Treatment of Hepatitis B: A Concise Review

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CLINICAL AND SYSTEMATIC REVIEWS
Treatment of Hepatitis B: A Concise Review
Ruma Rajbhandari, MD, MPH
1,2,3,4
and Raymond T. Chung, MD
1,2,34
Clinical and Translational Gastroenterology (2016) 7, e190; doi:10.1038/ctg.2016.46; published online 15 September 2016
Subject Category: Clinical Review
INTRODUCTION
Chronic infection with hepatitis B virus (HBV) affects 400
million people worldwide, including at least 1.25 million in the
United States. Those who develop chronic hepatitis B die, on
average, 22 years earlier compared with those without HBV
1
owing to complications of cirrhosis, hepatocellular carcinoma,
and liver failure. The burden of HBV is expected to grow in the
face of immigration patterns into the United States from highly
endemic countries.
Despite the approval of several anti-viral agents, very few
patients are actually on treatment.
2–5
There are many possible
reasons for this, including the need for lifelong treatment, lack
of education and awareness of the disease in largely
immigrant, non-English-speaking groups, under screening
for the condition in primary care settings, and concerns
regarding the requirement for liver biopsies to determine the
need for treatment in many cases. Guidelines for hepatitis B
treatment have also issued variable recommendations for the
treatment of some phases of the disease,
6–9
which can lead to
confusion for practitioners. In this review, we provide practical
recommendations for both primary care doctors and sub-
specialists on who should be treated for hepatitis B and how.
The viral life cycle. Hepatitis B virus (HBV), a hepadnavirus,
is a partially double-stranded DNA virus, composed of a
nucleocapsid core (HBcAg), surrounded by an outer envel-
ope containing the surface antigen (HBsAg) (Figure 1). The
viral DNA contains four major open reading frames:
1. The precore/core gene, coding for the nucleocapsid protein
and the precore protein (hepatitis B e antigen (HBeAg)).
2. The polymerase gene, coding for the reverse transcriptase/
HBV polymerase.
3. The PreS1/L, PreS2/M, and Surface/S genes, coding for
the three envelope proteins.
4. The X gene, coding for the regulatory X protein.
10
The life cycle of HBV is complex. The virus enters the
hepatocyte by binding to a receptor on the cell surface—the
sodium taurocholate cotransporting polypeptide, a bile acid
transporter.
11–13
After uncoating of the viral nucleic acid, the
viral genomic DNA is transferred to the cell nucleus and the
partially double-stranded viral DNA is then transformed into
covalently closed circular DNA (cccDNA), a highly stable
intermediate that serves as a template for transcription of viral
mRNAs, including the pregenomic RNA. The pregenomic
RNA serves as template for translation of viral proteins,
including the surface antigen, nucleocapsid, and polymerase
proteins. Taken together with the nucleocapsid and polymer-
ase proteins, the HBV pregenomic RNA is encapsidated in the
virus core particle. The first step is reverse transcription and
first-strand cDNA synthesis, catalyzed by the HBV polymer-
ase—the site of action of oral anti-HBV nucleoside/nucleotide
analog (NA) agents. The next step is second-strand DNA
synthesis to generate a partially double-stranded viral DNA
genome. The HBV polymerase lacks proofreading activity;
thus, mutations of the viral genome are frequent and result in
the coexistence of genetically distinct viral species in infected
individuals (quasispecies). Nucleocapsids associated with the
partially double-stranded HBV DNA can then either re-enter
the hepatocyte nucleus to replenish the pool of cccDNA or be
enveloped for secretion as complete virions via the endoplas-
mic reticulum. After budding into the ER lumen, the envelope
proteins are secreted from the cell either as non-infectious
subviral particles (HBsAg) or incorporated into infectious
virions known as Dane particles.
The persistence of the highly stable cccDNA accounts for
the challenge in eradicating chronic HBV. In addition, error-
prone replication of the HBV genome and generation of
mutants in the precore region (precore mutants) are additional
contributors to persistence of hepatitis B infection.
HBV proteins can also target key immune cells to
circumvent host anti-viral immunity. Adaptive immune
responses to HBV are blunted in CHB subjects when
compared with those who have resolved acute infection.
Studies have demonstrated that T cells responding to HBV
antigens from these subjects have an exhausted phenotype
and are less responsive to HBV antigens.
