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Updated Approaches for Treating Hepatitis B

Syllabus This CME/CE audioconference is part of the curriculum of the Advanced Certificate Program II: Management of Chronic Hepatitis B

Table of Contents Faculty Roster/Meeting Agenda. ............................................................. 3 Drugs or Investigational Agents Mentioned in This Presentation....... 4 CME/CE Information. ............................................................................ 5 Disclosure Information. ........................................................................... 5 Letter from the Chair. .............................................................................. 6 Overview.................................................................................................... 7 Suggested Readings................................................................................. 14

This independent CME/CE activity is supported by an educational grant from Bristol-Myers Squibb Company. Copyright © 2007. Projects In Knowledge, Inc. All rights reserved. Projects In Knowledge, Overlook at Great Notch, 150 Clove Road, Little Falls, NJ 07424 www.projectsinknowledge.com

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Updated Approaches for Treating Hepatitis B

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Faculty Roster Faculty

Co-Chair Adrian M. Di Bisceglie, md, facp Professor of Internal Medicine Chief of Hepatology Saint Louis University School of Medicine St. Louis, Missouri

Kris V. Kowdley, md Professor of Medicine Division of Gastroenterology/Hepatology University of Washington Medical Center Seattle, Washington

Adrian M. Di Bisceglie, md, facp, and Robert G. Gish, MD, co-chairs of Advanced Certificate Program II: Management of Chronic Hepatitis B, alternate to help develop content for the audioconferences. This audioconference was developed by Dr. Adrian M. Di Bisceglie and Dr. Kris V. Kowdley.

Agenda 60-minute audioconference to include: • Whom to Treat

- AASLD Guidelines: 2007 Update



- US Treatment Algorithm: Updated Recommendations 2006

• Treatment Options for Chronic Hepatitis B Virus Infection

- Lamivudine



- Adefovir



- Entecavir



- Peginterferon



- Telbivudine

• Resistance to Antiviral Agents • Conclusions and Clinical Recommendations



Updated Approaches for Treating Hepatitis B

Drugs or Investigational Agents Mentioned in This Presentation Projects In Knowledge requires that faculty disclose any reference(s) to unlabeled or unapproved uses of drugs or devices as part of their presentations. The audience is advised that this CME/CE activity will contain such discussion.

Drug List Generic

Trade Name(s)

Adefovir dipivoxil

Hepsera®*

Emtricitabine

Emtriva®

Emtricitabine/tenofovir

TruvadaTM

Entecavir

Baraclude®*

Interferon alfa-2b

Intron®*

Lamivudine

Epivir-HBV®*

Peginterferon alfa-2a

Pegasys®*

Telbivudine

TyzekaTM*

Tenofovir

Viread®

*Approved by the Food and Drug Administration (FDA) for the treatment of hepatitis B virus infection



Target Audience

Disclosure Information

This activity is designed for gastroenterologists, hepatologists, and other clinicians who care for patients with hepatitis B infection or those at increased risk for acquiring the infection.

The Disclosure Policy of Projects In Knowledge requires that presenters comply with the Standards for Commercial Support. All faculty are required to disclose any personal interest or relationship they or their spouse/partner have with the supporters of this activity or any commercial interest that is discussed in their presentation. Any discussions of unlabeled/unapproved uses of drugs or devices will also be disclosed.

Activity Goal The goal of this CME/CE activity is to examine the latest information about treating chronic hepatitis B virus (HBV) infection, taking into account the most current guidelines, recent FDA approvals, and new data, in order to effectively suppress viral replication.

Learning Objectives • S elect an appropriate antiviral agent for treating chronic HBV infection by considering current treatment guidelines and recent evidence-based data to improve patient responses. • M  onitor HBV DNA and adjust treatment approaches based on response and development of resistance in patients with hepatitis B in order to achieve and maintain viral suppression.

CME Information—Physicians Statement of Accreditation Projects In Knowledge is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

For complete prescribing information on the products discussed during this CME/CE activity, please see your current Physicians’ Desk Reference (PDR). Adrian M. Di Bisceglie, MD, FACP, has received grant/research support from Gilead Sciences, Inc, Idenix Pharmaceuticals, Roche Pharmaceuticals, SciClone Pharmaceuticals, and Vertex Pharmaceuticals Inc; is a consultant for Abbott Laboratories, Bristol-Myers Squibb Company, Chiron Corporation, Metabasis Therapeutics, and SciClone Pharmaceuticals; is on the speakers bureau of Bristol-Myers Squibb Company, Gilead Sciences, Inc, and Roche Pharmaceuticals; and is a member of advisory boards for Bristol-Myers Squibb Company, Idenix Pharmaceuticals, Inc, Novartis Pharmaceuticals Corporation, Pharmasset, Roche Pharmaceuticals, and Vertex Pharmaceuticals Incorporated. Kris V. Kowdley, MD, is on the speakers bureau of Gilead Sciences, Inc and Hoffmann-La Roche Inc; and is a consultant for Bristol-Myers Squibb Company and Gilead Sciences, Inc. Peer Reviewer has no significant relationships to disclose.

Credit Designation Projects In Knowledge designates this educational activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

CME Information—Physician Assistants Projects In Knowledge will issue a certificate of participation for each course the participant completes. Please check with your organization and/or society for reciprocity.

