Chronic Hepatitis B NEJM 2022
Chronic Hepatitis B NEJM 2022
Chronic Hepatitis B NEJM 2022
Review Article
C
hronic hepatitis B is caused by the hepatitis B virus (HBV), a hepa- From University College London (G.D.),
totropic DNA virus that can replicate at high levels and cause minimal Kings College Hospital London (G.D.,
K.A.), Kings College London (K.A.), and
disease or severe liver injury. The clinical spectrum of chronic hepatitis B the Institute of Immunity and Transplan-
ranges from no symptoms to progressive hepatic fibrosis, advanced cirrhosis, and tation, University College London (M.K.M.)
hepatocellular carcinoma. An estimated 296 million people have chronic hepatitis — all in London. Dr. Dusheiko can be
contacted at g.dusheiko@ucl.ac.uk or at
B, of whom 221 million live in low- and middle-income countries.1 Without inter- Kings College Hospital, Denmark Hill,
vention, deaths from HBV are expected to peak at 1.14 million by 2035.2 London SE5 NRS, United Kingdom.
lope that is outside a 30-nm nucleocapsid that encloses a circular 3.2-kb DNA
genome. The lipid bilayer of the virion envelope incorporates the large (42-kD)
hepatitis B virus surface protein (LHBs), the medium (33-kD) surface protein
(MHBs), and the small (26-kD) surface protein (SHBs). The minus-strand HBV
DNA genome is synthesized by reverse transcription of the 3.5-kb pregenomic
RNA (pgRNA), after copackaging of the pgRNA and HBV polymerase inside the
icosahedral nucleocapsids.
The RNA primer can remain bound to the direct repeat 1 region to prime linear
double-stranded DNA synthesis.3 Linear double-stranded integrants of the HBV
DNA genome are integrated into the hepatocyte genome at sites of DNA breaks.
The linear genomes do not circularize, and integrated HBV DNA is therefore un-
able to produce progeny virus. However, the randomly dispersed integrated HBV
genomes act as a source of subgenomic RNA transcripts encoding LHBs, MHBs,
SHBs, and possibly HBx. Integration could favor viral persistence, since the hepa-
titis B surface antigen (HBsAg) burden transcribed from integrated genomes may
contribute to T-cell and B-cell exhaustion. Insertion into hepatocellular DNA may
contribute to the pathogenesis of hepatocellular carcinoma by invoking a cis-
mediated oncogenic mechanism, driving downstream cellular transcription, or
through trans-mediated expression of viral proteins, particularly HBx.4,5
LHBs
HBV HBsAg
virion HBV
virion Blood vessel
RNA interference
NUCLEUS CYTOPLASM
B-cell–depleting therapy with rituximab high- ase levels despite high levels of viremia (>7 log10 IU
lights the contribution of memory B cells to HBV per milliliter) reflect the noncytopathic nature of
control; antibodies against HBsAg are inade- HBV. The absence of inflammation in this phase
quately produced by dysfunctional HBsAg-specific has been considered indicative of immunologic
B cells.9-11 tolerance.13 The observation that adolescents have
Several disease phases are recognized on the some functional HBV-specific T cells provides
basis of serum aminotransferase levels, hepatitis B evidence against central tolerance.6,14 Discernible
e antigen (HBeAg) status, HBV DNA levels, and HBV integrants and clonal expansion of hepato-
histologic characterization or noninvasive meth- cytes suggest progressive disease.15
ods (Table 1). None of the current phase termi- HBeAg-positive disease is characterized by
nologies are fully consistent with the virologic or elevated HBV DNA levels (typically 5 to 7 log10 IU
immunologic stages of the disease, but these per milliliter) and abnormal aminotransferase
definitions serve as indicators of clinical pheno- levels, with exacerbations leading to necroin-
types and treatment.12 flammation and hepatic fibrosis. Spontaneous
HBeAg-positive infection occurs predominant- HBeAg seroconversion occurs in approximately
ly in young persons. Near-normal aminotransfer- 15% of cases per annum. Depending on the tim-
ing, the transition to HBeAg-negative, inactive nating from covalently closed circular DNA
infection reduces the risk of progression, but the (cccDNA) and HBsAg derived from integrated
disease necessitates longitudinal monitoring.16 viral genomes.18 HBV DNA levels are an indicator
Conversely, HBeAg seroconversion can augur a of HBV replication, used to identify the phase of
change to HBeAg-negative disease, with muta- chronic hepatitis B infection, determine indica-
tions in the precore or basal core promoter tions for treatment, and assess the efficacy of
down-regulating HBeAg, despite continued HBV antiviral therapy.