14
Chronic hepatitis B has a complicated natural history with
three identified phases. The immune-tolerant phase is
characterized by high HBV DNA (usually 41 million IU/ml)
1
Gastroenterology Division, Massachusetts General Hospital, Boston, Massachusetts, USA;
2
Harvard Medical School, Boston, Massachusetts, USA and
3
Gastro-
enterology Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
Correspondence: Raymond T. Chung, MD, Gastroenterology Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
E-mail: rtchung@partners.org
4
All authors have approved the final version of the manuscript.
Received 26 June 2016; accepted 26 July 2016
Citation: Clinical and Translational Gastroenterology (2016) 7, e190; doi:10.1038/ctg.2016.46
&
2016 the American College of Gastroenterology 2155-384X/16
www.nature.com/ctg

and normal alanine aminotransferase (ALT) with minimal liver
disease. This phase is thought to occur most frequently in
persons who are infected perinatally. The immune-active
phase is marked by high HBV DNA and elevated ALT levels
with active liver inflammation. Finally, the inactive phase is
associated with low HBV DNA levels (o2,000 IU/ml) and
normal ALT with minimal liver inflammation and fibrosis.
Initial management of hepatitis B infection. In most
immunocompetent adults, acute HBV infection is self-
limiting and management is supportive. For those with
chronic infection, initial management should include a
complete history and physical examination to assess for
signs of cirrhosis, alcohol and metabolic risk factors, and
family history of hepatocellular carcinoma. Routine laboratory
tests should include assessment of liver disease activity and
function (complete blood count, aspartate aminotransferase,
ALT, total bili, alkaline phosphatase, albumin, international
normalized ratio), markers of HBV replication (HBeAg/anti-
HBe, HBV DNA quantitation), tests for coinfection with HCV,
HDV, and HIV, and assessment of HAV immunity to
determine need for vaccination. Patients should be educated
on measures to prevent transmission and prevention of
further liver damage (e.g., limiting alcohol intake and
medications or supplements that could be hepatotoxic) and
the importance of long-term monitoring, particularly with
regard to the risk for hepatocellular carcinoma. Patients older
than 40 years, with cirrhosis, or with a family history of
hepatocellular carcinoma should undergo ultrasonography
and α-fetoprotein testing every 6 months.
6
The main aim of the anti-viral therapy are to decrease
morbidity and mortality by suppressing HBV replication and
hepatic inflammation and preventing progression to cirrhosis
and hepatocellular carcinoma. Anti-viral treatment results in
normalization of ALT, suppression of HBV DNA, possible loss
of HBeAg and seroconversion to anti-HBe, possible loss of
HBsAg and seroconversion to anti-HBs, and histological
improvements with decreased inflammation and fibrosis.
The Food and Drug Administration has approved seven
anti-viral drugs for the treatment of chronic HBV: interferon-
a2b, pegylated interferon-a2α(peg-IFN), lamivudine (LAM),
adefovir, entecavir (ETV), telbivudine, and tenofovir (TDF).
Of these, the most commonly used first-line agents are peg-
IFN, TDF, and ETV.
Who should be treated?
Immune-active, HBeAg+, chronic hepatitis B. Patients with
hepatitis B e antigen-positive (HBeAg+) chronic hepatitis B,
who have ALT levels 42 times normal with HBV DNA
420,000 IU/ml, should be considered for treatment (Table 1
and Figure 2). These recommendations are based on AASLD
(American Association for the Study of Liver Diseases) and
APASL (Asian Pacific Association for the Study of the Liver)
guidelines. The EASL guidelines recommend considering
therapy if HBV DNA is 42,000 IU/ml, ALT is greater than
upper limit of normal, and there is moderate to severe active
Figure 1 Hepatitis B virus (HBV) life cycle showing novel approaches for viral targets.
94
The HBV life cycle can be grouped into six different targetable steps: (1) entry/
uncoating, (2) covalently closed circular DNA (cccDNA) formation, (3) POL/RT inhibitors,(4) capsid assembly, (5) cccDNA transcript and (6) morphogenesis. CsA, cyclosporine A;
DSS, disubstituted sulfonamide; ER, endoplasmic reticulum; MVB, multivesicular body; POL, HBV DNA polymerase; RT, reverse transcription.
Treatment of Hepatitis B
Rajbhandari and Chung
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Clinical and Translational Gastroenterology

necroinflammation and/or at least moderate fibrosis on liver
biopsy. Initiation of treatment should be delayed for up to
6 months in persons with compensated liver disease to
determine whether spontaneous HBeAg seroconversion
occurs. Treatment initiation with TDF, ETV, or peg-IFN are
preferred.