CE Information—Nurses This activity, Updated Approaches for Treating Hepatitis B, has been approved by the American Association of Critical-Care Nurses (AACN) for a maximum of 1.0 contact hour. Provider #00012705.

Projects In Knowledge’s staff members have no significant relationships to disclose. Conflicts of interest are thoroughly vetted by the Executive Committee of Projects In Knowledge. All conflicts are resolved prior to the beginning of the activity by the Trust In Knowledge peer review process. The opinions expressed in this activity are those of the faculty and do not necessarily reflect those of Projects In Knowledge. This CME/CE activity is provided by Projects In Knowledge solely as an educational service. Specific patient care decisions are the responsibility of the clinician caring for the patient. There is no fee for this activity. This independent CME/CE activity is supported by an educational grant from

Bristol-Myers Squibb Company.



Updated Approaches for Treating Hepatitis B

Dear Colleague: As a result of new therapies, updated guidelines, and data from recent studies, approaches to treating chronic hepatitis B virus (HBV) infection are evolving and being refined. Selection of an appropriate antiviral agent is critical for optimal suppression of HBV DNA in the short and long term and for prevention of treatment resistance. Initial selection of some previously standard antiviral therapies such as lamivudine may predispose patients to cross-resistance with other antivirals. It is now more important than ever that clinicians remain up-to-date about current thinking on the management of HBV infection. We are excited that you have decided to join us for this CME/CE audioconference, Updated Approaches for Treating Hepatitis B, which is part of the curriculum of the Advanced Certificate Program II: Management of Chronic Hepatitis B. This activity will provide the most current information about treatment of chronic infection with HBV, including 2006 updates to treatment guidelines and the newest data and expert opinions regarding use of lamivudine, adefovir, entecavir, peginterferon, and telbivudine. We are sure you will find these current perspectives helpful in furthering your care of patients infected with HBV. Sincerely, Adrian M. Di Bisceglie, md, facp Co-Chair



Overview Chronic HBV infection carries a risk of serious and even lifethreatening complications. Therapies for HBV rarely result in permanent remission of the disease. However, they can be effective tools for prevention of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and death by providing longterm suppression of HBV replication.

Current Guidelines on Managing Hepatitis B Current clinical guidelines help direct the selection of appropriate treatment candidates and the type of therapy. The American Association for the Study of Liver Diseases (AASLD) commissioned a set of guidelines by Lok and McMahon in 2001, with updates made in 2004 and 2007. Another US guideline, referred to as the US Treatment Algorithm, was developed by a panel of US hepatologists. Published in 2004, the US Treatment Algorithm was updated in 2006. Both guidelines utilize HBV DNA and alanine aminotransferase (ALT) levels to guide the decision to start treatment. Although the specific threshold levels vary between the guidelines, the shared core intention is to treat patients with active liver disease and high levels of HBV replication. Recommendations in the 2007 AASLD treatment guidelines vary according to the patient’s HBeAg, HBV DNA, and ALT status. For HBeAg-positive patients without cirrhosis, those with HBV DNA >20,000 IU/mL should be considered for treatment if ALT levels become elevated to >2 times the upper limit of normal (ULN). (Liver biopsy may be considered prior to treatment.) Biopsy should be considered if an HBeAgpositive patient with HBV DNA >20,000 IU/mL has an ALT level persistently above normal but ≤ 2 times the ULN, or if he/she is over age 40 years or has a family history of hepatocellular carcinoma. Treatment would then be considered if biopsy showed significant inflammation or fibrosis. For HBeAg-negative patients, treatment is recommended for those who have HBV DNA >20,000 IU/mL and ALT >2 times the ULN. Biopsy should be considered for HBeAg-negative patients with HBV DNA >2000 IU/mL and ALT of between 1 and 2 times the ULN. Treatment is otherwise not required for HBeAg-positive or -negative patients with lower HBV DNA and ALT levels, but ongoing monitoring for a change in HBV DNA or ALT is recommended.

For patients with cirrhosis, the treatment strategy is primarily dependent upon HBV DNA and compensation status. In patients with compensated cirrhosis, treatment should be considered for all patients with HBV DNA >2000 IU/mL, and those with lower HBV DNA levels who also have elevated ALT. If HBV DNA is undetectable, however, the patient with compensated cirrhosis should be observed. If the cirrhosis is decompensated, the patient should be referred for liver transplant regardless of whether HBV DNA or HBeAg is present, and the patient should be considered for treatment. The updated 2007 AASLD guidelines state that any of the six approved antiviral agents can be used in the treatment of chronic HBV infection; however, peginterferon, adefovir, or entecavir are preferred. For patients with compensated cirrhosis, adefovir or entecavir is preferred, and interferon and peginterferon should be avoided due to their risk of provoking hepatitis flare. For patients with decompensated cirrhosis, the preferred treatment is lamivudine/adefovir combination therapy; however, telbivudine/adefovir or entecavir may be alternatives, although there are fewer supportive data.

According to the updated US Treatment Algorithm, patients without cirrhosis who are HBeAg positive should receive treatment if HBV DNA is ≥20,000 IU/mL (≥105 copies/mL) and ALT is elevated. If HBV DNA is ≥20,000 IU/mL but ALT is normal, monitor every 3 to 12 months and consider a biopsy if the patient is older than 35 to 40 years. Treatment is warranted for those with significant histologic disease despite 

Updated Approaches for Treating Hepatitis B

the normal ALT. HBeAg-positive patients with lower HBV DNA levels (