Critical Issues in HBV

Critical Issues in HBV

Volume 1 • Number 1 • AUGUST 2014

VINDICOmedical education

Considerations in Optimizing HBV Treatment

V14-0196_HBV_Pub_Series_Issue1.indd 1V14-0196_HBV_Pub_Series_Issue1.indd 1 7/30/2014 4:40:52 PM7/30/2014 4:40:52 PM

DEPARTMENTS4 Editoral

Tram T. Tran, MD

11 Expert Interview:How Important is Monitoring TreatmentResponse 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 PatientWalid S. Ayoub, MD

22 CME Instructions and CME Posttest

23 CME: Registration Form

FEATURED ARTICLES

EARN CME CREDIT

LEARNING OBJECTIVESAt 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


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, MDPrincipal Robert G. Gish, Consultants LLCSenior Medical Director St. Joseph's Hospital and Medical Center, Liver ProgramPhoenix, ArizonaMedical Director Hepatitis B FoundationDoylestown, PennsylvaniaClinical Professor of MedicineUniversity of NevadaLas 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, MPHAssociate Professor of MedicineHarvard Medical SchoolDirector of Translational Liver Research Beth Israel Deaconess Medical CenterHarvard Medical SchoolBoston, Massachusetts

Asad Javaid, MD Liver Research Center, GastroenterologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBoston, Massachusetts

K. Rajender Reddy, MD, FACP, FACG, FRCPProfessor of MedicineProfessor of Medicine in SurgeryDirector of HepatologyDirector of Viral Hepatitis CenterUniversity of PennsylvaniaPhiladelphia, Pennsylvania

Tanya M. Pavri, BADivision of Gastroenterology and HepatologyUniversity of PennsylvaniaPhiladelphia, Pennsylvania

2 Volume 1 • Number 1 • August 2014 | CRITICAL ISSUES IN HBV



CHIEF MEDICAL EDITORTram T. Tran, MD

Medical Director of Liver Transplantation at the Liver Disease and Transplant Center

Cedars-Sinai Medical CenterLos Angeles, California

CONTRIBUTING FACULTYWalid S. Ayoub, MD

Clinical Associate Professor of Medicine UCLAAssistant Medical Director of Liver Transplant Program

Cedars Sinai Medical CenterLos Angeles, California

Robert G. Gish, MDPrincipal

Robert G. Gish, Consultants LLCSenior Medical Director, St Joseph’s Hospital and

Medical Center, Liver ProgramPhoenix, Arizona

Medical Director Hepatitis B FoundationDoylestown, Pennsylvania

Clinical Professor of Medicine, University of NevadaLas Vegas, Nevada

Harry Janssen, MD, PhDProfessor of Medicine

Francis Family Chair in Hepatology Head of the Liver Clinic

Toronto Western and Toronto General HospitalUniversity Health Network

Toronto, Canada

Asad Javaid, MD Liver Research Center, GastroenterologyBeth Israel Deaconess Medical Center,

Harvard Medical SchoolBoston, Massachusetts

Daryl T-Y Lau, MD, MSc, MPHAssociate Professor of Medicine, Harvard Medical School

Director of Translational Liver Research, Beth Israel Deaconess Medical Center, Harvard Medical School

Boston, Massachusetts

Tanya M. Pavri, BADivision of Gastroenterology and Hepatology

University of PennsylvaniaPhiladelphia, Pennsylvania

K. Rajender Reddy, MD, FACP, FACG, FRCPProfessor of Medicine

Professor of Medicine in SurgeryDirector of Hepatology

Director of Viral Hepatitis CenterUniversity of PennsylvaniaPhiladelphia, Pennsylvania

Robert J. Wong, MD, MSDepartment of Medicine, Division of Gastroenterology and

Hepatology, Stanford University Medical CenterStanford, California

EXTERNAL REVIEWERAlbert D. Min, MD

AccreditationVindico Medical Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit DesignationVindico Medical Education designates this enduring material for a maximum of 1.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This enduring material is approved for 1 year from the date of original release, August 1, 2014 to August 1, 2015.