6
Immune-active, HBeAg −chronic hepatitis B. Patients with
hepatitis B e antigen-negative (HBeAg −) chronic hepatitis B
(serum HBV DNA 42,000 IU/ml and elevated ALT 42 times
normal) should be considered for treatment (Figure 3).
For HBeAg −patients with lower HBV DNA levels (2,000–
20,000 IU/ml) and borderline normal or minimally elevated
ALT levels, liver biopsy should be considered and treatment
initiated if there is moderate/severe inflammation or signifi-
cant fibrosis on biopsy. Several studies have shown that
patients with normal ALT can have substantial liver fibrosis,
when ALT concentrations are at the high end of the normal
range, HBV DNA concentrations are high (410,000 IU), or
when they are older than 40 years.
15
Treatment with TDF,
ETV, or peg-IFN are preferred.
6
Compensated cirrhosis. Treatment should be considered for
any patient with cirrhosis and detectable HBV DNA regardless
of ALT levels. Patients with compensated cirrhosis are best
treated with NAs because of the risk of hepatic decompensation
Table 1 Who should be treated for hepatitis B?
Indication for treatment Treatment strategy Treatment end points/duration
Immune active, e Ag+, ALT42 × normal,
HBV DNA420,000 IU/ml
Peg-IFN, TDF or ETV Peg-IFN usually 48–52 weeks, NAs variable. Continue until HBeAg
seroconversion and undetectable serum HBV DNA and at least
6 months of additional treatment after appearance of anti-HBe.
Immune active, e Ag −,ALT42x normal,
HBV DNA 42,000 IU/ml
Peg-IFN, TDF or ETV Peg-IFN usually 48–52 weeks, NAs variable. Continue until HBsAg
clearance.
Compensated cirrhosis TDF or ETV Lifelong therapy.
Decompensated cirrhosis TDF or ETV Lifelong therapy.
Acute/symptomatic hepatitis B or
fulminant hepatitis B
ETV is preferred Treatment should be continued until HBsAg clearance is confirmed
or indefinitely in those who undergo liver transplantation.
Prevention of reactivation (in HBV carriers
who require immunosuppressive or
cytotoxic therapy)
TDF or ETV before the start
of chemotherapy or immu-
nosuppressive therapy
If baseline HBV DNA o2,000 IU/ml, continue treatment for
6 months after completion of chemo/immunosuppression. If high
baseline DNA 42,000 U/ml, continue treatment until treatment
end points reached as in immunocompetent patients.
Pregnant mothers with high viral load TDF preferred (telbivudine
or LAM also effective)
Initiate therapy at 28–30 weeks gestation and monitor for flares if
stopping therapy after delivery.
HBV/HIV coinfection TDF+(emtricitabine or
LAM) or ETV+fully sup-
pressive ARV regimen
Lifelong unless the patient has achieved HBeAg seroconversion
and has completed an adequate course of consolidation treatment.
ALT, alanine aminotransferase; ARV, antiretroviral; ETV, entecavir; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; LAM,
lamivudine; NA, nucleotide analog; peg-IFN, pegylated interferon-a2α; TDF, tenofovir.
Figure 2 Treatment algorithm for patient with chronic hepatitis B and positive HBeAg. ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B
surface antigen; ULN, upper limit of normal. Figure Adapted from Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007; 45: 507–539.
Treatment of Hepatitis B
Rajbhandari and Chung
3
Clinical and Translational Gastroenterology

associated with IFN-related flares of hepatitis. In view of the
need for long-term therapy, TDF or ETV is preferred.
Decompensated cirrhosis. Treatment should be promptly
initiated with an NA that can produce rapid viral suppression
with low risk of drug resistance. At the time of drafting of the
last AASLD guidelines in 2009, clinical data documenting the
safety and efficacy of TDF and ETV in patients with
decompensated cirrhosis was lacking. Since then, multiple
studies have confirmed safety and efficacy of these agents in
this subgroup.
16–19
Thus, TDF and ETV are the treatments of
choice in decompensated cirrhotics with HBV. Treatment
should be coordinated with a transplant center. IFN/peg-IFN
should not be used in patients with decompensated cirrhosis.
Acute/symptomatic hepatitis B or fulminant hepatitis B. Since
over 95% of immunocompetent adults with acute hepatitis B
recover spontaneously, treatment is not recommended in
most cases. Treatment is indicated only for patients with
fulminant hepatitis (defined by the rapid development of acute
liver injury with severe impairment of synthetic function and
hepatic encephalopathy) and those with protracted, acute
severe hepatitis persisting for 44 weeks.
