|

Received: 28 October 2016 Accepted: 1 November 2016

DOI: 10.1111/liv.13309

REVIEW ARTICLE

Treatment of chronic hepatitis B infection-2017

Guo-Feng Chen1,2|Cheng Wang1,3,4|George Lau1,3,5

1
Beijing 302-Hong Kong Humanity and Health
Hepatitis C Diagnosis and Treatment Center, Abstract
Beijing, China Since the registration of the first effective nucleoside analogue against the hepatitis B
2
Second Liver Cirrhosis Diagnosis and
virus almost two decades ago, major progress has been made in the management of
Treatment Center,302 Hospital, Beijing, China
3 chronic hepatitis B infection. However, hepatitis B-related morbidity and mortality
Division of Gastroenterology and
Hepatology,Humanity and Health Medical remain a major global health threat. This is partly due to the escalating costs and the
Centre, Hong Kong, SAR, China
decrease in compliance related to the need for prolonged therapy for most patients
4
State Key Laboratory of Organ Failure
Research,Guangdong Provincial who cannot be cured. New biomarkers such as quantitative hepatitis B surface
Key Laboratory of Viral Hepatitis antigen might help to determine if hepatitis B e antigen negative patients can be taken
Research,Department of Infectious
Diseases,Nanfang Hospital,Southern Medical off nucleos(t)ide analogues. On the other hand, novel compounds that target the viral
University, Guangzhou, China life cycle or modulate host immune response are in the pipeline. In the next few years,
5
Institute of Translational Hepatology,302 one should expect breakthrough advancement to be made leading to a cure for
Hospital, Beijing, China
patients with chronic hepatitis B infection by inducing hepatitis surface antigen loss
Correspondence with or without the development of the hepatitis B surface antibody. In addition,
George Lau, Division of Gastroenterology and
Hepatology, Humanity and Health Medical attention and necessary actions should also be taken in patients with hepatitis B
Centre, Hong Kong, SAR, China. infection who are being treated with immunosuppressive therapy and direct anti-viral
Email: gkklau@netvigator.com
(DAAs) agents for hepatitis C infection to prevent hepatitis from hepatitis B
Funding information
Cheng Si-yuan (China-international) hepatitis reactivation.
research foundation and Humanity and Health
Medical group. KEYWORDS
hepatitis B, hepatitis B reactivation, management, new therapy
Handling Editor: Mario Mondelli

1| INTRODUCTION
Chronic hepatitis B infection affects around 250 million people world-
wide (3.61% of the global population) and if left untreated, around
one-quarter of them will die of cirrhosis, liver failure or hepatocel-
lular carcinoma.1-6 Variations in hepatitis B surface antigen (HBsAg)
seroprevalence are wide it is the lowest in Norway and the UK
(0.01%) and the highest (more than 20%) in countries such as South
Sudan and Kiribati.5 The number of affected individuals is highest in
the Western Pacific region, defined by the World Health Organization
as 37 countries including China, Japan, South Korea, Philippines
and Vietnam, with 95.3 million (prevalence estimates of 5.26%) and
Africa, with 75.6 million (prevalence estimates of 8.83%) accounting
for nearly 70% of all chronic hepatitis B infection globally.5,7 (Figure1)
Despite recommendations for universal hepatitis B vaccination in
1992, it has not been fully implemented in endemic countries due
to economic and logistic constraints. This is further compounded by
the use of unsafe blood products and medical procedures in resource-
poor countries and has contributed to the increase in mortality and
disability-adjusted life years (DALYs) due to hepatitis B infection8
between 1990 and 2013. Thus, chronic hepatitis B (CHB) infection
remains one of the most important causes of morbidity and mortality
in humans.
This review represents my personal view on the treatment of
chronic hepatitis B infection based on the treatment guidelines pub-
lished by the three continental hepatology societies.1,4,6

Abbreviations: AFP, a-foetoprotein; ALT, alanine aminotransferase; BR, biologic relapse; cccDNA, covalently closed circular DNA; CHB, chronic hepatitis B; DAAs, direct-acting antivirals; DALYs,
disability-adjusted life years; eGRF, estimated glomerular filtration rate; HBeAg, hepatitis B e antigen; HBs, hepatitis B surface antigen; HCC, hepatocellular carcinoma; NPV, negative predictive
value; OBI, occult hepatitis B virus infection; PEG-IFN, pegylated interferon; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; VR, virological relapse.

