Critical Issues in HBV

Critical Issues in HBV
Volume 1 Number 1 AUGUST 2014

VINDICO
medical education
Considerations in
Optimizing HBV
Treatment
V14-0196_HBV_Pub_Series_Issue1.indd 1 7/30/2014 4:40:52 PM
DEPARTMENTS
4 Editoral
Tram T. Tran, MD
11 Expert Interview:
How Important is
Monitoring Treatment
Response in HBV Today?
Harry Janssen, MD, PhD
16 Meeting Coverage:
Meeting Highlights from
EASL - The International
Liver Congress 2014
20 Clinical Case:
Determining If and
When to Initiate
Treatment in the
Immunotolerant Patient
Walid S. Ayoub, MD
22 CME Instructions
and CME Posttest
23 CME: Registration Form
FEATURED ARTICLES
EARN CME CREDIT
LEARNING OBJECTIVES
At the conclusion of this activity participants should be able to:
Develop individualized treatment strategies based on current best evidence for initiation of HBV treatment.
Implement appropriate serologic, nucleic acid, and laboratory tests to characterize HBV infection and
treatment response.
Evaluate underlying causes of HBV treatment failure, considering adherence issues as well as the
development of resistance.
This continuing medical education
activity is provided by
VINDICO
medical education
This activity is supported by
an educational grant from
Gilead Sciences Medical Affairs
5 Implementing Best Practices When Initiating
Hepatitis B Virus Therapy
13 Evaluating Underlying Causes of HBV Treatment Failure
17 Long-term Safety of HBV Therapies and When to
Stop Therapy
Robert G. Gish, MD
Principal
Robert G. Gish, Consultants LLC
Senior Medical Director
St. Joseph's Hospital and Medical Center, Liver Program
Phoenix, Arizona
Medical Director
Hepatitis B Foundation
Doylestown, Pennsylvania
Clinical Professor of Medicine
University of Nevada
Las Vegas, Nevada
Robert J. Wong, MD, MS
Department of Medicine,
Division of Gastroenterology and Hepatology
Stanford University Medical Center
Stanford, California
Daryl T-Y Lau, MD, MSc, MPH
Associate Professor of Medicine
Harvard Medical School
Director of Translational Liver Research
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Asad Javaid, MD
Liver Research Center, Gastroenterology
Beth Israel Deaconess Medical Center
K. Rajender Reddy, MD, FACP,
FACG, FRCP
Professor of Medicine
Professor of Medicine in Surgery
Director of Hepatology
Director of Viral Hepatitis Center
University of Pennsylvania
Philadelphia, Pennsylvania
Tanya M. Pavri, BA
2
Volume 1 Number 1 August 2014 | CRITICAL ISSUES IN HBV
CHIEF MEDICAL EDITOR
Tram T. Tran, MD
Medical Director of Liver Transplantation at the
Liver Disease and Transplant Center
Cedars-Sinai Medical Center
Los Angeles, California
CONTRIBUTING FACULTY
Walid S. Ayoub, MD
Clinical Associate Professor of Medicine UCLA
Assistant Medical Director of Liver Transplant Program
Cedars Sinai Medical Center
Los Angeles, California
Robert G. Gish, MD
Principal
Robert G. Gish, Consultants LLC
Senior Medical Director, St Josephs Hospital and
Medical Center, Liver Program
Phoenix, Arizona
Medical Director Hepatitis B Foundation
Doylestown, Pennsylvania
Clinical Professor of Medicine, University of Nevada
Las Vegas, Nevada
Francis Family Chair in Hepatology
Head of the Liver Clinic
Toronto Western and Toronto General Hospital
University Health Network
Toronto, Canada
Asad Javaid, MD
Liver Research Center, Gastroenterology
Beth Israel Deaconess Medical Center,
Associate Professor of Medicine, Harvard Medical School
Director of Translational Liver Research, Beth Israel Deaconess
Medical Center, Harvard Medical School
Tanya M. Pavri, BA
K. Rajender Reddy, MD, FACP, FACG, FRCP
Professor of Medicine in Surgery
Director of Hepatology
Director of Viral Hepatitis Center
Department of Medicine, Division of Gastroenterology and
Hepatology, Stanford University Medical Center
Stanford, California
EXTERNAL REVIEWER
Albert D. Min, MD
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This enduring material is approved for 1 year from the date of
original release, August 1, 2014 to August 1, 2015.
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Obtain CME Credit
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and articles, complete the CME posttest, and ll-in and return
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relevant nancial relationships of the planners, teachers,
and authors involved in the development of CME content. An
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the individual has control.
Planning Committee and Faculty members
report the following relationship(s)
Walid S. Ayoub, MD
Consulting Fees: Gilead
Robert G. Gish, MD
Consulting Fees: Arrowhead, Bristol-Myers Squibb,
Genentech, Gilead
Speakers Bureau: Bristol-Myers Squibb, Gilead
Contracted Research: Bristol-Myers Squibb, Gilead
Ownership Interest: Arrowhead
Harry Janssen, MD, PHD
Consulting Fees: Abbott, Anadys, Bristol-Myers Squibb,
Gilead, Innogenetics, Medtronic, Merck, Novartis,
Roche, Santaris, Tibotec
Contracted Research: Abbott, Anadys, Bristol-Myers Squibb,
Gilead, Innogenetics, Medtronic, Merck,
Novartis, Roche, Santaris, Tibotec
Asad Javaid, MD
No relevant nancial relationships to disclose.
Consulting Fees: Arrowhead, Bristol-Myers Squibb, Gilead
Contracted Research: Asian Health Foundation, Gilead,
Merck
Tanya M. Pavri, BA
K. Rajender Reddy, MD, FACP, FACG, FRCP
Consulting Fees: AbbVie, Bristol-Myers Squibb, Genentech-
Roche, Gilead, Idenix, Janssen, Merck, Vertex
Contracted Research: AbbVie, Bristol-Myers Squibb, GEN-FIT,
Genentech-Roche, Gilead, Janssen, Merck, Vertex
Other: ViralEd-Development of Educational Material
Tram T. Tran, MD
Consulting Fees: Bristol-Myers Squibb, Gilead
Speakers Bureau: Bristol-Myers Squibb, Gilead
Reviewers report the following relationship(s):
Albert D. Min, MD
Consulting Fees: Bristol-Myers Squibb, Gilead
Speaker's Bureau: Bristol-Myers Squibb, Gilead
Ronald A. Codario, MD, FACP, FNLA, CCMEP
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ologists, hepatologists and other health care professionals in-
volved in the treatment of patients with hepatitis B virus (HBV).
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3
E
d
i
t
o
r
i
a
l
W
e have been very fortunate to
have progressed from the dis-
covery of the hepatitis B virus
(HBV) to a highly effective vaccine in a
relatively short period of time. Even with the
vaccine availability, providing it universally
to areas of high endemicity is still challeng-
ing. Unfortunately, for individuals chroni-
cally infected, approximately more than 400
million, risk for the end-stage manifestations
of cirrhosis and liver cancer remain globally
problematic. We now have efcacious, safe
therapies that work to suppress viral replica-
tion, but challenges and areas of opportunity
still exist in our management of patients in-
fected with HBV.
In this monograph, the timing and treat-
ment options for this disease are discussed,
and the goals of determining true immuno-
logic phenotypes based on more than ALT
and HBV DNA, which is clinically important
since many patients are in a gray zone that
does not t the current guidelines, are con-
cisely summarized.
Monitoring and determining the end-
points of HBV therapy are addressed and
a look at resistance, cross resistance, and
strategies for salvage are detailed.
Also, the available data on long-term
safety and options for therapeutic cessation is
assessed. Ending therapy is an evolving area
and it is clear that while HBsAg loss and sero-
conversion is the holy grail of hepatitis B, it
is rare and may take several years to achieve.
In addition, immune tolerance, as well
as the current status of treating young pa-
tients infected with the virus where the data
are relatively lacking, is also reviewed.
Highlighted is the data presented at the
recent EASL meeting in London, focusing
on HBV reactivation. Many patients are
not recognized until they are immunocom-
promised, at which time it may be too late.
Recognizing the potential serious adverse
outcomes of reactivation and the preven-
tion by antiviral prophylaxis is an important
message.
I think we are entering into a potentially
exciting time in hepatitis B research where
a better understanding of host immune re-
sponses may lead to the development of
new therapies that will give us the elusive
viral cure.
I would like to thank the faculty for their
valuable contributions to this educational
and informative monograph.
Editorial
Tram T. Tran, MD
4
H
epatitis B virus (HBV) in-
fection is a global epidemic
with a worldwide burden
of more than 400 million chroni-
cally infected individuals. Although
the majority of persons with chronic
hepatitis B virus (CHB) are located
in the Asia-Pacic regions, an esti-
mated 2 million individuals in the
U.S. are chronically infected with
HBV.
1-5
Individuals with CHB are at
increased risk of developing serious
complications, with up to 40% of
patients with CHB developing acute
HBV exacerbation, cirrhosis, or he-
patocellular carcinoma (HCC).
3,5-6

Early detection and treatment of
patients with CHB can signicantly
reduce the risk of HBV-related com-
plications.
5-8
However, the success of
this strategy of early detection and
treatment hinges on the ability to
accurately identify appropriate can-
didates for HBV-antiviral therapy
and to understand the available treat-
ment options to ensure that the most
effective therapy can be offered in a
timely manner.
Indications for HBV Therapy
The treatment goal for patients
with CHB is the reduction in risk of
progressive liver damage that leads
to the development of complica-
tions, such as cirrhosis, HCC, liver
transplantation, and death, as well
as a reduction in health care costs.
However, the decision to treat or not
treat a patient with CHB is complex,
as studies have demonstrated that not
all patients with CHB derive signi-
cant clinical benet from currently
available therapies and only 15%
to 45% of patients are at risk of life
threatening disease.
9-11
Current HBV
treatment guidelines recommend an-
tiviral therapy for patients with CHB
with elevated circulating viral DNA
levels, who may be HBV e-antigen
(HBeAg) positive or negative and
who have biochemical or histopatho-
logical evidence of liver damage.
2,11-13

Higher levels of HBV viral DNA are
associated with increased risk of de-
veloping HCC, especially if the DNA
remains elevated over time; reduction
of HBV DNA with antiviral therapy
subsequently decreases risk of HCC
and liver failure.
14-17
The initial approach in identify-
ing appropriate HBV-treatment can-
didates is determining the presence
of chronic HBV disease, dened as
the presence of HBV surface antigen
(HBsAg) for >6 months (Figure,
page 6). Subsequently, the evalua-
tion incorporates an accurate assess-
ment of a patients HBeAg status,
with some guidelines utilizing the
development of anti-HBe and loss
of HBeAg positivity as a potential
endpoint among patients who are
HBeAg positive at the time of treat-
ment initiation.
2
Chronic hepatitis B
is dened as elevated liver enzymes
and/or biopsy proven inammatory
disease concomitant with elevated
HBV DNA level. The importance
of HBeAg status is also reected
in certain treatment guidelines
(eg, American Association for the
Study of Liver Disease [AASLD]
and Asian Pacic Association for
the Study of the Liver [APASL]) that
dichotomize this disease and set dif-
ferent HBV viral DNA thresholds
for initiating HBV therapy based on
HBeAg status. Following the deter-
mination of HBeAg status, an as-
sessment of serum HBV viral DNA
levels and alanine aminotransferase
levels (ALT) further guides the ap-
propriate selection of treatment can-
didates. While different treatment
guidelines utilize different thresh-
olds for HBV viral DNA and ALT,
the driving principle is the ability
to identify individuals with active
disease, manifested by active HBV
viral replication (ie, high HBV viral
DNA) and active hepatic injury (eg,
elevated ALT). Patients with CHB
that do not meet treatment eligibil-
ity based on assessment of HBV vi-
ral DNA and ALT levels would still
benet from antiviral therapy if there
is evidence of advanced brosis or
cirrhosis.
2,11-13

