VOLUME 3, ISSUE 5
CURE OF HEPATITIS B: IS IT ACHIEVABLE?
In this Issue...
Chronic hepatitis B (CHB) is a major public health problem, affecting more than 400 million
people worldwide and greatly increasing their risk of developing liver disease, particularly
cirrhosis and hepatocellular carcinoma (HCC). Over the past 15 years, major progress has
been made in antiviral therapy of CHB, to the point where it can now be legitimately asked:
"Can this disease be cured?"
In this issue, we review recent studies providing evidence that begins to answer that
question.
LEARNING OBJECTIVES
After participating in this activity, the participant will demonstrate the ability to:
Describe current evidence showing that achieving viral suppression can significantly
improve fibrosis and decrease the incidence of hepatocellular carcinoma
Explain how HBsAg loss can be considered a serologic/virologic cure that allows
treatment cessation
Describe how, despite HBsAg clearance, reactivation of HBV and/or development of
hepatocellular carcinoma may occur
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IN THIS ISSUE
COMMENTARY from our Guest Authors
REGRESSION OF CIRRHOSIS WITH
ANTIVIRAL TREATMENT
REDUCING THE INCIDENCE OF
HEPATOCELLULAR CARCINOMA WITH
ANTIVIRAL TREATMENT
HBV SURFACE ANTIGEN CLEARANCE BY
INTERFERON TREATMENT: ROLE OF
IL28B POLYMORPHISMS
PREDICTION OF HBSAG CLEARANCE
DURING NUCLEOS(T)IDE ANALOGUE
(NA) THERAPY
HBSAG LEVELS—A SURROGATE
MARKER OF cccDNA LOSS DURING NA
THERAPY?
KINETICS OF cccDNA AND HBSAG
DECLINE DURING COMBINATION
THERAPY FOR CHB
Program Directors
Mark S. Sulkowski, MD
Professor of Medicine
Medical Director, Viral Hepatitis Center
Divisions of Infectious Diseases and
Gastroenterology/Hepatology
The Johns Hopkins University School of
Medicine
Baltimore, Maryland
Raymond T. Chung, MD
Associate Professor of Medicine
Harvard Medical School
Director of Hepatology
Vice Chief of Gastroenterology
Massachusetts General Hospital
Boston, Massachusetts
Julie McArthur, MS, CRNP
Adult Nurse Practitioner
Division of Infectious Disease
The Johns Hopkins University
School of Medicine
Baltimore, Maryland
GUEST AUTHORS OF THE MONTH
Commentary:
Fabien Zoulim, MD, PhD
Professor, Head of INSERM
Viral Hepatitis Laboratory
Medical School of Lyon,
Lyon 1 University
Hepatology Department,
Hospices Civils de Lyon
Lyon, France
Guest Faculty Disclosures
Fabien Zoulim, MD, PhD has
disclosed that he has received
grants/research support from Gilead
Sciences, Novira, Roche, and
Scynexis. He has served as a
consultant for Gilead Sciences and
Roche, and has been a speaker for
Bristol Myers-Squibb, Gilead and
Roche.
Unlabeled/Unapproved Uses
The authors have indicated that there
will be no references to
Kerstin Hartig-Lavie, MD
Hepatology Department
Hospices Civils de Lyon
Lyon, France
unlabeled/unapproved uses of drugs
or products.
Program Directors' Disclosures
COMMENTARY
Over the past 15 years, the growing efficacy of antiviral strategies to treat chronic hepatitis
B (CHB) infection has been remarkable. The use of pegylated interferon alpha has allowed
patients to obtain off-treatment responses related to immune control of the infection,
primarily in a selected population of patients having favorable predictive factors such as
high ALT levels and low HBV DNA levels.1 Several nucleoside analogues (NA) have been
approved over the years. The first generation of NA agents (lamivudine, adefovir dipivoxil,
and telbivudine) was associated with a high rate of antiviral drug resistance, which blunted
the initial virologic and clinical benefit of therapy. The availability of the second-generation
NAs (tenofovir disoproxil fumarate TFV and entecavir) provided both a potent antiviral
effect and a high barrier to resistance, which has enabled viral suppression in the majority
of patients.2 This is even true in patients who failed a previous line of antiviral therapy with
a low barrier to resistance NA, provided that treatment adaptation is based on the crossresistance
profile of the resistant strain. However, in patients who receive NA-based
therapy either de novo or after failure of interferon based therapy, long-term administration
of antiviral drug is necessary to avoid viral relapse because of the persistence of HBV
cccDNA, ie the viral minichromosome, in the liver of patients infected with HBV.2
In contrast to chronic HCV infection, which is a curable infection with a "short" duration of
antiviral treatment, the treatment of CHB remains clinically challenging. However, there are
several ways to envision how an HBV cure can be achievable.
The first aspect, as shown in some of the investigations reviewed herein, is the evidence
that the liver damage associated with CHB can be significantly improved and could be
seen as a true endpoint. Indeed, it was shown that with prolonged NA therapy with
entecavir or tenofovir, both the necroinflammatory activity and liver fibrosis scores can be
improved significantly after several years of therapy. More important, in the study by
Heathcote et al,3 regression of liver cirrhosis was also observed in patients with
compensated cirrhosis who received tenofovir (TDF). Clinically, this could be seen as a
"cure" of the liver disease, although it remains to be confirmed by extended observations
to see if this translates into a reduced incidence of HCC, as suggested by a very recent
study presented at the European Association for the Study of the Liver (EASL) conference
in Amsterdam.4
Another important aspect is that recently published cohort studies suggest that long-term
antiviral therapy, when associated with virologic response, is associated with a reduced
incidence of HCC. This was well demonstrated in the study by Hosaka et al discussed in
this newsletter.
There is now a body of evidence that antiviral therapy, especially when initiated not too
late in the natural history of the disease, has a significant impact on HCC development,
which can be seen as a big success of these treatments.
However, although these treatments can decrease the incidence of HCC, some cases of
HCC still develop during antiviral therapy. These incident cases are usually seen during
the first months of therapy and may reflect small HCC undetectable by clinically available
imaging techniques present at the beginning of therapy. Furthermore, viral genome
integration occurs early during the natural history of infection and may lead to chronic
necroinflammatory activity and clonal expansion of hepatocytes that may represent the
first step of HCC development. These observations may be an argument for proposing
antiviral therapy at earlier stages of the infection to control viral replication and prevent
viral genome integration events and liver damage to occur;5 this type of strategy would
obviously have to be validated with the aim to reduce even further the rate of occurrence
of HCC.
The second aspect is related to the virologic cure of HBV infection. The current treatment
endpoints of antiviral therapy with interferon or NA are to achieve HBe seroconversion in
patients who are HBeAg positive and to achieve viral suppression (undetectable HBV DNA
in patients' serum) in all patients. HBsAg loss associated with HBs seroconversion is the
next most desirable endpoint. The papers by Lampertico et al and Seto et al discussed in
this newsletter provide real-life data on treatment-induced HBsAg loss, which is achieved
in only approximately 10% of patients who received a one-year course of interferon when
followed for five years after treatment cessation and can be higher in patients with
favorable IL28B gene polymorphism. With long-term administration of NA, when
associated with virologic response, also approximately 10% of patients lose HBsAg after 5
to 10 years of therapy. HBsAg loss can be seen as a serologic cure of the infection, as it
may allow stoppage of treatment and is associated with a decreased incidence of HCC, at
least in patients who spontaneously lost HBsAg.
However, this serologic cure does not equate to full eradication of the viral genome. In our
experience, as well as in reports from other centers, HBV reactivation may occur despite
HBsAg loss. This happens in cases of severe immune depression as seen in patients with
AIDS, immune suppressant therapy for organ transplantation, or heavy chemotherapy.
This is because viral cccDNA persists in the infected liver, which is responsible for
reinitiating active replication when immune control of infection is lost. In these situations,
our experience is to recommend antiviral prophylaxis. The other complication that can be
seen even in patients with HBsAg loss is the occurrence of HCC as a consequence of
long-term infection with viral genome integration and accumulation of liver damage. For
this reason, in our institution, we recommend continued ultrasound monitoring of HCC in
patients with CHB after HBsAg clearance.
What are the new perspectives about antiviral therapy of CHB? Because of improved
clinical endpoints and the possibility to envision finite duration of treatment, HBsAg loss
has become the major goal of new antiviral strategies. The aim of future treatments will be
to increase the rate of HBsAg clearance. This will require the use of true combination
therapy and the identification of new treatment targets. Several lines of research are being
explored, with strategies aimed at decreasing the pool of viral cccDNA or silencing its
activity, and/or strategies aimed at restoring innate and adaptive immune responses
against HBV to clear or cure the remaining infected hepatocytes.6 Time will be needed to
validate these strategies in clinical trials. Meanwhile, there are new trials evaluating the
combination of pegylated interferon with NA based on different schedules of
administration, which may be the first step for a long-awaited improved (HBsAg loss)
success rate of therapy.
Reference
1. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, et al.
Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic
hepatitis B . N Engl J Med. 2005;352(26):2682-95.
2. Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues.
Gastroenterology. 2009;137(5):1593-608.
3. Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir
disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140(1):132-
43.
4. Chan HL, Chan CK, Chan AJ, et al. Tenofovir DF (TDF) compared to emtricitabine
(FTC)/TDF in HBeAg-positive, chronic hepatitis B (CNB) virus-infected patients in the
immune tolerant (IT) phase. Abstract 101. The International Liver Conference, EASL,
Amsterdam, April, 2013.
5. Zoulim F, Mason WS. Reasons to consider earlier treatment of chronic HBV infections.
Gut. 2012;61(3):333-6..
6. Zoulim F. Are novel combination therapies needed for chronic hepatitis B?Antiviral
research. 2012;96(2):256-9.
back to top
REGRESSION OF CIRRHOSIS WITH ANTIVIRAL
TREATMENT
Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir
disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet.