Liver International 2017; 37 (Suppl. 1): 5966 wileyonlinelibrary.com/journal/liv 2017 John Wiley & Sons A/S. | 59
Published by John Wiley & Sons Ltd
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60
2| WHO WILL I TREAT AND WITH WHAT?
The goal of therapy for CHB infection is to improve quality of life and
survival in infected persons by preventing disease progression to cir-
rhosis, decompensated cirrhosis, end-stage liver disease, hepatocel-
lular carcinoma (HCC) and death.1,4,6 This goal can be achieved with
significant suppression of HBV replication which has been shown to
correlate with a significant reduction in hepatic necroinflammation,
reversal of liver fibrosis and reduction in the development of cirrhosis
and HCC. The ideal endpoint in both hepatitis Be antigen (HBeAg)-
positive and HBeAg-negative patients is sustained off-therapy HBsAg
loss, with or without seroconversion to anti-HBs. This is associated
with complete and permanent remission of CHB activity and improved
long-term outcome.9 However, such a cure, with loss of HBsAg
with or without the development of HBsAb can rarely be achieved
with current registered therapies against CHB because eradication of
covalently closed circular DNA (cccDNA) in the nucleus of infected
hepatocytes and integrated hepatitis B virus (HBV) is very difficult.10
This is at least partly due to the inability of current therapeutic agents
to effectively repair virus-specific and global T-cell dysfunction medi-
ated by multiple regulatory mechanism, such as virus-specific IL-10
response, FOXP3+ regulatory T-cell frequency and T-cell expression
of PD-1 and CTLA-4.11 Thus, a more realistic endpoint is the induc-
tion of sustained or maintained virological remission. Induction of sus-
tained off-therapy virological response in both HBeAg-positive (with
sustained anti-HBe seroconversion) and HBeAg-negative patients is a
satisfactory endpoint, because it has been shown to be associated with
an improved prognosis. If a sustained off-therapy response cannot be
HBsAg seroprevalence (%)*
[0,0]
(0,2]
(2,4]
(4,10]
(10,22]
Age-standardized rates of deaths#
[2,3]
(3,5]
(5,11]
(11,16.5]
(16.5,22]
Chen etal.
Key points
Current therapy suppresses hepatitis B virus (HBV) repli-
cation but cannot lead to a cure with loss of HBsAg.
A better understanding of the HBV life cycle and its inter-
actions with the host led to new antiviral approaches,
focusing on interference with viral life cycle and spread,
immune modulation and cccDNA-targeted therapy.
Future therapy against hepatitis B infection may integrate
several strategies to achieve a better control of the virus
and perhaps even a cure.
HBV reactivation after immunosuppressive therapy or
pan-oral direct-acting antiviral agents for hepatitis C in-
fection, leading to liver-related morbidity and mortality,
can be prevented by increased awareness.
achieved then maintained, virological remission (undetectable HBV
DNA by a sensitive PCR assay) with long-term antiviral therapy in
HBeAg-positive patients who do not achieve anti-HBe seroconver-
sion and in HBeAg-negative patients is the next best endpoint.1,3,4,6
To better estimate the risk of the development of cirrhosis or HCC
and hence to allow one to prioritise therapy for CHB patients, various
risk models have been developed. Based on routinely available clini-
cal and laboratory data on CHB in Chinese, three prediction models
(REACH-B, CU-HCC and GAG-HCC) were developed. These models
allow one to predict the 5- and 10-year risk of HCC. At our centres in
Hong Kong and Beijing, all three models have been used to determine