Clinical studies estimate that
fewer than 50% of the total popula-
tion infected with HBV would be
eligible for antiviral therapy based
on current treatment guidelines.
9,18
In
addition, it has also been estimated
that approximately 70% of the U.S.
population infected with HBV are
unaware of their infection status.
9,18-19

Thus, the pool of patients eligible for
HBV antiviral therapy is likely much
greater than what has been currently
Implementing Best Practices
When Initiating Hepatitis B
Virus Therapy
Robert J. Wong, MD, MS and Robert G. Gish, MD
5
identied. While current HBV treat-
ment guidelines only identify a sub-
set of patients with CHB that warrant
initiation of antiviral therapy, several
studies have suggested that patients
with CHB with moderate levels of
circulating viral DNA and moder-
ately elevated ALT that do not meet
current treatment thresholds remain
at signicant risk of death from liver
disease compared to the general pop-
ulation.
15,20-22
For example, studies
have demonstrated that despite hav-
ing only mildly elevated serum ALT
(ie, less than twice the upper limit
of normal), patients with CHB with
elevated HBV viral DNA can have
signicant hepatic brosis and a sig-
nicantly elevated risk of developing
long-term hepatic complications.
9,23
Furthermore, 15% of patients in one
study developed HCC with HBV
DNA 10
3
copies/mL, a threshold
that would not qualify for HBV an-
tiviral therapy under current treat-
ment guidelines.
15,24
As a result of
these ndings, several groups have
advocated for initiating HBV anti-
viral therapy for certain high-risk
populations that do not fall within
current guidelines.
9-10
While the goals of HBV antiviral
therapy are suppression of viral repli-
cation and HBV DNA levels, thereby
reducing progressive liver inamma-
tion and brosis and decreasing the
risk of developing hepatic complica-
tions, the specic endpoints of treat-
ment have been debated. A complete
response, for example HBsAg loss
with biochemical normalization of
ALT levels and virologic response is
the ultimate goal for all patients on
HBV antiviral therapy and is often
termed functional cure.
24
The suc-
cess of achieving HBsAg loss with
currently available therapy is rela-
tively low, and patients are more likely
to meet other intermediate goals of
therapy. Among patients with HBeAg-
positive CHB, some guidelines have
suggested loss of HBeAg and the de-
velopment of anti-HBe followed by a
period of antiviral therapy consolida-
tion as a potential therapeutic endpoint
only if HBV DNA is negative dur-
ing treatment.
2,10-13
However, several
studies have demonstrated that over
two-thirds of patients with long-term
complications of CHB had previously
achieved HBeAg seroconversion, and
often the emergence of HBV DNA re-
lapse in the setting of HBeAg negative
disease reects the presence of preex-
isting core and precore mutations in
HBeAg positive disease.
24-27
As such,
the achievement of HBeAg serocon-
version and HBV DNA suppression
may not be a durable and effective
HBV Patient Identified
Step 1: Assessment for Chronic HBV
Persistence of HBsAg for > 6 months?
Or from a high risk country or setting
indicating HBV exposure early in life?
HBeAg Positive (+) HBeAg Negative () Step 2: Assessment of HBeAg Status
High HBV viral DNA
AND
High serum ALT
Low HBV viral DNA
OR
Healthy or
borderline elevated
serum ALT
High HBV viral DNA
AND
High serum ALT
Step 3: Assessment of fibrosis status,
HBV viral DNA* and serum alanine
aminotransferase (ALT)
#
Start HBV treatment
Start HBV treatment
Low HBV viral DNA
OR
Healthy or borderline
elevated serum ALT#
No treatment.
Reassess for other
indications (e.g. advanced
fibrosis or cirrhosis),
family history of
hepatocellular carcinoma,
elevated liver cancer
biomarkers, or to
decrease infectivity
No treatment.
Reassess for other
indications (e.g.
advanced fibrosis or
cirrhosis), family history
of hepatocellular
carcinoma, elevated
liver cancer biomarkers,
or to decrease infectivity
Note: *The threshold for defining low vs. high HBV
viral DNA varies based on the treatment guideline
utilized.
#
The threshold for defining healthy vs. high
serum ALT that would warrant a recommendation for
starting HBV antiviral therapy varies based on the
treatment guideline utilized (Table 1)
The initial approach in identifying appropriate HBV-treatment candidates is determining the presence of chronic HBV disease.
Source: Courtesy of Dr. Robert J. Wong and Dr. Robert G. Gish.
Figure. Algorithm for Identifying Appropriate Candidates for Starting HBV Treatment
6
long-term viral control in patients with
HBeAg positive CHB. Thus, a more
appropriate therapeutic endpoint for
HBeAg positive patients, albeit dif-
cult to achieve, is the combination
of HBsAg seroconversion with ALT
normalization and undetectable HBV
DNA, or a functional cure. While
the success of achieving a functional
cure with currently available thera-
pies is relatively low, the future holds
great promise for newer therapeutic
advancements that will allow a true
cure (clearance of covalently closed
circular DNA [cccDNA]) to take place
in patients with CHB.
Assessing Treatment Options
There are currently 7 drugs ap-
proved by the Food and Drug Ad-
ministration (FDA) for treatment of
CHB: 2 interferon-based immuno-
modulators (interferon alfa-2b and
peginterferon alfa-2a); 3 nucleoside
analogues (lamivudine, entecavir, and
telbivudine); and 2 nucleotide ana-
logues (adefovir and tenofovir). The
initial choice of antiviral treatment
incorporates many factors, includ-
ing the efcacy of viral suppression,
safety prole, medical comorbidi-
ties, and patient preference. Table 1
(page 8) provides an overview of the
main advantages and disadvantages
of these available therapies. Table 2
(page 9) provides a summary of the
efcacy of different HBV antiviral
agents in achieving different compo-
nents of viral suppression (eg, HB-
sAg seroconversion, normalization of
ALT, etc.). Table 3 (page 9) provides
long-term efcacy data for tenofovir
and entecavir.
Interferon-based Therapy
Interferon-based therapy is one
of the earlier regimens utilized in the
treatment of CHB. Among current
patients treated with interferon-based
HBV antiviral therapy, standard inter-
feron alfa-2b has been mostly replaced
by peginterferon alfa-2a, which offers
more convenient administration and
dosing with comparable or improved
rates of success.
28-30
The advantage of
interferon-based therapy is that it has
one of the highest reported rates of off-
treatment sustained response when de-
ned by DNA negativity and HBsAg
loss or seroconversion. Furthermore,
interferon-based HBV therapy con-
sists of a xed duration versus poten-
tial long-term therapy among patients
treated with nucleotide and nucleo-
side-based regimens. For example,
one study demonstrated that after 48
weeks of interferon therapy, rates of
HBeAg seroconversion were reported
as high as 27%, with undetectable
HBV DNA among 25% of patients;
HBsAg loss with subsequent develop-
ment of anti-HBs developed in 4% to
6% of patients at the 6-month follow-
up.
28-30
Despite these potential advan-
tages of interferon-based therapy, this
treatment regimen carries a signicant
adverse effect and safety prole com-
pared with newer available oral agents.
Nucleoside-based HBV Therapy
Lamivudine is an early nucle-
oside-based treatment regimen for
patients with CHB that has demon-
strated HBeAg seroconversion rates
from 16% to 18% after 12 months
of treatment, and increasing to 50%
HBeAg seroconversion after 5 years
of therapy although many of these
patients remain HBV DNA positive,
often with lamivudine-resistant mu-
tants.
31-33
Long-term studies of lami-
vudine-based therapy demonstrate
that the successful treatment of CHB
is associated with reduction in the
rate of brosis progression, as well
as HCC development, even among
patients who have already developed
advanced brosis or cirrhosis.
33-34