2013 Feb 9;381(9865):468-475. doi: 10.1016/S0140-6736(12)61425-1.
(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
View journal abstract View full article
Four hundred million people worldwide are infected with hepatitis B virus, and
epidemiologic studies estimate that up to 25% of these die of liver cirrhosis or
hepatocellular carcinoma (HCC). None of the currently available treatments can eliminate
with certitude the hepatitis B virus. In our clinical practice, therefore, it is important to focus
not only on the virus but also on the liver disease itself. This study investigated whether
HBV-induced liver disease can be cured or at least significantly improved.
This open label study examined the impact of tenofovir disoproxil fumarate (TDF) on
histological liver changes after 240 weeks of treatment. Patients were recruited in 2005-
2006 from different hepatology centers worldwide. The study contained a 48 week,
randomized, double blind comparison of TDF and adefovir dipivoxil, after which patients
were switched to open label TDF treatment. The study enrolled patients who had HBeAgnegative
or HBeAg-positive chronic hepatitis B with compensated liver disease and
pretreatment liver biopsy specimens that showed a Knodell necroinflammatory score of 3
or more (on a scale of 0 to 18). All patients had been HBsAg-positive for at least 6 months
before screening. Patients were HBV mono-infected and had received less than 12 weeks
of treatment with any nucleoside or nucleotide for HBeAg-positive patients, but could be
pretreated with lamivudine for more than 12 weeks for the HBeAg-negative group. Patients
with hepatocellular carcinoma or liver failure were excluded. The liver biopsies were
analyzed by an independent pathologist unaware of the treatment outcome.
Three hundred forty-eight patients had biopsy at baseline and again at week 240. The
results show that 304 patients (87%) had histological improvement of necroinflammatory
lesions as defined by a >= 2 point reduction in Knodell necroinflammatory score. In fact,
the proportion of patients with mild or no necroinflammation (Knodell 0-3) increased from
8% at baseline to 49% at year 1 (P < 0.001) and to 80% at year 5 (P < 0.001). One
hundred seventy-six patients (51%) had regression of fibrosis, defined by a >= 1 unit
regression of Ishak fibrosis score (P < 0.0001). At baseline 96 patients had cirrhosis; 71
(74%) of the patients with initial cirrhosis no longer had cirrhosis at week 240 (regression
of Ishak score of at least one unit). Only three patients without cirrhosis at baseline
progressed to cirrhosis at week 240. The difference between the proportion of patients
with cirrhosis regression and those with cirrhosis progression was significant (P < 0.0001).
Of the 96 patients with cirrhosis at baseline, all but one regressed more than 2 units of
Ishak score, and more than half had a decrease of 3 units in Ishak fibrosis score. Patients
with the highest liver injury score showed the greatest degree of improvement (P <
0.0001).
When comparing the patients who did not show fibrosis regression with those that did in
terms of demographic characteristics, the factors differing significantly between the two
groups were BMI < 25kg/m2 (P < 0.01), history of diabetes mellitus (P = 0.001), normal
ALT levels under treatment (P = 0.07), and Knodell score category 0-3 on biopsy at year 5
(P = 0.007).
This is the first large scale study demonstrating the histological benefit of antiviral
treatment with the new generation of nucleos(t)ide analogues. While two other studies
demonstrated the benefit of long-term entecavir treatment on liver histology,1,2 they
enrolled a smaller number of patients, and neither included equivalent numbers of patients
with cirrhosis. Here the regression of fibrosis was considerable, with decrease in Ishak
score of three units for more than half of the patients with cirrhosis. Improvement of liver
histology was higher when the initial liver injury was greater. Nonregression was shown to
be associated with overweight, presence of diabetes mellitus, and continuing liver
inflammation (high ALT and elevated Knodell score after five years of treatment). These
factors might be linked and should encourage us to check our patients for metabolic
syndrome, because nonalcoholic steatohepatitis is a liver-damaging factor.
This study demonstrates explicitly that effective antiviral treatment can prevent liver
fibrosis progression and even revert cirrhotic lesions to noncirrhotic liver. These findings
may pave the way toward a cure of HBV-induced liver damage. Further complications,
including hepatic decompensation and the development of hepatocellular carcinoma, can
therefore be significantly reduced — was previously demonstrated by Liaw et al3 with
lamivudine treatment of patients with advanced fibrosis. In the era of powerful
nucleos(t)ide analogues, the improvement of the liver damage is one of the main treatment
objectives and should be achievable in all patients with CHB.
References
1. Schiff ER, Lee SS, Chao YC, et al. Long-term treatment with entecavir induces reversal
of advanced fibrosis or cirrhosis in patients with chronic hepatitis B. Clin Gastroenterol
Hepatol. 2011 Mar;9(3):274-276. doi: 10.1016/j.cgh.2010.11.040. Epub 2010 Dec 8.
2. Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of
fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis
B. Hepatology. 2010 Sep;52(3):886-893. doi: 10.1002/hep.23785.
3. Liaw YF, Sung JJ, Chow WC, et al; Cirrhosis Asian Lamivudine Multicentre Study
Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl
J Med. 2004 Oct 7;351(15):1521-1531.
back to top
REDUCING THE INCIDENCE OF HEPATOCELLULAR
CARCINOMA WITH ANTIVIRAL TREATMENT
Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces
hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology.
2013 Jul;58(1):98-107.
(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
View journal abstract View full article
The previous article described improvement of liver fibrosis during long-term antiviral
treatment with TDF. A previous study by Liaw et al1 suggested a decrease of
hepatocellular carcinoma (HCC) incidence in patients treated with lamivudine (LAM);
however the long-term benefit was blunted by the emergence of antiviral drug resistance.
Potent nucleos(t)ide analogues (NA) with a high barrier to resistance, such as entecavir
(ETV) and tenofovir disoproxil fumarate (TDF), have been used more recently, but their
benefit for the development of HCC has not been demonstrated. Whether these more
potent antiviral treatments can reduce HCC incidence in the long-term is the important
clinical issue addressed by these investigators. Four hundred seventy-two patients monoinfected
with HBV and treated with ETV were recruited from 2004 to 2010 in Toranomon
Hospital in Japan and compared to 1143 patients with HBV mono-infection without
treatment. The patients treated with ETV had never been treated by NA before. Patients in
the control group were recruited retrospectively between 1973 and 1999 and had not
received any antiviral treatment during the observation period. Propensity score matching
eliminated the baseline differences, and finally 316 patients per cohort were compared.
Three HCC risk scales and risk scores based on recent publications 2-4 were applied to
both cohorts and included age, gender, cirrhosis status, levels of alanine
aminotransferase, HBeAg, baseline HBV DNA, albumin, and bilirubin.
A subanalysis of this study compared the incidence of HCC in patients treated with ETV to
patients treated with LAM. A cohort of 492 LAM-treated patients were retrospectively
recruited from 1995 to 2007. None of these patients had rescue therapy in case of viral
resistance. Propensity score matching in these two groups resulted in a matched cohort of
182 patients.
HCC diagnosis was made predominantly by imaging but confirmed by fine-needle
aspiration biopsy if imaging was not typical. The cumulative HCC incidence rates at five
years were significantly lower in the ETV group (3.7 %) compared to the control group
(13.7%; P < 0.001). When adjusting the patients for a number of known HCC risk factors
by Cox proportional hazard regression analysis, it turned out that patients in the ETV
group were less likely to develop HCC than those in the control group (hazard ratio: 0.37;
95% confidence interval: 0.15-0.91; P = 0.030). The greatest HCC risk reduction occurred
in patients scoring higher on the risk scales.
Comparisons of HCC incidence in the ETV-treated group, nonrescued LAM-treated group,
and control group showed a significant difference in cirrhotic patients. The HCC incidence
reduction effect was the highest in the ETV-treated group compared to the control group
(P < 0.001), also present in the LAM-treated group compared to the control group (p =
0.019), and significantly higher in patients treated with ETV compared to patients treated
with LAM (P = 0.043).
This study confirms that HCC incidence can be reduced by long-term effective antiviral
treatment. It clearly demonstrates that more powerful antiviral treatment with entecavir has
a greater impact on HCC incidence than treatment with lamivudine. The beneficial effect of
lamivudine is usually blunted by the high incidence of antiviral drug resistance. For
instance, Zhang et al5 reported recently on a meta-analysis of 3644 patients which
showed that patients who developed antiviral drug resistance had a 2.6 times higher risk of
developing long-term complications.
The results of these studies emphasize that, in the future, a major public health challenge
will be to expand access to these effective antiviral treatments in high endemic areas
where patients are infected at younger age and are thus exposed to a high risk of HCC
development.
Reference
1. Liaw YF, Sung JJ, Chow WC, et al; Cirrhosis Asian Lamivudine Multicentre Study
Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl
J Med. 2004 Oct 7;351)15):152-31.
2. Yang HI, Yuen MF, Chan HL, et al; REACH-B Working Group. Risk estimation for
hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of
a predictive score. Lancet Oncol. 2011 Jun;12(6):568-74.
3. Yuen MF, Tanaka Y, Fong DY, et al. Independent risk factors and predictive score for
the development of hepatocellular carcinoma in chronic hepatitis B. J Hepatol. 2009 Jan;
50(1):80-88. doi: 0.1016/j.jhep.2008.07.023. Epub 2008 Sep 21.
4. Wong VWS, Chan SL, Mo F, et alk. Clinical scoring system to predict hepatocellular
carcinoma in chronic hepatitis B carriers . J Clin Oncol. 2010 Apr 1;28(10):1660-5.
5. Zhang QQ, An X, Liu YH, et al. Long-term nucleos(t)ide analogues therapy for adults
with chronic hepatitis B reduces the risk of long-term complications: a meta-analysis. Virol
J. 2011 Feb 15;8:72.
back to top
HBV SURFACE ANTIGEN CLEARANCE BY
INTERFERON TREATMENT: ROLE OF IL28B
POLYMORPHISMS
Lampertico P, Viganò M, Cheroni C, et al. IL28B polymorphisms predict interferon-related
hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative
patients with chronic hepatitis B. Hepatology. 2013 Mar;57(3):890-896.
View journal abstract
Achieving HBV surface antigen clearance is the most desirable treatment endpoint leading
to a cure of HBV infection. While this goal can sometimes be achieved with interferon
treatment, success rates are low and the poor tolerability of interferon still limits its use.