F I G U R E 1 Global burden of hepatitis
B virus [Colour figure can be viewed at
wileyonlinelibrary.com]
*Data source: Schweitzer et al. Lancet
2015; 386: 1546-55.
# Age-standardized rates of deaths per
100,000 person years; Data source:
Stanaway et al. Lancet 2016; 388: 1081-88.
Stata command spmap was used to draw
the map.
Chen etal.
the frequency of monitoring, the need for HCC surveillance, and the
urgency of antiviral treatment. However, it is unclear whether these
models can be applied to patients outside Asia (genotypes B and C),
where the genotypes (mainly A and D) are different.12-15
Based on clinical evidence and experts opinion, the American,
Asian-Pacific and European Liver Associations (AASLD, APASL and
EASL) have formulated management guidelines to help physicians
make treatment decisions. All these guidelines are based on clinical
status, serum HBV DNA and alanine aminotransferase (ALT) levels,
1,3,4,6
HBeAg status, and the degree of liver fibrosis. All guidelines rec-
ommend starting treatment as soon as possible in patients with life-
threatening liver disease: acute liver failure, decompensated cirrhosis
or severe acute exacerbation of chronic hepatitis B, regardless of HBV
DNA and ALT levels. These guidelines also recommend antiviral treat-
ment for patients with compensated cirrhosis whatever the ALT levels
but there are minor differences in threshold HBV DNA levels for initi-
ating treatment. All guidelines agree that treatment should be initiated
in patients without cirrhosis with serum HBV DNA levels >20000IU/
mL and persistently elevated ALT levels and/or histological evidence of
moderate or severe inflammation or fibrosis. However, cut-off values
of ALT and the need for liver biopsy or the noninvasive assessment of
liver fibrosis to determine treatment indications differs among guide-
lines. All guidelines agree that serial HBV DNA and ALT levels are more
important than values at a single time point in making treatment deci-
sions, because HBV DNA and ALT levels fluctuate during the course
of chronic HBV infection. Furthermore, all guidelines recommend
that patients who do not start treatment should be monitored so that
treatment can be initiated later when HBV replication or liver disease
becomes more active. However, none of the guidelines have included
prediction models for cirrhosis or HCC into recommendations because
in real-life predicting how CHB patients will progress is difficult and
adapting indications16,17 to these risk models may not decrease the
incidence of HCC.18 Instead, CHB patients who do not meet treatment
criteria at presentation should be carefully monitored allowing timely
initiation of treatment.18 These guidelines emphasise that patient age,
a family history of HCC, occupational requirements, plans to start a
family (for women) and patient preference should also be considered
when making treatment decisions. There are many settings in which
a patients medical or social circumstances warrant a personalised
approach that may be at odds with the guidelines but appropriate for
the patient (Table1, Figures2 and 3).
In the past two decades, seven drugs have been approved for
the treatment of chronic hepatitis B infection, namely conventional
and pegylated interferon (PEG-IFN), and five nucleos(t)ide analogues
lamivudine, telbivudine, adefovir, entecavir and tenofovir.19-27 The
effectiveness of these antiviral therapies in reducing the risk of cir-
rhosis, decompensated liver diseases and hepatocellular carcinoma in
CHB patients with treatment indications, was supported by a recent