replication.17 HBsAg levels can remain high HBcAg induces both B-cell and T-cell respons-
(>1000 IU per milliliter), which reflects expres- es; anti-HBc indicates exposure to hepatitis B.
sion predominantly from integrated HBV ge- HBeAg is a secreted HBV protein, derived from
nomes.18 Spontaneous seroclearance of HBsAg the HBcAg reading frame with the use of the
has been associated with improved clinical out- first of the two start codons, but is not required
comes but is infrequent (accounting for an esti- to maintain infection (Fig. 3). HBeAg in serum
mated 1 to 2% of cases per year).19 signals high levels of replication and infectivity,
The annual incidence of hepatocellular carci- but since HBeAg expression is affected at the
noma is low among patients without cirrhosis transcriptional, translational, and post-transla-
but is increased, to up to 10%, among those tional levels, it may not necessarily correlate
with cirrhosis.20 Although there is a linear rela- with HBV DNA levels.
tionship between HBV DNA levels and the risks HBV has 10 listed genotypes and at least 24
of cirrhosis and hepatocellular carcinoma among subtypes. The evolution and distribution of HBV
HBeAg-negative patients,21 among HBeAg-posi- genotypes and subtypes can be traced to com-
tive patients, the immediate risk is lower for those plex introductions into host populations, as well
with HBV DNA levels exceeding 8 log10 IU per as to the movement of people in recent years.24-26
milliliter than for those with HBV DNA levels of HBV genotypes and subtypes influence clinical
5 to 7 log10 IU per milliliter.22 In HBeAg-positive outcomes, including HBeAg and HBsAg sero-
patients with active disease, the infection is conversion rates, mutational patterns in the pre-
likely to be transitioning from a low inflamma- core and core promoter regions, the risks of
tory–high replicative state to a different immu- cirrhosis and hepatocellular carcinoma, and the
nologic phenotype and phase. The transition is treatment response.27
characterized by a decrease in HBV DNA levels
and an increase in necroinflammatory damage, Quantitative HBsAg
which lead to an increase in hepatocyte turnover Low HBV DNA levels (<2000 IU per milliliter),
(and to the gradual selection of HBeAg-negative plus low HBsAg levels (<1000 IU per milliliter)
variants). and normal serum aminotransferase levels, sig-
nify an improved outcome. Long-read sequences
indicate that integrated HBV DNA becomes the
Di agnos t ic M a r k er s
predominant source of HBsAg in HBeAg-nega-
HBsAg, HBeAg, anti-HBc (antibodies against tive infection.16 Higher HBsAg levels increase the
hepatitis B core antigen [HBcAg]), and hepatitis risk of hepatocellular carcinoma among patients
B DNA are established markers of chronic hepa- with low HBV DNA levels,28 a finding that could
titis B (Table 1). Serologic assays for HBsAg de- reflect active transcription from accumulated
tect virion and subviral particles in blood. Non– HBV integrants and potentially influence carcino-
DNA-containing subviral HBsAg particles greatly genesis.
outnumber virions.23 SHBs antigen is the pre-
dominant component of 22-nm spherical parti- New Markers of cccDNA Transcription
cles; virion particles are enriched in LHBs anti- Although several technologies for quantifying
gen. The isoforms cannot be identified by cccDNA in liver tissue are in development, no
current immunoassays, which target the com- accepted quantitative standard is available.29 In-
mon antigenic epitope within the “a” determi- stead, two new serum markers, HBV RNA and
nant of HBsAg protein. Neither can current HBV core-related antigen (HBcrAg), can be used
HBsAg assays distinguish between HBsAg origi- to estimate transcription from cccDNA.30
Checkpoint
inhibitors
Engineered T cells Infused anti-HBs Exhausted endogenous
antibodies HBV-specific T cells
CD8
NK cell
CD8
Myeloid
PD-L1
cell PD-1
Hepatocyte
Infused soluble TCR
HBV
virion cccDNA
HBV integration
CYTOPLASM NUCLEUS
Endogenous
Blood vessel
anti-HBs antibodies
TLR 7/8
HBV
agonists
virion
Plasma
cell
Dysfunctional endogenous
HBs-specific B cells Immunoregulatory cells
Myeloid
HBsAg
Memory antigen NK cell PD-L1 cells
Treg
B cell
Immunoregulatory
Exhausted endogenous TRAIL cytokines
TCR HBV-specific T cells MDSC
Tfh PD-1 Antiviral cytokines
CD4
Therapeutic CD8 TCR
vaccination
Variable Phase
HBsAg HBsAg
HBcrAg level High High Low or undetected Lower than HBeAg- May be detected Data not available
positive states
HBV RNA level High High Low or undetected Lower than HBeAg- May be detected Data not available
* The abbreviation cccDNA denotes covalently closed circular DNA, HBcrAg HBV core-related antigen, HBeAg hepatitis B e antigen, HBsAg hepatitis B surface antigen, and ULN upper
limit of the normal range.