The known predictive factors of good response to interferon are often underrepresented in
a particular geographical area (young age, elevated baseline transaminases, low baseline
viremia) or vary over time, and are thus difficult to apply. Il28B polymorphism has proved
to predict viral clearance during antiviral therapy for chronic hepatitis C. Whether IL28B
genotyping is useful in interferon treatment of patients infected with HBV is unknown. This
is particularly true in patients who are negative for HBeAg, who are rarely treated with
interferon and for whom robust predictive factors of response are lacking. The authors
tried to answer to this question in this study.
This study retrospectively analyzed 110 patients with HBV monoinfection and were
negative for HBeAg, most of them infected with genotype D (92%). All patients in this
cohort had been treated with standard Interferon or pegylated interferon α2a for 10-48
months (median 23 months), with a follow-up of 1-17 years (median 11 years). The IL28B
polymorphism was analyzed for all patients: 48 patients were found to be CC, 42 patients
CT, and 11 patients TT. The 3 IL28B groups were comparable in age, gender, serum ALT
levels, HBV DNA levels, cirrhosis, type of IFN administered, duration of treatment, and
follow-up.
End of treatment response (defined by undetectable HBV DNA or < 2000 IU/ml at end of
treatment) and sustained virological response (defined by undetectable HBV DNA or <
2000 IU/ml at six months post-treatment) were significantly higher in patients with CC than
those without (end of treatment response was 69% in CC vs 44% in non-CC, P = 0.014
and sustained virological response was 31% in CC vs 13% in non-CC, P = 0.025). During
a median follow-up of 11 years post-treatment, 21 patients (21%) cleared HBsAg and 15
developed anti-HBs titers > 10 IU/mL. HBsAg clearance rates were 29% (14 patients) in
CC, 7% (3 patients) in CT, and 36% (4 patients) in TT. By univariate analysis, baseline
HBV DNA, ALT, duration of treatment, post-treatment follow-up, and IL28B polymorphisms
— but not age, gender, cirrhosis, HBV genotype, and type of IFN — were significantly
associated with HBsAg clearance. At multivariate analysis, baseline HBV DNA levels (OR,
0.31; 95% CI: 0.15-0.62; P = 0.001), ALT levels (OR, 1.0; 95% CI: 1.0-1.0; P = 0.03),
duration of IFN therapy (OR, 1.20; 95% CI: 1.04-1.39; P = 0.012), and genotype CC (OR,
3.6; 95% CI: 1.05-12.5; P = 0.04) predicted HBsAg seroclearance. By combining HBV
DNA, ALT, and IL28B genotype, patients were classified into four different groups
characterized by increasing rates of HBsAg loss. In the group with low viral DNA (< 6 log
cp/mL) and high ALT levels (>136 U/l) and IL 28 B polymorphism CC, the HBsAg
clearance rate was as high as 60%.
This study is another step toward HBV treatment optimization and individualization. As the
tolerability of interferon is poor, finite duration of treatment and better criteria to accurately
identify possibly responders to interferon are needed. In patients positive for HBeAg, the
IL28B polymorphism has been described to predict response to pegylated interferon
treatment for HBeAg clearance but not HBsAg clearance.1 To date there have been no
data concerning patients who are negative for HBeAg.
The results of this study show that HBsAg clearance in the subgroup of patients with IL28B
CC, low HBV DNA levels, and high ALT levels was as high as 60%, indicating that IL28B
might therefore be a strong predictor for HBsAg clearance. This predictor is independent of
the phase of HBV infection. This study also confirmed the previously known predictive
factors of favorable response, ie ALT level and viral load, as demonstrated in other studies
2. Previous studies attempted to define stopping rules (lack of HBsAg and HBV DNA
decline at week 12 compared to baseline) to avoid unnecessarily prolonged interferon
treatment in patients who were negative for HBeAg.3 Gradually, more data are becoming
available to optimize our treatment strategies by identifying patients who are negative for
HBeAg, offering a better chance of response to interferon therapy and avoiding useless
extension of treatment duration.
One can argue that the study was performed on a small number of patients and the results
must be confirmed by larger prospective studies. Furthermore, the restriction of the study
population to viral genotype D infection limits its use in clinical practice. Since viral
genotype influences the response to interferon treatment, more data are needed to confirm
the predictive value of IL28B polymorphism in patients infected with other genotypes.4
Reference
1. Sonneveld MJ, Wong VW, Woltman AM, et al. Polymorphisms Near IL28B and
Serologic Response to Peginterferon in HBeAg-Positive Patients With Chronic Hepatitis B.
Gastroenterology. 2012 Mar;142(3):513-520.e1. doi: 10.1053/j.gastro.2011.11.025. Epub
2011 Nov 19.
2. Bonino F, Marcellin P, Lau GK, et al. Predicting response to peginterferon alpha-2a,
lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut. 2007
May;56(5):699-705. Epub 2006 Nov 24.
3. Rijckborst V, Hansen BE, Cakaloglu Y, et al. Early on-treatment prediction of response
to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV
DNA levels. Hepatology. 2010 Aug;52(2):454-461. doi: 10.1002/hep.23722.
4. Moucari R, Martinot-Peignoux M, Mackiewicz V, et al. Influence of genotype on hepatitis
B surface antigen kinetics in hepatitis B e antigen-negative patients treated with pegylated
interferon-alpha2a. Antivir Ther. 2009 14(8):1183-1188. doi: 10.3851/IMP1458.
back to top
PREDICTION OF HBSAG CLEARANCE DURING
NUCLEOS(T)IDE ANALOGUE (NA) THERAPY
Seto WK, Wong DK, Fung J, et al. Reduction of hepatitis B surface antigen levels and
HBsAg seroclearance in chronic hepatitis B patients receiving 10 years of nucleoside
analogue therapy. Hepatology. 2013 Mar 6. [Epub ahead of print]
View journal abstract View full article
The Holy Grail of antiviral therapy of chronic hepatitis B (CHB) is to achieve HBsAg loss
and seroconversion. In that respect, the quantification of serum HBsAg levels may
represent a clinically relevant tool to monitor the effect of antiviral treatment.
Although serum HBsAg levels have been demonstrated to predict sustained viral
suppression after pegylated interferon therapy in CHB, the role of serum HBsAg
measurement during NA therapy has not been well-defined. Most recent studies have
been based on relatively small number of patients and short-term duration of NA
administration.
In this study, the authors have investigated the kinetics of HBsAg clearance in patients
who received long-term lamivudine therapy with a maintained virologic response (HBV
DNA below 2,000 IU/mL). From 1994 to 2002, 322 Chinese patients with CHB were
started on lamivudine in their center. Patients were recruited if they had been continuously
treated with lamivudine for at least 10 years and maintained favorable virologic responses
throughout therapy (HBV DNA < 2,000 IU/mL). HBsAg and HBV DNA levels were
measured serially, and the predictability of HBsAg kinetics in determining NA-related
HBsAg seroclearance was determined. Seventy patients were recruited for this study, of
whom 43 (61.4%) were positive for HBeAg. Fifty-two (74.3%) had undetectable viremia
(HBV DNA < 20 IU/mL) during therapy. Fifteen patients (21.4%) were followed up for 15
years. The median rate of HBsAg reduction was 0.104 log IU/mL/year, with no significant
difference found when comparing patients who were positive or negative for HBeAg-,
genotype B versus C, and detectable versus undetectable viremia during therapy (all P >
0.05). Seven patients (10%) achieved HBsAg seroclearance, and when compared with the
remaining 63 patients, had a significantly lower median baseline HBsAg levels (P = 0.012)
and a greater median rate of HBsAg reduction (P < 0.001). Baseline HBsAg levels and the
rate of HBsAg reduction achieved an AUROC of 0.860 (P = 0.004, 95% confidence interval
0.742-0.978) and 0.794 (P = 0.018, 95% confidence interval 0.608-0.979), respectively.
Baseline HBsAg < 1,000 IU/mL and on-treatment reduction of HBsAg > 0.166 log
IU/mL/year were optimal cut-off levels in predicting subsequent HBsAg seroclearance
(negative predictive values 98.1% and 97.8% respectively). The authors concluded that
low baseline HBsAg levels and greater rate of HBsAg reduction achieved high predictive
values for predicting HBsAg seroclearance, strengthening the prognostic role of HBsAg
measurements during NA therapy.
This is an interesting study showing the kinetics of HBsAg decay observed in patients
receiving long-term lamivudine therapy associated with a good virologic response. It
showed that in the majority of patients, despite viral suppression, the kinetics of HBsAg
loss are similar to those observed during the natural history of the disease. The
identification of factors predicting HBsAg loss at baseline and during therapy could also be
clinically valuable for managing the patients under NA therapy.
However, other studies with tenofovir disoproxil fumarate1 showed that patients who
achieved HBsAg loss had a high baseline Knodell necroinflammatory score and higher
HBV DNA and HBsAg levels; and were mainly infected with non-Asian viral genotypes
(genotype A (60%), D (35%), or F (5%); all were non-Asian; 65% had bridging fibrosis or
cirrhosis; and the majority were male.
These different clinical observations may not be contradictory, but may reflect the
heterogeneity of patients and viral disease, including host genetic factors, viral factors
such as viral genome heterogeneity, liver disease severity, and other unknown factors
related to the fine interplay between HBV replication and the host responses. More studies
are therefore required to identify clinical predictors of HBsAg loss during NA therapy that
would be applicable to different patient populations around the world.
Reference
1. Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir
disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140:132-43.
back to top
HBSAG LEVELS—A SURROGATE MARKER OF
cccDNA LOSS DURING NA THERAPY?
Wong DK, Seto WK, Fung J, et al. Reduction of Hepatitis B Surface Antigen and
Covalently Closed Circular DNA by Nucleos(t)ide Analogues of Different Potency. Clin
Gastroenterol Hepatol. 2013 Aug;11(8):1004-1010.
