Seminar: Wen-Juei Jeng, George V Papatheodoridis, Anna S F Lok

Seminar
Hepatitis B
Wen-Juei Jeng, George V Papatheodoridis, Anna S F Lok
Hepatitis B virus (HBV) infection is a major public health problem, with an estimated 296 million people chronically Lancet 2023; 401: 1039–52
infected and 820 000 deaths worldwide in 2019. Diagnosis of HBV infection requires serological testing for HBsAg Published Online
and for acute infection additional testing for IgM hepatitis B core antibody (IgM anti-HBc, for the window period February 9, 2023
https://doi.org/10.1016/
when neither HBsAg nor anti-HBs is detected). Assessment of HBV replication status to guide treatment decisions
S0140-6736(22)01468-4
involves testing for HBV DNA, whereas assessment of liver disease activity and staging is mainly based on
Department of
aminotransferases, platelet count, and elastography. Universal infant immunisation, including birth dose vaccination Gastroenterology and
is the most effective means to prevent chronic HBV infection. Two vaccines with improved immunogenicity have Hepatology, Linkou Medical
recently been approved for adults in the USA and EU, with availability expected to expand. Current therapies, Center, Chang Gung Memorial
pegylated interferon, and nucleos(t)ide analogues can prevent development of cirrhosis and hepatocellular carcinoma, Hospital, Taoyuan, Taiwan
(Prof W-J Jeng MD); College of
but do not eradicate the virus and rarely clear HBsAg. Treatment is recommended for patients with cirrhosis or with Medicine, Chang Gung
high HBV DNA levels and active or advanced liver disease. New antiviral and immunomodulatory therapies aiming University, Taoyuan, Taiwan
to achieve functional cure (ie, clearance of HBsAg) are in clinical development. Improved vaccination coverage, (Prof W-J Jeng); Academic
Department of
increased screening, diagnosis and linkage to care, development of curative therapies, and removal of stigma are
Gastroenterology, Medical
important in achieving WHO’s goal of eliminating HBV infection by 2030. School of National and
Kapodistrian University of
Introduction HBV survives in the environment for 7 days or more Athens, Laiko General Hospital,
Athens, Greece
Hepatitis B virus (HBV) infection can be prevented by and is more infectious than HIV.10,11 HBV can be detected
(Prof G V Papatheodoridis MD);
vaccination, and sequelae of chronic hepatitis B (CHB) in breastmilk, but there are no reports of transmission Division of Gastroenterology
infection—cirrhosis, liver failure, and hepatocellular to breastfeeding infants of mothers who are HBsAg and Hepatology, University of
carcinoma (HCC)—can be prevented by antiviral therapy. positive.12 The most common modes of transmission Michigan, Ann Arbor, MI, USA
(Prof A S F Lok MD)
In 2016, WHO set the goals to reduce the incidence of include sexual contacts, perinatal or vertical
Correspondence to:
viral hepatitis by 90%, and its associated mortality by 65%, transmission from mothers who are HBsAg positive to
Prof Anna S F Lok,
by 2030.1 In 2019, WHO estimated there were 1·5 million newborns, horizontal intrafamilial spread (especially in Division of Gastroenterology
new cases of CHB and 820 000 deaths related to HBV, children) through inapparent parenteral exposure and Hepatology,
putting many metrics used to gauge success toward viral (presumably by open cuts and sores), and transmission University of Michigan,
Ann Arbor, MI 48109, USA
hepatitis elimination at risk.2 This Seminar provides an through contaminated syringes or needles among
[email protected]
update on epidemiology, natural history, and HBV people who inject drugs. The risk of progression from
treatment, and discusses strategies to meet the WHO acute to chronic infection is inversely proportional to
goals of viral hepatitis elimination. the age at infection, approximately 90% when infection
occurs in newborns, 20% in children, and less than 5%
Epidemiology in immunocompetent adults.10,11,13 High-risk groups for
In 2019, 296 million people were positive for hepatitis B HBV infection are people born in regions of
surface antigen (HBsAg) worldwide, and the global intermediate or high endemicity, people who inject
prevalence of CHB infection was approximately 3·5%.2 drugs, men who have sex with men, people with HIV
The prevalence of HBsAg or CHB infection varies widely infection, and sexual partners, needle-sharing contacts,
in different parts of the world (figure 1).3 In all countries, and household contacts of people who are HBsAg
both incidence of acute and prevalence of chronic HBV positive 10,11
infection have declined, especially among children and
young adults, mainly due to universal infant vaccination.4
However, outbreaks still occur even in high-income Search strategy and selection criteria
countries, such as the USA, where the epidemic of opioid We focused on advances in the management of hepatitis B
use coupled with low vaccination rates among adults in the past 5 years. We searched PubMed using the terms
have been associated with an increase in incidence of “hepatitis B”, “hepatitis B virus”, “HBV”, and “chronic
acute HBV infection.5 In addition, prevalence of CHB hepatitis B” for articles published in English or with English
infection in low-endemic countries might not be abstract in print or online between Jan 1, 2017, and
decreasing due to new immigrants from intermediate- Dec 31, 2021. We also searched the WHO and the US Centers
endemic or high-endemic countries.6,7 The ageing of for Disease Prevention and Control websites for the most
people with CHB infection with increased prevalence of current epidemiological data and reference lists of articles
comorbidities increases the risks of both liver and non- identified by this search strategy and included any papers
liver complications.8,9 we deemed relevant. Landmark articles published before
HBV is transmitted through percutaneous or mucosal 2016 were also included. We did not include studies with
exposure of non-immune individuals to infectious low quality or few patients.
biological material such as blood, semen, and saliva.
www.thelancet.com Vol 401 March 25, 2023 1039

Seminar
All-age HBsAg prevalence in 2019

0% to 0·4% 2·0% to 2·9%
0·5% to 0·9% 3·0% to 3·9%
1·0% to 1·4% 4·0% to 7·9%
1·5% to 1·9% 8·0% to 13·0%
Figure 1: Global prevalence of HBsAg or chronic hepatitis B virus infection