† Quantitative HBsAg levels are derived from baseline data in clinical trials of small interfering RNA. Ranges can vary significantly in HBeAg-negative patients, depending on the HBV
genotype and HBsAg expression.
‡ The low number of infected cells in some HBeAg-negative patients, the low cccDNA copy number (1 to 10 per infected cell), and the lack of standards for quantitation allow only a
qualitative assumption of cccDNA copy number.
§ The presence of integrated HBV DNA is usually assumed.
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New Approaches to Chronic Hepatitis B
Figure 3. HBV Genome Open Reading Frames, RNA Transcripts, Protein Products, and Biomarkers.
The cccDNA serves as the template for transcription of pgRNA and subgenomic messenger RNAs (mRNAs) and encodes the large, me-
dium, and small surface proteins, precore hepatitis B e antigen (HBeAg), and core, polymerase, and X proteins. The linear delineation of
the four HBV open reading frames is shown (colored boxes), as are the dual sources of HBsAg from integrated HBV DNA and cccDNA.
The mRNA transcripts derived from cccDNA and integrated viral genomes are also shown. The protein products are listed. Biomarkers
in serum, including HBsAg, HBeAg, HBV RNA, and HBV core-related antigen (HBcrAg), are shown at the bottom of the figure. (Untran-
scribed pgRNA is also secreted.) The polymerase open reading frame encodes the large polymerase and core protein. Hepatitis B core
antigen (HBcAg) and HBeAg are two translation products of the precore–core open reading frame that share homologous amino acid
sequences but have different properties. The core proteins are assembled in the nucleocapsid. Translation from the upstream initiation
codon and processing from the precore protein result in HBeAg, a soluble, dimeric protein that is secreted into serum. The first 19 aa
of the extra 29 aa encoded by the precore region serve as the signal peptide directing the precore–core protein to the secretory pathway.
A 2.4-kb pre-S1 mRNA transcript encodes the LHBs protein, a 2.1-kb pre-S2/S mRNA encodes the medium surface HBV (MHBs) protein
and the small surface (SHBs) protein, and a 0.7-kb X mRNA encodes the X protein. The transcripts from cccDNA are shown with a com-
mon polyadenylation site. The S transcripts from HBV integrations indicate transcription from chromosomal DNA.
Nucleoside analogues are safe and effective.45 hepatitis B and decompensated cirrhosis. They
Decreases in renal function and bone mineral can be prescribed at appropriate doses in pa-
density may occur with tenofovir, effects that are tients with renal failure and in children and
lessened in trials of tenofovir alafenamide.46 adolescents. Other indications include preven-
Current guidelines suggest a change to entecavir tion of HBV reactivation during immunosup-
or tenofovir alafenamide for patients who are pressive treatment. Prevention of a recurrence
older than 60 years of age or have renal dysfunc- after liver transplantation by means of preemp-
tion. Cholesterol and low-density lipoprotein tive nucleoside analogue treatment is now the
levels increase after a switch to tenofovir alafen- rule. Treatment complements HBV vaccination
amide.47 Weight gain has been reported. and safe sexual practices to reduce the risk of
The goals of treatment are to reduce HBV sexually transmitted HBV infection.