28,29
systemic review and meta-analysis. In addition, based on recent
encouraging phase 3 data, tenofovir alafenamide (TAF), a new form
of tenofovir, is expected to be the next registered agent for the treat-
ment of CHB. TAF has been shown to be as effective as the teno-
fovir disoproxil fumarate (TDF) formulation in both HBeAg-positive
|
61
and -negative patients, but with fewer detrimental effects on bone
and kidney biomarkers. In both studies, patients receiving TAF experi-
enced a significantly smaller mean percentage decrease from baseline
in hip and spine bone mineral density at week 48 compared to patients
receiving TDF. Smaller increases in serum creatinine were observed in
HBeAg-positive patients receiving TAF. Moreover, the median change
in estimated glomerular filtration rate (eGFR) from baseline to week 48
favoured TAF in both studies.30,31
All guidelines recommend initial treatment with PEG-IFN, entecavir
or tenofovir as monotherapy.1,3,4,6 Although IFN is not recommended
in patients with acute liver failure, decompensated cirrhosis or severe
exacerbations of chronic hepatitis B, it may be used with caution in
patients with compensated cirrhosis. While guidelines consider PEG-
IFN, entecavir and tenofovir to be equivalent first-line anti-HBV drugs,
in our clinical practice as do many others, entecavir and tenofovir are
used much more often than PEG-IFN even in patients with no contra-
indications to the use of IFN. This is related to patients preference for
route of administration (injection vs oral) and the presence of medical/
psychiatric comorbidities that contraindicate use of or decrease tol-
erance to IFN, as well as the cost of the treatment. However, in some
circumstances, other factors such as the desire to raise a family in the
near future in female patients or the desire to use a more finite rather
than long-term therapy (PEG-IFN for 1year vs >3years of nucleos(t)
ide analogues) can make PEG-IFN more preferable. Recently, the cost
has become a less important concern because entecavir and tenofovir
has or will soon go off-patent, and both drugs have markedly lower
rates of drug resistance (0-1% after 5-6years of continuous therapy)
compared to lamivudine, adefovir or telbivudine. Tenofovir and ente-
cavir have similar potencies and barriers to antiviral resistance, and
either drug may be used as first-line treatment in nucleoside-nave
patients. Because of a low risk of nephrotoxicity, entecavir is preferred
in older patients, patients with baseline impaired renal function and
those with other medical conditions such as hypertension or diabetes
that increase the risk of renal insufficiency. Although telbivudine has
been reported to improve renal function,25 the high risk of antiviral
drug resistance and the potential for other adverse reactions such as
myopathy and polyneuropathy make this a poor choice as a first-line
treatment.20 Tenofovir effectively suppresses not only wild type HBV
but also lamivudine, telbivudine or entecavir resistant HBV and to a
lesser extent adefovir resistant HBV. It is therefore a better choice in
patients who have been previously treated with other nucleos(t)ide
analogues. Tenofovir is also a preferred choice for women of reproduc-
tive age because of its safety record in pregnancy.27
Recently, the use of PEG-IFN was further fine-tuned with the use
of a 12-week stopping rule, based on no decline or a <0.5 log10 decline
of qHBsAg or qHBsAg >20000 as the stopping rule. However, these
rules are based on retrospective analyses of data from large clinical
