatitis B. Sci. Rep. 7, 173 (2017).
166. Wong, D. K.‑H. et al. Hepatitis B virus core-related
antigen as a surrogate marker for covalently closed
circular DNA. Liver Int. 37, 995–1001 (2017).
167. Toyoda, H., Kumada, T. & Tada, T. Hepatitis B core-
related antigen: a possible indicator for the
termination of prophylactic nucleos(t)ide analogue
therapy in patients after immunosuppressive therapy.
Am. J. Gastroenterol. 112, 969–970 (2017).
168. Riveiro-Barciela, M. et al. Serum hepatitis B core-
related antigen is more accurate than hepatitis B
surface antigen to identify inactive carriers, regardless
of hepatitis B virus genotype. Clin. Microbiol. Infect.
23, 860–867 (2017).
169. Zhang, Z.‑Q. et al. Measurement of the hepatitis B
core-related antigen is valuable for predicting the
pathological status of liver tissues in chronic hepatitis
B patients. J. Virol. Methods 235, 92–98 (2016).
170. Jung, K. S. et al. Clinical outcomes and predictors for
relapse after cessation of oral antiviral treatment in
chronic hepatitis B patients. J. Gastroenterol. 51,
830–839 (2015).
171. Honda, M. et al. Hepatitis B virus (HBV) core-related
antigen during nucleos(t)ide analog therapy is related
to intra-hepatic HBV replication and development
of hepatocellular carcinoma. J. Infect. Dis. 213,
1096–1106 (2015).
antigen (HBcrAg): an emerging marker for chronic
hepatitis B virus infection. Aliment. Pharmacol. Ther.
47, 43–54 (2018).
This review summarizes the application of HBcrAg
level in different scenarios of hepatitis B disease.
173. Lam, A. M. Hepatitis B virus capsid assembly
modulators, but not nucleoside analogs, inhibit the
production of extracellular pregenomic RNA and
spliced RNA variants. Antimicrob. Agents Chemother.
61, e00680‑17 (2017).
174. Giersch, K., Allweiss, L., Volz, T., Dandri, M.
& Lütgehetmann, M. Serum HBV pgRNA as a clinical
marker for cccDNA activity. J. Hepatol. 66, 460–462
(2017).
175. Block, T. M., Locarnini, S., McMahon, B. J.,
Rehermann, B. & Peters, M. G. Use of current and new
endpoints in the evaluation of experimental hepatitis
B therapeutics. Clin. Infect. Dis. 64, 1283–1288
(2017).
176. Wang, J. et al. Serum hepatitis B virus RNA is
encapsidated pregenome RNA that may be associated
with persistence of viral infection and rebound.
J. Hepatol. 65, 700–710 (2016).
177. Lok, A. S., Zoulim, F., Dusheiko, G. & Ghany, M. G.
Hepatitis B cure: From discovery to regulatory
approval. Hepatology 66, 1296–1313 (2017).
178. Wooddell, C. I. et al. RNAi-based treatment of
chronically infected patients and chimpanzees reveals
that integrated hepatitis B virus DNA is a source of
HBsAg. Sci. Transl Med. 9, eaan0241 (2017).
This is the first study showing the prevailing HBV
integration in HBeAg-negative patients resulting in
relatively suboptimal efficacy of short interfering
RNA in knocking down virus transcriptions.
179. Yuen, M.‑F. et al. RNA interference therapy with
ARC‑520 Injection results in long term off-therapy
antigen reductions in treatment naïve, HBeAg positive
and negative patients with chronic HBV. J. Hepatol.
68, S526 (2018).
180. Mak, L.‑Y., Wong, D. K.‑H., Seto, W.‑K., Lai, C.‑L.
& Yuen, M. F. Hepatitis B core protein as a therapeutic
target. Expert Opin. Ther. Targets 21, 1153–1159
(2017).
181. Bazinet, M. et al. Safety and efficacy of REP 2139 and
pegylated interferon alfa‑2a for treatment-naive
patients with chronic hepatitis B virus and hepatitis D