In severe acute HBV with prolonged prothrombin time and
increased bilirubin, interferon failed to be effective,
20–23
but
NAs have been shown to be effective. A randomized controlled
trial of 80 patients found that early treatment with LAM leads to
a greater decrease in HBV DNA levels, better clinical
improvement, and mortality improvement but with a lower
HBsAg and HBeAg seroconversion rate.
24
Multiple rando-
mized studies have produced results consistent with this
randomized controlled trial.
25–28
Furthermore, most patients
who died or required transplantation despite LAM therapy
were started on LAM at advanced stages compared with those
who survived. These findings suggest that prompt and timely
anti-viral therapy is crucial.
Multicenter double-blind randomized trials to compare the
efficacy between LAM and ETV or even TDF in acute severe
HBV cases are lacking because of the difficulty of accruing
cases. However, given the safety and efficacy of these agents
in other cases of acute hepatitis B (e.g., reactivation in patients
receiving chemotherapy),
29–37
the AASLD recommends
treatment with an NA for fulminant and acute/symptomatic
hepatitis B. In one prospective randomized trial of TDF vs.
placebo in 27 patients with spontaneous reactivation of
chronic hepatitis B who presented with acute on chronic liver
failure, the 3-month probability of survival was higher in the
TDF group compared with that in the placebo group (57% vs.
15%, P=0.03).
33
Because of their anti-viral potency, ETV or
TDF are the preferred agents for the treatment of acute or
fulminant hepatitis B. Treatment should be continued until
HBsAg clearance is confirmed or indefinitely in those who
undergo liver transplantation. IFN is contraindicated and has
not been shown to be effective in fulminant hepatitis B.
Prevention of reactivation (hepatitis B carriers who require
immunosuppressive or cytotoxic therapy). HBV persists in
the body of all patients with infection, even those with
evidence of serological recovery. Thus, individuals with a
history of HBV infection who receive immunosuppressive
therapy are at risk for HBV reactivation and a flare of their
HBV disease with resultant increased serum aminotransfer-
ase levels, fulminant hepatic failure, and possible death.
38
For
example, in an analysis of HBV reactivation in over 450 B-cell
lymphoma patients treated with rituximab from the Asia
Lymphoma Study Group, HBV reactivation was found in
27.8% of HBsAg+ patients. The frequency of reactivation was
much lower in those receiving anti-viral prophylaxis com-
pared with those who did not (22.9% vs. 59.1%; Po0.001).
39
Another randomized controlled trial showed that anti-viral
prophylaxis can potentially prevent rituximab-associated HBV
reactivation in patients with lymphoma and resolved hepatitis
B (i.e., anti-HBc+, HBsAg −).
40
Thus, to prevent reactivation of HBV replication, which can
lead to hepatitis and liver failure, prophylactic anti-viral therapy
with ETV or TDF is recommended in HBsAg+ patients who will
be receiving anti-CD20 therapy (e.g., rituximab), hematopoie-
tic cell transplantation, high-dose glucocorticoids (e.g.,
≥20 mg per day for at least 4 weeks), the anti-CD52 agent
alemtuzumab, cytotoxic chemotherapy without glucocorti-
coids, anti-TNF therapy, and antirejection therapy for solid
Figure 3 Treatment algorithm for patient with chronic hepatitis B and negative HBeAg. ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B
surface antigen HBV, hepatitis B virus; ULN, upper limit of normal. Figure adapted from Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007; 45: 507–539.
Treatment of Hepatitis B
Rajbhandari and Chung
4
Clinical and Translational Gastroenterology

organ transplants. Prophylactic anti-viral therapy is also
recommended for patients who are HBsAg −and anti-HBc+
and who will be receiving potent immunosuppressive thera-
pies such as rituximab or myeloablation before hematopoietic
stem cell transplantation, to prevent reappearance of HBsAg.
HBsAg+ individuals are at low risk of reactivation if they
receive methotrexate or azathioprine and thus in these low-
risk patients prophylactic therapy is not indicated but they
should be monitored for possible reactivation and treated with
an anti-viral should this occur.
41
Pregnant mothers with high viral load in the third trimester.
Infants born to mothers who are HBeAg+ with concomitant
high HBV DNA levels have a substantial risk of infection
despite passive–active immunoprophylaxis. In one retro-
spective study of over 4,000 infants born to HBsAg+ mothers
in the United States, the rates of infection were 3.37 per 100
births in HBeAg+ mothers and 0.04 for HBeAg −mothers.