However, signicantly high rates of
resistance development have limited
the effectiveness of long-term therapy
with lamivudine, with studies report-
ing resistance rates as high as 65% to
70% after 5 years of therapy.
2,31
Approved for the treatment of
CHB in 2005, entecavir is a potent
nucleoside that has demonstrated
superiority in achieving virologic re-
sponse, histologic improvement, and
normalization of serum ALT com-
pared to lamivudine. In one study
evaluating the long-term outcomes
of entecavir-based HBV therapy,
94% of patients treated with ente-
cavir achieved undetectable HBV
DNA at 5 years, and 96% of patients
demonstrated histologic improve-
ment at 6 years.
35
Compared with
lamivudine and adefovir, entecavir
has a relatively higher genetic bar-
rier to the development of resistance.
Among nucleoside-naive patients,
the rate of resistance remained at
1.2% after 6 years of entecavir ther-
apy.
36
However, rates of resistance
are signicantly higher among treat-
ment-experienced patients who have
previously developed resistance to
lamivudine, approaching 50% at
5 years.
36
Telbivudine is a relatively newer
oral nucleoside analog for the treat-
ment of CHB. Compared to lamivu-
dine, telbivudine has signicantly
improved efcacy, achieving HBeAg
seroconversion in 30% of patients
and HBV DNA viral suppression in
60% after 24 months of therapy.
37-38
However, telbivudine therapy is
also complicated by the develop-
ment of resistance, with resistance
rates up to 21.6% after 2 years of
therapy among HBeAg positive pa-
tients.
39
One potential advantage of
telbivudine compared with other
nucleoside regimens is its more fa-
vorable pregnancy category B safety
rating. However, cases of myopathy
have been reported with telbivudine
therapy, and when combined with
interferon, cases of neuropathy have
been observed.
40
Nucleotide-based HBV Therapy
Adefovir was the rst oral nu-
cleotide analog approved for the
7
treatment of CHB. Among patients
treated with adefovir for 12 months,
HBeAg seroconversion rates of
12% and histologic improvement
rates of 53% were achieved among
HBeAg-positive patients.
41-42
While
adefovir has a favorable durabil-
ity of response, with over 90% of
patients sustaining HBeAg sero-
conversion, development of resis-
tance mutations also complicates
adefovir therapy, with resistance
rates of 0%, 3%, 18%, and 29% re-
ported after 1, 2, 4, and 5 years of
therapy, respectively.
43
Tenofovir is the most recent oral
nucleotide analog approved for treat-
ment of CHB. Tenofovir has mostly
replaced adefovir in clinical practice
due to its superior efcacy prole
along with low reported rates of re-
sistance. When compared to adefovir
in 2 double-blind randomized phase
3 trials, 48 weeks of tenofovir therapy
demonstrated signicantly higher
rates of viral suppression (76% vs.
13%), normalization of serum ALT
(68% vs. 54%), histologic improve-
ment (67% vs. 12%), and HBsAg
loss (3.2% vs. 0%).
44
In addition to
signicantly improved treatment ef-
cacy, tenofovir also demonstrates
better treatment durability, with sus-
tained viral suppression among 99%
to 100% of patients after 4 years of
therapy, and no evidence of resis-
tance up to 5 years of therapy has
been reported.
45-46
Like telbivudine,
tenofovir also holds a pregnancy
category B rating, and many of the
studies evaluating its safety prole
include both patients with HIV and
HBV cohorts.
The Initial Approach
The initial approach in the man-
agement of CHB includes under-
standing the eligibility for initiating
antiviral therapy, and once treatment
candidacy is conrmed, assessing
treatment options that are available.
As discussed, peg-interferon based
therapy is an option for patients who
prefer a nite course of treatment,
provided there are no medical or psy-
chiatric contraindications. However,
the availability of newer oral nucle-
oside-based and nucleotide-based
HBV therapy offers signicantly im-
proved treatment success rates, better
ease of administration, and improved
safety prole. Therefore, mono-
therapy with nucleoside-based and
nucleotide-based therapy has largely
replaced interferon-based therapy.
With the signicantly improved ef-
cacy of newer agents, such as en-
tecavir and tenofovir, monotherapy
with these agents has become rst-
line therapy in many world regions,
including the United States. Combi-
nation therapy with nucleoside and
Class of Therapy
Antiviral
Therapy
Advantages Disadvantages
Immunomodulator Interferon-
based
therapy
Finite duration of therapy
Finite cost
Moderate rate of HBsAg loss
Absence of selection for resistance mutations
Parenteral administration
Frequent adverse effects
Contraindicated in: acute liver failure, hepatic
decompensation, portal hypertension, severe HBV
reactivation, psychiatric comorbidities
Lowest rate of SVR defined by DNA suppression off therapy
Nucleoside Lamivudine Oral administration
Good safety profile
Relative low cost
Abundant studies among patients with end-stage
liver disease and pregnant women
High rate of resistant mutations
High treatment failure rates
High relapse rates off treatment
Nucleoside Entecavir Oral administration
Most potent nucleoside in lowering HBV DNA
Very low rate of resistant mutations
Very rare adverse events
Decreased treatment response and increased resistance in
patients with lamivudine resistance
Pregnancy category C
Nucleoside Telbivudine Oral administration
Well-tolerated safety profile
High potency in lowering HBV DNA
Pregnancy category B
Risk profile includes myopathy and peripheral neuropathy
Intermediate resistant mutation
Nucleotide Adefovir Oral administration
Well-tolerated safety profile
Studied in patients with end-stage liver disease
Relatively lower potency
Relatively higher rate of resistance mutations
Nephrotoxicity
Bone toxicity
Nucleotide Tenofovir Oral administration
More effective than adefovir
Low rate of resistance mutations
Studied in HBV/HIV-coinfection
Pregnancy category B
Effective for lamivudine-resistant mutations
Risk of nephrotoxicity in HIV-coinfection and data from
community-based treatment
Adapted from: Wong RJ, et al. J Clin Outcomes Manage. 2013:20:36-47.
Table 1. Advantages and Disadvantages of HBV Treatment Regimens
8
nucleotide agents is seen primarily in
the management of patients who have
developed resistance to initial HBV
therapy.
2,12-13
However, given the su-
perior efcacy, high durability of re-
sponse, and low rate of resistance of
tenofovir, monotherapy with tenofo-
vir is an option that is also available
for patients developing resistance to
initial therapy with other nucleoside
or nucleotide agents or use with en-
tecavir, which has a much higher bar-
rier to resistance than emtricitabine,
adefovir, or telbivudine.
2,12-13
Summary
In summary, CHB is a global epi-
demic with a signicant worldwide
disease burden. The importance of in-
stituting effective HBV screening pro-
grams lies in the ability to detect HBV
early so that close monitoring will al-
low initiation of appropriate therapy
to prevent the long-term complica-
tions associated with untreated HBV.
However, a thorough understanding of
treatment eligibility and treatment op-
tions is crucial to ensure that patients
who would benet the most from anti-
viral therapy are treated with the most
effective regimens. The current newer
treatment options available for CHB
offer high rates of viral suppression,
high rates of ALT normalization, and
low rates of resistance.
References
1. Lai CL, et al. Lancet. 2003;362(9401):
2089-2094.
2. Lok AS, et al. Hepatology. 2009;50(3):
661-662.
3. Hepatitis B fact sheet. www.who.int/
mediacentre/factsheets/fs204/en/index.
html. Accessed March 18, 2014.
4. Ganem D, et al. N Engl J Med. 2004;
350(11):1118-1129.
Tenofovir
48 weeks
Entecavir
48 weeks
Adefovir
48 weeks
Telbivudine
52 weeks
Lamivudine
48 - 52 weeks
PegIFN
48 weeks
Standard IFN
12 - 24 weeks
Loss of HBsAg 3.2% 2% 0% 0% 1% 3% 7.8%
Undetectable
HBV viral DNA
76% 67% 21% 60% 40-44% 25% 37%
HBeAg
seroconversion
21% 21% 12% 22% 16-21% 27% 22-24%
ALT
normalization
68% 68% 48% 77% 41-75% 39% 30-57%
Histologic
improvement
74% 72% 53% 65% 49-56% 38% N/A
B) Treatment-Nave HBeAg Negative
Tenofovir
48 weeks
Entecavir
48 weeks
Adefovir
48 weeks
Telbivudine
52 weeks
Lamivudine
48 - 52 weeks
PegIFN
48 weeks
Standard IFN
12 - 24 weeks
Undetectable
HBV viral DNA
93% 90% 51% 88% 60-73% 63% 60-70%
ALT
normalization
76% 78% 72% 74% 60-79% 38% 60-70%
Histologic
improvement
72% 70% 64% 67% 60-66% 48% N/A
HBeAg-
positive
Tenofovir
5-years
1
HBeAg-
positive
Entecavir
5-years
2
HBeAg-
negative
Tenofovir
5-years
1
HBeAg-
negative
Entecavir
5-years
3
Undetectable
HBV viral DNA
97% 94% 99% 100%
ALT
normalization
73% 80% 85% 100%
HBeAg
seroconversion
40% 23% ----- -----
HBsAg loss 10% 1.4% 1% NR
N/A not available.
Adapted from: Lok AS, et al. Hepatology. 2009;50(3):661-662.
NR not reported.
Adapted from:
1
Marcellin P, et al. Lancet. 2013;381(9865):468-475.
2
Chang TT, et al. Hepatology. 2010;51(2):422-430.
3
Luo J, et al. Int J Med Sci. 2013;10(4):427-433.
Table 2. Treatment Response Rates Among CHB Patients Who Are HBeAg Positive (+) and HBeAg Negative (-)
A) Treatment-Nave HBeAg Positive
Table 3. Treatment Response Rates at 5-years Among CHB Patients
Treated with Tenofovir or Entecavir
9
5. Kuo A, et al. Clin Liver Dis. 2012;
16(2):347-369.
6. Chang TT, et al. Hepatology. 2010;52(3):
886-893.
7. Lim YS, et al. Gastroenterology. 2014.
[Epub ahead of print]
8. Triolo M, et al. Liver Int. 2014;34(Suppl
1):139-145.
9. Evans AA, et al. Antivir Ther. 2013;
18(2):229-235.
10. Tong MJ, et al. J Gastroenterol Hepatol.
2011;26(5):829-835.
11. Keeffe EB, et al. Clin Gastroenterol Hep-
atol. 2008;6(12):1315-1341.
12. European Association For The Study Of
The Liver. J Hepatol. 2009;50(2):227-242.
13. Liaw YF, et al. Hepatol Int. 2008;2(3):
263-283.
14. Chen C, et al. JAMA. 2006;295(1):65-73.
15. Chen G, et al. Am J Gastroenterol. 2006;
101(8):1797-1803.
16. Liaw YF, et al. N Engl J Med. 2004;
351(15):1521-1531.
17. Yuen MF, et al. Antivir Ther. 2007;12(8):
1295-1303.
18. Cohen C, et al. J Viral Hepat. 2011;
18(6):377-383.
19. Gish RG, et al. J Viral Hepat. 2006;
13(12):787-798.
20. Tai Dl, et al. Hepatology. 2009;49(6):
1859-1867.
21. Tong MJ, et al. Dig Dis Sci. 2010; 55(3):
826-835.
22. Tong MJ, et al. Clin Gastroenterol Hepa-
tol. 2009;7(8):889-893.
23. Yuen MF, et al. Gut. 2005;54(11):1610-
1614.
24. Fung J, et al. Aliment Pharmacol Ther.
2007;26(3):377-382.
25. Cho SW, et al. Hepatology. 2000;32(5):
1163-1169.
26. Lok AS, et al. Hepatology. 2000;32(5):
1145-1153.
27. Block TM, et al. Antiviral Res. 2013;
98(1):27-34.
28. Janssen HL, et al. Lancet. 2005;
365(9454):123-129.
29. Lau GK, et al. N Engl J Med. 2005;
352(26):2682-2695.
30. Buster EH, et al. Gastroenterology. 2009;
137(6):2002-2009.
31. Dienstag JL, et al. N Engl J Med. 1999;
341(17):1256-1263.
32. Liaw YF, et al. Gastroenterology. 2000;
119(1):172-180.
33. Lok AS, et al. Gastroenterology. 2003;
125(6):1714-1722.
351(15):1521-1531.
35. Chang TT, et al. Hepatology. 2010;
51(2):422-430.
36. Tenney DJ, et al. http://www.hivandhepa-
titis.com/2009icr/ddw/posters/DDW_
Poster%201805_6%20yr%20Resistance.
pdf. Accessed July 11, 2014.
37. Lai CL, et al. N Engl J Med. 2007;
357(25):2576-2588.
38. Liaw YF, et al. Gastroenterology. 2009;
136(2):486-495.
39. Han GR, et al. J Hepatol. 2011; 55(6):
1215-1221.
40. Fleischer RD, et al. J Hepatol. 2009;
51(4):787-791.
41. Marcellin P, et al. N Engl J Med. 2003;
348(9):808-816.
42. Hadziyannis SJ, et al. N Engl J Med.
2003;348(9):800-807.
43. Hadziyannis SJ, et al. Gastroenterology.
2006;131(6):1743-1751.
44. Marcellin P, et al. N Engl J Med. 2008;
359(23):2442-2455.
45. Heathcote EJ, et al. Hepatology. 2010;
52(Suppl 4):556A.
46. Marcellin P, et al. Hepatology. 2011;
54(Suppl 1):430A.
Full references are available at www.healio.
com/gastroenterology/education-lab and www.
opencme.org.
10
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What medication-resistant hepatitis B variants
have emerged in clinical practice?
Dr. Janssen: You have different levels of antivirals. So the rst ones,
are lamivudine and adefovir, and they carry a high rate of resis-
tance. In the case of lamivudine, rates of resistance are roughly 80%
after 5 years, and for adefovir, it is a bit lower.
So these were really the rst antivirals for hepatitis B which are
by far not optimal. Then telbivudine was developed, which also has
resistance, and the last 2 drugs developed are really the besten-
tecavir and tenofovir. Both entecavir and tenofovir do not carry any
resistance potential or very limited resistance, less than 2%, allowing
you to treat for many years. Currently, most patients have 7 to 8 years
of follow-up without any resistance. So it is of no surprise that ente-
cavir and tenofovir are now recommended by all global guidelines
as the rst-line treatment options whereas lamivudine, adefovir, and
telbivudine are not recommended as rst-line options.
Still, there are many patients in the world being treated with
lamivudine and adefovir because these medications are cheap-
er, and hepatitis B is a disease occurring in developing coun-
tries, very often with limited resources. As a result, you have
patients who become resistant to lamivudine and adefovir, and
on a global scale, resistance to lamivudine is by far the most
important one seen. There are many patients in China, other
parts of the Far East, or South America who have resistance to
lamivudine. If resistance occurs, the best thing to do is to switch
to tenofovir, which negates lamivudine resistance, or add on
adefovir. There are 5 hepatitis B antivirals : the nucleoside ana-
logues, which are lamivudine, telbivudine, and entecavir; and
the nucleotide analogues, which are adefovir and tenofovir. In
general, if you get resistance to a nucleoside analogue, then you
should switch to the strongest nucleotide analogue, that is teno-
fovir, and vice versa. If your patient gets resistance to a nucleo-
tide analogue, you have to switch to a nucleoside analogue, and
there the strongest one would be entecavir.
What are some risk factors that make patients more
prone to resistance or not prone to resistance?
Dr. Janssen: There are several risk factors that make patients
more prone to resistance. First of all, being prescribed a drug
with low barrier to resistance is by far the biggest risk factor.
The second risk factor is poor patient compliance. Just like
with antibiotics or antituberculosis medications, if the patient
rarely takes the medications or takes it intermittently, then the
viral load decline is limited and they have a higher chance of
resistance developing.
Finally, the third factor, is the baseline viral load of the pa-
tient. If the baseline viral load is extremely high, then it is very
difcult to get the patient to fully undetectable levels. These
patients have a higher chance of resistance.
So, in summary, if you hit the virus very fast and very hard,
and the viral load goes down very quickly to undetectable, the
chances of resistance are low. If the virus is still detectable in
the lower range while on therapy, then with time you have a
higher chance of resistance.
How do you monitor patients in your practice
for resistance?
Dr. Janssen: I treat most of my patients with tenofovir or ente-
cavir, so the chances of resistance are very limited, approximately
less than 1%. In my practice, I check the patient's viral load in the
rst year every 6 months, and if they are fully suppressed and very
compliant, I check it on a yearly basis, but if they are not fully sup-
pressed and/or compliant, I continue to check it every 6 months.
However, if you treat a patient with lamivudine, you will
need to have the viral load checked every 3 months or 4 times
a year continuously for years and years.
Some say that lamivudine is a good medication because it
is inexpensive. However, resistance can develop to the drug
and the HBV DNA should be measured every 3 months or 4
times a year during therapy.
What are the appropriate laboratory tests
to assess both liver disease and the level of
hepatitis B viral activity?
Dr. Janssen: For liver disease, you have 2 components. The rst
component is the amount of inammation, which is measured
by serum transaminases, mostly the ALT.
The second test for liver function is the synthetic liver func-
tion. The ALT reects the amount of inammation, the amount
of damage done to the liver. But then there are other liver tests
which reect whether the liver is still working well, and those
are bilirubin, albumin, and coagulation factors.
For example, albumin and coagulation factors are proteins
made by the liver. So if the liver is not working, you have end-stage
How Important is Monitoring Treatment
Response in HBV Today?
11
liver failure, those factors go down. We do not see that very
often and usually when we see it, the patients are very sick and
some patients will need to be transplanted. Liver function and
inammation are the 2 factors we use to measure how the liver
itself is doing.
Regarding the virus, we measure the HBV DNA, by the viral
load. So if the viral load is high, it is not good. If the viral load
is undetectable, it is good, and the patient usually does not
have progressive disease. And, there is the HBsAg seroconver-
sion, which is an indicator of disease cure when treatment
could be stopped.
Is there any serologic testing that should be
done to monitor response to treatment?
Dr. Janssen: Yes, the serologic testing, HBeAg and the HBsAg.
You want to monitor in e-positive patients, whether the pa-
tients undergo some e-seroconversion. This should be moni-
tored approximately once a year. The s antigen is measured
to detect a surface -seroconversion, which you measure with
about the same frequency, approximately once a year.
How frequent are you monitoring patients
with hepatitis B who are receiving treatment?
Dr. Janssen: With regard to the antivirals, they have become
so strong that we are able to monitor patients less frequently
than in the past. If the medications carry signicant resistance,
you should monitor at least 4 times a year. However, if the
patient is taking his medication, he is compliant and is fully
suppressed with the virus, you can test 2 times a year.
Still, the challenge for hepatitis B in the future is how to
cure the disease, how to reach a "functional cure". The sur-
face seroconversion percentage is very low, from 10% to 15%,
and we are capable to suppress the virus and to suppress the
hepatitis B disease but we are not able to achieve "functional
cure". That is the next challenge for research is in the coming
years. Particularly now that hepatitis C is a curable disease with
very easy treatment, I think many companies have reinvested
resources into getting a "functional cure" for hepatitis B.
How would you dene a therapeutic endpoint
for therapy?
Dr. Janssen: The closest denition to the cure of the disease is
hepatitis B surface antigen (HBsAg) seroconversion; that means
the loss of HBsAg and the development of anti-HBs antibody, but
that is very difcult to reach. The endpoint is only reached in 10%
to 15% of the patients treated with interferon and for the patients
treated with a nucleoside analogue, it is hardly ever reached.
A weaker endpoint would be hepatitis B e antigen (HBeAg)
seroconversion, which is the loss of HBeAg and the develop-
ment of HBe antibody (anti-HBe), and for treatment with the
antiviral nucleoside and nucleotide analogues, undetectable
HBV DNA. So undetectable viral load is your best endpoint.
So, it depends on what type of treatment you administer.
With hepatitis B, you have immune-modifying agents like inter-
feron treatment that takes over the immune system in order to
get immune control over the virus or you have direct antiviral
agents that do little more than completely suppress the viral
replication. Depending on the treatment administered, you
have different endpoints. The endpoint of viral load undetect-
ability, as well as surface antigen seroconversion, have been as-
sociated with the clear reduction in liver cancer, with reduction
in the development of liver cirrhosis, and potentially the reduc-
tion of all-cause mortality, but we do not have those analyses
yet. For liver cancer and for cirrhosis, it has clearly been shown
that those are reduced by the endpoints given.
What is the most appropriate treatment end-
point in HBeAg-negative disease?
Dr. Janssen: The most important endpoint to reach for these
patients would be HBsAg seroconversion. If you would reach
that, then these patients are usually cured and you can stop
treatment, but that very rarely happens in HBeAg-negative dis-
ease. Then you have to aim for suppression of the viral loads
which is the second best endpoint, whereas the disease is qui-
escent but it means that you have to continue current therapy.
But as the viral load is suppressed, you are just suppress-
ing the disease but the immune system of the patient does not
have any control over the virus. If you stop treatment at this
point, you will most likely get a rebound of disease, whereas if
you get HBsAg seroconversion and you stop the disease, you are
likely not to get a rebound of disease.
Are these therapeutic endpoints the same
thing as a "functional cure"?
Dr. Janssen: Yes, HBsAg seroconversion is what we would call
"functional cure" and HBV DNA suppression, so undetectable
viral load is just the suppression of the disease. You could
either try to cure hepatitis B, using an immune-modifying
medication, or you could treat hepatitis B just like you treat
HIV. Give an antiviral, suppress the virus, but if you stop the
treatment, then the virus will likely come back.
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12
H
epatitis B virus (HBV) infec-
tion is a global public health
issue that is responsible for
signicant morbidity and mortality
from chronic liver disease. Chronic
hepatitis B (CHB) is dened by the
persistence of serum hepatitis B sur-
face antigen (HBsAg) for 6 months or
longer.
1
The natural history of CHB
can be classied into 4 major clinical
phases based on levels of serum ALT,
HBV DNA, and presence of HBeAg.
2