Reproduced from GBD 2019 Hepatitis B Collaborators. HBsAg=hepatitis B surface antigen.
People with HBV infection can be co-infected Asia suggest that genotype C is associated with higher
with other viruses that share common modes of HCC risk than genotype B,25 and many studies have found
transmission. Hepatitis D virus (HDV), a defective genotype A to be associated with higher chance of HBsAg
virus, can only infect people who are HBsAg positive clearance after pegylated-interferon-alfa therapy.26,27
and is estimated to affect 5% of people with CHB The precore and core promoter variants, which block
worldwide.14,15 Co-infection with hepatitis C virus (HCV) and decrease HBeAg production, respectively, are more
can be present in 1–15%16 and with HIV in 1–2% of commonly found in HBeAg-negative patients.28,29 These
people with CHB.15,17 variants have predilection for specific HBV genotypes,
accounting for regional differences,28–30 and core promoter
Virology variants have been shown to be associated with increased
HBV is a DNA virus belonging to the Hepadnaviridae HCC risk.31
family. HBV enters hepatocytes through a receptor
sodium taurocholate cotransporting polypeptide Pathophysiology
(figure 2).18 The relaxed circular DNA in the virion is HBV has been considered to be non-cytopathic and liver
converted to covalently closed circular DNA (cccDNA), injury is mostly immune mediated.32 Whereas vigorous
which is transcribed into the pregenomic RNA (a T-cell responses are detected after recovery from acute
template for reverse transcription into HBV DNA) and HBV infection, people with CHB have impaired innate
mRNAs for translation into HBV proteins.19 Persistence and adaptive immune responses to HBV.32,33 Impairment
of cccDNA in the liver is the main reason for the difficulty in HBV-specific T-cell response in CHB is mostly due to
in eradicating HBV and for reactivation of HBV immune exhaustion rather than deletion of T cells, as
replication in recovered people when immuno restoration of T-cell response has been observed in
suppressed.20 HBV DNA can be integrated into the host patients with spontaneous or treatment-related HBeAg
genome and can be a source of HBsAg, as well as a or HBsAg clearance.34 B-cell immune response is
contributor to hepatocarcinogenesis.21,22 important in recovery from acute infection, and high
There are at least ten HBV genotypes (A–J). The levels of hepatitis B surface antibody can be detected
prevalence of HBV genotypes varies geographically, many decades after recovery. The high risk of HBV
with genotype A found mainly in northern Europe, reactivation in patients with CHB receiving B-cell-
North America, India, and Africa; genotypes B and C in depleting therapies suggests that B cells also play an
east Asia; genotype D in southern Europe, the Middle East, important role in the control of chronic infection.32,35
India, and Africa; genotype E in west Africa; and
genotypes F and H in central and South America.23 Data Prevention
on other genotypes are scarce. The increasing migration Vaccination is the most effective way to prevent HBV
in recent years has affected the distribution of HBV infection. Recombinant HBV vaccines are safe, highly
genotypes6—eg, genotypes B and C, which are most effective, and available as single vaccines or combination
common in Asia, are now dominant in the USA because vaccines with other antigens used in infancy immunisation
more than 70% of Americans who are HBsAg-positive programmes, or with hepatitis A virus vaccine for use in
See Online for appendix migrated from Asian countries.24 The clinical significance all age groups (appendix).36,37 Age and immunocompetency
of HBV genotypes remains unclear, although studies in are key factors influencing immunogenic response to
1040 www.thelancet.com Vol 401 March 25, 2023

Seminar
vaccination.36,38 After a primary series of three (or four, Virion (Dane particle) SVP Virion (Dane particle)
for many infants) doses, protective anti-HBs levels
(≥10 mIU/mL) develop in more than 95% of infants, HBeAg
children, and young adults, but in only 60–75% of people
older than 60 years. Factors that decrease vaccination
efficacy include obesity, smoking, genetic factors, and
comorbidities such as chronic renal failure, chronic liver
(8) Coating and
disease, and diabetes.38 secretion
Given the high risk of chronicity after HBV infection
during infancy, universal infant immunisation (including (10) Subviral
particle
birth dose) is the most effective means of preventing (1) Entry via Uncoating secretion
NTCP receptor HBs HBe
chronic HBV infection. As of 2020, 98% of countries
worldwide have adopted universal infant HBV vaccination rc DNA
(9) Capsid recycling
with 83% coverage of the three to four-dose series,39 but
timely coverage of birth dose remains less than 50%.2 HBx
(2) Nuclear
HBV prevalence among children younger than 5 years entry (3) Transcription (–) DNA
has decreased from 4·7% before 2000 to less than 1% modulation
rcDNA (7) Reverse
after 2016.2 In countries such as Taiwan, where universal Pol transcription
HBV vaccination was initiated in 1984, decrease in HBV mRNAs
(4) Transcription (5) Translation
prevalence as well as incidence of HCC has been observed cccDNA HBc pgRNA
pgRNA
not only in children, but also among young adults.40 (6) Capsid
Since many adults remain susceptible, adult pgRNA
formation
vaccination is required in high-risk populations (people (11) Integrated
DNA
who have high-risk sexual behaviours [multiple sex dslDNA dslDNA
partners, men who have sex with men] and people who
inject drugs) to reduce HBV infection.36,38 In 2022, the
recommendations for adult HBV vaccination in the USA Figure 2: Lifecycle of HBV and the potential sites of action of antiviral therapies, approved and in clinical
were broadened to include all people younger than development
60 years and those aged 60 years or older who seek (1) HBV enters hepatocytes through attachment to the NTCP receptor. (2) After uncoating, the rcDNA in the viral
capsid enters the hepatocyte nucleus where the second strand HBV DNA is completed, forming the cccDNA.
protection.41 Safe sex practices, global implementation of (3, 4) cccDNA serves as a template for transcription of pgRNA and mRNAs; this step is modulated by HBx
blood safety strategies, and reduction of unsafe injections protein. (5) HBV mRNAs are translated into viral proteins (core, polymerase, X, e [processed from precore or core]
are also important in preventing transmission. and S [large, middle, and small]). (6) pgRNA, core, and polymerase proteins are packaged into capsids, inside
Although anti-HBs decrease over time, protection which (7) pgRNA is reverse transcribed into HBV DNA. (8) Capsids with rcDNA can be enveloped with surface
proteins for secretion as virions or (9) recycled back to the nucleus to replenish the cccDNA pool. (10) HBV also
appears to last for 30 years or more after vaccination due secretes an excess of subviral particles that contain HBs proteins but not HBV DNA. (11) A minority of pgRNA is
to immune memory. Thus, a booster dose is not reverse transcribed into dslDNA which can be integrated into host DNA. Integrated HBV DNA is not replication
recommended in healthy, fully vaccinated children or competent but can be translated into S proteins and are secreted as SVP. Sites of action of antiviral therapies in HBV
immunocompetent adults, but only in dialysis patients lifecycle: entry inhibitors (1), transcription modulation (3), capsid assembly modulators (6, and possibly 2 and 9),
translation inhibitors (5), nucleos(t)ide analogues at reverse transcription (7), secretion inhibitors (8, 10).
in whom annual testing shows anti-HBs levels less than dslDNA=double-stranded linear DNA. HBc=hepatitis B core. HBs=hepatitis B surface. HBsAg=hepatitis B virus
10 mIU/mL.36–38,42 surface antigen. HBx=hepatitis B X. HBV=hepatitis B virus. NTCP=sodium taurocholate cotransporting polypeptide.
Testing for HBV markers before vaccination is not pgRNA=pregenomic RNA. cccDNA=covalently closed circular DNA. Pol=polymerase. rcDNA=relaxed circular DNA.
routinely recommended and should not be a deterrent to
vaccination.36–38 Prevaccination testing in high-risk burden. HepB-CpG (Heplisav-B) contains a potent
groups and those living in endemic areas can identify adjuvant and is administered in two doses, and might be
infected people so they can receive appropriate care. most appropriate when rapid achievement of immune
Postvaccination anti-HBs testing 1–2 months after protection is desired.43–46 PreHevbrio (VBI vaccines, MA,
completion of the vaccine series is recommended only USA) contains all three surface antigens (large, middle,
in people with decreased probability of response or high and small) and is administered in three doses.47–49 These
risk of exposure (eg, patients on dialysis, infants of new vaccines have not been approved for children, and
HBsAg-positive mothers, and sexual partners of HBsAg- safety and effectiveness in pregnant women and dialysis
positive people).36,42 Non-responders can receive a second patients have not been established.43,44,46,47
course of the same vaccine at the usual or double dose or Hepatitis B immune globulin (HBIG) usually in
one of the new vaccines described later in this Seminar. combination with the first vaccine dose, can be admi
Two new recombinant vaccines, which increase the nistered to non-immune people with exposure to
response rates in people older than 60 years or immuno- biological materials from HBsAg-positive people, to
compromised people, have been recently licensed for use newborns from HBsAg-positive mothers, or patients who
in adults in the USA and EU, and their availability is underwent liver transplantation for HBV-related liver
expected to expand to other countries with a greater disease.10,11,36