trials and have never been tested prospectively.2,3,7-14 An ideal stop-
ping rule should have a negative predictive value (NPV) of 95% for
both intermediate-term and long-term response and should be applied
to all patients. The NPV from these studies varies between 72% and
97%, with the lowest NPV in Asian patients. Furthermore, different
stopping rules have been identified to predict a long-term response
 |
62
T A B L E 1 Comparison of AASLD, APASL and EASL guideline recommendations regarding treatment of hepatitis B
AASLD (2015)
HBV DNA cut-off level, IU/mL
HBeAg-positive 20000
HBeAg-negative 2000
ALT cut-off level, U/L 30 for men, 19 for women
Recommendations for treatment and monitoring
Noncirrhotic patients
HBeAg-positive HBV DNA >20000IU/mL,
ALT>2x ULN
Monitor for 3-6months
Treat if no spontaneous
HBeAg loss
Liver biopsy before treatment
is optional
HBV DNA >20000IU/mL,
ALT2x ULN
Monitor every 3-6months
Consider biopsy in patients
>40years, ALT persistently
1-2 ULN, or with family history
of HCC
Treat if biopsy shows
moderate/severe inflammation
or significant fibrosis
HBeAg-negative HBV DNA >20000IU/mL, ALT
>2x ULN
Treatment is clearly indicated,
liver biopsy is option
HBV DNA 2000-20000IU/mL,
ALT 1-2x ULN
Consider liver biopsy
Treat if liver biopsy shows
moderate/severe
fibrosis is recommended
Treat if biopsy shows
moderate-severe inflammation
or significant fibrosis
HBV DNA2000IU/mL,
ALTULN
Monitor
Cirrhosis
Compensated HBV DNA >2000IU/mL
Treat regardless of ALT level
HBV DNA <2000IU/mL
Treat regardless of ALT level
Decompensated Regardless of HBV DNA or ALT
level
Treat and refer for liver
transplantation
HCC surveillance US every 6months
APASL (2015)
20000
2000
Traditional cut-off value of 40U/L
HBV DNA >20000IU/mL, ALT>2x ULN
Monitor for 3months
Treat if no spontaneous HBeAg loss
Histology should be obtained or assessed
noninvasively
HBV DNA >20000IU/mL, ALT 1-2x ULN
Monitor every 3months
Consider biopsy in patients >35years, ALT
persistently >ULN, or with family history of
HCC
Treat if biopsy shows moderate/severe
inflammation or fibrosis
HBV DNA >2000IU/mL, ALT >2x ULN
Treatment is clearly indicated, liver biopsy
is optional
HBV DNA >2000IU/mL, ALT 1-2x ULN
Monitor ALT and HBV DNA every
1-3months. Consider liver biopsy if patient
is 40years. Treat if biopsy shows
moderate/severe inflammation or fibrosis
HBV DNA2000IU/mL, ALTULN
Monitor
HBV DNA >2000IU/mL
Treat regardless of ALT level
HBV DNA <2000IU/mL
Consider treatment if ALT>ULN
Regardless of HBV DNA or ALT level
Treat and refer for liver transplantation
US and AFP every 6months
Chen etal.
EASL (2012)
2000
2000
Traditional cut-off value of
40U/L
HBV DNA >2000IU/mL, ALT
>ULN
Monitor for 3-6months
Liver biopsy (or noninvasive
markers of fibrosis) is recom-
mended
Treat if no spontaneous HBeAg
loss and biopsy shows
moderate-severe inflammation
and/or at least moderate fibrosis
HBV DNA >20000IU/mL,
ALT<ULN
Monitor every 3-6months
Consider biopsy in patients
>30years, ALT persistently 1-2
ULN, or with family history of
HCC
Treat if biopsy shows moderate-
severe inflammation or
significant fibrosis
HBV DNA >20000IU/mL, ALT
>2x ULN
Treatment is clearly indicated,
liver biopsy is optional
HBV DNA >2000IU/mL,
ALT>ULN Liver biopsy (or
noninvasive markers of fibrosis)
is recommended
Treat if biopsy shows moderate-
severe inflammation and/or at
least moderate fibrosis
HBV DNA2000IU/mL,
ALTULN
Monitor
HBV DNA detectable
Treat regardless of ALT level
Regardless of HBV DNA or ALT
level
Treat and refer for liver
transplantation
US every 6months
Chen etal. |
63