42
The rates of failure of immunoprophylaxis have been shown
to correlate with the levels of viral load.
43
Telbivudine or LAM
use in late pregnancy from 28 weeks gestation to 4 weeks
postpartum has been shown to safely reduce perinatal
transmission of hepatitis B from highly viremic HBeAg+
mothers (HBV DNA 46 log 10 copies per ml) to their
infants.
37,44–47
ALT flares were observed in 17.1% of treated
mothers vs. 6.3% of untreated mothers (Po0.001).
37
In
another retrospective study, TDF during the second and third
trimester in HBeAg+ women with HBV DNA 410
7
copies per
ml reduced perinatal transmission of HBV, with no adverse
events reported in mothers or infants.
48
Given these findings, the AASLD recommends the con-
sideration of NAs with favorable resistance and safety profiles,
such as TDF, during pregnancy to reduce the risk of mother-to-
infant transmission. However, there is no consensus on the
cutoff HBV DNA concentration for recommending anti-viral
therapy and when anti-viral therapy should be started. At our
institution, we have used the algorithm shown in Figure 4.
HBV/HIV coinfection. It is estimated that up to 5 million of the
33 million HIV-infected persons worldwide in 2009 have
concomitant HBV infection. Recent discoveries in the
pathophysiology of HIV in the liver has found that it may
contribute to a more rapid progression of liver fibrosis,
especially when there is underlying chronic hepatitis
infection.
49
Furthermore, because of impaired immune
control attributed to HIV infection, the rate of acute infections
evolving into chronic HBV is five times higher in HIV
compared with that in non-HIV-infected adults.
50
Coinfected
patients have an excess risk of all-cause mortality as high as
36% compared with HIV-monoinfected patients
51
and 10
times higher risk of dying from liver-related causes compared
with HIV- or HBV-monoinfected patients.
52
HIV thus accel-
erates HBV liver disease and administration of successful
antiretroviral therapy has been demonstrated to slow fibrosis
progression and to decrease liver disease-associated
mortality.
53–55
Given recent changes designed to initiate
antiretroviral therapy earlier regardless of HIV DNA or CD4
levels,
56
those with coinfection should be treated with agents
active against both HBV and HIV. The recommended agents
include TDF with either emtricitabine or LAM.
56
If HBV treatment is needed and TDF cannot safely be used,
the alternative recommended HBV therapy is ETV in addition
to a fully suppressive antiretroviral regimen (to prevent
selection of the M184V mutation that confers HIV resistance
to LAM and emtricitabine), or peg-IFNαmonotherapy for
48 weeks, particularly in patients with HBV genotype A, high
ALT, and low HBV DNA level.
56
When HAART (highly active
antiretroviral therapy) regimens are altered, drugs that are
effective against HBV should not be discontinued without
substituting another drug that has activity against HBV, unless
Figure 4 Algorithm for management of pregnant mothers with high HBV viral load in pregnancy. ALT, alanine aminotransferase; HBIG, hepatitis B immunoglobulin; HBsAg,
hepatitis B surface antigen; HBV DNA, hepatitis B virus DNA level.
Treatment of Hepatitis B
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Clinical and Translational Gastroenterology

the patient has achieved HBeAg seroconversion and has
completed an adequate course of consolidation treatment.
Discontinuation of agents with anti-HBV activity may cause
serious hepatocellular damage resulting from reactivation
of HBV.
Who should NOT be treated?. Patients in the immune-
tolerant state in whom HBV DNA levels are very high
(410
8
IU/ml), HBeAg is positive, and ALT levels are normal
should not be treated. Liver biopsy may be considered in
patients with fluctuating or minimally elevated ALT levels,
especially in those above 40 years of age. Treatment should
be initiated if there is moderate or severe necroinflammation
or significant fibrosis on liver biopsy. However, it should be
acknowledged that there may be theoretical benefits to
treating patients in the immune-tolerant stage such as
decreasing accumulation of cccDNA and abrogating infection
early. Clinical trials are needed in this population to help
address this question.
In addition, patients in the inactive carrier state (HBsAg+,
HBeAg −, HBeAb+) in whom both HBV DNA levels are very
low (o2,000 IU/ml) or undetectable and ALT levels are normal
should not be treated but rather monitored on a biannual basis
with ALT and HBV DNA levels, as well as with hepatocellular
carcinoma screening in high-risk patients.
Finally, those who are HBeAg −with an intermediate viral
load (between 2,000 and 20,000 IU/ml) and borderline normal
or minimally elevated liver function tests should not be treated
but should be considered for liver biopsy and treated if there is
moderate or severe necroinflammation or significant fibrosis.