These phases are immune tolerance,
HBeAg-positive CHB, inactive car-
rier, and HBeAg-negative CHB. The
disease is often variable and unpre-
dictable. Patients may not proceed
through all phases of the disease dur-
ing the course of their chronic disease.
2

There are 7 agents approved for the
treatment of CHB by the U.S. Food
and Drug Administration (FDA).
1,3

The agents are peginterferon and
standard interferon-alpha (pegIFN-,
IFN-); nucleoside (lamivudine, ente-
cavir, and telbivudine); and nucleotide
(adefovir, tenofovir) analogues. The
combination of tenofovir and em-
tricitabine has potent activity against
HBV, but is currently only FDA-
approved for treatment of human
immunodeciency virus (HIV). The
nucleoside and nucleotide analogues
(NUCs), given as monotherapy, have
been shown to produce virologic,
biochemical, and histological benet
for both HBeAg positive and negative
CHB. Sustained inhibition of HBV
replication has been shown to be
associated with normalization of
serum aminotransferases and histo-
logical improvement. However, the
need for prolonged therapy can be
associated with the development of
drug-associated resistance and medi-
cation nonadherence.
Drug resistance and cross
resistance
Antiviral resistance is dened as
the selection of HBV mutants confer-
ring reduced susceptibility to a drug
that results in primary or secondary
treatment failure. While resistance is
more likely the cause of secondary
treatment failure, it may cause pri-
mary treatment failure due to trans-
mission of resistant HBV mutants or
due to cross resistance resulting from
previous therapies.
4
The risks of the
emergence of drug-resistant mutants
in the HBV DNA polymerase/reverse
transcriptase increases with duration
of therapy, high baseline serum HBV
DNA level, incomplete viral suppres-
sion during the rst 6 months of ther-
apy, noncompliance to therapy, and
prior exposure to NUCs.
1,5
There is no
risk of drug resistance with standard
interferon or pegylated interferon.
Lamivudine is associated with the
highest rate of resistance, reaching
nearly 70% by year 4 of continuous
therapy.
2
The primary mutations as-
sociated with lamivudine resistance
are located in the YMDD catalytic
motif of the C domain of the HBV re-
verse transcriptase (RT) (rtM204V/I),
while compensatory mutations (rt-
V173L, rtL180M) are identied in
domain B.
6
The main effect of the
compensatory mutations is to restore
replication tness of the drug-associ-
ated HBV mutant. Thus, HBV DNA
level usually increases with continu-
ous therapy after the emergence of
the primary mutation.
6,7
Adefovir
is generally effective against both
wild type HBV and lamivudine re-
sistance mutants.
8
There is evidence
to support the addition of adefovir
to lamivudine in the presence of la-
mivudine resistance to prevent the
subsequent development of adefovir
resistance.
9
With the availability of
tenofovir, the alternative is to add te-
nofovir or switch to the combination
pill of tenofovir and emtricitabine in
the setting of lamivudine resistance.
Despite the initial low resistance
rate with adefovir (ADV), the cu-
mulative resistance rate increased to
29% by year 5.
10,11
The primary site of
adefovir-associated resistance muta-
tion, rtN236T, is located in domain D
of the HBV reverse transcriptase. This
mutation results in a 3- to 6-fold reduc-
tion in susceptibility to ADV in vitro
and remains susceptible to nucleoside
analogues, such as lamivudine, tel-
bivudine, and entecavir. In contrast,
the rtA181V/T mutation of adefovir
in domain B was found to have re-
duced responsiveness to lamivudine
and telbivudine in phenotypic assays.
It remains susceptible to entecavir and
tenofovir.
6,8,12