virus co‑infection (REP 301 and REP 301‑LTF):
a non-randomised, open-label, phase 2 trial.
Lancet Gastroenterol. Hepatol. 2, 877–889 (2017).
182. Seto, W.‑K. & Yuen, M.‑F. New pharmacological
approaches to a functional cure of hepatitis B.
Clin.  Liver Dis. 8, 83–88 (2016).
183. Yuen, M.‑F. et al. Dose response and safety of the
daily, oral RIG‑I agonist Inarigivir (SB 9200) in
treatment naïve patients with chronic hepatitis B:
results from the 25 mg and 50 mg cohorts in the
ACHIEVE trial. J. Hepatol. 68, S509–S510 (2018).
184. Roholm, K. & Iversen, P. Changes in the liver in acute
epidemic hepatitis (catarrhal jaundice) based on
38 aspiration biopsies. Acta Pathol. Microbiol. Scand.
16, 427–442 (2010).
185. Blumberg, B. S. A ‘new’ antigen in leukemia sera.
JAMA 191, 541 (1965).
This is the first publication reporting the discovery
of Australia antigen.
186. Prince, A. M. An antigen detected in the blood during
the incubation period of serum hepatitis. Proc. Natl
Acad. Sci. USA 60, 814–821 (1968).
187. Sutnick, A. I. Anicteric hepatitis associated with
Australia antigen. JAMA 205, 670 (1968).
188. Krugman, S. Infectious hepatitis. Evidence for two
distinctive clinical, epidemiological, and immunological
types of infection. JAMA 200, 365–373 (1967).
189. Dane, D. S., Cameron, C. H. & Briggs, M. VIRUS-like
particles in serum of patients with Australia-antigen-
associated hepatitis. Lancet 295, 695–698 (1970).
This is the first study to describe the morphology
of HBV particles under electron microscopy.
190. Maini, M. K. & Gehring, A. J. The role of innate
immunity in the immunopathology and treatment of
HBV infection. J. Hepatol. 64, S60–S70 (2016).
191. Doherty, D. G. et al. The human liver contains multiple
populations of NK cells, T cells, and CD3+CD56+
natural T cells with distinct cytotoxic activities and
Th1, Th2, and Th0 cytokine secretion patterns.
J. Immunol. 163, 2314–2321 (1999).
192. Raimondo, G. et al. Statements from the Taormina
expert meeting on occult hepatitis B virus infection.
J. Hepatol. 49, 652–657 (2008).
193. Wagner, A. A. et al. Serological pattern ‘anti-hepatitis
B core alone’ in HIV or hepatitis C virus-infected
patients is not fully explained by hepatitis B surface
antigen mutants. AIDS 18, 569–571 (2004).
194. Carimo, A. A. et al. First report of occult hepatitis B
infection among ART naïve HIV seropositive
individuals in Maputo, Mozambique. PLoS ONE 13,
e0190775 (2018).
195. Bréchot, C. et al. Evidence that hepatitis B virus has a
role in liver-cell carcinoma in alcoholic liver disease.
N. Engl. J. Med. 306, 1384–1387 (1982).
196. Wong, D. K. H. et al. Occult hepatitis B infection and
HBV replicative activity in patients with cryptogenic
cause of hepatocellular carcinoma. Hepatology 54,
829–836 (2011).
This study reports a high percentage of the
presence of HBV in patients with HCC without
obvious identifiable causes.
197. Yuen, M.‑F. Need to improve awareness and
management of hepatitis B reactivation in patients
receiving immunosuppressive therapy. Hepatol. Int.
10, 102–105 (2016).
198. Hughes, S. A., Wedemeyer, H. & Harrison, P. M.
Hepatitis delta virus. Lancet 378, 73–85 (2011).
199. Koh, C. et al. Oral prenylation inhibition with lonafarnib
in chronic hepatitis D infection: a proof‑of‑concept
randomised, double-blind, placebo-controlled phase 2A
trial. Lancet Infect. Dis. 15, 1167–1174 (2015).