How To Participate in this Activity and Obtain CME CreditTo participate in this CME activity, you must read the objectives and articles, complete the CME posttest, and fi ll-in and return the registration form and evaluation. Provide only one (1) correct answer for each question. A satisfactory score is defi ned as answering 70% of the posttest questions correctly. Upon receipt of the completed materials, if a satisfactory score on the posttest is achieved, Vindico Medical Education will issue an AMA PRA Category 1 Credit(s)™ certifi cate.

DisclosuresIn accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support, all CME providers are required to disclose to the activity audience the relevant fi nancial relationships of the planners, teachers, and authors involved in the development of CME content. An individual has a relevant fi nancial relationship if he or she has a fi nancial relationship in any amount occurring in the last 12 months with a commercial interest whose products or services are discussed in the CME activity content over which the individual has control.

Planning Committee and Faculty members report the following relationship(s)Walid S. Ayoub, MD

Consulting Fees: Gilead

Robert G. Gish, MDConsulting Fees: Arrowhead, Bristol-Myers Squibb, Genentech, GileadSpeaker’s Bureau: Bristol-Myers Squibb, GileadContracted Research: Bristol-Myers Squibb, GileadOwnership Interest: Arrowhead

Harry Janssen, MD, PHDConsulting Fees: Abbott, Anadys, Bristol-Myers Squibb, Gilead, Innogenetics, Medtronic, Merck, Novartis, Roche, Santaris, TibotecContracted Research: Abbott, Anadys, Bristol-Myers Squibb, Gilead, Innogenetics, Medtronic, Merck, Novartis, Roche, Santaris, Tibotec

Asad Javaid, MDNo relevant fi nancial relationships to disclose.

Daryl T-Y Lau, MD, MSc, MPHConsulting Fees: Arrowhead, Bristol-Myers Squibb, GileadContracted Research: Asian Health Foundation, Gilead, Merck

Tanya M. Pavri, BANo relevant fi nancial relationships to disclose.

K. Rajender Reddy, MD, FACP, FACG, FRCPConsulting Fees: AbbVie, Bristol-Myers Squibb, Genentech- Roche, Gilead, Idenix, Janssen, Merck, VertexContracted Research: AbbVie, Bristol-Myers Squibb, GEN-FIT, Genentech-Roche, Gilead, Janssen, Merck, VertexOther: ViralEd-Development of Educational Material

Tram T. Tran, MDConsulting Fees: Bristol-Myers Squibb, GileadSpeaker’s Bureau: Bristol-Myers Squibb, GileadContracted Research: Bristol-Myers Squibb, Gilead

Robert J. Wong, MD, MSNo relevant fi nancial relationships to disclose.

Reviewers report the following relationship(s):Albert D. Min, MD

Consulting Fees: Bristol-Myers Squibb, GileadSpeaker's Bureau: Bristol-Myers Squibb, GileadContracted Research: Bristol-Myers Squibb, Gilead

Ronald A. Codario, MD, FACP, FNLA, CCMEPNo relevant fi nancial relationships to disclose.

Vindico Medical Education staff report the following relationship(s):No relevant fi nancial relationships to disclose.

Signed disclosures are on fi le at Vindico Medical Education, Offi ce of Medical Affairs and Compliance.

Target Audience The intended audience for this activity series is gastroenter-ologists, hepatologists and other health care professionals in-volved in the treatment of patients with hepatitis B virus (HBV).

Unlabeled and Investigational UsageThe audience is advised that this continuing medical education activity may contain references to unlabeled uses of FDA-approved products or to products not approved by the FDA for use in the United States. The faculty members have been made aware of their obligation to disclose such usage. All activity participants will be informed if any speakers/authors intend to discuss either non-FDA approved or investigational use of products/devices.

VINDICO MEDICAL EDUCATIONMedical Director

Ronald A. Codario, MD, FACP, FNLA, CCMEP

Vice President, Offi ce of Medical AffairsJames T. Magrann

Scientifi c DirectorJennifer Frederick, PharmD, BCPS

Director of Medical EducationChris Rosenberg

Medical EditorSharon Powell

Program ManagerKristin Riday

Publication DesignKimi Dolan

David BarkerTheresa McIntire


Created and published by Vindico Medical Education, 6900 Grove Road, Building 100, Thorofare, NJ 08086-9447. Telephone: 856-994-9400; Fax: 856-384-6680. Printed in the USA. Copyright © 2014 Vindico Medical Education. All rights reserved. No part of this publication may be reproduced without written permission from the publisher. The material presented at or in any of Vindico Medical Education continuing medical education activities does not necessarily refl ect

the views and opinions of Vindico Medical Education. Neither Vindico Medical Education nor the faculty endorse or recommend any techniques, commercial products, or manufacturers. The faculty/authors may discuss the use of materials and/or products that have not yet been approved by the US Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or utilizing any product.