View journal abstract View full article
Wong et al addressed an important question: could the quantification of serum HBsAg be
a surrogate marker of intrahepatic cccDNA? The study also tried to obtain information
about the magnitude of NUC-induced viral suppression in the liver, as well as the kinetics
of clearance of cccDNA and HBsAg during NUC therapy.
The authors had access to paired liver biopsy samples taken at baseline and after one
year of therapy from a group of 124 patients who were treated with one of the five NUCs
(lamivudine, adefovir, entecavir, telbivudine, or clevudine). Among the 117 patients who
did not develop resistance, the evaluation of viral suppression showed an average
reduction of approximately 0.2 log10 IU/mL in HBsAg, 5 log10 IU/mL in serum level of
HBV DNA, 2 log10 copies/cell in intrahepatic total HBV DNA, and 1 log10 copy/cell in
cccDNA. Although 88/117 patients (75%) had undetectable serum levels of HBV DNA (<
12 IU/mL), all had detectable levels of HBsAg, and only five (4%) had undetectable levels
of cccDNA. Patients with greater reductions in levels of cccDNA had greater reductions in
HBsAg, but these reductions did not reach statistically significant correlations.
These results are consistent with previous observations that the kinetics of cccDNA
clearance are slow, with the same magnitude of reduction as that observed previously in
adefovir or lamivudine studies.1,2 Assuming that the kinetics would be identical beyond
one year of therapy, it was predicted that more than 14 years of therapy would be needed
to eradicate cccDNA.1 Interestingly, Wong's group found that the reduction of cccDNA
levels after one year of therapy was similar across all five NUCs studied, regardless of
their antiviral potencies.3 This indicates that, despite a different magnitude of inhibition of
viral DNA synthesis and virion DNA release, the pool of cccDNA was affected in a similar
manner during the observation period. Unfortunately, data are still missing on cccDNA
kinetics beyond one year of therapy with entecavir and tenofovir, the two most potent
drugs with a high barrier to resistance. One recent study showed that, in a cohort of
patients with HIV-HBV coinfection, the decline of cccDNA in liver biopsies obtained three
years apart was very slow.4
Another important question is whether serum HBsAg quantification could be a surrogate
Another important question is whether serum HBsAg quantification could be a surrogate
marker of intrahepatic cccDNA levels. A number of studies have analyzed the clinical
relevance of HBsAg quantification for monitoring antiviral therapy with interferon alpha or
NUCs, as well as for deciding treatment adaptation.5 Most of these studies have shown
that the kinetics of HBsAg decay are very slow in the majority of NUC treated patients;6,7
the prediction is that more than 50 years of therapy would be needed to obtain HBsAg loss
with the currently available treatments.6 The current analysis by Wong et al is also
consistent with those previous observations.3 The question about using HBsAg
quantificatin to predict the levels of intrahepatic cccDNA was also previously addressed.
Different results were obtained in different studies when assessing these two parameters
on a single time point,1,8 probably because the regulation of HBsAg expression is complex
and includes more parameters than the amount of cccDNA in infected cells. The only trend
that has been consistently found is a parallel decrease of serum HBsAg and intrahepatic
cccDNA.1, 9
The results of all these clinical studies are consistent with the fact that prolonged
administration of NUC is required to achieve a significant decrease of serum HBsAg
and/or intrahepatic cccDNA levels in the majority of patients.
Reference
1. Werle-Lapostolle B, Bowden S, et a;. Persistence of cccDNA during the natural history
of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology.
2004;126:1750-1758.
2. Sung JJ, Wong ML, Bowden S, Let al. Intrahepatic hepatitis B virus covalently closed
circular DNA can be a predictor of sustained response to therapy. Gastroenterology.
2005;128:1890-1897.
3. Wong DK, Seto WK, Fung J, et al. Reduction of Hepatitis B Surface Antigen and
Covalently Closed Circular DNA by Nucleos(t)ide Analogues of Different Potency. Clinical
Gastroenterol Hepatol. 2013 Aug:11(8):1004-1010.
4. Lacombe K, Boyd A, Lavocat F, et al. High incidence of treatment-induced and vaccineescape
hepatitis B virus mutants among HIV-hepatitis B infected patients. Hepatology.
2013 Mar 6 [Epub ahead of print]
5. Janssen HL, Sonneveld MJ, Brunetto MR. Quantification of serum hepatitis B surface
antigen: is it useful for the management of chronic hepatitis B? Gut. 2012;61:641-5.
6. Chevaliez S, Hezode C, Bahrami S, et al. Long-term hepatitis B surface antigen
(HBsAg) kinetics during nucleoside/nucleotide analogue therapy: Finite treatment duration
unlikely. J Hepatol. 2013 Apr;58(4):676-83. doi: 10.1016/j.jhep.2012.11.039. Epub 2012
Dec 3.
7. Borgniet O, Parvaz P, Bouix C, et al. Clearance of serum HBsAg and anti-HBs
seroconversion following antiviral therapy for chronic hepatitis B. J Med Virol.
2009;81:1336-1342.
8. Thompson AJ, Nguyen T, Iser D, et al. Serum hepatitis B surface antigen and hepatitis
B e antigen titers: disease phase influences correlation with viral load and intrahepatic
hepatitis B virus markers. Hepatology. 2010;51:1933-44.
9. Wursthorn K, Lutgehetmann M, Dandri M, et al. Peginterferon alpha-2b plus adefovir
induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B.
Hepatology. 2006;44:675-684.
back to top
KINETICS OF cccDNA AND HBSAG DECLINE DURING
COMBINATION THERAPY FOR CHB
Lutgehetmann M, Volzt T, Quaas A, et al. Sequential combination therapy leads to
biochemical and histological improvement despite low ongoing intrahepatic hepatitis B
virus replication. Antivir Ther. 2008;13(1):57-66.
View journal abstract
In this paper, the authors sought to determine whether sequential combination therapy of
pegylated interferon (peg-IFN) with adefovir dipivoxil (ADV) followed by ADV monotherapy
could lead to improved virologic and clinical efficacy. This was an important study because
previous clinical trials of de novo combination therapy of lamivudine with pegylated
interferon did not show a benefit in terms of virologic or clinical off-treatment responses. It
was therefore clinically relevant to evaluate new schedules of administration of a NUC with
peg-IFN.
The design of this pilot study was to administer 48 weeks of combination therapy with
pegylated interferon-alpha2b and adefovr dipivoxil, followed by 96 weeks of ADV
monotherapy in 24 patients with chronic hepatitis B. In a previous paper, these authors
observed marked decreases of HBV covalently closed circular DNA (cccDNA) (-2.4 log10
copies/ml) during the phase of combination therapy. They now report the final outcome
after 144 weeks of sequential antiviral treatment.
At week 144, 12 of 15 patients positive for HBeAg had lost HBeAg; ALT levels were
normal in 23 patients (96%); and median serum HBV DNA had decreased by -4.9 log10
copies/ml and was undetectable (<100 copies/ml) in 11 of 24 patients (46%). Median total
intrahepatic HBV DNA had decreased by -2.2 log. Overall, four of the 24 patients achieved
HBsAg loss. Although no further significant cccDNA changes occurred between week 48
and week 144, two years of ADV monotherapy proved capable of controlling cccDNA
levels in most patients. Analysis of intrahepatic HBV DNA species demonstrated that
combination therapy with PEG-IFN and ADV inhibited viral productivity by 99% and
subsequent ADV monotherapy by 76%, respectively. Virus suppression to undetectability
within the first 12 weeks of treatment was strongly associated with long-term virological
response and HBeAg and HBsAg seroconversion. Histological improvement was
determined in 11 of 16 patients at week 144. Two patients developed ADV resistance
during the third year of treatment. The authors concluded that reduction of intrahepatic
viral load achieved after 48 weeks of combination therapy with PEG-IFN and ADV was
maintained at 96 weeks of ADV monotherapy and translated into long-term clinical benefit
for most of the treated patients.
The results of this study are interesting in that they show that maximal viral suppression—
evaluated by intrahepatic viral DNA, including cccDNA, and serum markers including
quantification of HBV DNA and HBsAg — was observed during the first phase of
combination therapy. The magnitude of viral suppression was maintained in most patients
during the second phase of ADV monotherapy. These findings may reflect the combined
action of ADV on the intracellular recycling pathway of cccDNA2 and that of peg-IFN on
the inhibition of the transcriptional activity of cccDNA.
On the other hand, other recent studies1-4 have shown that restoration of specific
CD4/CD8 T cell responses are observed after several years of NUC-induced viral
suppression. This may open the possibility to study other regimens of combination based
on peg-IFN add-on after obtaining viral suppression and restoration of cellular immune
responses with long-term NUC administration.
These clinical data suggest a potential benefit for a combination of peg-IFN and NUC to
enhance viral suppression and eventually achieve HBsAg loss; however, they also point
out that the optimal schedule of administration might depend on each individual patient
situation.
Reference
1. Wursthorn K, Lutgehetmann M, Dandri M, Volz T, Buggisch P, Zollner B, Longerich T,
Schirmacher P, Metzler F, Zankel M, Fischer C, Currie G, Brosgart C, Petersen J.
Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction
in patients with chronic hepatitis B. Hepatology. 2006 Sep;44(3):675-684.
2. Werle-Lapostolle B, Bowden S, Locarnini S, Wursthorn K, Petersen J, Lau G, Trepo C,
Marcellin P, Goodman Z, Delaney WEt, Xiong S, Brosgart CL, Chen SS, Gibbs CS, Zoulim
F. Persistence of cccDNA during the natural history of chronic hepatitis B and decline
during adefovir dipivoxil therapy. Gastroenterology 2004;126:1750-1758.
3. Belloni L, Allweiss L, Guerrieri F, Pediconi N, Volz T, Pollicino T, Petersen J, Raimondo
G, Dandri M, Levrero M. IFN-alpha inhibits HBV transcription and replication in cell culture
and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA
minichromosome. J Clin Invest. 2012;122:529-537.
4. Boni C, Laccabue D, Lampertico P, Giuberti T, Vigano M, Schivazappa S, Alfieri A,
Pesci M, Gaeta GB, Brancaccio G, Colombo M, Missale G, Ferrari C. Restored function of
HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues.eViralHepatitis Review
VOLUME 3, ISSUE 5
CURE OF HEPATITIS B: IS IT ACHIEVABLE?