Seminar
Passive–active immunisation at birth has an overall delivery, and with monitoring for serum alanine
efficacy of approximately 95% in preventing mother-to- aminotransferase (ALT) flares every 1–3 months for
For more on The Antiretroviral child transmission50 (MTCT). This involves screening all 6 months afterwards. TDF has established safety in
Pregnancy Registry see pregnant women for HBsAg and administering one dose pregnancy even when administered during the first
http://www.apregistry.com
of HBIG and HBV vaccine within 12 h of birth followed trimester and can be continued in breastfeeding mothers
by three-dose vaccination series starting at month 1. if indicated.10,11 Implementation of the above measures
Confirmation of immunity is recommended by testing can completely eliminate MTCT of HBV, but can be
infants for anti-HBs between months 9 and 15. MTCT challenging in countries where a substantial percentage
might occur due to delays or failure in administering of births occur at home, access to diagnostic tests in
HBIG or the birth dose vaccine, failure to complete the particular HBV DNA assays is low, and HBIG is not
vaccine series, or transmission from highly viraemic available or affordable. There is no evidence that HBV
mothers. Antiviral therapy administered to these mothers can be transmitted through breastmilk and breastfeeding
during the third trimester can further reduce the risk of should not be discouraged if the preventive measures
MTCT. Thus, the current recommendation is to screen all described are followed.
pregnant women for HBsAg and to test HBV DNA levels
in those who are HBsAg positive. Tenofovir disoproxil Diagnosis
fumarate (TDF) starting at week 24–32 of pregnancy is The incubation period of HBV ranges from 1–6 months.
recommended in people with a HBV DNA concentration Clinical manifestation of acute infection varies from
of more than 200 000 IU/mL.10,11 Treatment can be stopped asymptomatic (approximately 70%), to symptomatic
immediately or continued for an additional 12 weeks after hepatitis presenting with non-specific symptoms, such as
fatigue, anorexia, nausea, right upper quadrant discomfort,
and jaundice (approximately 30%); and fulminant hepatitis
A (encephalopathy and coagulopathy) in 0·1–1% of
Incubation (1–6 months) immunocompetent adults. Serological testing for HBsAg
HBsAg
Anti-HBs
and IgM anti-HBc is essential in diagnosing acute HBV
Anti-HBc IgM infection, because clinical symptoms and elevations in
Symptoms or increased ALT (<1–6 months)
Anti-HBc IgG liver enzymes cannot differentiate hepatitis B from other
HBeAg Anti-HBe types of acute hepatitis. During the early phase, patients
Titre in blood
HBV DNA have positive HBsAg, IgM anti-HBc and HBeAg, and high
HBV DNA levels. During recovery, HBsAg becomes
undetectable, and patients seroconvert to anti-HBs, but
there can be a period of 1–6 months when neither HBsAg
>20 years
nor anti-HBs is detected, and diagnosis relies on IgM anti-
HBc. After recovery, patients remain anti-HBs and IgG
Month 0 3 6 9 12 120
anti-HBc positive, HBV DNA is undetectable in circulation
Infection Acute and Resolved and immune but can persist in the liver (figure 3A).
infectious Chronic HBV infection is defined by persistent
detection of HBsAg for more than 6 months, along with
B
positive IgG anti-HBc. During the early phase, HBeAg
HBeAg Anti-HBe and high HBV DNA levels are detected, although anti-
HBV DNA HBe and variable HBV DNA levels are present in later
phases (figure 3B).
Concomitant detection of anti-HBs has been reported
Titre in blood
in less than 10% of HBsAg-positive patients,51 who should

be managed similarly to other HBsAg-positive patients.
Some people have isolated IgG anti-HBc; most had
chronic HBV infection with spontaneous HBsAg loss
>20 years (occult HBV) or recovered acute HBV infection with
Month 0 3 6 9 12 360 spontaneous anti-HBs loss, particularly in endemic areas
and high-risk populations (eg, those with HIV or HCV
Infection Acute Chronic
co-infection). A minority could have false-positive anti-
Figure 3: Serological profile during acute (A) and chronic (B) HBV infection HBc or be in the phase of acute HBV infection when IgM
During acute infection, there might be a period between the loss of HBsAg and anti-HBc would be positive.
the appearance of anti-HBs of 1–6 months when diagnosis has to rely on IgM Quantification of serum HBV DNA is the cornerstone
anti-HBc. Chronic infection is defined as persistence of HBsAg for more than
6 months. Anti-HBc=hepatitis B core antibody. Anti-HBe=hepatitis B e antibody.
in assessing HBV replication status to guide treatment
ALT=alanine aminotransferase. HBeAG=hepatitis B e-antigen. HBsAg=hepatitis decisions and to assess response. It can also predict risk of
B virus surface antigen. HBV=hepatitis B virus. cirrhosis and HCC.52,53 However, HBV DNA levels vary