3


Volume 1 • Number 1 • August 2014 | CRITICAL ISSUES IN HBV


Edito

rial

We 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 effi cacious, 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 fi 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.

EditorialTram T. Tran, MD



Hepatitis 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-Pacifi c 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 signifi cantly 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 TherapyThe 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 signifi -cant clinical benefi t 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, defi ned 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 patient’s 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 defi ned as elevated liver enzymes and/or biopsy proven infl ammatory disease concomitant with elevated HBV DNA level. The importance of HBeAg status is also refl ected in certain treatment guidelines

(eg, American Association for the Study of Liver Disease [AASLD]and Asian Pacifi c 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 benefi t from antiviral therapy if there is evidence of advanced fi 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 TherapyRobert J. Wong, MD, MS and Robert G. Gish, MD

5Volume 1 • Number 1 • August 2014 | CRITICAL ISSUES IN HBV


identifi ed. 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 signifi cant 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 signifi cant hepatic fi brosis and a sig-nifi cantly elevated risk of developing long-term hepatic complications.9,23

Furthermore, 15% of patients in one study developed HCC with HBV DNA �103 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 fi 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 infl amma-tion and fi brosis and decreasing the risk of developing hepatic complica-tions, the specifi c 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 refl ects 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 HBVPersistence of HBsAg for > 6 months?Or from a high risk country or settingindicating HBV exposure early in life?

HBeAg Positive (+) HBeAg Negative ( ) Step 2: Assessment of HBeAg Status

High HBV viral DNAANDHigh serum ALT

Low HBV viral DNAORHealthy orborderline elevatedserum ALT

High HBV viral DNAANDHigh serum ALT

Step 3: Assessment of fibrosis status,HBV viral DNA* and serum alanineaminotransferase (ALT)#

Start HBV treatment Start HBV treatment

Low HBV viral DNAORHealthy or borderlineelevated serum ALT#

No treatment.Reassess for otherindications (e.g. advancedfibrosis or cirrhosis),family history ofhepatocellular carcinoma,elevated liver cancerbiomarkers, or todecrease infectivity

No treatment.Reassess for otherindications (e.g.advanced fibrosis orcirrhosis), family historyof hepatocellularcarcinoma, elevatedliver cancer biomarkers,or to decrease infectivity

Note: *The threshold for defining low vs. high HBVviral DNA varies based on the treatment guidelineutilized. #The threshold for defining healthy vs. highserum ALT that would warrant a recommendation forstarting HBV anti viral therapy varies based on thetreatment 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



long-term viral control in patients with HBeAg positive CHB. Thus, a more appropriate therapeutic endpoint for HBeAg positive patients, albeit dif-fi 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 OptionsThere 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 effi cacy of viral suppression, safety profi le, 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 effi cacy 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 effi cacy data for tenofovir and entecavir.

Interferon-based TherapyInterferon-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-fi ned by DNA negativity and HBsAg loss or seroconversion. Furthermore, interferon-based HBV therapy con-sists of a fi 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 signifi cant adverse effect and safety profi le com-pared with newer available oral agents.

Nucleoside-based HBV TherapyLamivudine 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 fi brosis progression, as well as HCC development, even among patients who have already developed advanced fi brosis or cirrhosis.33-34 However, signifi cantly 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 signifi cantly 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 signifi cantly improved effi cacy, 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 TherapyAdefovir was the fi rst oral nu-

cleotide analog approved for the



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 effi cacy profi le 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 signifi cantly 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 signifi cantly improved treatment ef-fi 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 profi le include both patients with HIV and HBV cohorts.