A number of studies reported that
lamivudine monotherapy can also
promote the emergence of rtA181T
mutation in adefovir treatment nave
patients.
6,13
This single substitution at
position rt181 appears to be sufcient
to induce cross-resistance between
lamivudine and adefovir. In the spe-
cic setting of lamivudine resistance
Evaluating Underlying Causes
of HBV Treatment Failure
Daryl T-Y Lau, MD, MSc, MPH and Asad Javaid, MD
13
with the presence of both rtM204V/I
and rtA181T substitutions, adefovir
will not be effective. The addition of
tenofovir to lamivudine or switch to
emtricitabine 200 or tenofovir 300
are the therapy of choice in this case
based on the available in vitro data and
limited clinical presentations. These
observations with lamivudine and ad-
efovir therapy highlight the important
roles of both genotypic and phenotypic
assays in identifying the antiviral drug-
associated mutations and in inform-
ing the selection of the subsequent
salvage therapy.
The development of entecavir resis-
tance requires pre-existing lamivudine-
resistance mutations and additional
changes in the HBV polymerase/re-
verse transcriptase: T184 in domain B,
S202 in domain C, or M250 in domain
E.
14,15
The relatively low resistance rate
of entecavir at 1% in 5 years among
previous treatment-nave patients can
be explained by a combination of its
high genetic barrier requiring multiple
mutations to reduce its efcacy and
its antiviral potency.
16
In contrast, for
patients with pre-existing lamivudine
resistance who were subsequently
switched to entecavir, entecavir-re-
sistance rate increased to 43% after
5 years of continuous therapy.
16
This
illustrates the important concept of the
emergence of drug resistance in the
setting of reduced genetic barrier.
Even though both entecavir and
telbivudine have excellent antiviral
potency, telbivudine monotherapy is
associated with much higher rate of
resistance, up to 22% for HBeAg posi-
tive CHB at 2 years.
17,18
This could be
partially explained by the difference in
genetic barrier in the development of
resistance between the 2 drugs. Unlike
entecavir, telbivudine only requires the
single mutation to confer resistance.
Cross-resistance between lamivudine
and telbivudine is unavoidable since
both drugs induce mutations at HBV
reverse transcriptase (rt) position 204.
Similar to lamivudine, the presence of
telbivudine resistance would likely
predispose to the emergence of ente-
cavir resistance based on the in vitro
data.
12,19
There is evidence that telbi-
vudine can also promote the emer-
gence of rtA181T in treatment nave
patients. To date, there has not been
resistance associated with long-term
tenofovir use.
Monitoring and Management
of Antiviral Resistance
Antiviral resistance is the major
limitation of prolonged NUC therapy.
Careful consideration is needed to se-
lect rst-line therapy in order to avoid
the emergence of resistance, especially
those that may limit future treatment
choices due to cross-resistance with
other agents. Lamivudine, telbuvu-
dine, and adefovir are no longer con-
sidered a rst-line monotherapy for
CHB because of their high rate of re-
sistance. HBV DNA quantication is
important for initial patient evaluation,
for monitoring treatment response,
and for early detection of virologic
breakthrough on therapy. The real-
time PCR quantication assays are
recommended for HBV DNA baseline
determination and monitoring during
therapy.
20,21
All patients should have
baseline serum HBV DNA, ALT, liver
function tests, HBeAg/anti-HBe prior
to initiating the treatment. Thereafter,
serum HBV DNA and ALT should be
checked every 3 to 6 months to ensure
adequate response to the treatment and
early detection of treatment failure.
4

For NUC, the antiviral effect is
dened as 1 log
10
decrease in HBV
DNA within 3 months of starting the
treatment.
4
Treatment failure can be
primary and secondary. Primary treat-
ment failure is dened as decrease in
serum HBV DNA of 1 log
10
IU/
mL from baseline after 3 months of
starting therapy.
4
Secondary treat-
ment failure is a rebound of serum
HBV DNA resulting in an increase of
1 log
10
IU/mL in patients with ini-
tial antiviral treatment effect.
4,22
This
should be conrmed by 2 consecutive
determinations at a 1-month interval.
For patients with primary or second-
ary treatment failure, medication non-
compliance should be excluded and
if drug resistance is suspected, resis-
tance testing should be performed.
4,22

Depending on the sensitivity of the
genotyping assay, drug-resistant
mutations can be detected months pri-
or to the rise of the serum HBV DNA.
The subsequent biochemical break-
through with increased serum ami-
notransferases tends to occur 3 to 6
months after virologic breakthrough.
23

Antiviral resistance can be associated
with acute hepatitis are with decom-
pensation of liver disease, especially
among those with advanced bro-
sis.
24
These observations underscore
the importance of regular monitoring
for early virologic breakthrough and
adjustment of antiviral therapy to pre-
vent biochemical breakthrough.
Medication Nonadherence
Adherence with medication us-
age is dened as the proportion of
prescribed doses of medication actu-
ally taken by a patient over a speci-
ed time period.
25
Patient adher-
ence rates with medication used for
chronic conditions in clinical settings
are highly variable. Antiviral therapy
for chronic hepatitis B has a prole
that should favor high adherence
rates given the once-daily dosing of
a single nucleoside or nucleotide tab-
let that is well tolerated. The need for
long-term suppression, however, can
be a challenge. Medication noncom-
pliance can occur for many different
reasons that include patient-, doctor-,
nancial-, and medication-related
factors. Language barriers between
patients and doctors are another
factor in suboptimal compliance of
patients.
26
Other factors affecting
patient adherence are forgetfulness,
uncertainty regarding the benecial
impact of medication, emotional or
cultural reasons.
14
There are different methods to
measure patient compliance that in-
clude self-reporting, pill counting,
and tracking prescription rells, but
none of these methods are ideal. Self-
reporting is a simple and inexpensive
way of measuring compliance but pa-
tients tend to exaggerate their medica-
tion compliance.
25
The pharmacy rell
claims data are easy to use but there is
the possibility of administrative errors
resulting in misclassication.
25
Differ-
ent adherence rates for hepatitis B an-
tiviral therapy are reported in various
studies depending on the patient popu-
lations and study methods.
Patients with CHB in general are
more compliant in taking medications
compared to other chronic conditions.
The average compliance rate among
patients on nucleoside or nucleo-
tide was reported to be from 81% to
99%.
27-29
In a retrospective study based
on a national pharmacy rell database
that included 11,100 patients represent-
ing 25% of the market for hepatitis B
treatment between 2007 and 2009,
patient-oriented adherence to antiviral
therapy was evaluated.
28
The overall
adherence rate was high with a mean
of 87.8%, and 55.3% of the patients
had >90% adherence. Independent
predictors of good adherence included
patients older than 45 years, and those
who received NUCs other than lamivu-
dine. Patients who were already receiv-
ing antiviral therapy were more likely
to be compliant than those starting new
therapy. There was a rapid drop-off
in rell prescription within the rst 6
months of cohort enrollment; the rell
rate declined by 9.1% and 22.4% by
6 months in existing and new patients,
respectively. Data from this study sug-
gested that target educational programs
are crucial to maintain medication ad-
herence, especially among younger and
new patients on antiviral therapy.
Differentiating between virologic
breakthrough due to medication nonad-
herence and drug resistance is impor-
tant since they are managed differently.
Viral suppression can be restored in
nonadherent patients by increasing pa-
tient compliance, but virologic break-
through due to drug resistance requires
change in medication.
30
Monitoring
antiviral resistance and patient com-
pliance are equally important as they
can both lead ultimately to treatment
failure.
31
With the availability of potent
and high genetic barrier to resistance
antiviral agents, such as entecavir and
tenofovir, a number of studies indicate
that nonadherence is, in fact, the most
important factor for hepatitis B treat-
ment failure.
32-34
In a clinical trial with
tenofovir, patients with 94% medi-
cation adherence, calculated through
pill count, had lower HBV DNA at 48
weeks of treatment compared to pa-
tients with an adherence rate 68%.
29
Summary
Both physicians and patients
must understand the importance of
medication compliance before the
start of antiviral therapy to prevent
development of drug resistance.
35

Patients should be monitored and
asked about medication adher-
ence every 3 to 6 months.
36
Studies
showed that when physicians spend
>3 minutes discussing medication
compliance during the ofce visit,
patients are more likely to follow the
physicians advice.
37