Seminar
markedly (<10 IU/mL to >10⁹ IU/mL) during chronic HBV Natural history of chronic HBV infection
infection and serial assessment is crucial in management The natural course of CHB infection is dynamic, reflecting
and prognostication. the balance between host immune control and virus
Historically, liver biopsy was used to assess liver disease, replication. The clinical course can be categorised into five
but it has been largely replaced by non-invasive tests, phases on the basis of HBsAg and HBeAg status, HBV
such as panels of blood markers and elastography. Low DNA and ALT levels; however, not all patients go through
platelet count is an early indicator of cirrhosis. Elevated all phases, and some revert from a later to an earlier
alanine aminotransferase (ALT) and aspartate amino phase (figure 410,11,62). Recent studies showed that
transferase (AST) levels indicate hepatic inflammation, HBsAg, HBcrAg, and HBV RNA concentrations also
with an AST:ALT ratio of more than 1 being a marker of differ across these phases, but they provide minimal
advanced fibrosis or cirrhosis. Among the blood markers, incremental value in differentiating these phases.63
APRI (AST:platelet ratio index) and FIB-4 index (age, AST, The first phase, immune-tolerant or HBeAg-positive
ALT, platelets), are widely used.54 Low APRI and low FIB-4 chronic infection, is defined by HBeAg-positive, very high
have excellent performance in ruling out cirrhosis, but HBV DNA (usually >7 log11 IU/mL) and HBsAg levels
high scores have only modest performance in diagnosing (>3 log11 IU/mL), and persistently normal ALT. Most
cirrhosis. Elastography measures liver stiffness, a fibrosis patients are young Asians infected perinatally via vertical
indicator, and can be accomplished using vibration transmission.24 The term immune-tolerant was based on
controlled transient elastography (VCTE), ultrasound the combination of normal ALT and high HBV DNA
shear wave, or MRI plus low-frequency vibration. Both concentrations, suggesting absence of immune-mediated
blood markers and elastography are more accurate in liver injury. Recent studies showed that although HBV-
dichotomising advanced fibrosis or cirrhosis from no or specific immune response in immune-tolerant patients is
moderate fibrosis than in differentiating fibrosis stages, weak, it is not substantially different from that in immune-
might yield falsely high readings in patients with ALT active patients.64,65 Despite high HBV DNA levels, prog
flares, and cannot reliably assess fibrosis regression nosis of immune-tolerant patients is favourable, with
during therapy.55–57 The sensitivity of VCTE varies from cumulative 10-year HCC incidence similar to that in
64% to 93%, and specificity varies from 38% to 92%, for inactive carriers.66,67 One study found that the HCC risk
predicting at least moderate fibrosis (stage ≥2) depending was higher in untreated immune tolerant, than treated,
on patient selection. Sensitivity increases to 70–100% and HBeAg-positive patients with CHB, but the median age of
specificity to 82–92% for predicting cirrhosis (stage 4).58 immune-tolerant patients was 38 years, and many would
In general, elastography is more accurate than blood- have met treatment indications.68
based markers, and a two-tier approach using blood tests Among people with perinatally acquired infection, the
to rule out advanced fibrosis or cirrhosis, followed by transition from the immune-tolerant to immune-active or
elastography in the remainder who do not have low scores HBeAg-positive CHB phase usually occurs between the
to identify those with advanced fibrosis or cirrhosis, has ages of 20 years and 40 years. Patients with immune
been proposed to decrease the percentage of patients who active, HBeAg-positive CHB have high HBV DNA
have scores between low cutoff and high cutoff with (5–7 log11 IU/mL) and HBsAg (>3 log11 IU/mL) levels and
indeterminate fibrosis stage.59 elevated ALT. Patients in this phase can clear HBeAg with
Recently, three additional HBV tests have emerged; seroconversion to anti-HBe. The estimated annual sponta
namely, quantification of HBsAg, HBV RNA, and neous HBeAg seroconversion rate ranges from 2% to 15%
HBcrAg.7 These tests are not necessary for diagnosis but with lower rates in people who are male, Asian, younger
might help in differentiating CHB phases and predicting than 30 years, acquired the infection through vertical
clinical outcomes and treatment response. HBsAg levels transmission, have normal ALT, and an absence of core
are higher in HBeAg-positive patients, generally more promoter or precore mutations.69–72 High ALT is thought
than 1000 IU/mL, and might vary between 10 IU/mL and to reflect immune-mediated clearance of infected
more than 1000 IU/mL in HBeAg-negative patients. The hepatocytes, although not all patients who clear HBeAg
main use of HBsAg level in untreated patients is to have ALT flares. Most ALT flares are asymptomatic,
identify HBeAg-negative inactive carriers with a HBV but some can be accompanied by jaundice, and
DNA concentration of less than 2000 IU/mL who have approximately 2–3% by hepatic decompensation (ascites,
low likelihood of HCC and of transitioning to HBeAg- variceal bleeding, or hepatic encephalopathy).73 Protracted
negative CHB.61 HBV RNA and HBcrAg are more reliable immune active phase, with or without recurrent flares,
serum markers of cccDNA transcription than HBV DNA increases the risk of cirrhosis and HCC.74 Patients with
or HBsAg concentrations (which can be derived from late (after age 40 years) compared with people with early
both cccDNA and integrated HBV DNA) and might play a (before age 30 years) HBeAg seroconversion have 5·2-fold
role in assessing response to new antiviral therapies,60 higher HCC risk.75
although tests for HBV RNA and serum hepatitis B core- After HBeAg seroconversion, most patients enter the
related antigen (HBcrAg) are still being standardised and inactive-carrier or HBeAg-negative chronic infection
not yet commercially available. phase, when they are HBeAg negative, anti-HBe positive,