Selection of anti-viral agents. Peg-IFN, ETV, or TDF are
recommended as first-line monotherapy by all major guide-
lines in patients with CHB or compensated cirrhosis
(Table 2).
6,7,57
The choice of first-line monotherapy should
be based on several factors including host, virus, and drug-
related factors. Consideration should be given to the safety
and efficacy of the treatment, risks of drug resistance, costs
of the treatment (medication, lab tests, and clinic visits), as
well as patient and provider preferences, and for women—
when and whether they plan to start a family. The pros and
cons of the approved first-line treatments are summarized in
Table 2.
IFN monotherapy. Peg-IFN has dual immunomodulatory and
anti-viral activity. Although the efficacy is not substantially
different, peg-IFN is superior to standard IFN −because of its
more convenient dosing schedule with once weekly subcuta-
neous injections. The most favorable candidates for peg-IFN are
those with low HBV DNA levels, high ALT and HBV genotype A
or B rather than C or D, and those without advanced disease.
Advantages of peg-IFN include finite duration of therapy, higher
rates of anti-HBe and anti-HBs seroconversion with 12 months
of therapy, and the absence of resistance.
58–60
Disadvantages
include inferior tolerability with many side effects (including flu-
like symptoms, fatigue, anorexia and nausea, weight loss, hair
loss, emotional lability and depression, bone marrow suppres-
sion, worsening of autoimmune disease, and hypothyroidism),
need for weekly subcutaneous injections, and only moderate
anti-viral effect. Contraindications to peg-IFN include a history of
suicidal tendency, uncontrolled psychiatric or autoimmune
conditions, severe leukopenia or thrombocytopenia, concurrent
severe systemic disorders, decompensated cirrhosis, and
pregnancy.
NA monotherapy. TDF and ETV are both NAs that inhibit the
dual function HBV DNA polymerase. TDF is administered
orally at a dose of 300 mg daily, whereas ETV is administered
orally at a dose of 0.5 mg daily in those with no prior LAM
treatment and 1.0 mg daily in those who are refractory/
resistant to LAM. The other second-line agents, LAM,
adefovir, and telbivudine are not recommended because of
their limited potency and lower barrier to resistance.
Overall, all NAs have an excellent safety profile across a
wide spectrum of persons with chronic hepatitis B and any side
effects are infrequent.
61
Adverse events associated with TDF
are rare and include renal insufficiency, Fanconi’s syndrome,
proximal tubular acidosis, and decreased bone density,
particularly in children, in whom the drug is
contraindicated.
61–65
If TDF is used in patients with renal
insufficiency, the dose must be adjusted for creatinine
clearance. Adverse events with ETV are mild to moderate
and include headache, upper respiratory tract infection,
cough, nasopharyngitis, fatigue, and upper abdominal
Table 2 Comparison of approved first-line treatments for chronic hepatitis B
Peg-IFN ETV TDF
Indications
HBeAg+, normal ALT Not indicated Not indicated Not indicated
HBeAg+ chronic hepatitis Indicated Indicated Indicated
HBeAg −chronic hepatitis Indicated Indicated Indicated
Duration of treatment
HBeAg+ chronic hepatitis 12 months ≥1 year until e Ag
seroconversion
≥1 year until e Ag seroconversion
HBeAg −chronic hepatitis 1 year 41 year, likely lifelong until
HBsAg clearance
41 year, likely lifelong until HBsAg
clearance
Route Subcutaneous Oral Oral
Side effects Many Negligible Negligible
Drug resistance Not applicable 1.2% up to year 5 0% up to year 5
Cost Moderate as limited
duration of therapy
High especially with lifelong
therapy
High especially with lifelong therapy
ETV, entecavir; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; peg-IFN, pegylated interferon-a2α; TDF, tenofovir.
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Clinical and Translational Gastroenterology

pain.
66
Severe lactic acidosis has been reported in a case
series of patients with advanced cirrhosis (MELD score ≥20)
and thus ETV should be used with caution in patients with
decompensated liver disease. ETV should also be adjusted for
creatinine clearance.