The Initial ApproachThe initial approach in the man-

agement of CHB includes under-standing the eligibility for initiating

antiviral therapy, and once treatment candidacy is confi rmed, assessing treatment options that are available. As discussed, peg-interferon based therapy is an option for patients who prefer a fi 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 signifi cantly im-proved treatment success rates, better ease of administration, and improved safety profi le. Therefore, mono-therapy with nucleoside-based and nucleotide-based therapy has largely replaced interferon-based therapy. With the signifi cantly improved ef-fi cacy of newer agents, such as en-tecavir and tenofovir, monotherapy with these agents has become fi rst-line therapy in many world regions, including the United States. Combi-nation therapy with nucleoside and

Class of TherapyAntiviral 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



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 effi cacy, 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

SummaryIn summary, CHB is a global epi-

demic with a signifi cant 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 benefi t 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.

References1. 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.

Tenofovir48 weeks

Entecavir48 weeks

Adefovir48 weeks

Telbivudine52 weeks

Lamivudine48 - 52 weeks

PegIFNα48 weeks

Standard IFNα12 - 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-Naïve HBeAg Negative

Tenofovir48 weeks

Entecavir48 weeks

Adefovir48 weeks

Telbivudine52 weeks

Lamivudine48 - 52 weeks

PegIFNα48 weeks

Standard IFNα12 - 24 weeks


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

Tenofovir5-years1

HBeAg-positive

Entecavir5-years2

HBeAg-negativeTenofovir5-years1

HBeAg-negativeEntecavir5-years3


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: 1Marcellin P, et al. Lancet. 2013;381(9865):468-475. 2Chang TT, et al. Hepatology. 2010;51(2):422-430.3Luo 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-Naïve HBeAg Positive

Table 3. Treatment Response Rates at 5-years Among CHB Patients Treated with Tenofovir or Entecavir



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.


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.



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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 fi 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 fi 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 best—en-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 fi rst-line treatment options whereas lamivudine, adefovir, and telbivudine are not recommended as fi 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 diffi cult 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 fi 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 fi rst component is the amount of infl ammation, which is measured by serum transaminases, mostly the ALT.

The second test for liver function is the synthetic liver func-tion. The ALT refl ects the amount of infl ammation, the amount of damage done to the liver. But then there are other liver tests which refl ect 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? Harry Janssen, MD, PhD



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 infl ammation 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 signifi cant 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 defi ne a therapeutic endpoint for therapy?

Dr. Janssen: The closest defi nition 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 diffi cult 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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Hepatitis B virus (HBV) infec-tion is a global public health issue that is responsible for

signifi cant morbidity and mortality from chronic liver disease. Chronic hepatitis B (CHB) is defi ned by the persistence of serum hepatitis B sur-face antigen (HBsAg) for 6 months or longer.1 The natural history of CHB can be classifi ed 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-α, IFN-α); 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 immunodefi ciency virus (HIV). The nucleoside and nucleotide analogues (NUCs), given as monotherapy, have been shown to produce virologic, biochemical, and histological benefi t 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 defi ned 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 fi 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 identifi ed in domain B.6 The main effect of the compensatory mutations is to restore replication fi 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 naïve patients.6,13 This single substitution at position rt181 appears to be suffi cient to induce cross-resistance between lamivudine and adefovir. In the spe-cifi c setting of lamivudine resistance

Evaluating Underlying Causes of HBV Treatment FailureDaryl T-Y Lau, MD, MSc, MPH and Asad Javaid, MD



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-naïve patients can be explained by a combination of its high genetic barrier requiring multiple mutations to reduce its effi cacy 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 naïve 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 fi 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 fi rst-line monotherapy for CHB because of their high rate of re-sistance. HBV DNA quantifi cation is important for initial patient evaluation, for monitoring treatment response, and for early detection of virologic breakthrough on therapy. The real-time PCR quantifi cation 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 defi ned as �1 log10 decrease in HBV DNA within 3 months of starting the treatment.4 Treatment failure can be primary and secondary. Primary treat-ment failure is defi ned as decrease in serum HBV DNA of �1 log10 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 log10 IU/mL in patients with ini-tial antiviral treatment effect.4,22 This

should be confi rmed 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 fl are with decom-pensation of liver disease, especially among those with advanced fi 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 NonadherenceAdherence with medication us-

age is defi ned as the proportion of prescribed doses of medication actu-ally taken by a patient over a speci-fi 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 profi le 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-, fi 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 benefi cial impact of medication, emotional or cultural reasons.