Seminar
inactive carrier phase during follow-up, some remain in

HBsAg Anti-HBs
the indeterminate zone, and others transition to HBeAg-
HBeAg Anti-HBe negative CHB.80
cccDNA +++++ +++++ ++ ++ + Patients who clear HBsAg enter the last phase of CHB
9 (resolved or occult HBV infection), being HBsAg negative
8 and IgG anti-HBc positive, with or without anti-HBs.
7
HBV DNA is usually not detected in blood, but persists in
(log11IU/mL)
HBV DNA
6
5 the liver and can reactivate on immune suppression.20
4 HBsAg clearance occurs at an average annual rate of 1%,
3
2 LLQ (1·3) but its incidence is not linear, occurring rarely during the
1 early years and accelerating after age 50 years.81 Older age
0
than 50 years, male gender, HBeAg negativity, and low
5 HBsAg levels are predictors for spontaneous HBsAg
(log11IU/mL)
4
clearance.82 HBsAg clearance is associated with improved
HBsAg
3
2 clinical outcomes compared with patients remain ing
1
0 LLQ (–1·3) HBsAg-positive and undetectable HBV DNA.83,84 However,
HCC can still develop in patients who clear HBsAg after
1000 cirrhosis development or older than 50 years.85
Studies in untreated patients estimated that about 25%
ALT (U/L)
500
100
of men and 8% of women with CHB acquired perinatally
ULN
0
will die from HBV-related cirrhosis or HCC.86 Several host
Infection (male gender, older age or longer duration of infection,
(years) diabetes, and family history of HCC), virus (persistently
Clinical Immune Immune Inactive HBeAg- Resolved or HBeAg positive; persistently high HBV DNA; HBV
phases tolerant active carrier immune occult HBV
(HBeAg+chronic (HBeAg+CHB) (HBeAg–chronic active infection
genotype; or HIV, HCV, and HDV co-infection), liver
infection) infection) (HBeAg-CHB) (persistent ALT elevation and concomitant liver diseases),
and environmental factors (smoking and alcohol) increase
the risks of cirrhosis and HCC.87–89 The incidence of HCC
Figure 4: Phases of chronic hepatitis B virus infection has been estimated to be 0·02 per 100 person-years in
During the early phases, patients are HBeAg positive, whereas during later phases patients are HBeAg negative, anti-
HBe positive. Some patients eventually become HBsAg negative. Not all patients go through all phases and although
inactive carriers, 0·3 per 100 person-years in patients with
most transitions progress from early to late phases, occasionally some patients can revert to early phases. Dotted CHB without cirrhosis, and 2·2 per 100 person-years in
lines depict LLQ or ULN. ALT=alanine aminotransferase. Anti-HBe=hepatitis B e antibody. Anti-HBs= hepatitis B people with compensated cirrhosis.90 Patients with CHB
surface antibody. CHB=chronic hepatitis B. HBeAG=hepatitis B e-antigen. HBsAG=hepatitis B virus surface antigen. and concomitant metabolic fatty liver have increased risk
cccDNA=covalently closed circular DNA. LLQ=lower limit of quantification. ULN=upper limit of normal.
of HCC and non-HCC cancer, and all-cause mortality.91
with persistently normal ALT and usually low HBV DNA Management
(<2000 IU/mL) and HBsAg (<1000 IU/mL) levels. Acute HBV infection
Roughly 5% might revert to HBeAg-positive phase and Most (>95%) immunocompetent adults with acute HBV
10–25% might progress directly or later to HBeAg- infection recover spontaneously and do not require
negative CHB.72,76 The prognosis of patients who remain specific treatment.9,10,61 Management of acute HBV
in the inactive carrier phase is favourable, particularly if infection is focused on supportive care and prevention of
liver injury before HBeAg clearance was mild. The risk HBV transmission to household and sexual contacts.
for disease progression is very low (annual incidence Antiviral therapy can be considered in people with
less than 0·2% for cirrhosis and less than 0·1% for protracted or severe hepatitis. Although robust data
HCC),77 and one study showed that HCC incidence, supporting a benefit is lacking, nucleos(t)ide analogue
liver-related mortality and all-cause mortality were therapy is safe and can decrease the risk of re-infection
similar to age-matched and gender-matched controls.78 should liver transplantation be necessary. Differentiation
HBeAg-negative, immune-active phase or HBeAg- between severe acute hepatitis B and severe exacerbation
negative CHB is characterised by absence of HBeAg of previously undiagnosed CHB can be difficult, unless
and, usually, presence of anti-HBe, and fluctuating HBV there is a history of recent exposure or evidence of
DNA (usually >2000 IU/mL) and ALT (usually elevated) cirrhosis, because IgM anti-HBc can be positive in the
levels. latter setting. Nucleos(t)ide analogue therapy should be
Some HBeAg-negative patients have indeterminate initiated when in doubt.
characteristics, perhaps transitioning from one phase to
another, or having concomitant causes of liver injury, Chronic HBV infection
often steatosis, especially those with low HBV DNA and Evaluation of patients with CHB should include an
elevated ALT.79 Most of these patients transition to the assessment of HBV replication (HBeAg status and HBV

Seminar
DNA level); activity (ALT) and stage of liver disease; Treatment is not recommended for patients in the
screening for HIV, HCV, and HDV coinfection; and immune tolerant (HBeAg-positive chronic infection)
evaluation for hepatitis A immunity. The course of CHB phase, except for those older than 30 or 40 years
is characterised by fluctuations in HBV replication and
liver inflammatory activity; thus, long-term monitoring A
is required even in patients with low-level HBV Chronic HBV
replication, normal ALT, and no cirrhosis (figure 5). HBsAg positive for >6 months or HBsAg positive, IgM anti-HBc negative
As a consequence of CHB, HBV-related HCC is often
diagnosed late and has high mortality. Many models have
ALT or AST, HBeAg or anti-HBe, HBV DNA, and NIT for fibrosis or liver biopsy, or both
been developed to predict HCC risk to guide treatment
decisions and assess need for surveillance. Most models in
untreated Asian patients comprise age, cirrhosis, and HBV
DNA level with good to excellent accuracies for HCC Cirrhosis No cirrhosis
prediction over 5–10 years.92 HCC surveillance with
ultrasonography and optional alpha-fetoprotein every
6 months should be conducted in patients with increased
HBV DNA detectable HBV DNA undetectable HBeAg positive HBeAg negative
HCC risk, including people with cirrhosis, family history of (figure 5B) (figure 5C)
HCC, Asian men younger than 40 years, Asian women
older than 50 years, and African men younger than Consider other causes
40 years.10,11,62 Race-based recommendations for HCC of liver disease.
surveillance stem from data showing higher incidence and Monitor closely with
ALT and HBV DNA
earlier age at occurrence of HCC in Asian and African
patients, which is likely related to earlier age at infection, Recommendations
although other factors, such as HBV genotypes or
Treat regardless of ALT, HBeAg status, and HBV DNA level.
environmental carcinogens, could also contribute.93,94 Since
alcohol and smoking are associated with increased risk of Monitor closely with ALT and HBV DNA.
HCC and concomitant metabolic fatty liver has been shown Endoscopy for varices every 2–3 years and HCC surveillance with ultrasonography with or without AFP every
to accelerate progression to cirrhosis,95,96 patients should be 6 months for all patients with cirrhosis, regardless of treatment. Refer to liver centre if decompensated.
counselled to limit alcohol intake, avoid smoking, and to B
maintain healthy diet and exercise regularly. HBeAg positive, no cirrhosis
Treatment
Goals of treatment
The goal of treatment is to prevent progression to ALT less than 2 × ULN or ALT ≥2 × ULN and
HBV DNA ≤20 000 IU/mL, or both HBV DNA >20 000 IU/mL
cirrhosis, liver failure, and HCC. Response to treatment
is assessed using surrogate measures: biochemical (ALT
normalisation), virological (undetectable HBV DNA), ALT every 1–3 months for 6 months
and repeat HBV DNA
and serological (HBeAg to anti-HBe seroconversion in
HBeAg-positive patients, and HBsAg to anti-HBs
seroconversion). Sustained virological response has been
shown to decrease liver inflammation, decrease risk of ALT ≤ULN ALT >ULN
cirrhosis and HCC, and reverse fibrosis even in patients
with established cirrhosis.10,11,62
HBV DNA HBV DNA HBV DNA HBV DNA
Indications for treatment >20 000 IU/mL ≤20 000 IU/mL ≥2000 IU/mL <2000 IU/mL
Indications for antiviral treatment are the same for
children and adults, and include all patients with
Monitor with ALT every 3–6 Consider other causes of liver disease.
cirrhosis and detectable HBV DNA regardless of HBeAg months, HBeAg or HBV DNA every Monitor with ALT every
status or ALT level, acute liver failure, or severe 6–12 months, NIT for fibrosis every 3–6 months, HBeAg or HBV DNA every
exacerbations of CHB (figure 5A). Among patients 1–2 years 6–12 months, NIT for fibrosis every 1–2 years
without cirrhosis, treatment is recommended for those Recommendations

with HBeAg-positive or HBeAg-negative CHB—the
Treat
second and fourth immune-active phases of CHB
(figure 5B and figure 5C).10,11,62 Patients with a family Assess disease severity using NIT or liver biopsy, or both. If moderate or severe inflammation, or fibrosis, or age older
history of HCC have increased risk of HCC97 and could than 30 years or older than 40 years, treat; otherwise, monitor
be considered for treatment even if HBV DNA or ALT

levels are low or normal.10,11,62 (Figure 5 continues on next page)