67
TDF or ETV are the only therapeutic options in patients with
decompensated liver disease, in patients undergoing
immunosuppressive treatment, and in patients with other
contraindications to or unwilling to receive peg-IFN. In HBeAg
+ patients, treatment can be discontinued after a 12-month
consolidation period following documented HBeAg
seroconversion with undetectable HBV DNA. Close monitor-
ing for relapse is nonetheless required following therapy
discontinuation. In HBeAg −patients, long-term therapy is
required until HBsAg loss is documented. Advantages
of NAs include potent anti-viral effect (viral suppression in
495% of patients over 5 years with fibrosis regression and
prevention of cirrhosis),
68–70
good tolerability with minimal side
effects, and oral administration. Disadvantages include
indefinite duration of therapy, particularly in HBeAg −patients,
and risk of resistance along with unknown long-term safety.
Fortunately, the risk of drug resistance has thus far been
minimal (1.2% with ETV after 6 years and 0% with TDF after
5 years).
70–72
Combination therapy. There is no added benefit from de
novo combination therapy with two NAs. In addition, the
combination of peg-IFN and NAs has not yielded higher rates
of off-treatment serological or virological responses and is not
currently recommended by AASLD.
73,74
However, a recent
randomized controlled trial has shown that a significantly
greater proportion of patients receiving TDF plus peg-IFN for
48 weeks had HBsAg loss (9.1%) compared with those
receiving TDF (0%) or peg-IFN alone (2.8%) or a shorter
course of peg-IFN (16 weeks) with 48 weeks of TDF
(2.8%).
75
Although further study is required, consideration
may be given to a combination approach to enhance HBsAg
loss rates (Table 3).
Duration of therapy. In HBeAg+ chronic hepatitis B,
treatment should be continued until the patient has achieved
HBeAg seroconversion and undetectable serum HBV DNA
and completed at least 12 months of additional consolidation
treatment after appearance of anti-HBe.
73,76
The optimal
duration of consolidation therapy after HBV seroconversion is
not known, but studies show better outcomes with longer
duration of consolidation.
77
In HBeAg −chronic hepatitis B,
treatment should be continued until the patient has achieved
HBsAg clearance.
Lifelong treatment is recommended for all patients with
recurrent hepatitis B after liver transplantation and in all
cirrhotics, both compensated and decompensated, due to
concerns for potential reactivation and death when treatment
is stopped.
73,76,78
In addition, there appears to be an association between
quantitative level of HBsAg and relapse after anti-viral therapy
for chronic HBV infection.
79
All guidelines recommend peg-IFN for 48–52 weeks in both
HBeAg+ and HBeAg −patients. Irrespective of the underlying
liver disease and the treatment used, patients need to be
closely monitored for viral relapse and ALT flares when
treatment is stopped, so that treatment can be reinitiated
promptly.
80
Prevention of HBV. Prevention is far simpler than treatment,
particularly in the case of HBV, which requires lifelong
treatment in most cases. Besides avoiding transmission from
infected people via blood supply screening and universal
precautions, vaccination is the most important means of
reducing the global burden of disease. Vaccination in adults
is recommended in high-risk groups at risk for infection by
sexual exposure (e.g., men who have sex with men, people
with multiple sexual partners, those seeking evaluation and
treatment for sexually transmitted disease), or in persons at
risk for infection by percutaneous or mucosal exposure to
blood (e.g., injection drug users, household contacts of
HBsAg+ patients, patients on hemodialysis, institutionalized
patients, health-care workers, and public safety workers).
Vaccination is also recommended in international travelers to
regions with high or intermediate endemicity for HBV
infection, persons with chronic liver disease, and with HIV
infection.
81
Postexposure prophylaxis with the hepatitis B
vaccine and/or hepatitis B immune globulin is also recom-
mended for health-care workers not immune to HBV virus.
Vaccination in children is recommended as part of the regular
schedule of childhood immunizations. Thirty-five years after
the availability of a safe and effective vaccine, universal
vaccination of all children is finally available now in 184 of 196
countries in the world. Global vaccine coverage with all three
doses of vaccine is estimated at 82%.
82
How do we cure HBV?. A functional cure for HBV poses
unique challenges given the stability and latency of cccDNA,
along with the fact that replication of HBV DNA is uncoupled
from protein (HBsAg) synthesis. In this regard, polymerase
inhibitors can bring about DNA suppression without the loss
of HBsAg. Because HBsAg can subvert the host immune
response secretion, a successful functional cure for HBV
(HBsAg loss, sAb seroconversion) will likely require a
multipronged, multimechanism approach, including potential
approaches to target both the virus and the host.
83
An
examination of all of the novel approaches for viral targets is
beyond the scope of this review, but we will briefly consider
the major approaches below.