DNA to undetectable levels, normalize serum
aminotransferase levels, and reduce inflamma- Disadvantages and Limitations of Nucleoside
tion and fibrosis. In addition, tenofovir is used Analogues
to reduce viremia in pregnant women in order to Nucleoside analogues target a late stage in the
limit mother-to-child transmission of HBV. Nu- viral life cycle. They act on the reverse-transcrip-
cleoside analogues are used to treat fulminant tion step of formation of progeny virus but exert
Table 2. New Anti-HBV Compounds in Clinical Development. tively identified as the HSP40 (heat-shock pro-
tein, 40 kD) chaperone DNAJB12 and thus inhib-
Type and Compound Originator Phase* its trafficking of 22-nm HBsAg subviral particles.
Capsid assembly modula- The efficacy of REP 2139 has been tested in
tors combination with tenofovir and pegylated inter-
Vebicorvir (ABI-H0731) Assembly Biosciences Phase 2 terminated feron. After 48 weeks of follow-up, HBsAg was
ABI-H3733 Phase 1 undetectable in 14 of 40 study participants. It
ABI-4334 Preclinical studies
remains to be proved that alanine aminotrans-
ferase flares during treatment are indicative of
Morphothiadin (GLS4) HEC Pharma Phase 2
immune reconstitution.62
JNJ-6379 Janssen Phase 2b
EDP-514 Enanta Phase 2 Capsid Assembly Modulators
RG7907 Roche Phase 2 Several classes of oral, small-molecule CAMs
QL-007 Qilu Phase 1 have been developed that interfere with capsid
Canocapavir Zhimeng Biopharma Not available assembly through allosteric binding to the core
ALG-000184 Aligos Therapeutics Phase 1
dimer and thereby misdirect capsid formation
and disrupt encapsidation of pgRNA63 (Figs. 1 and
AB-836 Arbutus Phase 1 and 2
2 and Table 2). These agents result in decreases in
VNRX-9945 Venatorx Phase 1 terminated serum HBV DNA levels (up to 4 log10 IU per milli
O7049839 Roche Phase 1 liter) and HBV RNA levels (up to 3 log10 copies
siRNA agents† per milliliter) within 28 days. Declines in HBsAg
RG6346 (RO7445482) Roche/Dicerna Phase 2 levels are negligible, since CAMs do not reduce
JNJ-3989 Janssen Phase 2b established cccDNA levels or transcription from
cccDNA and have no direct effect on HBsAg
AB7-29–001 Arbutus Phase 2
derived from integrated HBV genomes. HBV
VIR-2218 Vir Biotechnology Phase 2
RNA and HBcrAg rebound after discontinuation
ALG-125755 Aligos Therapeutics Phase 1 of treatment, underscoring the inability of CAMs
Antisense oligonucleotides to eradicate the pool of cccDNA. The place of
Bepirovirsen GSK Phase 2 CAMs in curative strategies remains uncertain.
(GSK3228836)
RO7062931 Roche Phase 1 RNA Interference
ALG-020572–401 Aligos Therapeutics Phase 1 RNA-interfering agents, including siRNA and
Nucleic acid polymers: REP Replicor Phase 2 antisense oligonucleotides (ASOs) exploit a com-
2139, REP 2165 plementary sequence of the target RNA to trig-
Active-site polymerase in- Antios Phase 2 ger specific RNA degradation and perturb trans-
hibitor: ATI-2173 lation (Figs. 1 and 4 and Table 2). Current
Entry inhibitor: bulevirtide Gilead Phase 3 (hepatitis D) RNA-interfering agents, targeted to X or S RNA,
Transcriptional inhibitor: Romark Laboratories/ Phase 2 are designed to silence all HBV transcripts de-
nitazoxanide Lupin rived from cccDNA or integrated genomes.64
levels of less than 100 IU per milliliter within 24 level below 20 IU per milliliter 24 weeks after
to 48 weeks, with a relatively slow rebound after discontinuing bepirovirsen. Among participants
treatment.65 with a low baseline HBsAg level of no more than
The results of the first large phase 2b clinical 3 log10 IU per milliliter who did not receive nu-
trials of the combination of an siRNA and CAM cleoside analogue treatment, 25% reached the
have recently been reported. The six-group REEF-1 primary end point, as compared with 16% of
study, involving 470 patients, investigated the those who received nucleoside analogue treat-
efficacy of JNJ-3989 (an siRNA), injected every ment. HBsAg levels declined to less than 100 IU
4 weeks, plus the CAM JNJ-6379, plus a nucleo- per milliliter at the end of treatment in 63% of
side, given for 48 weeks. In the group treated those who received 300 mg of bepirovirsen plus
with 200 mg of JNJ-3989 alone, 74% of patients a nucleoside analogue and in 59% of those who
had an HBsAg level of less than 100 IU per milli did not receive a nucleoside analogue.70
liter, but no patients had a functional cure at The dose-dependent decline in HBsAg during
week 24 of follow-up. An unexplained antago- treatment and the prolonged effect with siRNA
nistic effect of the CAM combined with the and ASOs are encouraging findings, and even
siRNA occurred.66 though the end points for a functional cure have
REEF-2 assessed the efficacy of 48 weeks of not been met to date, these data indicate that an
treatment with the combination of JNJ-3989 HBsAg reduction to less than 100 IU per millili-
(200 mg every 4 weeks), JNJ-6379 (250 mg daily), ter can be achieved in the majority of patients.