Seminar
C Pegylated interferon alfa has modest antiviral activity, but

HBeAg negative, no cirrhosis can enhance degradation of cccDNA and immune
response against HBV. Nucleos(t)ide analogues inhibit
reverse transcription of pregenomic RNA to HBV DNA,
but have no direct effect on cccDNA, and viral relapse is
ALT <2 × ULN, or ALT ≥2 × ULN and almost universal when treatment is stopped. Current
HBV DNA ≤2000 IU/mL, or both HBV DNA >2000 IU/mL
treatments are effective in suppressing HBV replication,
decreasing liver inflammation and fibrosis and risk of
ALT every 1–3 months for cirrhosis and HCC but HBsAg loss rarely occurs and
6–12 months and repeat HBV DNA
1–2 times HCC risk remains albeit at lower rates.10
Pegylated interferon alfa

ALT ≤ULN ALT >ULN
Pegylated interferon alfa is administered as 180 μ once
a week (pegylated interferon alfa 2a subcutaneous
injections) for 48 weeks in both HBeAg-positive and
HBeAg-negative patients with CHB. Although only about
HBV DNA HBV DNA HBV DNA HBV DNA 30% of patients achieve HBeAg clearance and
≥2000 IU/mL <2000 IU/mL ≥2000 IU/mL <2000 IU/mL
3·7% HBsAg clearance within 6 months after treatment,
increasing rates might be observed during long-term
Monitor with ALT every Consider other causes follow-up (table).103–105 Pegylated interferon alfa is associated
6–12 months, HBV DNA every of liver disease
12 months, NIT for fibrosis
with many side-effects including influenza-like symptoms
periodically that are universal during the first 1–2 weeks, neutropenia,
Recommendations thrombocytopenia, and depression, and less commonly
exacerbation or unmasking of autoimmune illnesses.
Treat Moreover, it can induce hepatitis flares, which can be
Assess disease severity using NIT or liver biopsy, or both. If moderate or severe inflammation or fibrosis, treat; severe and result in hepatic decompensation.106 Pegylated
otherwise, close monitoring (ALT every 3–6 months, HBV DNA every 6–12 months, NIT every 1–2 years) interferon alfa is contraindicated in patients with
pregnancy, decompensated cirrhosis, autoimmune
Figure 5: Monitoring and decisions on treatment for patients with chronic HBV infection in relation to illnesses, or depression, and should be used with caution
presence of cirrhosis and HBeAg status in patients with compensated cirrhosis. Given its side-
(A) For patients with cirrhosis, most guidelines,10,11 recommend treatment for patients with decompensated or
compensated cirrhosis if HBV DNA is detectable regardless of HBeAg status and ALT levels. (B) For HBeAg-positive
effects, pegylated interferon alfa is less commonly used
patients without cirrhosis, all guidelines10,11,62 recommend treatment for patients with ALT ≥2 x ULN and HBV DNA than nucleos(t)ide analogues except in young HBeAg-
>20 000 IU/mL; ALT >ULN and HBV DNA ≥2000 IU/mL with at least moderate inflammation (Metavir activity positive patients who do not want to embark on a long or
grade 2–3, range 0–3) or fibrosis (Metavir fibrosis stage ≥2, range 0–4), or both; and ALT ≤ULN and HBV DNA indefinite treatment course, particularly if they have
>20 000 IU/mL who are older than 30 years11 or 40 years.10 (C) For HBeAg-negative patients without cirrhosis, all
guidelines10,11,62 recommend treatment for patients with ALT ≥2 x ULN and HBV DNA >2000 IU/mL; and HBV DNA
genotype A infection.
≥2000 IU/mL and at least moderate inflammation or fibrosis, or both, regardless of ALT. For patients with HBV
DNA <2000 IU/mL, treatment is recommended only if ALT is persistently >ULN or there is at least moderate Nucleos(t)ide analogues
inflammation or fibrosis, or both, and other causes of liver disease have been excluded. Patients who do not meet Six nucleos(t)ide analogues have been approved for oral
treatment indications should be regularly tested for ALT, HBV DNA, and liver fibrosis. Frequency of monitoring,
particularly testing for HBV DNA and liver fibrosis, might vary depending on availability of resources. NIT can be
use. Entecavir, TDF, and tenofovir alafenamide are
used in place of liver histology to assess stage of liver fibrosis. Patients with cirrhosis and those with increased risk preferred, because of their potent antiviral activity and low
for HCC should undergo surveillance with ultrasonography with or without AFP every 6 months. risk of viral resistance compared with the earlier nucleos(t)
AFP=alphafetoprotein. ALT=alanine aminotransferase. HCC=hepatocellular carcinoma. HBV=hepatitis B virus. ide analogues: lamivudine, adefovir, and telbivudine. TDF
HBeAg=hepatitis B e-antigen. HBsAg=hepatitis B surface antigen. NIT=noninvasive tests. ULN=upper limit of
normal. Adapted from Terrault and colleagues,10 by permission of Wiley. or tenofovir alafenamide is preferred in patients with
previous exposure to lamivudine or telbivudine, although
(figure 4).10,11,98 Treatment is also not recommended for entecavir or tenofovir alafenamide is preferred in patients
patients in the inactive carrier phase (HBeAg-negative with risk factors for renal impairment or osteoporosis.
chronic infection; figure 4). However, treatment can be Some studies suggest that compared with entecavir, TDF
warranted for patients with significant liver fibrosis is more efficacious in decreasing HCC incidence; however,
(stage ≥2) and close monitoring is recommended in these studies might be confounded.107 Only 27–38% of
patients with HBsAg of more than 1000 IU/mL. Patients HBeAg-positive patients clear HBeAg and only 3–5% of
who do not meet treatment criteria must be monitored, patients clear HBsAg after 10–year treatment (table).98,100–102
such that treatment can be initiated when HBV replication Thus, nucleos(t)ide analogues are usually administered
or liver inflammation becomes active (figure 5). orally for many years and often for life, particularly in
patients with cirrhosis, to prevent severe hepatitis flares
Current treatments due to viral relapse.
Currently available treatments include pegylated In patients without cirrhosis, nucleos(t)ide analogues
interferon alfa and nucleos(t)ide analogues (table).99–102 can be discontinued in HBeAg-positive patients who