F I G U R E 2 Algorithm showing guideline

recommendations for the treatment of
patients with HBeAg-positive CHB
* APASL indicates treatment may be
initiated in patients with normal ALT level
if the biopsy shows moderate-severe
inflammation or significant fibrosis. EASL:
age,>30 years; APASL: age >35 years;
AASLD: age >40 years.

F I G U R E 3 Algorithm showing guideline

recommendations for the treatment of
patients with HBeAg-negative CHB
*APASL and EASL indicate treatment may
be initiated in patients with normal ALT
level if the biopsy shows moderate-severe
inflammation or fibrosis.

and it has been shown that some patients who meet criteria for stop-
ping treatment based on a low probability of intermediate response
might have a late response with HBsAg clearance. These data show
that one universal stopping rule probably cannot provide sufficiently
accurate predictions for a response to PEG-IFN for it to be applied in
clinical practice.
3|HEPATOCELLULAR
CARCINOMA SURVEILLANCE
Most deaths related to hepatocellular carcinoma are due to a late diag-
nosis. Indeed, early detection by monitoring offered the best chance
of having resectable HCC and thus a cure. The AASLD, EASL and
APASL guidelines recommend HCC surveillance for HBV carriers who
are Asian men older than 40 and Asian women older than 50, patients
with cirrhosis, with a family history of HCC, first- generation African
Americans older than 20, and any carrier older than 40 with persis-
tent or intermittent increased ALT and/or HBV DNA levels >2000IU/
mL.1,3,4,6 Ultrasound surveillance at 6-month intervals is recommended
by EASL and AASLD guidelines.5,13,14 The APASL recommends a combi-
nation of ultrasound and a-foetoprotein testing every 6months.4
4|CAN WE STOP TREATMENT WITH
NUCLEOS(T)IDE ANALOGUES?
With the wide availability of nucleos(t)ide analogues for nearly two dec-
ades, many patients with chronic hepatitis B infection have been main-
tained on treatment. One of the frequent concerns is the long-term safety
and cost of this infinite treatment. Most of these patients have been
treated with entecavir or tenofovir because these drugs have a very low
rate of drug resistance. Recommendations on when to stop nucleos(t)ide
analogues vary. All guidelines recommend that nucleos(t)ide analogues
be stopped in HBeAg-positive patients when the patient has completed
6-12months of consolidation therapy after HBeAg seroconversion. EASL
guidelines recommend continuing treatment until HBsAg loss in patients
with advanced fibrosis or cirrhosis to avoid flares associated with viral
relapse. AASLD and EASL guidelines recommend that nucleos(t)ide ana-
logues be continued in HBeAg-negative patients until HBsAg loss while
APASL guidelines state that treatment may be withdrawn after completing
at least 2years of treatment with undetectable HBV DNA documented on
three occasions 6months apart. All three guidelines recommend lifelong
nucleos(t)ide analogue treatment in patients with cirrhosis before treat-
ment unless they had compensated cirrhosis and had cleared HBsAg.
 |
64 Chen etal.

T A B L E 2 HBsAg loss to monotherapies and combination therapies in chronic hepatitis B patients

Monotherapies Combination therapies

Treatment PEG-IFN TDF+PEG- ETV+PEG-IFN ADV+PEG-

response 3TC ADV ETV LdT TDF IFN IFN ETV+TDF

HBeAg-positive patients
At week 48 or 52
HBsAg loss, % <1 0 2 0 3 3 6 1 3 1
Cumulative percentage during extended treatment
HBsAg loss, % 0-3 (2-3) 2 (5) 5 (2) 1.3 (2) 10 (5) 11 (3.5) 9 (1.5) 1 (2.5) 3 (0.5) 5 (2)
(in years)
HBeAg-negative patients
At week 48 or 52
HBsAg loss, % <1 0 <1 <1 0 4 5 0
Cumulative percentage during extended treatment
HBsAg loss, % <1 (4) 5 (5) NA <1 (2) 0.3 (5) 8 (3) 5 (1.5) 0 (2)
(in years)

3TC, lamivudine; ADV, adefovir; CHB, chronic hepatitis B; ETV, entecavir; LdT, telbivudine; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface anti-
gen; PEG-IFN, pegylated interferon; TDF, tenofovir disoproxil fumarate.