References
1. Hollinger FB, et al. Gastroenterol Clin North
Am. 2006;35(4):895-931.
2. Lok AS, et al. Gastroenterology. 2001;
120(7):1828-1853.
3. Hoofnagle JH, et al. Hepatology. 2007;
45(4):1056-1075.
4. Pawlotsky JM, et al. Gastroenterology.
2008;134(2):405-415.
5. Kim JH, et al. J Gastroenterol Hepatol.
2007;22(8):1220-1225.
6. Locarnini S. Semin Liver Dis. 2005;25(Suppl
1):9-19.
7. Liu CJ, et al. Hepatology. 2001;34(3):583-589.
8. Ono-Nita SK, et al. J Clin Invest. 1999;
103(12):1635-1640.
9. Lampertico P, et al. Gastroenterology. 2007;
133(5):1445-1451.
10. Hadziyannis SJ, et al. N Engl J Med.
2005; 352(26):2673-2681.
11. Papatheodoridis GV, et al. Hepatology.
2005;42(1):121-129.
12. Zoulim F. Semin Liver Dis.
2006;26(2):171-180.
13. Villet S, et al. J Hepatol. 2008;48(5):747-
755.
14. Colonno RJ, et al. Hepatology. 2006;
44(6):1656-1665.
15. Tenney DJ, et al. Antimicrob Agents Che-
mother. 2004;48(9):3498-3507.
16. Tenney DJ, et al. Hepatology. 2009;
49(5):1503-1514.
17. Lai CL, et al. N Engl J Med. 2007;
357(25):2576-2588.
atol. 2008;6(3):268-274.
19. Yang H, et al. Antivir Ther.
2005;10(5):625-633.
20. Gordillo RM, et al. J Clin Microbiol.
2005; 43(7):3504-3507.
21. Lole KS, et al. J Virol Methods. 2006;
135(1):83-90.
22. Lok AS, et al. Hepatology.
2007;45(2):507-539.
23. Lau DT, et al. Hepatology. 2000;32(4 Pt
1):828-834.
351(15):1521-1531.
25. Osterberg L, et al. N Engl J Med. 2005;
353(5):487-497.
26. Giang L, et al. World J Hepatol. 2012;
4(2):43-49.
27. Chotiyaputta W, et al. J Viral Hepat.
2012;19(3):205-212.
28. Chotiyaputta W, et al. J Hepatol. 2011;
54(1):12-18.
29. Berg T, et al. Gastroenterology. 2010;
139(4):1207-1217.
30. Hongthanakorn C, et al. Hepatology.
2011; 53(6):1854-1863.
31. Paterson DL, et al. Ann Intern Med. 2000;
133(1):21-30.
32. Ha NB, et al. Dig Dis Sci. 2011;56(8):2423-
2431.
33. Kamezaki H, et al. Scand J Gastroenterol.
2011;46(9):1111-1117.
34. Lee GH, et al. Liver Int. 2013;33(4):642-
646.
35. Heathcote EJ. Clin Med. 2007;7(5):472-
477.
36. Morgan M, et al. Minerva Gastroenterol
Dietol. 2007;53(1):25-41.
37. Kravitz RL, et al. Arch Intern Med.
1993;153(16):1869-1878.
opencme.org
15
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16
Meeting Highlight from EASL -
The International Liver Congress 2014
Prevention of HBV Reactivation with Tenofovir:
Preliminary Study Results (PREBLIN Study)
Patients with malignancies who are positive for
hepatitis B surface antigen (HBsAg) or core anti-
body (anti-HBc) are at risk of severe hepatitis B vi-
rus (HBV) reactivation during or after they are being
treated with the immunosuppression therapy. Histori-
cally, although the risk is reduced by prophylaxis with
the nucleoside analog antiviral agent lamivudine, it is
not eliminated.
A randomized, open-label multicenter clinical trial
(PREBLIN Study) is exploring the safety and efcacy
of the more potent nucleotide analog antiviral, tenofovir
(TDF), at preventing HBV reactivation. The study is en-
rolling patients who are HBsAg-negative, anti-HBc-posi-
tive with hematological malignancy and are scheduled to
receive treatment with rituximab (RTX). Before starting 18
months of RTX, participants are randomized 1:1 to receive
either TDF or to undergo observation, with follow-up test-
ing scheduled at 2-month intervals after RTX treatment
begins. The primary endpoint is the proportion of patients
that experience HBV reactivation after 18 months of RTX
treatment, with reactivation that occurs during the trial in-
cluded as a secondary endpoint. Reactivation is dened as
HBV-DNA levels 1 log
10
IU/mL above baseline, and/or
seroreversion evidenced by the reappearance of HBsAg.
Enrollment of 98 subjects planned. Currently, 69 pa-
tients have been screened and 50 enrolled. Six months
of follow-up have been completed for 22 randomized
patients, 11 in each group. Six-month data are also
available for 3 additional patients who had detectable
HBV-DNA at baseline and, per protocol, were given
open-label TDF. The 25 patients are 66% male, with a
median age of 70 years (range, 31 to 86). Most patients
had non-Hodgkin lymphoma (62%) or chronic lympho-
cytic leukemia (29%). None of the 14 patients given
TDF experienced HBV reactivations during the 6-month
follow-up period, compared with 2 (18%) patients in the
observation group (P=.2). The reactivations were identi-
ed at the 4-month visit for each patient and were based
on HBV-DNA elevations without HBsAg seroreversion.
TDF rescue therapy was initiated, and both patients had
undetectable HBV-DNA at 6 months.
These early results show successful prophylaxis of
HBV reactivation in patients taking RTX during 6 months
of treatment with TDF. The preliminary data revealed that
18% of the observation group experienced HBV reactiva-
tion by 4 months after starting RTX treatment.
Tram T. Tran, MD: Commentary
Hepatitis B reactivation is an increasingly recognized
clinical issue across many disciplines including oncol-
ogy, rheumatology, dermatology, and gastroenterology.
The Centers for Disease Control and the AASLD Hepa-
titis B Practice Guidelines recommend that all individ-
uals undergoing immune suppression be screened for
hepatitis B. Recognizing that patients who are HBsAg
positive have a high risk of reactivation is important,
and studies have shown that antiviral prophylaxis is of
benet in reducing risk of reactivation in those who are
chronically infected. However, it is important to note
that recent data have suggested that even patients who
are HBsAg negative, who have been previously exposed
to hepatitis B (anti-HBc positive), are still at risk of re-
activation. Analysis of the FDA safety reports regard-
ing reactivation with rituximab and other anti-CD20
agents found over 100 fatal cases of HBV reactivation,
with 69% occurring in those who seroconverted from
HBsAg negative to HBsAg positive.
This interim analysis of randomizing patients who
are anti-HBc positive only (HBsAg negative) undergo-
ing rituximab treatment to prophylaxis versus no pro-
phylaxis will give us important information conrming
the FDA safety reports, assessing reactivation rate, and
timing of reactivation. Thus far, tenofovir has prevent-
ed reactivation in all patients receiving prophylaxis,
while 2 patients experienced reactivation with no pro-
phylaxis. While preliminary, reactivation during che-
motherapy may lead to delay in oncologic therapy and
higher risk of both liver failure and oncologic relapse.
Buti M, et al. Abstract P1040. Tenofovir for the Prophylaxis
of HBV Reactivation in Anti-HBC-Positive Patients with
Hematologic Malignancies Treated with Rituximab:
Preliminary Results of a Randomized Study (Preblin Study)
EASL 2014.
T
here are 7 approved thera-
pies for the hepatitis B virus
(HBV) and these include the
2 interferon-based immunomodulators
(interferon alfa-2b and peginterferon
alfa-2a); and the antivirals: lamivudine,
adefovir, telbivudine, entecavir, and te-
nofovir. The primary objective of thera-
py is to eradicate/suppress HBV DNA,
thereby reducing hepatic inammation
and improving hepatic biochemical
tests. The rst-line therapies are pe-
gylated interferon, tenofovir, and ente-
cavir. Tenofovir and entecavir are po-
tent HBV inhibitors with a high barrier
to resistance and can be safely used as
rst-line monotherapies. The second-
line therapies, which pose risks of viral
resistance, are lamivudine, adefovir,
and telbivudine; these agents should
only be used when the rst-line treat-
ments are inaccessible or inappropri-
ate. Historically, pegylated interferon
has been associated with on-treatment
adverse events, such as fatigue, mal-
aise, nausea, and irritability. Long-term
residual adverse events are uncommon.
Compared to pegylated interferon alfa,
the nucleoside and nucleotide analogs
have superior tolerability; however,
indenite treatment duration, risk of
resistance, and unknown long-term
safety are challenges that persist with
some of the oral agents.
Safety of Current Oral Antiviral
HBV Therapies
In order to prevent and diminish
the progression of liver disease due to
HBV infection, prolonged treatment
with oral nucleoside and nucleotide an-
alogs is recommended for selected pa-
tients with chronic HBV infection until
disease remission and/or serological
endpoints, such as hepatitis B e antigen
(HBeAg) seroconversion, have been
achieved.
1
Indenite antiviral treatment
is advised for patients with chronic
hepatitis B (CHB) with advanced liver
disease because there is a risk of dis-
ease are and hepatic decompensation.
Generally, the oral agents have favor-
able side-effect proles and thus have
been deemed benecial for use beyond
1 year. Therefore, the known antiviral
resistance with lamivudine, adefovir,
telbivudine, and to some extent with
entecavir in patients with lamivudine
resistance, requires careful selection
of therapy, particularly if there is a
long-term requirement for treatment.
Additionally, rare but serious adverse
events such as myopathy, neuropathy,
and pancreatitis, as well as reversible
renal impairment, have been reported
during the postmarketing period of la-
mivudine, adefovir, and telbivudine.
Additionally, all nucleoside and nucle-
otide analogs have a black box warning
due to their potential to inhibit human
DNA polymerase gamma, which can
lead to mitochondrial toxicity.
2
Clinical
manifestations of mitochondrial toxic-
ity may include myopathy, neuropathy,
hepatic steatosis, pancreatitis, macro-
cytosis, hyperlactemia and lactic acido-
sis, and nephrotoxicity.
Lamivudine had been the most
widely used oral antiviral agent for
HBV infection worldwide and has been
effective and well-tolerated in patients
with decompensated cirrhosis due to
HBV. However, since the prevalence
of lamivudine-resistant HBV increases
over time (70% after 5 years), lamivu-
dine is now considered a second-line
therapy for treatment-nave patients
(Table, page 18).
1
Adefovir and teno-
fovir are associated with a dose-de-
pendent but generally reversible prox-
imal renal tubular toxicity. In general,
dosing adjustments and/or increased
dosing intervals are recommended
for patients with renal insufciency.
The nephrotoxicity is usually revers-
ible if therapy is discontinued rapidly.
With continued adefovir or tenofovir
use, renal insufciency, renal tubular
acidosis, and hypophosphatemia can
occur. Other potential risks associ-
ated with prolonged adefovir therapy
include the emergence of adefovir-
resistant strains of HBV, which can
occur in 28% of treated patients after
5 years and contribute to liver disease
ares (Table).
3,4
In preliminary trials,
the adverse-effect prole of tenofovir
was generally favorable and similar to
the comparator arm of adefovir. Most
episodes of nephrotoxicity associated
with tenofovir use were reversible
with early discontinuation. However,
cautious and systematic surveillance
should be undertaken in HBV patients
with underlying risk factors for renal
impairment, such as diabetes mellitus,
atherosclerotic disease, and older age.
Long-term use of tenofovir has also
been reported to cause reduced bone
mineral density and osteomalacia in
patients with human immunodecien-
cy virus (HIV) infection.
5
Across HBV trials of tenofovir,
treatment-emergent amino acid substi-
tutions have been reported in viremic
patients; however, no specic substitu-
tions occurred at a sufcient frequency
to be associated with resistance to teno-
fovir in either genotypic or phenotypic
17
Long-term Safety of HBV Therapies
and When to Stop Therapy
K. Rajender Reddy, MD, FACP, FACG, FRCP and Tanya M. Pavri, BA
analyses.
6
In a multicenter European
prospective cohort study in clinical prac-
tice (n=302), tenofovir monotherapy
was administered to patients who are
nucleoside or nucleotide nave for a
median of 28 months (range: 0 to 60).
Virologic breakthrough occurred in 2%
of patients, with no resistance-associat-
ed mutants being found. Additionally,
no signicant changes in renal function
were observed.
6
In other clinical trials of
patients who are HBV-monoinfected,
over a 4-year period creatinine clearance
rates were stable and 1% of patients
had conrmed elevations in creatinine
levels of 0.5 mg/dL.
7
The safety proles in clinical prac-
tice studies of virologic resistance
emerging during entecavir (ETV) with
over 1000 patients have been predomi-
nantly consistent with those of phase 3
trials; no major safety issues or serious
adverse events have been documented
to date. Notably, ETV has a low capac-
ity for inhibiting polymerase gamma,
substantiated by a low rate of adverse
events associated with mitochondrial
toxicity. Although most adverse events
associated with ETV have been mild
to moderate, severe lactic acidosis has
been reported in a case series of pa-
tients with advanced cirrhosis (MELD
score 20).
8
Caution should be exer-
cised when using ETV in patients with
decompensated cirrhosis, and dose
should be adjusted for creatinine clear-
ance. In a European multicenter co-
hort study between the years 2005 and
2010, patients who were nucleoside or
nucleotide nave were treated with ETV
monotherapy. Five of 243 patients had
virologic breakthrough, and no muta-
tions associated with resistance to ETV
were identied at the end of a median
follow-up period of 19 months (range:
3 to 45).
6
Nevertheless, drug resistance
against entecavir remains a challenge in
patients who are lamivudine-resistant.
Patients with lamivudine-resistant HBV
have been shown to have an increas-
ing risk of developing entecavir-resis-
tant HBV during prolonged treatment
(up to 37% at 4 years); in certain cases,
this was associated with liver disease
ares.
9,10

When to Stop HBV Therapy
Clinical proles of chronic HBV
In CHB, therapy is guided by the
clinical prole of the HBV infection.
Patients chronically infected with
HBV are at increased risk of develop-
ing cirrhosis, hepatic decompensation,
and hepatocellular carcinoma (HCC).
Although most patients who are in-
fected will not develop complications
of liver disease from CHB, 15% to
40% will develop serious sequelae
during their lifetime.
11
Chronic HBV
infection typically consists of 4 phases,
2 of which are HBeAg-positive while
2 are HBeAg-negative. The patients
who are HBeAg-positive are further
characterized as immune-tolerant
(predominantly Asian children and
young adults with normal ALT lev-
els and high viremia) and immune-
active chronic HBV (characterized by
abnormal ALT, active liver disease,
and high viremia). Patients who are
HBeAg-negative are characterized as
either inactive carrier (normal ALT
and low level viremia) or pre-core/
core promoter mutation (abnormal
ALT, intermediate viremia, and active
liver disease). HBeAg seroconversion
has been determined as a treatment
endpoint for immune-active HBeAg+
patients. In such patients with el-
evated ALT levels, the annual rate of
Lamivudine Adefovir
Entecavir Telbivudine
Tenofovir
Year of approval 1998 2002 2005 2006 2008
Potential adverse
effects
Negligible Nephrotoxicity at high
doses
Solid tumors in
animal models (?)
Negligible Nephrotoxicity in
animal models
Adverse effects in
licensing trials at 1
year
Similar to placebo Similar to placebo Similar to
lamivudine
Grade 3/4 CPK
7% at 1 year
12% at 2 years
Similar to adefovir
Post-marketing
adverse events
Rare myopathy,
neuropathy, pancreatitis
Minor nephrotoxicity risk
(in 3% to 8% at 5 years)
Negligible Myopathy Minor risk of
nephrotoxicity
Pregnancy category C** C** C** B* B*
Detection in human
breast milk
Yes Unknown Unknown
(in rats)
Yes Yes
Drug resistance ~20%, year 1 70%, year 5 None, year 1
29%, year 5
~1% up to year 5
~50%, after 5 years
in LAM-refractory
patients
~25% up to
year 2
None up to 5 years
*Category B: not a known teratogen or embryotoxic in animals but inadequate human studies
**Category C: embryotoxic or teratogenic in animals but inadequate human studies
Not preferred drug due to high rate of resistance.
Entecavir resistance reported within year 1 in patients with prior lamivudine resistance.
Sources: Lok, ASF and McMahon BJ. AASLD Practice Guideline Update, Chronic Hepatitis B: Update 2009.
UpToDate: Entecavir in the treatment of chronic hepatitis B virus infection. April 25 2014.
Table: Long-term Safety of Approved Oral Antiviral Agents for Chronic HBV
18
spontaneous clearance of HBeAg av-
erages between 8% and 12%.
12,13