In this Issue...
Chronic hepatitis B (CHB) is a major public health problem, affecting more than 400 million
people worldwide and greatly increasing their risk of developing liver disease, particularly
cirrhosis and hepatocellular carcinoma (HCC). Over the past 15 years, major progress has
been made in antiviral therapy of CHB, to the point where it can now be legitimately asked:
"Can this disease be cured?"
In this issue, we review recent studies providing evidence that begins to answer that
question.
LEARNING OBJECTIVES
After participating in this activity, the participant will demonstrate the ability to:
Describe current evidence showing that achieving viral suppression can significantly
improve fibrosis and decrease the incidence of hepatocellular carcinoma
Explain how HBsAg loss can be considered a serologic/virologic cure that allows
treatment cessation
Describe how, despite HBsAg clearance, reactivation of HBV and/or development of
hepatocellular carcinoma may occur
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IN THIS ISSUE
COMMENTARY from our Guest Authors
REGRESSION OF CIRRHOSIS WITH
ANTIVIRAL TREATMENT
REDUCING THE INCIDENCE OF
HEPATOCELLULAR CARCINOMA WITH
ANTIVIRAL TREATMENT
HBV SURFACE ANTIGEN CLEARANCE BY
INTERFERON TREATMENT: ROLE OF
IL28B POLYMORPHISMS
PREDICTION OF HBSAG CLEARANCE
DURING NUCLEOS(T)IDE ANALOGUE
(NA) THERAPY
HBSAG LEVELS—A SURROGATE
MARKER OF cccDNA LOSS DURING NA
THERAPY?
KINETICS OF cccDNA AND HBSAG
DECLINE DURING COMBINATION
THERAPY FOR CHB
Program Directors
Mark S. Sulkowski, MD
Professor of Medicine
Medical Director, Viral Hepatitis Center
Divisions of Infectious Diseases and
Gastroenterology/Hepatology
The Johns Hopkins University School of
Medicine
Baltimore, Maryland
Raymond T. Chung, MD
Associate Professor of Medicine
Harvard Medical School
Director of Hepatology
Vice Chief of Gastroenterology
Massachusetts General Hospital
Boston, Massachusetts
Julie McArthur, MS, CRNP
Adult Nurse Practitioner
Division of Infectious Disease
The Johns Hopkins University
School of Medicine
Baltimore, Maryland
GUEST AUTHORS OF THE MONTH
Commentary:
Fabien Zoulim, MD, PhD
Professor, Head of INSERM
Viral Hepatitis Laboratory
Medical School of Lyon,
Lyon 1 University
Hepatology Department,
Hospices Civils de Lyon
Lyon, France
Guest Faculty Disclosures
Fabien Zoulim, MD, PhD has
disclosed that he has received
grants/research support from Gilead
Sciences, Novira, Roche, and
Scynexis. He has served as a
consultant for Gilead Sciences and
Roche, and has been a speaker for
Bristol Myers-Squibb, Gilead and
Roche.
Unlabeled/Unapproved Uses
The authors have indicated that there
will be no references to
Kerstin Hartig-Lavie, MD
Hepatology Department
Hospices Civils de Lyon
Lyon, France
unlabeled/unapproved uses of drugs
or products.
Program Directors' Disclosures
COMMENTARY
Over the past 15 years, the growing efficacy of antiviral strategies to treat chronic hepatitis
B (CHB) infection has been remarkable. The use of pegylated interferon alpha has allowed
patients to obtain off-treatment responses related to immune control of the infection,
primarily in a selected population of patients having favorable predictive factors such as
high ALT levels and low HBV DNA levels.1 Several nucleoside analogues (NA) have been
approved over the years. The first generation of NA agents (lamivudine, adefovir dipivoxil,
and telbivudine) was associated with a high rate of antiviral drug resistance, which blunted
the initial virologic and clinical benefit of therapy. The availability of the second-generation
NAs (tenofovir disoproxil fumarate TFV and entecavir) provided both a potent antiviral
effect and a high barrier to resistance, which has enabled viral suppression in the majority
of patients.2 This is even true in patients who failed a previous line of antiviral therapy with
a low barrier to resistance NA, provided that treatment adaptation is based on the crossresistance
profile of the resistant strain. However, in patients who receive NA-based
therapy either de novo or after failure of interferon based therapy, long-term administration
of antiviral drug is necessary to avoid viral relapse because of the persistence of HBV
cccDNA, ie the viral minichromosome, in the liver of patients infected with HBV.2
In contrast to chronic HCV infection, which is a curable infection with a "short" duration of
antiviral treatment, the treatment of CHB remains clinically challenging. However, there are
several ways to envision how an HBV cure can be achievable.
The first aspect, as shown in some of the investigations reviewed herein, is the evidence
that the liver damage associated with CHB can be significantly improved and could be
seen as a true endpoint. Indeed, it was shown that with prolonged NA therapy with
entecavir or tenofovir, both the necroinflammatory activity and liver fibrosis scores can be
improved significantly after several years of therapy. More important, in the study by
Heathcote et al,3 regression of liver cirrhosis was also observed in patients with
compensated cirrhosis who received tenofovir (TDF). Clinically, this could be seen as a
"cure" of the liver disease, although it remains to be confirmed by extended observations
to see if this translates into a reduced incidence of HCC, as suggested by a very recent
study presented at the European Association for the Study of the Liver (EASL) conference
in Amsterdam.4
Another important aspect is that recently published cohort studies suggest that long-term
antiviral therapy, when associated with virologic response, is associated with a reduced
incidence of HCC. This was well demonstrated in the study by Hosaka et al discussed in
this newsletter.
There is now a body of evidence that antiviral therapy, especially when initiated not too
late in the natural history of the disease, has a significant impact on HCC development,
which can be seen as a big success of these treatments.
However, although these treatments can decrease the incidence of HCC, some cases of
HCC still develop during antiviral therapy. These incident cases are usually seen during
the first months of therapy and may reflect small HCC undetectable by clinically available
imaging techniques present at the beginning of therapy. Furthermore, viral genome
integration occurs early during the natural history of infection and may lead to chronic
necroinflammatory activity and clonal expansion of hepatocytes that may represent the
first step of HCC development. These observations may be an argument for proposing
antiviral therapy at earlier stages of the infection to control viral replication and prevent
viral genome integration events and liver damage to occur;5 this type of strategy would
obviously have to be validated with the aim to reduce even further the rate of occurrence
of HCC.
The second aspect is related to the virologic cure of HBV infection. The current treatment
endpoints of antiviral therapy with interferon or NA are to achieve HBe seroconversion in
patients who are HBeAg positive and to achieve viral suppression (undetectable HBV DNA
in patients' serum) in all patients. HBsAg loss associated with HBs seroconversion is the
next most desirable endpoint. The papers by Lampertico et al and Seto et al discussed in
this newsletter provide real-life data on treatment-induced HBsAg loss, which is achieved
in only approximately 10% of patients who received a one-year course of interferon when
followed for five years after treatment cessation and can be higher in patients with
favorable IL28B gene polymorphism. With long-term administration of NA, when
associated with virologic response, also approximately 10% of patients lose HBsAg after 5
to 10 years of therapy. HBsAg loss can be seen as a serologic cure of the infection, as it
may allow stoppage of treatment and is associated with a decreased incidence of HCC, at
least in patients who spontaneously lost HBsAg.
However, this serologic cure does not equate to full eradication of the viral genome. In our
experience, as well as in reports from other centers, HBV reactivation may occur despite
HBsAg loss. This happens in cases of severe immune depression as seen in patients with
AIDS, immune suppressant therapy for organ transplantation, or heavy chemotherapy.
This is because viral cccDNA persists in the infected liver, which is responsible for
reinitiating active replication when immune control of infection is lost. In these situations,
our experience is to recommend antiviral prophylaxis. The other complication that can be
seen even in patients with HBsAg loss is the occurrence of HCC as a consequence of
long-term infection with viral genome integration and accumulation of liver damage. For
this reason, in our institution, we recommend continued ultrasound monitoring of HCC in
patients with CHB after HBsAg clearance.
What are the new perspectives about antiviral therapy of CHB? Because of improved
clinical endpoints and the possibility to envision finite duration of treatment, HBsAg loss
has become the major goal of new antiviral strategies. The aim of future treatments will be
to increase the rate of HBsAg clearance. This will require the use of true combination
therapy and the identification of new treatment targets. Several lines of research are being
explored, with strategies aimed at decreasing the pool of viral cccDNA or silencing its
activity, and/or strategies aimed at restoring innate and adaptive immune responses
against HBV to clear or cure the remaining infected hepatocytes.6 Time will be needed to
validate these strategies in clinical trials. Meanwhile, there are new trials evaluating the
combination of pegylated interferon with NA based on different schedules of
administration, which may be the first step for a long-awaited improved (HBsAg loss)
success rate of therapy.
Reference
1. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, et al.
Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic
hepatitis B . N Engl J Med. 2005;352(26):2682-95.
2. Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues.
Gastroenterology. 2009;137(5):1593-608.
3. Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir
disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140(1):132-
43.
4. Chan HL, Chan CK, Chan AJ, et al. Tenofovir DF (TDF) compared to emtricitabine
(FTC)/TDF in HBeAg-positive, chronic hepatitis B (CNB) virus-infected patients in the
immune tolerant (IT) phase. Abstract 101. The International Liver Conference, EASL,
Amsterdam, April, 2013.
5. Zoulim F, Mason WS. Reasons to consider earlier treatment of chronic HBV infections.
Gut. 2012;61(3):333-6..
6. Zoulim F. Are novel combination therapies needed for chronic hepatitis B?Antiviral
research. 2012;96(2):256-9.
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REGRESSION OF CIRRHOSIS WITH ANTIVIRAL
TREATMENT
Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir
disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet.