In a recent meta-analysis including 25 studies with more than
1700 patients in whom nucleos(t)ide analogues were discontinued, the
duration of an on-therapy virological response was shown to be the
most important predictor of a durable off-therapy virological relapse
(VR) with a significantly increased pooled probability (12months: 36%
vs 75%) in patients who remained in VR under nucleos(t)ide analogues
for more than 24months. These findings contradict APASL guide-
lines, which recommend discontinuation of nucleos(t)ide analogues
in HBeAg CHB who remain in VR for only 18months. However, the
optimal duration of on-therapy VR before stopping nucleos(t)ide ana-
logues remains unknown.32 On the other hand, recent data suggest the
usefulness of end-of-therapy and post-treatment quantitative hepati-
tis B surface antigen (qHBsAg) to predict VR and biological relapse
(BR). The usefulness of end-of-treatment qHBsAg in predicting a sus-
tained viral response after stopping nucleos(t)ide analogue treatment
has been explored. It has been suggested that end-of-treatment serum
33
qHBsAg levels can predict off-therapy sustained virological response
and patients with a low qHBsAg level <10IU/mL did not relapse.34
However, larger prospective studies are certainly needed for valida-
tion. Nevertheless, patients with CHB and without cirrhosis who are
receiving nucleos(t)ide analogues with virological response >2years
can stop treatment as long as they can be closely monitored.32
5| HBV REACTIVATION SHOULD
DRAW MORE ATTENTION PRE-
EMPTIVE TREATMENT WITH NUCLEOS(T)
IDE ANALOGUES
Hepatitis B reactivation in patients with CHB who were treated with
immunosuppressive or chemotherapeutic agents, can lead to fatal
liver failure. With careful prospective serial serological testing, it is
now known that liver damage due to HBV reactivation is a two-stage
process. Initially, there is markedly enhanced viral replication during
intense cytotoxic or immunosuppressive therapy reflected by increases
in serum levels of HBV DNA, hepatitis Be antigen (HBeAg) and HBV
DNA polymerase, resulting in widespread infection of hepatocytes.
With the restoration of immune function following withdrawal of cyto-
toxic or immunosuppressive therapy, there is rapid immune-mediated
destruction of HBV-infected hepatocytes, resulting clinically in hepa-
titis, hepatic failure and even death.35 All of these fatal hepatic events
can be prevented by identifying a patients HBV status (HBsAg and
hepatitis B core antibody) before beginning immunosuppressive or
chemotherapy and by pre-emptive treatment with nucleos(t)ide ana-
logues.36 Although this has been clearly set out in all treatment guide-
lines, fatal hepatitis due to HBV reactivation still occurs due to lack
of HBV screening and timely administration of antiviral therapy.37
Recently, with the advent of pan-oral direct-acting antiviral agents for
chronic hepatitis C infection, there is increased awareness of HBV reac-
tivation in CHC patients with HBV coinfection treated with pan-oral
direct acting antivirals (DAAs).38 The severity of hepatitis ranged from
HBV reactivation without hepatitis to fulminant hepatic failure, requir-
ing liver transplantation. The underlying mechanisms of HBV reactiva-
tion during pan-oral DAAs therapy for CHC remain speculative. Several
previous reports have documented that de novo HCV superinfection
in patients with CHB can result in HBeAg seroconversion and in some
cases, clearance of HBsAg. This suggests that HCV infection can sup-
press HBV replication, but the detailed mechanism is not clear. New
insights have been obtained from cell culture studies, where HBV and
HCV were shown to replicate in the same hepatocyte without evidence
of interference. This suggests that HCV suppresses HBV replication via
an indirect immune mechanism.39 Like patients with occult hepatitis B
virus infection (OBI) treated with intense immunosuppressive therapy,
life-threatening fulminant hepatitis due to HBV reactivation has also
Chen etal. |
65