However, the spontaneous clearance
is much lower in patients who are
immune tolerant. Older age, higher
ALT, and HBV genotype B (ver-
sus C) are linked to higher rates of
spontaneous clearance of HBeAg.
14

HBeAg seroconversion, whether
spontaneous or induced by immu-
nomodulatory or antiviral thera-
py, lowers the risk of progression
of liver disease while improving
survival.
15
The rate of loss of hepa-
titis B surface antigen in chronic
HBV is approximately 0.5% per
year; most will develop antibodies
to HBsAg.
13,16
HBeAg-positive chronic HBV
In patients with immune active
chronic HBV, the treatment endpoint
is HBeAg seroconversion. The treat-
ment duration with pegylated inter-
feron is nite while with oral agents
the treatment is of prolonged dura-
tion. In patients who are immune-
tolerant, treatment is generally not
recommended; however, cautious
monitoring of ALT levels and disease
activity is advised. If the patient is at
high risk of liver disease progression,
it is advisable to follow the treatment
algorithm for patients who are non-
cirrhotic immune-active.
HBeAg-negative chronic HBV
In patients who are HBeAg-
negative, the objective of treatment
is to suppress HBV DNA, improve
transaminase levels, and reduce in-
ammation. In these patients, a high
rate of relapse has been reported fol-
lowing cessation of therapy and thus
treatment is often indenite. Approx-
imately 5% of patients clear HBsAg
with prolonged therapy.
3

Treatment Duration
Recommendations
The optimal duration of therapy
for the oral antiviral agents has not
been clearly established. Most
patients receiving nucleoside or nu-
cleotide analog therapy will require
at least 4 to 5 years of treatment, and
select patients may require indenite
treatment. Patients in whom HBeAg
seroconversion has occurred and
serum HBV DNA has become unde-
tectable should be treated for at least
6 months after seroconversion has
been conrmed (by laboratory test-
ing at 2 time points at least 2 months
apart) to lower the risk of viral relapse.
Discontinuation of treatment carries
its own risks, as viral relapse may lead
to hepatitis ares and hepatic decom-
pensation. In patients who have main-
tained undetectable HBV DNA levels
but have not cleared HBeAg, treat-
ment continuation is recommended, as
HBeAg seroconversion may occur in
the future. Treatment may be stopped
in patients who have loss of HBsAg
(conrmed by laboratory testing at 2
time points at least 2 months apart),
though this is rare. Although uncom-
mon, sustained off-therapy virologic
and biochemical response in patients
who are HBeAg-negative (after a pro-
longed course of therapy) is a reason-
able endpoint, as this has been shown
to be associated with improved prog-
nosis.
17
However, patients who are
HBeAg-negative tend to relapse after
cessation of therapy and thus are likely
to require indenite therapy.
Cirrhosis
In patients with CHB, with both
compensated and decompensated cir-
rhosis, indenite antiviral treatment is
recommended in order to mitigate the
risk of HBV reactivation.
17
Treatment
discontinuation can be considered
if HBsAg seroconversion occurs. In
compensated cirrhosis, interferon may
be used with caution but nucleosides
or nucleotides are safer and due to the
need for long-term treatment, enteca-
vir or tenofovir is preferred of these
agents. Interferon is contraindicated in
patients with hepatic decompensation.
Summary
The rationale for treatment in pa-
tients with CHB is to lower the risk
of the long-term sequelae of chronic
HBV, such as cirrhosis and hepatocel-
lular carcinoma. While HBV treat-
ments have been shown to be safe and
effective in clinical trials that typically
last from 1 to 5 years, data describing
long-term safety of these oral antivi-
ral agents are limited and caregivers
should consider the risks and benets
of prolonged treatments when they are
administered for durations greater than
those of the clinical trials, which is of-
ten necessary in clinical practice.
References
atol. 2006;4(8):936-962.
2. Fontana RJ. Hepatology. 2009;49(5 Sup-
pl): S185-S195.
3. Hadziyannis SJ, et al. Gastroenterology.
2006;131(6):1743-1751.
4. Marcellin P, et al. Hepatology. 2008;
48(3):750-758.
5. Cassetti I, et al. HIV Clin Trials.
2007;8(3):164-172.
6. Pol S, et al. J Viral Hepat. 2012;19(6):377-
386.
7. Heathcote EJ, et al. Gastroenterology.
2011;140(1):132-143.
8. Lange CM, et al. Hepatology. 2009;
50(6):2001-2006.
9. Sherman M, et al. Gastroenterology.
2006;130(7):2039-2049.
10. Tenney DJ, et al. Antimicrob Agents Che-
mother. 2007;51(3):902-911.
11. Bosch FX, et al. Liver Dis. 2005;9(2):191-
211, v.
12. Hoofnagle JH, et al. Ann Intern Med.
1981;94(6):744-748.
13. McMahon BJ, et al. Ann Intern Med.
2001;135(9):759-768.
14. Lok AS, et al. Hepatology. 2004;39(3):857-
861.
15. Liaw YF, et al. N Engl J Med.
2004;351(15):1521-1531.
16. Liaw YF, et al. Hepatology. 1991;
13(4):627-631.
17. European Association For The Study Of
The Liver. J Hepatol. 2012;57(1):167-185.
opencme.org.
19
C
l
i
n
i
c
a
l

C
a
s
e
Determining If and When to Initiate
Treatment in the Immunotolerant Patient
Walid S. Ayoub, MD
C
linicians are commonly faced with the question of
whether to start treatment in a young patient with
normal alanine transaminase (ALT) and elevated hepa-
titis B virus (HBV) DNA. If treatment is initiated with
oral therapy, the duration of therapy can be lifelong.
There is a concern about committing young patients to
life-long therapy, especially when the majority of these
patients are of childbearing age.
Natural History of Hepatitis B Infection
The outcome of HBV infection is dependent on the time
of acquisition of the infection and the status of the immune
system. Age and immune competence at the time of in-
fection can inuence whether acute HBV will evolve into
CHB. While acute HBV infection is usually asymptomatic
and leads to higher rates of chronic infection in neonates
and young children, infection in adulthood is often symp-
tomatic and leads to clearance of the HBV surface antigen.
The natural course of CHB can be divided into 4 phas-
es:
1
the immune-tolerance phase, the immune-clearance
(HBeAg-positive CHB) phase, the inactive-carrier phase,
and the reactivation (HBeAg-negative CHB) phase.
1
How-
ever, not every patient will experience all of the 4 phases.
The immune-tolerance phase can last from 1 to 4 decades.
This phase is characterized by the presence of hepatitis B e-
antigen (HBeAg) and elevated HBV DNA levels 20,000
IU/mL in the setting of normal ALT. Histologically, the
inammation and brosis are usually absent or minimal
in this phase and the rate of HBeAg seroconversion is less
than 5% per year. Patients in the immune-tolerance phase
are considered highly contagious due to the presence of sig-
nicant HBV viremia. The immune-tolerance phase is fol-
lowed by the immune-clearance phase. The immune-clear-
ance phase describes a uctuation in the HBV DNA and
ALT levels. This phase is characterized by the presence of
various degrees of inammation and brosis. If the immune
response in this phase is successful in controlling the HBV,
loss of HBeAg and the development of hepatitis B-e anti-
body (HBeAb) follow. This usually signals the transition
to the next phase, the inactive-carrier phase. The inactive
phase is characterized by the absence of HBeAg, the pres-
ence of anti-HBe, low HBV DNA 2000 IU/mL, normal
ALT level, and no/minimal inammation on liver biopsy.
Reactivation phase describes a are of HBV characterized
by intermittent/persistent elevation of ALT and HBV DNA
levels along with inammation on liver biopsy.
Can Treatment Alter the Natural History of the
Immune-Tolerance Phase?
While treatment of CHB is usually indicated for patients
in the immune active and reactivation phases by the major
liver societies,
2-4
treatment in the immune-tolerance phase
is not indicated due to concern of long-term therapy, risk of
development of viral resistance, low yield of serological se-
roconversion, and lack of data supporting an impact on the
natural history of the disease.
2,5
For the last decade, there
have been many studies focusing on the relationship of the
viral replication as reected by the HBV viral load and its
relationship to the risk of developing cirrhosis, HCC, and
liver-related deaths.
6,7
Therefore, the notion of treating pa-
tients in the immune-tolerant phase is appealing since re-
ducing the HBV viral load has been linked to improved
outcomes in patients with CHB.
The REVEAL study is a population-based study of
3582 untreated Taiwanese patients with CHB who were
followed every 6 to 12 months for 11 years.
7
The study
demonstrated a direct relationship between the HBV DNA
levels 1 million copies/mL at enrollment and the risk of
developing cirrhosis (relative risk [RR] 9.8, 95% con-
dence interval [CI] 6.7-14.4; P0.01). Furthermore, higher
levels of HBV DNA levels were associated with increased
incidence of cirrhosis with cumulative incidence of cir-
rhosis of 4.5%, 5.9%, 9.8%, 23.5%, and 36.2% in patients
with serum HBV DNA 300 copies/mL, between 300 and
9.9 x 10
3
copies/mL, 1.0 to 9.9 x 104 copies/mL, and 1.0
to 9.9 x 10
5
copies/mL respectively. A similar relationship
was found between HBV DNA levels and risk of devel-
opment of HCC.
6,7
When looking in detail at the patients
characteristics of the REVEAL study, one nds that the
majority of the patients, with a median age of 45 years,
have HBeAg-negative CHB. Therefore, the data from the
REVEAL study does not truly apply to patients in the im-
mune-tolerance phase who are usually in their 20s and with
HBeAg-positive CHB.
Hui and colleagues
8
attempted to address the natural
history of patients in the immune-tolerance phase by fol-
lowing 48 untreated Chinese patients (median age 31
years) with elevated HBV DNA levels 107 copies/mL
20
C
l
i
n
i
c
a
l