2013 Feb 9;381(9865):468-475. doi: 10.1016/S0140-6736(12)61425-1.
(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
View journal abstract View full article
Four hundred million people worldwide are infected with hepatitis B virus, and
epidemiologic studies estimate that up to 25% of these die of liver cirrhosis or
hepatocellular carcinoma (HCC). None of the currently available treatments can eliminate
with certitude the hepatitis B virus. In our clinical practice, therefore, it is important to focus
not only on the virus but also on the liver disease itself. This study investigated whether
HBV-induced liver disease can be cured or at least significantly improved.
This open label study examined the impact of tenofovir disoproxil fumarate (TDF) on
histological liver changes after 240 weeks of treatment. Patients were recruited in 2005-
2006 from different hepatology centers worldwide. The study contained a 48 week,
randomized, double blind comparison of TDF and adefovir dipivoxil, after which patients
were switched to open label TDF treatment. The study enrolled patients who had HBeAgnegative
or HBeAg-positive chronic hepatitis B with compensated liver disease and
pretreatment liver biopsy specimens that showed a Knodell necroinflammatory score of 3
or more (on a scale of 0 to 18). All patients had been HBsAg-positive for at least 6 months
before screening. Patients were HBV mono-infected and had received less than 12 weeks
of treatment with any nucleoside or nucleotide for HBeAg-positive patients, but could be
pretreated with lamivudine for more than 12 weeks for the HBeAg-negative group. Patients
with hepatocellular carcinoma or liver failure were excluded. The liver biopsies were
analyzed by an independent pathologist unaware of the treatment outcome.
Three hundred forty-eight patients had biopsy at baseline and again at week 240. The
results show that 304 patients (87%) had histological improvement of necroinflammatory
lesions as defined by a >= 2 point reduction in Knodell necroinflammatory score. In fact,
the proportion of patients with mild or no necroinflammation (Knodell 0-3) increased from
8% at baseline to 49% at year 1 (P < 0.001) and to 80% at year 5 (P < 0.001). One
hundred seventy-six patients (51%) had regression of fibrosis, defined by a >= 1 unit
regression of Ishak fibrosis score (P < 0.0001). At baseline 96 patients had cirrhosis; 71
(74%) of the patients with initial cirrhosis no longer had cirrhosis at week 240 (regression
of Ishak score of at least one unit). Only three patients without cirrhosis at baseline
progressed to cirrhosis at week 240. The difference between the proportion of patients
with cirrhosis regression and those with cirrhosis progression was significant (P < 0.0001).
Of the 96 patients with cirrhosis at baseline, all but one regressed more than 2 units of
Ishak score, and more than half had a decrease of 3 units in Ishak fibrosis score. Patients
with the highest liver injury score showed the greatest degree of improvement (P <
0.0001).
When comparing the patients who did not show fibrosis regression with those that did in
terms of demographic characteristics, the factors differing significantly between the two
groups were BMI < 25kg/m2 (P < 0.01), history of diabetes mellitus (P = 0.001), normal
ALT levels under treatment (P = 0.07), and Knodell score category 0-3 on biopsy at year 5
(P = 0.007).
This is the first large scale study demonstrating the histological benefit of antiviral
treatment with the new generation of nucleos(t)ide analogues. While two other studies
demonstrated the benefit of long-term entecavir treatment on liver histology,1,2 they
enrolled a smaller number of patients, and neither included equivalent numbers of patients
with cirrhosis. Here the regression of fibrosis was considerable, with decrease in Ishak
score of three units for more than half of the patients with cirrhosis. Improvement of liver
histology was higher when the initial liver injury was greater. Nonregression was shown to
be associated with overweight, presence of diabetes mellitus, and continuing liver
inflammation (high ALT and elevated Knodell score after five years of treatment). These
factors might be linked and should encourage us to check our patients for metabolic
syndrome, because nonalcoholic steatohepatitis is a liver-damaging factor.
This study demonstrates explicitly that effective antiviral treatment can prevent liver
fibrosis progression and even revert cirrhotic lesions to noncirrhotic liver. These findings
may pave the way toward a cure of HBV-induced liver damage. Further complications,
including hepatic decompensation and the development of hepatocellular carcinoma, can
therefore be significantly reduced — was previously demonstrated by Liaw et al3 with
lamivudine treatment of patients with advanced fibrosis. In the era of powerful
nucleos(t)ide analogues, the improvement of the liver damage is one of the main treatment
objectives and should be achievable in all patients with CHB.
References
1. Schiff ER, Lee SS, Chao YC, et al. Long-term treatment with entecavir induces reversal
of advanced fibrosis or cirrhosis in patients with chronic hepatitis B. Clin Gastroenterol
Hepatol. 2011 Mar;9(3):274-276. doi: 10.1016/j.cgh.2010.11.040. Epub 2010 Dec 8.
2. Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of
fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis
B. Hepatology. 2010 Sep;52(3):886-893. doi: 10.1002/hep.23785.
3. Liaw YF, Sung JJ, Chow WC, et al; Cirrhosis Asian Lamivudine Multicentre Study
Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl
J Med. 2004 Oct 7;351(15):1521-1531.
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REDUCING THE INCIDENCE OF HEPATOCELLULAR
CARCINOMA WITH ANTIVIRAL TREATMENT
Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces
hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology.
2013 Jul;58(1):98-107.
(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
View journal abstract View full article
The previous article described improvement of liver fibrosis during long-term antiviral
treatment with TDF. A previous study by Liaw et al1 suggested a decrease of
hepatocellular carcinoma (HCC) incidence in patients treated with lamivudine (LAM);
however the long-term benefit was blunted by the emergence of antiviral drug resistance.
Potent nucleos(t)ide analogues (NA) with a high barrier to resistance, such as entecavir
(ETV) and tenofovir disoproxil fumarate (TDF), have been used more recently, but their
benefit for the development of HCC has not been demonstrated. Whether these more
potent antiviral treatments can reduce HCC incidence in the long-term is the important
clinical issue addressed by these investigators. Four hundred seventy-two patients monoinfected
with HBV and treated with ETV were recruited from 2004 to 2010 in Toranomon
Hospital in Japan and compared to 1143 patients with HBV mono-infection without
treatment. The patients treated with ETV had never been treated by NA before. Patients in
the control group were recruited retrospectively between 1973 and 1999 and had not
received any antiviral treatment during the observation period. Propensity score matching
eliminated the baseline differences, and finally 316 patients per cohort were compared.
Three HCC risk scales and risk scores based on recent publications 2-4 were applied to
both cohorts and included age, gender, cirrhosis status, levels of alanine
aminotransferase, HBeAg, baseline HBV DNA, albumin, and bilirubin.
A subanalysis of this study compared the incidence of HCC in patients treated with ETV to
patients treated with LAM. A cohort of 492 LAM-treated patients were retrospectively
recruited from 1995 to 2007. None of these patients had rescue therapy in case of viral
resistance. Propensity score matching in these two groups resulted in a matched cohort of
182 patients.
HCC diagnosis was made predominantly by imaging but confirmed by fine-needle
aspiration biopsy if imaging was not typical. The cumulative HCC incidence rates at five
years were significantly lower in the ETV group (3.7 %) compared to the control group
(13.7%; P < 0.001). When adjusting the patients for a number of known HCC risk factors
by Cox proportional hazard regression analysis, it turned out that patients in the ETV
group were less likely to develop HCC than those in the control group (hazard ratio: 0.37;
95% confidence interval: 0.15-0.91; P = 0.030). The greatest HCC risk reduction occurred
in patients scoring higher on the risk scales.
Comparisons of HCC incidence in the ETV-treated group, nonrescued LAM-treated group,
and control group showed a significant difference in cirrhotic patients. The HCC incidence
reduction effect was the highest in the ETV-treated group compared to the control group
(P < 0.001), also present in the LAM-treated group compared to the control group (p =
0.019), and significantly higher in patients treated with ETV compared to patients treated
with LAM (P = 0.043).
This study confirms that HCC incidence can be reduced by long-term effective antiviral
treatment. It clearly demonstrates that more powerful antiviral treatment with entecavir has
a greater impact on HCC incidence than treatment with lamivudine. The beneficial effect of
lamivudine is usually blunted by the high incidence of antiviral drug resistance. For
instance, Zhang et al5 reported recently on a meta-analysis of 3644 patients which
showed that patients who developed antiviral drug resistance had a 2.6 times higher risk of
developing long-term complications.
The results of these studies emphasize that, in the future, a major public health challenge
will be to expand access to these effective antiviral treatments in high endemic areas
where patients are infected at younger age and are thus exposed to a high risk of HCC
development.
Reference
1. Liaw YF, Sung JJ, Chow WC, et al; Cirrhosis Asian Lamivudine Multicentre Study
Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl
J Med. 2004 Oct 7;351)15):152-31.
2. Yang HI, Yuen MF, Chan HL, et al; REACH-B Working Group. Risk estimation for
hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of
a predictive score. Lancet Oncol. 2011 Jun;12(6):568-74.
3. Yuen MF, Tanaka Y, Fong DY, et al. Independent risk factors and predictive score for
the development of hepatocellular carcinoma in chronic hepatitis B. J Hepatol. 2009 Jan;
50(1):80-88. doi: 0.1016/j.jhep.2008.07.023. Epub 2008 Sep 21.
4. Wong VWS, Chan SL, Mo F, et alk. Clinical scoring system to predict hepatocellular
carcinoma in chronic hepatitis B carriers . J Clin Oncol. 2010 Apr 1;28(10):1660-5.
5. Zhang QQ, An X, Liu YH, et al. Long-term nucleos(t)ide analogues therapy for adults
with chronic hepatitis B reduces the risk of long-term complications: a meta-analysis. Virol
J. 2011 Feb 15;8:72.
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HBV SURFACE ANTIGEN CLEARANCE BY
INTERFERON TREATMENT: ROLE OF IL28B
POLYMORPHISMS
Lampertico P, Viganò M, Cheroni C, et al. IL28B polymorphisms predict interferon-related
hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative
patients with chronic hepatitis B. Hepatology. 2013 Mar;57(3):890-896.
View journal abstract
Achieving HBV surface antigen clearance is the most desirable treatment endpoint leading
to a cure of HBV infection. While this goal can sometimes be achieved with interferon
treatment, success rates are low and the poor tolerability of interferon still limits its use.