T A B L E 3 Emerging treatments for chronic hepatitis B virus infection

Target Example drug Mechanism of action Phase of clinical trial

Virus replication cycle

Viral entry Myrcludex B Targets sodium taurocholate cotransporting 2
polypeptide to inhibit virus entry
HBV DNA polymerase Tenofovir alafenamide Besifovir DNA polymerase inhibition 3
DNA polymerase inhibition 3
HBV cccDNA Zinc finger proteins CCC-0975/ Block transcription of cccDNA Inhibit cccDNA Preclinical
CCC-0346 MC2791/ production Repression of cccDNA transcriptional Preclinical
MC3119CRISPR/Cas activity Gene editing to mutate cccDNA Preclinical
Preclinical
HBV gene expression ARC-520 siRNA/ddRNA HBV RNA interference 2
Preclinical
RNAi-based gene silencing
Viral nucleocapsid Bay 41-4109 Destabilisation of HBV nucleocapsids 1
GLS4 Destabilisation of HBV nucleocapsids 1
GLP-26 HBV capsid disruption Preclinical
Viral protein secretion REP 2139-Ca Inhibits the release of HBsAg 2
Host immune system
Innate immune response GS-9620 TLR-7 agonist 2
Pegylated interferon lambda Stimulates cell-mediated immune responses 2
STING agonists Produces type I IFN-dominant cytokine response Preclinical
Adaptive immune NASVAC HBsAg/HBcAg-based therapeutic vaccine 3
response HBsAg-HBIG Immunogenic vaccine 3
GS-4774 Therapeutic vaccines 2
ABX 203 Therapeutic vaccines 2
DV-601 Therapeutic vaccines 1
PD-1/PD-L1 inhibitors Restoration of T-cell function Preclinical

cccDNA, covalently closed circular DNA; HBV, hepatitis B virus; HBcAg, hepatitis B core antigen; HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B
surface antigen; TLR, toll-like receptor.

been reported in CHC patients with OBI treated with NS3/4A protease
inhibitor- containing regimens. These events have recently prompted
the US FDA to issue a box warning about the risk of HBV reactivation,
to have the warning added to the drug labels of these DAAs, and to
direct healthcare professionals to screen and monitor for HBV in all
patients receiving DAA treatment. Thus, it is highly important to evalu-
ate HBV status (HBsAg and hepatitis B core antibody) before initiating
pan-oral DAAs therapy, especially in HBV endemic areas.
6|NEW THERAPEUTIC AGENTS FOR
CHRONIC HEPATITIS B TO MEET THE
UNMET NEED: A CURE
have been combined in various fashions (sequential or concomitant)
with little success (Table2). Thus, new therapeutic agents are clearly
needed. To date, various anti-HBV drugs or biological agents that
are directed at specific steps in the viral life cycle and spread, that
increase and restore host immune response and target cccDNA, are
in the development pipeline, either in the preclinical or early clinical
phases40 (Table3). Among them, siRNA, HBsAg inhibitors and capsid
inhibitors have reached clinical trials. However, none of these agents
are expected to become available before the next few years and
these agents will probably need to be combined with existing ones.
7|CONCLUDING REMARKS

In 2017, PEG-IFN and nucleos(t)ide analogues with high resistant bar-

None of the existing anti-HBV agents is effective in achieving the
ideal goal of therapy-HBsAg loss (functional cure) or HBsAg sero-
conversion (complete cure). This is mainly because current therapy is
ineffective in clearing cccDNA or preventing transcriptional cccDNA
activity. Even following 48weeks of PEG-IFN, HBsAg loss will only
occur in less than ten per cent of the patients. This means that most
patients must be maintained on lifelong nucleos(t)ide analogue ther-
apy, resulting in escalating costs and an increased risk of side effects.
In an attempt to increase the rate of HBsAg loss, registered agents
riers (tenofovir and entecavir) are expected to remain the mainstay of
treatment for CHB, based on guidelines from the different continental
hepatology societies. In the near future, TAF will become available to
provide safer long-term use of nucleotide analogues in CHB patients.
With the development of new therapeutic agents targeting various key
steps in the viral life cycle and/or improving the host immune response
to the virus, a cure for CHB can be expected in the next decade. This,
together with full implementation of the HBV vaccine programme,
should pave the way to a Hepatitis B free generation by 2030.
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66
CO NFLI CTS OF I NTE RE S T
None.
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