There are different methods to measure patient compliance that in-clude self-reporting, pill counting, and tracking prescription refi lls, 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 refi ll claims data are easy to use but there is the possibility of administrative errors resulting in misclassifi cation.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 refi ll 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 refi ll prescription within the fi rst 6 months of cohort enrollment; the refi ll 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

SummaryBoth 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 offi ce visit, patients are more likely to follow the physician’s advice.37

References1. 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.

18. Keeffe EB, et al. Clin Gastroenterol Hep-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.


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.

Full references are available at www.healio.com/gastroenterology/education-lab and www.opencme.org



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Meeting Highlight from EASL - The International Liver Congress 2014Prevention 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 effi cacy 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 defi ned as HBV-DNA levels �1 log10 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-fi 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: CommentaryHepatitis 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 benefi t 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 confi rming 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.


There 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 infl ammation and improving hepatic biochemical tests. The fi 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 fi 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 fi 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, indefi nite 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 Indefi nite antiviral treatment is advised for patients with chronic hepatitis B (CHB) with advanced liver disease because there is a risk of dis-ease fl are and hepatic decompensation. Generally, the oral agents have favor-able side-effect profi les and thus have been deemed benefi cial 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-naïve 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 insuffi ciency. The nephrotoxicity is usually revers-ible if therapy is discontinued rapidly. With continued adefovir or tenofovir use, renal insuffi ciency, 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 fl ares (Table).3,4 In preliminary trials, the adverse-effect profi le 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 immunodefi cien-cy virus (HIV) infection.5

Across HBV trials of tenofovir, treatment-emergent amino acid substi-tutions have been reported in viremic patients; however, no specifi c substitu-tions occurred at a suffi cient frequency to be associated with resistance to teno-fovir in either genotypic or phenotypic


Long-term Safety of HBV Therapies and When to Stop TherapyK. 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 naïve 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 signifi cant 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 confi rmed elevations in creatinine levels of 0.5 mg/dL.7

The safety profi les 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 naïve were treated with ETV monotherapy. Five of 243 patients had virologic breakthrough, and no muta-tions associated with resistance to ETV were identifi ed 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 fl ares.9,10

When to Stop HBV TherapyClinical profi les of chronic HBV

In CHB, therapy is guided by the clinical profi le 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 CPK7% at 1 year12% 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



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 HBVIn patients with immune active

chronic HBV, the treatment endpoint is HBeAg seroconversion. The treat-ment duration with pegylated inter-feron is fi 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 HBVIn patients who are HBeAg-

negative, the objective of treatment is to suppress HBV DNA, improve transaminase levels, and reduce in-fl ammation. In these patients, a high rate of relapse has been reported fol-lowing cessation of therapy and thus treatment is often indefi nite. 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 indefi nite 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 confi rmed (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 fl 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 (confi rmed 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 indefi nite therapy.

CirrhosisIn patients with CHB, with both

compensated and decompensated cir-rhosis, indefi nite 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.

SummaryThe 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 benefi ts of prolonged treatments when they are administered for durations greater than those of the clinical trials, which is of-ten necessary in clinical practice.

References1. Keeffe EB, et al. Clin Gastroenterol Hep-

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.


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.


Full references are available at www.healio.com/gastroenterology/education-lab and www.opencme.org.



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Determining If and When to Initiate Treatment in the Immunotolerant PatientWalid S. Ayoub, MD

Clinicians 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 InfectionThe 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 infl uence 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 infl ammation and fi 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-nifi cant HBV viremia. The immune-tolerance phase is fol-lowed by the immune-clearance phase. The immune-clear-ance phase describes a fl uctuation in the HBV DNA and ALT levels. This phase is characterized by the presence of various degrees of infl ammation and fi 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 infl ammation on liver biopsy. Reactivation phase describes a fl are of HBV characterized

by intermittent/persistent elevation of ALT and HBV DNA levels along with infl ammation 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 refl ected 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% confi -dence interval [CI] 6.7-14.4; P�0.01). 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 103 copies/mL, 1.0 to 9.9 x 104 copies/mL, and 1.0 to 9.9 x 105 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 fi 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 colleagues8 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



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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 fi brosis score and there was no change in infl ammatory activity between the initial biopsy and the biopsy at 5 years. Four patients with stage 1 fi brosis had regression of fi brosis during the study period. Additionally, all patients remained with signifi -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, D’Antiga and colleagues9 treated 23 chil-dren (predominantly Asians) with a mean age of 10 years, persistently normal ALT, and minimal or mild infl ammatory 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 study10 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 benefi t from treatment of patients in the immune-tolerance phase, larger and longer studies are needed to confi rm these observations.