The known predictive factors of good response to interferon are often underrepresented in
a particular geographical area (young age, elevated baseline transaminases, low baseline
viremia) or vary over time, and are thus difficult to apply. Il28B polymorphism has proved
to predict viral clearance during antiviral therapy for chronic hepatitis C. Whether IL28B
genotyping is useful in interferon treatment of patients infected with HBV is unknown. This
is particularly true in patients who are negative for HBeAg, who are rarely treated with
interferon and for whom robust predictive factors of response are lacking. The authors
tried to answer to this question in this study.
This study retrospectively analyzed 110 patients with HBV monoinfection and were
negative for HBeAg, most of them infected with genotype D (92%). All patients in this
cohort had been treated with standard Interferon or pegylated interferon α2a for 10-48
months (median 23 months), with a follow-up of 1-17 years (median 11 years). The IL28B
polymorphism was analyzed for all patients: 48 patients were found to be CC, 42 patients
CT, and 11 patients TT. The 3 IL28B groups were comparable in age, gender, serum ALT
levels, HBV DNA levels, cirrhosis, type of IFN administered, duration of treatment, and
follow-up.
End of treatment response (defined by undetectable HBV DNA or < 2000 IU/ml at end of
treatment) and sustained virological response (defined by undetectable HBV DNA or <
2000 IU/ml at six months post-treatment) were significantly higher in patients with CC than
those without (end of treatment response was 69% in CC vs 44% in non-CC, P = 0.014
and sustained virological response was 31% in CC vs 13% in non-CC, P = 0.025). During
a median follow-up of 11 years post-treatment, 21 patients (21%) cleared HBsAg and 15
developed anti-HBs titers > 10 IU/mL. HBsAg clearance rates were 29% (14 patients) in
CC, 7% (3 patients) in CT, and 36% (4 patients) in TT. By univariate analysis, baseline
HBV DNA, ALT, duration of treatment, post-treatment follow-up, and IL28B polymorphisms
— but not age, gender, cirrhosis, HBV genotype, and type of IFN — were significantly
associated with HBsAg clearance. At multivariate analysis, baseline HBV DNA levels (OR,
0.31; 95% CI: 0.15-0.62; P = 0.001), ALT levels (OR, 1.0; 95% CI: 1.0-1.0; P = 0.03),
duration of IFN therapy (OR, 1.20; 95% CI: 1.04-1.39; P = 0.012), and genotype CC (OR,
3.6; 95% CI: 1.05-12.5; P = 0.04) predicted HBsAg seroclearance. By combining HBV
DNA, ALT, and IL28B genotype, patients were classified into four different groups
characterized by increasing rates of HBsAg loss. In the group with low viral DNA (< 6 log
cp/mL) and high ALT levels (>136 U/l) and IL 28 B polymorphism CC, the HBsAg
clearance rate was as high as 60%.
This study is another step toward HBV treatment optimization and individualization. As the
tolerability of interferon is poor, finite duration of treatment and better criteria to accurately
identify possibly responders to interferon are needed. In patients positive for HBeAg, the
IL28B polymorphism has been described to predict response to pegylated interferon
treatment for HBeAg clearance but not HBsAg clearance.1 To date there have been no
data concerning patients who are negative for HBeAg.
The results of this study show that HBsAg clearance in the subgroup of patients with IL28B
CC, low HBV DNA levels, and high ALT levels was as high as 60%, indicating that IL28B
might therefore be a strong predictor for HBsAg clearance. This predictor is independent of
the phase of HBV infection. This study also confirmed the previously known predictive
factors of favorable response, ie ALT level and viral load, as demonstrated in other studies
2. Previous studies attempted to define stopping rules (lack of HBsAg and HBV DNA
decline at week 12 compared to baseline) to avoid unnecessarily prolonged interferon
treatment in patients who were negative for HBeAg.3 Gradually, more data are becoming
available to optimize our treatment strategies by identifying patients who are negative for
HBeAg, offering a better chance of response to interferon therapy and avoiding useless
extension of treatment duration.
One can argue that the study was performed on a small number of patients and the results
must be confirmed by larger prospective studies. Furthermore, the restriction of the study
population to viral genotype D infection limits its use in clinical practice. Since viral
genotype influences the response to interferon treatment, more data are needed to confirm
the predictive value of IL28B polymorphism in patients infected with other genotypes.4
Reference
1. Sonneveld MJ, Wong VW, Woltman AM, et al. Polymorphisms Near IL28B and
Serologic Response to Peginterferon in HBeAg-Positive Patients With Chronic Hepatitis B.
Gastroenterology. 2012 Mar;142(3):513-520.e1. doi: 10.1053/j.gastro.2011.11.025. Epub
2011 Nov 19.
2. Bonino F, Marcellin P, Lau GK, et al. Predicting response to peginterferon alpha-2a,
lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut. 2007
May;56(5):699-705. Epub 2006 Nov 24.
3. Rijckborst V, Hansen BE, Cakaloglu Y, et al. Early on-treatment prediction of response
to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV
DNA levels. Hepatology. 2010 Aug;52(2):454-461. doi: 10.1002/hep.23722.
4. Moucari R, Martinot-Peignoux M, Mackiewicz V, et al. Influence of genotype on hepatitis
B surface antigen kinetics in hepatitis B e antigen-negative patients treated with pegylated
interferon-alpha2a. Antivir Ther. 2009 14(8):1183-1188. doi: 10.3851/IMP1458.
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PREDICTION OF HBSAG CLEARANCE DURING
NUCLEOS(T)IDE ANALOGUE (NA) THERAPY
Seto WK, Wong DK, Fung J, et al. Reduction of hepatitis B surface antigen levels and
HBsAg seroclearance in chronic hepatitis B patients receiving 10 years of nucleoside
analogue therapy. Hepatology. 2013 Mar 6. [Epub ahead of print]
View journal abstract View full article
The Holy Grail of antiviral therapy of chronic hepatitis B (CHB) is to achieve HBsAg loss
and seroconversion. In that respect, the quantification of serum HBsAg levels may
represent a clinically relevant tool to monitor the effect of antiviral treatment.
Although serum HBsAg levels have been demonstrated to predict sustained viral
suppression after pegylated interferon therapy in CHB, the role of serum HBsAg
measurement during NA therapy has not been well-defined. Most recent studies have
been based on relatively small number of patients and short-term duration of NA
administration.
In this study, the authors have investigated the kinetics of HBsAg clearance in patients
who received long-term lamivudine therapy with a maintained virologic response (HBV
DNA below 2,000 IU/mL). From 1994 to 2002, 322 Chinese patients with CHB were
started on lamivudine in their center. Patients were recruited if they had been continuously
treated with lamivudine for at least 10 years and maintained favorable virologic responses
throughout therapy (HBV DNA < 2,000 IU/mL). HBsAg and HBV DNA levels were
measured serially, and the predictability of HBsAg kinetics in determining NA-related
HBsAg seroclearance was determined. Seventy patients were recruited for this study, of
whom 43 (61.4%) were positive for HBeAg. Fifty-two (74.3%) had undetectable viremia
(HBV DNA < 20 IU/mL) during therapy. Fifteen patients (21.4%) were followed up for 15
years. The median rate of HBsAg reduction was 0.104 log IU/mL/year, with no significant
difference found when comparing patients who were positive or negative for HBeAg-,
genotype B versus C, and detectable versus undetectable viremia during therapy (all P >
0.05). Seven patients (10%) achieved HBsAg seroclearance, and when compared with the
remaining 63 patients, had a significantly lower median baseline HBsAg levels (P = 0.012)
and a greater median rate of HBsAg reduction (P < 0.001). Baseline HBsAg levels and the
rate of HBsAg reduction achieved an AUROC of 0.860 (P = 0.004, 95% confidence interval
0.742-0.978) and 0.794 (P = 0.018, 95% confidence interval 0.608-0.979), respectively.
Baseline HBsAg < 1,000 IU/mL and on-treatment reduction of HBsAg > 0.166 log
IU/mL/year were optimal cut-off levels in predicting subsequent HBsAg seroclearance
(negative predictive values 98.1% and 97.8% respectively). The authors concluded that
low baseline HBsAg levels and greater rate of HBsAg reduction achieved high predictive
values for predicting HBsAg seroclearance, strengthening the prognostic role of HBsAg
measurements during NA therapy.
This is an interesting study showing the kinetics of HBsAg decay observed in patients
receiving long-term lamivudine therapy associated with a good virologic response. It
showed that in the majority of patients, despite viral suppression, the kinetics of HBsAg
loss are similar to those observed during the natural history of the disease. The
identification of factors predicting HBsAg loss at baseline and during therapy could also be
clinically valuable for managing the patients under NA therapy.
However, other studies with tenofovir disoproxil fumarate1 showed that patients who
achieved HBsAg loss had a high baseline Knodell necroinflammatory score and higher
HBV DNA and HBsAg levels; and were mainly infected with non-Asian viral genotypes
(genotype A (60%), D (35%), or F (5%); all were non-Asian; 65% had bridging fibrosis or
cirrhosis; and the majority were male.
These different clinical observations may not be contradictory, but may reflect the
heterogeneity of patients and viral disease, including host genetic factors, viral factors
such as viral genome heterogeneity, liver disease severity, and other unknown factors
related to the fine interplay between HBV replication and the host responses. More studies
are therefore required to identify clinical predictors of HBsAg loss during NA therapy that
would be applicable to different patient populations around the world.
Reference
1. Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir
disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140:132-43.
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HBSAG LEVELS—A SURROGATE MARKER OF
cccDNA LOSS DURING NA THERAPY?
Wong DK, Seto WK, Fung J, et al. Reduction of Hepatitis B Surface Antigen and
Covalently Closed Circular DNA by Nucleos(t)ide Analogues of Different Potency. Clin
Gastroenterol Hepatol. 2013 Aug;11(8):1004-1010.