Direct virologic approaches include HBV capsid inhibitors,
small interfering RNA targeted to viral mRNA, and cccDNA
targeting strategies. The HBV capsid is polyfunctional, as it is
essential for HBV genome packaging, reverse transcription,
intracellular trafficking, maintenance of cccDNA, and inhibition of
host innate immune responses. Thus, it is an attractive target for
HBV therapies. Several capsid inhibitors being evaluated include
NVR 3-778, GLS-4, and phenylpropenamide derivatives.
84
Small interfering RNAs directed against conserved HBV RNA
sequences could knock down HBV RNA, proteins, and DNA
levels. To this end, the HBV small interfering RNA ARC-520 is
currently being evaluated in a phase 2 trial. cccDNA targeting
strategies include prevention of cccDNA formation (e.g.,
disubstituted sulfonamide DSS), elimination of cccDNA by
inhibition of viral or cellular factors contributing to cccDNA
stability/formation (e.g., APOBEC3A, B agonists) or physical
elimination of cccDNA (e.g., zinc-finger, transcription activator-
Treatment of Hepatitis B
Rajbhandari and Chung
7
Clinical and Translational Gastroenterology

like effector nucleases or TALEN, CRISPR/Cas9 nucleases),
and silencing of cccDNA transcription.
84–87
Indirect acting host target inhibitors include entry inhibitors,
epigenetic modifiers (sirtuin inhibitors such as sirtinol),
morphogenesis inhibitors (glucosidase inhibitors), and secre-
tion inhibitors (Rep 9AC). A promising target is the inhibition of
the sodium taurocholate cotransporting polypeptide receptor
by which HBV/HDV enters hepatocytes (e.g., agents include
myrcludex B, cyclosporine A, and ezetimibe),
12
although there
may be limitations in terms of the clinical implications of
inhibiting bile salt transport.
Immunomodulatory approaches include targeting innate
and adaptive immune responses. Innate targets include IFN-α,
TLR7 agonists, and STING agonists.
88,89
Adaptive immune
agents include therapeutic T-cell vaccines and PD-1/PD-L1
antagonists. Targeting the T-cell response to HBV is important
because, in contrast to HCV, there is a robust T cell (CTL) that
spontaneously clears natural HBV infection with high fre-
quency in adults. Chronic HBV is associated with attenuated
CTL responses (high PD-1/PD-L1 expression) and thus
inhibitors of PD-1/PD-L1 could reawaken these vigorous
responses. A combination of these inhibitors with directly
acting anti-virals against HBV could have merit, although
caution will need to be exercised regarding the risk of
triggering autoimmunity and hepatic flares.
90–93
Conclusion
Chronic infection with HBV remains a major public health
problem. Treatment of hepatitis B is indicated in immune-
active patients, in those with cirrhosis or fulminant hepatitis B,
in prevention of reactivation in HBV carriers who require
immunosuppressive or cytotoxic therapies, in pregnant
mothers with high viral load, and in HIV/HBV coinfection. Most
of the effective anti-viral agents that are available require
indefinite treatment; thus, efforts are being devoted to
approaches to enhance functional cure rates and permit
cessation of therapy. A true virologic cure for HBV is much
more elusive, in contrast to HCV, because of its highly stable
latent form (HBV cccDNA). However, a rich array of viral and
host targets is being explored for manipulation. It is highly
likely that a multimodality approach will be essential for the
achievement of a functional and virologic cure.
CONFLICT OF INTEREST
Guarantor of the article: Ruma Rajbhandari, MD, MPH and
Raymond T. Chung, MD.
Specific author contributions: RR compiled the various
studies and articles for initial review, drafted the initial
manuscript and was involved in all subsequent revisions. RTC
was involved in critical review of the manuscript. RR and RTC
have both approved the final draft of the manuscript.
Financial support: Dr Ruma Rajbhandari was supported by a
grant from the National Institutes of Health (T32 DK007191).
Dr Raymond Chung is supported, in part, by a grant from the
National Institutes of Health (K24 DK078772).
Potential competing interests: Dr Raymond T. Chung
receives research grant support (to institution) from Gilead
Sciences and Bristol-Myers-Squibb.
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73,75
Peg-IFN (%) ETV (%) TDF (%) Combination therapy (TDF+peg-INF for 48 weeks) (%)
HBeAg positive
HBeAg seroconversion 29–36 21–22 21 23.1% (at 48 weeks)
25.0% (at 72 weeks)
HBsAg loss 2–7 (at 6 months)
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HBeAg negative
HBsAg loss 4 (at 6 months)
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0–1 (at 1 year) 0 (at 1 year) 5.1 (at 48 weeks)
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