The potential benefi t 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-leagues11 studied the T-cell function in the group studied by D’Antiga9 and demonstrated that the HBV specifi c re-sponse before therapy was weak. However, a change in the immune system occurred at weeks 28 and 52 of therapy. The HBV specifi c T-cell proliferation and the frequency of CD8+ T cells producing interferon-� increased signifi -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 107 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 fl are.

ConclusionThere is no clear benefi t 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 benefi cial 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 benefi cial based on the data from the pivotal trials of D’Antiga9 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.

References1. Yapali S, et al. Clin Gastroenterol Hepatol. 2014;12(1):16-26.



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.



1. Current treatment guidelines recommend initiatingHBV antiviral therapy in all the following patients with CHB, except:A. HBeAg-positive with elevated circulating viral DNA levelB. HBeAg-negative with elevated circulating viral DNA levelC. HBeAg-negative without signifi cant 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 DNAB. Normalization of serum ALT levelsC. 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. AdefovirB. EntecavirC. LamivudineD. Tenofovir

5. The best strategy to improve adherence to CHB antiviral therapy is: A. Asking patients about medication adherence every

12 monthsB. Spending 3 minutes or more with patients discussing

medication compliance during the offi ce visitC. Providing pamphlets written only in EnglishD. 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 therapyB. Low baseline serum HBV DNA levelC. Incomplete viral suppression during the fi rst 3 monthsD. Prior interferon treatment

7. A patient with CHB presents to your offi ce 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 fi rst-line for CHB therapy in this patient?A. LamivudineB. TenofovirC. AdefovirD. 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 seroconversionB. 3 months after seroconversionC. 6 months after seroconversionD. 12 months after seroconversion

10. The antiretroviral nucleoside/nucleotide analogs utilized to treat CHB have the following safety warning: A. Mitochondrial toxicityB. HypophosphatemiaC. OsteomalaciaD. Hyperglycemia


CME PosttestCME 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

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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 1I will develop individualized treatment strategies based on current best evidence for initiation of HBV treatment. Y N 2 1I will implement appropriate tests to characterize HBV infection and treatment response. Y N 2 1I will evaluate underlying causes of HBV treatment failure. Y N 2 1Other (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 ❏ Diffi culty in keeping up with evolving evidence to make treatment decisions ❏ Coordination of care with other care providers ❏ Other (Please provide below.)___________________________________________

_____________________________________________________________________

13. How confi dent are you in selecting the appropriate treatment for patients with chronic HBV infection?

❏ Extremely Confi dent❏ Very Confi dent❏ Somewhat Confi dent❏ Not at All Confi dent

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

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Questions about CME? Call us at 856-994-9400 ext. 504, Fax 856-384-6680

OFFICE USE ONLYEnduring 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 identifi ed learning objectives. Yes No2. This activity better prepared me to care for my patients. Yes No3. The content covered was useful and relevant to my practice. Yes No4. The activity was presented objectively and was free of commercial bias.* Yes No 5. Future activities concerning this subject matter are necessary. Yes No6. The activity addressed and provided strategies for overcoming barriers

to optimal patient care. Yes No7. 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 specifi c.

________________________________________________________________________

________________________________________________________________________

9. Approximately what percentage of the activity’s 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 1Will improve patient outcomes in your practice? Y N 1Helped you to have a better understanding of the topics? Y N 1Gave you a new perspective on the information which may help toimprove your practice? Y N 1Provided you with resources to use in your practice and/or withyour patients? Y N 1

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CME Registration Form

Volume 1 • Number 1 • August 2014 | CRITICAL ISSUES IN HBV




VINDICOmedical education6900 Grove Road • Building 100Thorofare, NJ 08086-9447

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6900 Grove Road, Bldg 100, Thorofare, NJ 08086 USAphone: 856-994-9400 • fax: 856-384-6680 • VindicoMedEd.com


Critical Issues in HBV

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