View journal abstract View full article
Wong et al addressed an important question: could the quantification of serum HBsAg be
a surrogate marker of intrahepatic cccDNA? The study also tried to obtain information
about the magnitude of NUC-induced viral suppression in the liver, as well as the kinetics
of clearance of cccDNA and HBsAg during NUC therapy.
The authors had access to paired liver biopsy samples taken at baseline and after one
year of therapy from a group of 124 patients who were treated with one of the five NUCs
(lamivudine, adefovir, entecavir, telbivudine, or clevudine). Among the 117 patients who
did not develop resistance, the evaluation of viral suppression showed an average
reduction of approximately 0.2 log10 IU/mL in HBsAg, 5 log10 IU/mL in serum level of
HBV DNA, 2 log10 copies/cell in intrahepatic total HBV DNA, and 1 log10 copy/cell in
cccDNA. Although 88/117 patients (75%) had undetectable serum levels of HBV DNA (<
12 IU/mL), all had detectable levels of HBsAg, and only five (4%) had undetectable levels
of cccDNA. Patients with greater reductions in levels of cccDNA had greater reductions in
HBsAg, but these reductions did not reach statistically significant correlations.
These results are consistent with previous observations that the kinetics of cccDNA
clearance are slow, with the same magnitude of reduction as that observed previously in
adefovir or lamivudine studies.1,2 Assuming that the kinetics would be identical beyond
one year of therapy, it was predicted that more than 14 years of therapy would be needed
to eradicate cccDNA.1 Interestingly, Wong's group found that the reduction of cccDNA
levels after one year of therapy was similar across all five NUCs studied, regardless of
their antiviral potencies.3 This indicates that, despite a different magnitude of inhibition of
viral DNA synthesis and virion DNA release, the pool of cccDNA was affected in a similar
manner during the observation period. Unfortunately, data are still missing on cccDNA
kinetics beyond one year of therapy with entecavir and tenofovir, the two most potent
drugs with a high barrier to resistance. One recent study showed that, in a cohort of
patients with HIV-HBV coinfection, the decline of cccDNA in liver biopsies obtained three
years apart was very slow.4
Another important question is whether serum HBsAg quantification could be a surrogate
Another important question is whether serum HBsAg quantification could be a surrogate
marker of intrahepatic cccDNA levels. A number of studies have analyzed the clinical
relevance of HBsAg quantification for monitoring antiviral therapy with interferon alpha or
NUCs, as well as for deciding treatment adaptation.5 Most of these studies have shown
that the kinetics of HBsAg decay are very slow in the majority of NUC treated patients;6,7
the prediction is that more than 50 years of therapy would be needed to obtain HBsAg loss
with the currently available treatments.6 The current analysis by Wong et al is also
consistent with those previous observations.3 The question about using HBsAg
quantificatin to predict the levels of intrahepatic cccDNA was also previously addressed.
Different results were obtained in different studies when assessing these two parameters
on a single time point,1,8 probably because the regulation of HBsAg expression is complex
and includes more parameters than the amount of cccDNA in infected cells. The only trend
that has been consistently found is a parallel decrease of serum HBsAg and intrahepatic
cccDNA.1, 9
The results of all these clinical studies are consistent with the fact that prolonged
administration of NUC is required to achieve a significant decrease of serum HBsAg
and/or intrahepatic cccDNA levels in the majority of patients.
Reference
1. Werle-Lapostolle B, Bowden S, et a;. Persistence of cccDNA during the natural history
of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology.
2004;126:1750-1758.
2. Sung JJ, Wong ML, Bowden S, Let al. Intrahepatic hepatitis B virus covalently closed
circular DNA can be a predictor of sustained response to therapy. Gastroenterology.
2005;128:1890-1897.
3. Wong DK, Seto WK, Fung J, et al. Reduction of Hepatitis B Surface Antigen and
Covalently Closed Circular DNA by Nucleos(t)ide Analogues of Different Potency. Clinical
Gastroenterol Hepatol. 2013 Aug:11(8):1004-1010.
4. Lacombe K, Boyd A, Lavocat F, et al. High incidence of treatment-induced and vaccineescape
hepatitis B virus mutants among HIV-hepatitis B infected patients. Hepatology.
2013 Mar 6 [Epub ahead of print]
5. Janssen HL, Sonneveld MJ, Brunetto MR. Quantification of serum hepatitis B surface
antigen: is it useful for the management of chronic hepatitis B? Gut. 2012;61:641-5.
6. Chevaliez S, Hezode C, Bahrami S, et al. Long-term hepatitis B surface antigen
(HBsAg) kinetics during nucleoside/nucleotide analogue therapy: Finite treatment duration
unlikely. J Hepatol. 2013 Apr;58(4):676-83. doi: 10.1016/j.jhep.2012.11.039. Epub 2012
Dec 3.
7. Borgniet O, Parvaz P, Bouix C, et al. Clearance of serum HBsAg and anti-HBs
seroconversion following antiviral therapy for chronic hepatitis B. J Med Virol.
2009;81:1336-1342.
8. Thompson AJ, Nguyen T, Iser D, et al. Serum hepatitis B surface antigen and hepatitis
B e antigen titers: disease phase influences correlation with viral load and intrahepatic
hepatitis B virus markers. Hepatology. 2010;51:1933-44.
9. Wursthorn K, Lutgehetmann M, Dandri M, et al. Peginterferon alpha-2b plus adefovir
induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B.
Hepatology. 2006;44:675-684.
back to top
KINETICS OF cccDNA AND HBSAG DECLINE DURING
COMBINATION THERAPY FOR CHB
Lutgehetmann M, Volzt T, Quaas A, et al. Sequential combination therapy leads to
biochemical and histological improvement despite low ongoing intrahepatic hepatitis B
virus replication. Antivir Ther. 2008;13(1):57-66.
View journal abstract
In this paper, the authors sought to determine whether sequential combination therapy of
pegylated interferon (peg-IFN) with adefovir dipivoxil (ADV) followed by ADV monotherapy
could lead to improved virologic and clinical efficacy. This was an important study because
previous clinical trials of de novo combination therapy of lamivudine with pegylated
interferon did not show a benefit in terms of virologic or clinical off-treatment responses. It
was therefore clinically relevant to evaluate new schedules of administration of a NUC with
peg-IFN.
The design of this pilot study was to administer 48 weeks of combination therapy with
pegylated interferon-alpha2b and adefovr dipivoxil, followed by 96 weeks of ADV
monotherapy in 24 patients with chronic hepatitis B. In a previous paper, these authors
observed marked decreases of HBV covalently closed circular DNA (cccDNA) (-2.4 log10
copies/ml) during the phase of combination therapy. They now report the final outcome
after 144 weeks of sequential antiviral treatment.
At week 144, 12 of 15 patients positive for HBeAg had lost HBeAg; ALT levels were
normal in 23 patients (96%); and median serum HBV DNA had decreased by -4.9 log10
copies/ml and was undetectable (<100 copies/ml) in 11 of 24 patients (46%). Median total
intrahepatic HBV DNA had decreased by -2.2 log. Overall, four of the 24 patients achieved
HBsAg loss. Although no further significant cccDNA changes occurred between week 48
and week 144, two years of ADV monotherapy proved capable of controlling cccDNA
levels in most patients. Analysis of intrahepatic HBV DNA species demonstrated that
combination therapy with PEG-IFN and ADV inhibited viral productivity by 99% and
subsequent ADV monotherapy by 76%, respectively. Virus suppression to undetectability
within the first 12 weeks of treatment was strongly associated with long-term virological
response and HBeAg and HBsAg seroconversion. Histological improvement was
determined in 11 of 16 patients at week 144. Two patients developed ADV resistance
during the third year of treatment. The authors concluded that reduction of intrahepatic
viral load achieved after 48 weeks of combination therapy with PEG-IFN and ADV was
maintained at 96 weeks of ADV monotherapy and translated into long-term clinical benefit
for most of the treated patients.
The results of this study are interesting in that they show that maximal viral suppression—
evaluated by intrahepatic viral DNA, including cccDNA, and serum markers including
quantification of HBV DNA and HBsAg — was observed during the first phase of
combination therapy. The magnitude of viral suppression was maintained in most patients
during the second phase of ADV monotherapy. These findings may reflect the combined
action of ADV on the intracellular recycling pathway of cccDNA2 and that of peg-IFN on
the inhibition of the transcriptional activity of cccDNA.
On the other hand, other recent studies1-4 have shown that restoration of specific
CD4/CD8 T cell responses are observed after several years of NUC-induced viral
suppression. This may open the possibility to study other regimens of combination based
on peg-IFN add-on after obtaining viral suppression and restoration of cellular immune
responses with long-term NUC administration.
These clinical data suggest a potential benefit for a combination of peg-IFN and NUC to
enhance viral suppression and eventually achieve HBsAg loss; however, they also point
out that the optimal schedule of administration might depend on each individual patient
situation.
Reference
1. Wursthorn K, Lutgehetmann M, Dandri M, Volz T, Buggisch P, Zollner B, Longerich T,
Schirmacher P, Metzler F, Zankel M, Fischer C, Currie G, Brosgart C, Petersen J.
Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction
in patients with chronic hepatitis B. Hepatology. 2006 Sep;44(3):675-684.
2. Werle-Lapostolle B, Bowden S, Locarnini S, Wursthorn K, Petersen J, Lau G, Trepo C,
Marcellin P, Goodman Z, Delaney WEt, Xiong S, Brosgart CL, Chen SS, Gibbs CS, Zoulim
F. Persistence of cccDNA during the natural history of chronic hepatitis B and decline
during adefovir dipivoxil therapy. Gastroenterology 2004;126:1750-1758.
3. Belloni L, Allweiss L, Guerrieri F, Pediconi N, Volz T, Pollicino T, Petersen J, Raimondo
G, Dandri M, Levrero M. IFN-alpha inhibits HBV transcription and replication in cell culture
and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA
minichromosome. J Clin Invest. 2012;122:529-537.
4. Boni C, Laccabue D, Lampertico P, Giuberti T, Vigano M, Schivazappa S, Alfieri A,
Pesci M, Gaeta GB, Brancaccio G, Colombo M, Missale G, Ferrari C. Restored function of
HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues.