Seminar
Pegylated interferon alfa Entecavir (on therapy) Tenofovir disoproxil Tenofovir alafenamide
48–52 weeks (post therapy) fumarate (on therapy) (on therapy)
6 months 3 years 1 year 7–10 years* 1 year 10 years† 1 year 5 years‡
HBeAg positive
ALT normalisation 32–41% 57% 68% 78–79% 68% 78% 72% 76%
HBeAg seroconversion 29–32% 35% 21% 38% 21% 27% 10% 27%
HBV DNA undetectable§ 7–14% 25% 67% 80–97% 76% 98% 64% 93%
HBsAg clearance 3–7% 11% 2% 4% 3% 5% 1% 1%
HBeAg negative
ALT normalisation 59% 31% 78% 78–79% 76% 83% 83% 76%
HBV DNA undetectable§ 19% 23–26% 90% 80–97% 93% 100% 94% 93%
HBsAg clearance 4% 8–14% 0 4% 0 3% 0 1%
HBV definition: HBeAG=hepatitis B e-antigen. HBsAG=hepatitis B virus surface antigen. Results from randomised controlled trials or follow-up studies of these trials. Not
direct comparison. Response rates reported during long-term follow-up are imprecise because not all patients in the original cohorts were followed up and some studies
reported combined results for HBeAg-positive and HBeAg-negative patients. ALT=alanine aminotransferase. HBV=hepatitis B virus. *Entecavir year 7–10 response rates were
mainly based on one study in Japan and included both HBeAg-positive and HBeAg-negative patients; HBeAg clearance, but not HBeAg seroconversion rates, were reported.99
Another study from China provided combined virological response rates at year-10 in HBeAg-positive and HBeAg-negative patients.100 †Tenofovir disoproxil fumarate year
10 response rates were based on follow-up of phase 3 trial cohort, but only 32% completed year-10 follow-up.101 ‡Tenofovir alafenamide year-5 response rates were based on
follow-up of phase 3 trial cohorts and included both HBeAg-positive and HBeAg-negative patients.102 §Lower limit of detection of HBV DNA assays varied from 10 IU/mL to
80 IU/mL for studies on entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide. HBV DNA less than 2000 IU/mL was used as definition of virological response in
pegylated interferon alfa trials.
Table: Efficacy of approved hepatitis B therapies in patients with HBeAg-positive or HBeAg-negative chronic hepatitis B99–102
seroconverted to anti-HBe and completed an additional entecavir, relapse occurs earlier after TDF withdrawal,
12 months consolidation therapy.10,11,62 Approximately 40% but the overall relapse rates were similar.116,117 Despite
of patients will remain in the inactive carrier phase, careful patient selection and exclusion of patients with
although others might revert to HBeAg-positive or cirrhosis, severe hepatitis flares and decompensations
progress to HBeAg-negative CHB. Nucleos(t)ide have been reported occasionally,111 and the decision to
analogues can be discontinued in HBeAg-negative withdraw nucleos(t)ide analogues should be made jointly
patients who cleared HBsAg. Given the rarity of HBsAg between patients and physicians.
clearance and the observation that, whereas viral relapse Nucleos(t)ide analogues have excellent long-term safety.
is universal when nucleos(t)ide analogue is stopped, TDF is associated with a small risk of renal impair
only 40–60% experience clinical relapse within 2 years of ment and decreased bone mineral density. Tenofovir
stopping nucleos(t)ide analogue,108 the Asian Pacific alafenamide, a new formulation of tenofovir, has
Association for the Study of the Liver and the European improved renal and bone safety.118 Nucleos(t)ide analogues
Association for the Study of the Liver guidelines are dosed daily in patients with normal renal function.
recommend that nucleos(t)ide analogues can be stopped Entecavir and TDF are dosed at reduced frequencies if
in selected HBeAg-negative patients who have completed creatinine clearance is less than 50 mL/min. Tenofovir
more than 2–3 years of treatment with undetectable HBV alafenamide does not require dose adjustment in patients
DNA and agree to close follow-up.11,62,109 Paradoxically, with creatinine clearance of at least 15 mL/min and
patients who stopped nucleos(t)ide analogues had higher should not be used in patients with creatinine clearance
HBsAg clearance rates than patients who continued of less than 15 mL/min who are not on haemodialysis.
nucleos(t)ide analogues.110,111 Two randomised controlled For patients on haemodialysis, TAF should be dosed after
trials in Europe (>85% White) of HBeAg-negative each dialysis. Viral resistance is manifested as virological
patients confirmed higher HBsAg clearance rates among breakthrough defined as more than 1 log increase in HBV
patients who stopped, versus patients who continued DNA levels during treatment and can be accompanied by
nucleos(t)ide analogues,112,113 but a similarly designed trial ALT increase and even hepatic failure. Resistance to
in Canada (96% Asian) showed no benefit in increasing entecavir after 5 years is observed in approximately 1% of
HBsAg clearance.114 The difference in outcomes might be lamivudine-naive and in up to 50% of lamivudine-
due to differences in race, HBV genotypes, or duration of experienced patients.119 Resistance was not observed in
HBV infection. A retrospective study including patients patients receiving TDF for up to 10 years100 or tenofovir
from North America, Europe, and Asia found that non- alafenamide for up to 3 years.120 TDF and tenofovir
Asian people had 8·3-fold higher odds of HBsAg alafenamide are active against lamivudine-resistant,
clearance compared with Asians who stopped nucleos(t) telbivudine-resistant, entecavir-resistant, and adefovir-
ide analogues. Low HBsAg level at nucleos(t)ide analogue resistant HBV. TDF monotherapy has similar efficacy in
withdrawal is the strongest predictor of HBsAg suppressing these resistance variants as combination of
clearance.115 Some studies found that compared with TDF and entecavir or emtricitabine.121,122