C
a
s
e
and normal ALT (7 to 53 U/L for men and 7 to 31 U/L
for women). Patients were prospectively followed every 6
months for 5 years and had a liver biopsy at the entry into
the study and at 5 years. A large percentage of the patients,
85.4%, did not have any change in the brosis score and
there was no change in inammatory activity between the
initial biopsy and the biopsy at 5 years. Four patients with
stage 1 brosis had regression of brosis during the study
period. Additionally, all patients remained with signi-
cantly elevated HBV DNA levels through the observation
period. Therefore, this study suggested that patients in the
immune-tolerance phase are at a low risk for disease pro-
gression despite having elevated HBV DNA levels.
In a pilot study, DAntiga and colleagues
9
treated 23 chil-
dren (predominantly Asians) with a mean age of 10 years,
persistently normal ALT, and minimal or mild inammatory
histologic changes with lamivudine for 8 weeks followed
by a combination of lamivudine and interferon-alpha 2b for
44 weeks. As a result, 78% became HBV DNA negative at
the end of treatment, 22% developed hepatitis B antibodies
(anti-HBe), and 17% developed hepatitis B surface antigen
(HBsAg) seroconversion. None of the patients developed
tyrosine-methionine-aspartate-aspartate (YMDD) muta-
tion. The response rate persisted after a median follow-up of
40 months. Similar results were also found in a more recent
study
10
using the same treatment protocol where HBeAg se-
roconversion was noted in 10 to 28 children with HBsAg
loss and development of hepatitis B surface antibody (HB-
sAb) in 6 to 28 (21%) children 6 months after end of thera-
py. While such pilot studies suggest a potential benet from
treatment of patients in the immune-tolerance phase, larger
and longer studies are needed to conrm these observations.
The potential benet of sequential or combination
therapy of an immune modulator like interferon and an
oral agent stems from the effect of interferon on the im-
mune system. Therefore, the addition of interferon to
an oral agent, such as lamivudine, also leads to a lower
rate of development of YMDD mutation. Carey and col-
leagues
11
studied the T-cell function in the group studied
by DAntiga
9
and demonstrated that the HBV specic re-
sponse before therapy was weak. However, a change in the
immune system occurred at weeks 28 and 52 of therapy.
The HBV specic T-cell proliferation and the frequency
of CD8+ T cells producing interferon- increased signi-
cantly in responders than at baseline and in nonresponders.
In addition, there was a negative correlation between the
T-cell proliferation response and the HBV DNA viral load.
A multicenter study in 11 countries failed to support
routine treatment of patients in the immune-tolerant phase
with oral agents with either the use of a combination of
emtricitabine/tenofovir (FTC/TDF) or tenofovir. These
agents were given for 192 weeks in patients (89% Asians)
with normal ALT, elevated HBV DNA 1.7 x 10
7
IU/mL,
and mean age of 33 years.
12
More patients on FTC/TDF
(76%) achieved HBV DNA 69 IU/mL at week 92 than
patients in the TDF group (55%), but more patients in the
TDF group achieved HBeAg seroconversion (6%) com-
pared to none in the FTC/TDF group. None of the patients
had HBsAg loss during the study period or developed TDF
resistance. All of the patients had a rebound viremia within
4 weeks of the end of the therapy with one patient having
an ALT are.
Conclusion
There is no clear benet for treating patients in the im-
mune-tolerant phase based on the available data. Although
the risk of disease progression in the immune-tolerance
phase is believed to be low, the risk of HCC development is
relatively unknown and unpredictable. In addition, there is
no clear evidence that current available therapy will change
the natural course of the disease. The recommendations from
AASLD, EASL, and APASL remain standing. Although the
concern of the development of resistance to oral agents is
less with combination oral therapy, there is no proof that such
therapy is benecial in the management of the immune-tol-
erant patient. Perhaps a combination of an immune-modula-
tor agent, such as interferon, with an agent with a high barrier
to resistance, such as tenofovir, emtricitabine/tenofovir, or
entecavir, can be more benecial based on the data from the
pivotal trials of DAntiga
9
and Carey.
11
Only further studies
in this population will be able to answer which approach will
alter the natural history of HBV. Only further studies in this
population will be able to answer which approach will alter
the natural history of HBV.
References
1. Yapali S, et al. Clin Gastroenterol Hepatol. 2014;12(1):16-26.
2. Lok AS, et al. Hepatology. 2009;50(3):661-662.
3. European Association For The Study Of The Liver. J Hepatol.
2012;57(1):167-185.
4. Liaw Y-F, et al. Hepatology International. 2012;6(3):531-561.
5. Jonas MM, et al. Hepatology. 2010;52(6):2192-2205.
6. Chen CJ, et al. JAMA. 2006;295(1):65-73.
7. Iloeje UH, et al. Gastroenterology. 2006;130(3):678-86.
8. Hui CK, et al. Hepatology. 2007;46(2):395-401.
9. D'Antiga L, et al. J Pediatr. 2006;148(2):228-233.
10. Poddar U, et al. J Viral Hepat. 2013;20(5):311-316.
11. Carey I, et al. J Virol. 2011;85(5):2416-2428.
12. Chan HL, et al. Gastroenterology. 2014;146(5):1240-1248.
Full references are available at www.healio.com/gastroenterology/educa-
tion-lab and www.opencme.org.
21
1. Current treatment guidelines recommend initiating
HBV antiviral therapy in all the following patients with
CHB, except:
A. HBeAg-positive with elevated circulating viral DNA level
B. HBeAg-negative with elevated circulating viral DNA level
C. HBeAg-negative without signicant histologic disease
D. Decompensated cirrhosis and detectable HBV DNA level
2. What percentage of people infected with HBV in the U.S. are
unaware of their infection status?
A. 30%
B. 50%
C. 70%
D. 85%
3. In a patient on HBV antiviral therapy, a functional cure is
considered:
A. HBV surface antigen loss with biochemical response and
undetectable HBV viral DNA
B. Normalization of serum ALT levels
C. Undetectable HBV DNA levels
D. Development of anti-HBe in HBV e-antigen positive patients
4. The antiviral used for CHB associated with the highest rate of
resistance is:
A. Adefovir
B. Entecavir
C. Lamivudine
D. Tenofovir
5. The best strategy to improve adherence to CHB antiviral
therapy is:
A. Asking patients about medication adherence every
12 months
B. Spending 3 minutes or more with patients discussing
medication compliance during the ofce visit
C. Providing pamphlets written only in English
D. Having patients self-report adherence
6. The risk of emergence of drug-resistant mutants in the HBV
DNA polymerase/reverse transcriptase increase with:
A. Duration of therapy
B. Low baseline serum HBV DNA level
C. Incomplete viral suppression during the rst 3 months
D. Prior interferon treatment
7. A patient with CHB presents to your ofce for management.
They are HBV e-antigen positive with HBV DNA levels of
25,000 IU/mL and ALT 91 IU/L. Which of the following
therapies is the best option for rst-line for CHB therapy in
this patient?
A. Lamivudine
B. Tenofovir
C. Adefovir
D. Telbivudine
8. The immune-tolerance phase of CHB is characterized by the:
A. Absence of hepatitis B e-antigen, the presence of hepatitis
B-e antibody, low HBV DNA 2000 IU/mL and normal
ALT level
B. Presence of hepatitis B e-antigen, elevated HBV DNA
levels 20,000 IU/mL in the setting of normal ALT levels
C. Presence of hepatitis B e-antigen, low HBV DNA 2000
IU/mL and normal ALT level
D. Only the absence of hepatitis B e-antigen
9. To lower the risk of viral relapse, patients with HBV
e-antigen seroconversion and undetectable serum HBV
DNA levels should be treated for at least:
A. 1 month after seroconversion
B. 3 months after seroconversion
C. 6 months after seroconversion
D. 12 months after seroconversion
10. The antiretroviral nucleoside/nucleotide analogs utilized to
treat CHB have the following safety warning:
A. Mitochondrial toxicity
B. Hypophosphatemia
C. Osteomalacia
D. Hyperglycemia
22 Volume 1 Number 1 August 2014 | CRITICAL ISSUES IN HBV
CME Posttest
CME Instructions
1. Review the activity learning objectives stated on page 2.
2. Read the articles, including the tables and illustrative materials.
3. Proceed to the CME Registration Form. Type or print your name,
address, and date of birth in the spaces provided.
4. Answer each test question by circling the letter corresponding
to the correct answer or by entering it in the space provided on the
Registration Form. Be sure to retain a copy of your answers for
your records.
5. Complete the evaluation portion of the CME Registration Form.
CME Registration Forms will be returned to you if the evaluation
is not completed.
6. CME Registration Forms will not be accepted after the expiration date.
Return the CME Registration Form before the test expires to:
Vindico Medical Education
PO Box 36
Thorofare, NJ 08086-0036
Or Fax to: 856-384-6680
7. The CME test and downloadable educational tools will also be available
online (within 1 month of mailing date) at:
www.Healio.com/Gastroenterology/Education-Lab and
www.opencme.org
22
POSTTEST
VOLUME 1 NUMBER 1
11. Planned Changes to Practice - Please respond to the statements below using the
following scale: Y=Yes N=No 2=I Already Do This in My Practice 1=N/A
I plan to make the following changes to my practice.
I will discuss new treatment options with newly diagnosed
HBV patients. Y N 2 1
I will develop individualized treatment strategies based on current
best evidence for initiation of HBV treatment. Y N 2 1
I will implement appropriate tests to characterize HBV infection and
treatment response. Y N 2 1
I will evaluate underlying causes of HBV treatment failure. Y N 2 1
Other (Please provide below.)_______________________________________________
_____________________________________________________________________
12. Barriers to Practice - These are the barriers I face in my current practice setting
that may impact patient outcomes: (Select all that apply)
Lack of evidence-based guidelines
Changing standards of care and evidence-based guidelines
Lack of time to spend with my patients
Organizational/institutional limitations
Cost of therapies and reimbursement issues
Patient adherence/compliance issues
Treatment-related adverse events
Contraindications to therapies
Resistance to therapy
Difculty in keeping up with evolving evidence to make treatment decisions
Coordination of care with other care providers
Other (Please provide below.)___________________________________________
_____________________________________________________________________
13. How condent are you in selecting the appropriate treatment for patients with
chronic HBV infection?
Extremely Condent
Very Condent
Somewhat Condent
Not at All Condent
14. Approximately how many patients do you see per month with chronic HBV?
Less than 10 10 to 30 31 to 50 More than 50 N/A
15. Please indicate your degree. (Please select one only.)
MD/DO PhD Other____________________
NP PA
RN/BSN/MSN RPh/PharmD
16. Please indicate your specialty (Please select one only.)
Gastroenterology Hospital Medicine Infectious Disease
Hepatology Family/General Practice Other____________________
Internal Medicine Pharmacy
17. How many years have you been in practice?
0-5 years 6-15 years 16-25 years 26-30 years 31+ years
18. Would you recommend this activity to your peers? Yes No
CME ACTIVITY REQUEST
Yes, I would like the opportunity to earn CME credits through activities sponsored by
Vindico Medical Education.
*Required Field
1 2 3 4 5 6 7 8 9 10
Questions about CME? Call us at 856-994-9400 ext. 504, Fax 856-384-6680
OFFICE USE ONLY
Enduring material: Other
August 2014 J64A
*Time spent on this activity: Hours
Minutes
(reading articles and completing the learning assessment and evaluation)

This information MUST be completed in order for the quiz to be scored.
THE MONOGRAPH AND TEST EXPIRE AUGUST 1, 2015
PRINT OR TYPE
Last Name First Name Degree
Mailing Address
City State Zip Code
Date of Birth (used for tracking credits ONLY)
Phone Number FAX Number E-mail
EVALUATION (must be completed for your CME Quiz to be scored)
Your evaluation of this activity is extremely important as it allows for us to plan for future
educational programs. Please take a moment to answer the following questions.
1. Overall the activity supported achievement of the identied learning objectives. Yes No
2. This activity better prepared me to care for my patients. Yes No
3. The content covered was useful and relevant to my practice. Yes No
4. The activity was presented objectively and was free of commercial bias.* Yes No
5. Future activities concerning this subject matter are necessary. Yes No
6. The activity addressed and provided strategies for overcoming barriers
to optimal patient care. Yes No
7. The activity reinforced my current practice patterns. Yes No
*If you indicated that the activity was not free of commercial bias, please provide
additional comments here:
________________________________________________________________________
________________________________________________________________________
8. What educational topics would be of value to you, for future CME activities?
Please be specic.
________________________________________________________________________
________________________________________________________________________
9. Approximately what percentage of the activitys content was NEW to you?
0% 25% 50% 75% 100%
10. Do you believe this program: Y=Yes N=No 1=N/A
Increased your knowledge about the subject matter? Y N 1
Will improve patient outcomes in your practice? Y N 1
Helped you to have a better understanding of the topics? Y N 1
Gave you a new perspective on the information which may help to
improve your practice? Y N 1
Provided you with resources to use in your practice and/or with
your patients? Y N 1
23
CME Registration Form
VINDICO
medical education
VINDICO
medical education
VINDICO
medical education
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Thorofare, NJ 08086-9447

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Volume 1 Number 1 AUGUST 2014

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