and a nucleoside analogue, as compared with a Given these results, a partial functional cure is
nucleoside analogue alone, in 140 HBeAg-nega- being posited, defined as a decline in HBsAg to
tive patients. Although 71% of the patients re- less than 100 IU per milliliter 6 months after
ceiving combination therapy had an HBsAg level finite treatment, resulting in a lower replicative
of less than 100 IU per milliliter at week 48 of state in HBsAg-positive patients and possibly im-
treatment (which was reduced to 46% at 48 weeks mune activation or restoration. A summary of the
after cessation of treatment), no patients had efficacy of current trials is presented in Table S1.
HBsAg seroclearance at week 24 of follow-up
without restarting nucleoside analogue treat- Preclinical Research Approaches
ment.67 A participant in the control group re- There are several preclinical research approaches.
quired liver transplantation for hepatic decom- These include X gene targeting, cccDNA or RNA
pensation after withdrawal of the nucleoside destabilization or cccDNA reduction, host tar-
analogue, underscoring the need for stringent gets or targeting by CRISPR-Cas9 (clustered
criteria to enable cessation of nucleoside ana- regularly interspaced short palindromic repeats
logue treatment.68 and associated Cas9 homing endonucleases) to
base edit cccDNA.
ASOs
ASOs are synthetic, single-stranded oligonucleo Immunomodulatory Therapy
tides with various biochemical characteristics. Early data suggest that new direct antiviral
ASOs bind to complementary HBV RNA tran- agents alone are insufficient to restore effective
scripts to form a hybrid ASO-RNA complex, immunologic control. Therefore, immunomodu-
resulting in cleavage by ribonuclease H. Serum latory treatments to restore and replenish ex-
aminotransferase levels can increase after the hausted, sparse, or dysfunctional HBV-specific
HBsAg level has reached a nadir.69 In the recently T-cell and B-cell responses by activating or re-
reported phase 2b B-Clear study of bepirovirsen placing endogenous immunity are being re-
involving participants with chronic HBV infec- searched (Fig. 2 and Table S3).
tion, 9% of participants who received 300 mg Pegylated interferon alfa is being added to
of bepirovirsen subcutaneously once weekly for siRNA and nucleic acid polymers in current
24 weeks plus a nucleoside analogue and 10% clinical trials. Several oral selective toll-like re-
who received bepirovirsen alone reached the ceptor agonists are being tested, but promising
primary end point of an undetectable HBsAg results in animal models have not been con-
level (<0.05 IU per milliliter) and an HBV DNA firmed in clinical studies to date.71
the search for a cure for chronic hepatitis B been diagnosed in only 2% of the 82 million
presents myriad challenges. persons living with hepatitis B in this region
Current levels of diagnosis and treatment of and only 0.1% of the currently infected persons
hepatitis B are inadequate. Approximately 10% had received treatment. While we look beyond
of people living with hepatitis B knew their sta- current treatments, we should not lose sight of
tus in 2019. Of this group, only about 6.6 mil- the cardinal responsibility to improve awareness
lion people with a diagnosis of hepatitis B re- and access to treatment of hepatitis B with exist-
ceived treatment in 2019. The WHO African ing antiviral therapies.
region leads the way in HIV testing and treat- Disclosure forms provided by the authors are available with
ment, but by the end of 2019, hepatitis B had the full text of this article at NEJM.org.
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