Seminar
Factors associated with response aberrant or empty capsids (thereby inhibiting HBV DNA
High pretreatment ALT and low pretreatment HBV DNA replication) and interference with disassembly
are associated with high rates of HBeAg and HBsAg of incoming virions and intracellular recycling of
responses to both pegylated interferon alfa and nucleos(t) capsids (thereby inhibiting cccDNA establishment and
ide analogues.123–125 HBV genotype A is associated with replenish ment). Combination of capsid-assembly
the highest rate of HBeAg and HBsAg clearance after modulators and nucleos(t)ide analogues has an additive
pegylated interferon alfa therapy,27 but HBV genotype is effect in decreasing HBV DNA and HBV RNA levels, but
not predictive of response to nucleos(t)ide analogues. it has a minimal effect on HBeAg and HBsAg
concentrations.132,133
HBV reactivation and HBV–HIV coinfection Translation inhibitors silence HBV RNA, thereby
Patients with chronic or past HBV infection receiving decreasing viral antigen production. Translation inhibition
immunosuppressive or immunomodulatory therapies are can be achieved using small interfering RNAs or antisense
at risk of HBV reactivation, which could lead to potentially oligonucleotides. Both approaches can decrease HBsAg
fatal hepatitis flares. All patients who will be initiating levels, with effects lasting more than 6 months after
these therapies should be screened for HBsAg and IgG completion of dosing, but sustained HBsAg clearance is
anti-HBc. HBsAg-positive and HBsAg-negative, anti-HBc- rare.134,135,136 Upregulation of HBV-specific immune
positive patients who require therapies with moderate-to- responses has been observed in some patients following
high HBV reactivation risk should receive nucleos(t)ide decline in HBsAg concentrations.
analogue prophylaxis before or simultaneously with the Nucleic acid polymers in combination with pegylated
start of these therapies; nucleos(t)ide analogues should be interferon alfa have resulted in sustained HBsAg clearance
continued for 6–12 months after completion of most such in one small study, but most patients had marked ALT
therapies,10,11,20,62,126 and for at least 12 months after flares.137
completion of B-cell depleting therapies due to their Previous approaches to stimulate or remove blockade of
prolonged immunosuppressive effects. Patients who HBV-specific immune responses have not been
require therapies with low HBV reactivation risk can be successful.138–140 Recent studies suggest that therapeutic
monitored with ALT or HBV DNA in HBsAg positive vaccines expressing antigens from HBV core or poly
patients and with ALT, HBsAg or HBV DNA in HBsAg merase regions might be more effective than those from
negative, anti-HBc positive patients with initiation of the surface region and addition of immune checkpoint
nucleos(t)ide analogue at the first sign of HBV reactivation. inhibitors might augment the effect of these vaccines.141,142
All patients coinfected with HBV and HIV should Multiple steps need to be satisfied to achieve the goal of
receive combination antiviral therapy that has activity functional HBV cure: complete suppression of HBV DNA
against both viruses, regardless of HBV DNA and ALT replication, inhibition of HBsAg production, and
levels, and any changes in antiretroviral regimen must restoration of innate and HBV-specific immune response.
ensure that the new regimen is effective in inhibiting both As such, combination of several classes of drugs will be
viruses.10,11,62,127 necessary to achieve this goal in a high percentage of
patients. Nucleos(t)ide analogues will remain a backbone
New therapies in development in suppressing HBV DNA replication and pegylated
Nucleos(t)ide analogues are safe and effective in interferon alfa could continue to have a role in HBsAg
suppressing HBV replication but rarely clear HBsAg, clearance.
and long-term treatment is needed to prevent relapse.
Thus, several classes of direct-acting antivirals and Future directions
immuno modulatory therapies are in development HBV infection remains a major global health problem.
(figure 2) with the goal of functional cure defined as Although many tools are available, achievement of WHO’s
sustained undetectable HBsAg and HBV DNA after a goals will require concerted efforts of community health
finite course of treatment.128 HBsAg clearance is providers, physicians, health authorities, and industry
associated with lower HCC risk compared with HBV researchers to ensure universal vaccination—in particular
DNA suppression without HBsAg clearance, and birth-dose vaccination—is implemented worldwide;
minimal risk of relapse after treatment discontinuation.129 increase screening, diagnosis, and linkage to care of those
There are no data from phase 3 trials for these new infected; and remove the stigma of HBV infection. Race
drugs, and their safety, clinical efficacy, and optimal dose is a social construct and could reflect unmeasured
regimens are being studied. confounders; however, race in the context of HBV is
Entry inhibitors such as bulevirtide block HBV entry associated with mode of transmission, age at infection,
into hepatocytes. Bulevirtide alone and in combination and genotypes, factors that influence the course of chronic
with pegylated interferon alfa has shown promise in infection and outcomes. Future studies should examine
chronic HDV but data in chronic HBV mono-infection whether social determinants of health, timing of infection,
are scarce.130,131 Capsid-assembly modulators can act at HBV genotypes, or host biology account for the race-
multiple steps in the HBV lifecycle, including assembly of specific observations.

Seminar
Contributors 19 Martinez MG, Boyd A, Combe E, Testoni B, Zoulim F. Covalently

ASFL conceptualised the study concept. W-JJ conducted the literature closed circular DNA: the ultimate therapeutic target for curing
search. W-JJ, GVP, and ASFL conducted data collection, manuscript HBV infections. J Hepatol 2021; 75: 706–17.
writing, revisions, and approved final manuscript. 20 Raimondo G, Locarnini S, Pollicino T, et al. Update of the
statements on biology and clinical impact of occult
Declaration of interests hepatitis B virus infection. J Hepatol 2019; 71: 397–408.
W-JJ has served as advisor and lecturer for Bristol Myers Squibb and
21 Wooddell CI, Yuen MF, Chan HL, et al. RNAi-based treatment of
Gilead; and received grants for research and attendance of meetings chronically infected patients and chimpanzees reveals that
from Chang Gung Medical Foundation and National Science Council of integrated hepatitis B virus DNA is a source of HBsAg.
Taiwan. GVP has served as advisor and lecturer for Amgen, Gilead, Sci Transl Med 2017; 9: eaan0241.
GlaxoSmithKline, Ipsen, Janssen, Novo Nordisk, Roche, and Takeda; 22 Bousali M, Papatheodoridis G, Paraskevis D, Karamitros T.
received support for attendance of meetings from Gilead Sciences, Hepatitis B virus DNA integration, chronic infections and
Ipsen, Janssen, Merck Sharp & Dohme, Novo Nordisk, Roche, and hepatocellular carcinoma. Microorganisms 2021; 9: 1787.
Takeda; and received research grants from Gilead. ASFL has received 23 Liu CJ, Kao JH. Global perspective on the natural history of
research grants from Bristol Myers Squibb, Gilead, and TARGET chronic hepatitis B: role of hepatitis B virus genotypes A to J.
Pharma, and royalties from Wolters Kluwer (UpToDate) and Wiley Semin Liver Dis 2013; 33: 97–102.
(textbooks); and served as advisor and consultant for Ambys, Amgen, 24 Ghany MG, Perrillo R, Li R, et al. Characteristics of adults in the
Arbutus, Chroma, CLEAR-B, Eli Lilly, Enanta, Enochian, hepatitis B research network in North America reflect their
GlaxoSmithKline, GNI, Huahui, Janssen, TARGET, and Virion. country of origin and hepatitis B virus genotype.
Clin Gastroenterol Hepatol 2015; 13: 183–92.
Editorial note: the Lancet Group takes a neutral position with respect to 25 Lin CL, Kao JH. Natural history of acute and chronic hepatitis B:
territorial claims in published maps and institutional affiliations. the role of HBV genotypes and mutants.
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All-age HBsAg prevalence in 2019

Figure 1: Global prevalence of HBsAg or chronic hepatitis B virus infection

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in less than 10% of HBsAg-positive patients,51 who should

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inactive carrier phase during follow-up, some remain in

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without cirrhosis, treatment is recommended for those Recommendations

be considered for treatment even if HBV DNA or ALT

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C Pegylated interferon alfa has modest antiviral activity, but

Pegylated interferon alfa

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Contributors 19 Martinez MG, Boyd A, Combe E, Testoni B, Zoulim F. Covalently

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