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18035 | 19

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

200. Yan, H., Liu, Y., Sui, J. & Li, W. NTCP opens the door
for hepatitis B virus infection. Antiviral Res. 121,
24–30 (2015).
201. Vaillant, A. Nucleic acid polymers: Broad spectrum
antiviral activity, antiviral mechanisms and
optimization for the treatment of hepatitis B and
hepatitis D infection. Antiviral Res. 133, 32–40
(2016).
202. Livingston, C., Ramakrishnan, D., Strubin, M.,
Fletcher, S. & Beran, R. Identifying and characterizing
interplay between hepatitis B virus X protein and
Smc5/6. Viruses 9, 69 (2017).
203. You, C. R., Lee, S. W., Jang, J. W. & Yoon, S. K. Update
on hepatitis B virus infection. World J. Gastroenterol.
20, 13293–13305 (2014).
204. Lam, Y.‑F. et al. Seven-year treatment outcome of
entecavir in a real-world cohort: effects on clinical
parameters, HBsAg and HBcrAg levels. Clin. Transl
Gastroenterol. 8, e125 (2017).
205. Buti, M. et al. Seven-year efficacy and safety of
treatment with tenofovir disoproxil fumarate for
chronic hepatitis B virus infection. Dig. Dis. Sci. 60,
1457–1464 (2015).
206. Ogawa, E., Furusyo, N. & Nguyen, M. H. Tenofovir
alafenamide in the treatment of chronic hepatitis B:
design, development, and place in therapy. Drug Des.
Devel. Ther. 11, 3197–3204 (2017).
Author contributions
Introduction (M.-F.Y.); Epidemiology (D.-S.C.); Mechanisms/
pathophysiology (S.A.L. and C.-L.L.); Diagnosis, screening and
prevention (G.M.D.); Management (C.-L.L., D.T.Y.L., H.L.A.J.
and M.G.P.); Quality of life (D.T.Y.L.); Outlook (M.-F.Y.);
Overview of Primer (M.-F.Y.).
Competing interests
M.-F.Y. has received research grants and/or served as an
adviser for AbbVie, Arrowhead Pharmaceuticals, Biocartis,
B r i s to l M
­ ye rs S q u i b b, F u j i re b i o , G i l e a d S c i e n c e s,
GlaxoSmithKline, LF Asia Limited, Merck Sharp & Dohme,
Novartis Pharmaceuticals, Roche Molecular Systems and
Sysmex Corporation. D.S.C. has served as an adviser for
Bristol-Myers Squibb and Merck Sharp & Dohme. G.M.D. has
received research grants and/or served as an adviser for
Abbott Laboratories, AbbVie, Bristol-Myers Squibb, Gilead
Sciences, Janssen, Merck Sharp & Dohme and Transgene.
H.L.A.J. has received grants and/or served as consultant for
AbbVie, Arbutus, Bristol-Myers Squibb, Gilead Sciences,
Janssen, Medimmune, Merck and Roche Molecular Systems.
D.T.Y.L. has received research grants from Bristol-Myers
Squibb, Gilead Sciences and Roche Molecular Systems and has
served as consultant for AbbVie and Gilead Sciences. S.A.L.
has served as an adviser and received consulting fees from
Arrowhead Pharmaceuticals, AusBio Ltd., Gilead Sciences,
Roche Molecular Systems and Janssen and has contract
research grants with Arrowhead Pharmaceuticals, Gilead
Sciences and Spring Bank Pharmaceuticals, Inc. M.G.P.’s
spouse is employed at Hoffman‑La Roche. C.-L.L. has received
speaker fees from Bristol-Myers Squibb, Gilead Sciences and
Novartis and is an advisory board member of Gilead Sciences.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
Reviewer information
Nature Reviews Disease Primers thanks M. Buti and the
other, anonymous referee(s) for their contribution to the peer
review of this work.

20 | ARTICLE NUMBER 18035 | VOLUME 4 www.nature.com/nrdp

©
2
0
1
8
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.