SYMPOSIA: HBV AND ITS THERAPY - The Canadian Association of ...

including the third annualcasl winter meetingSymposiA:Hbv AndIts Therapycanadian association for the study of the liverSunday, February 18, 20079am-10:30amFairmont Banff SpringsVan Horne A BallroomBanff, Alberta

WelcomeWelcome to the Symposia“Hepatitis B and its Therapy”There have been recent developments in our understanding of the molecular biology ofHBV leading to innovations in diagnostic testing and monitoring of patients. An expert panel hasprepared a current program to link these recent advances to emerging technology to test for viralload, genotype and drug resistant mutations.As well the recent introduction in Canada of new antiviral agents to treat HBV, is changingour therapeutic approach. A summary of the recent Canadian Consensus document will be presentedand discussed.Dr. Marc Deschênes, MDsymposia: hbv and its therapy Page 1

Learning ObjectivesCo-Chair1. To understand the role of new molecular tests in managing HBV patients.Dr. Marc Deschênes, md2. To understand the role of HBV DNA monitoring in the care of HBV patients.3. To understand the newly developed Canadian treatment guidelines in relationto other published documents.Dr. Marc Deschênes, MD is the Director, Division of Hepatology, McGill UniversityHealth Centre and he is the Medical Director of Liver Transplantation. He is Assistant Professor ofMedicine at McGill University (Division of Gastroenterology, Department of Medicine).After graduating from McGill University, with his Doctor of Medicine and Masterof Surgery (MD, CM) in 1988, Dr. Deschênes specialized in internal medicine and gastroenterology(1988-1994). He did his Hepatology Fellowship at Hôpital St-Luc – Université deMontréal (1994-1995) and then did a Liver Transplant Fellowship at the University of California,San Francisco (1995-1996).Over his career, Dr. Deschênes has be involved in clinical trials and lectured widely. He haswritten numerous scientific articles. He has participated in provincial and national working groups,special initiatives or co-chaired consensus guidelines addressing the management of patients withviral hepatitis, portal hypertension, and following liver transplantation. He is a member of ExaminationBoard in Gastroenterology, Royal College of Physician and Surgeons of Canada.In 2003 he was the Recipient of Certificate of Distinguished Service from the CanadianAssociation for the Study of the Liver. He was elected President of the CASL for 2 years starting inthe spring of 2006.The following faculty has indicated that he does have a significant financial interest and that the content of his presentationwill not include discussion of investigative use or off-label application of medicines, medical devices, or procedures:Faculty: Marc Deschênes Applicable Date: February 18Comment: Consultant: Hoffmann-La Roche, Novartis, ScheringPage 2 canadian association for the study of the liversymposia: hbv and its therapyPage 3

Co-Chair & SpeakerSpeakerDr. Morris Sherman, mdDr. Emmet B. Keeffe, md, macpUndergraduate training - University of Witwatersrand, graduated MB BCh in 1972.Internship and residency at Baragwanath Hospital in Johannesburg and Groote SchuurHospital in Cape Town.Research training at University of Cape Town. PhD granted in 1982.Post doctoral training at Albert Einstein College of Medicine in New York 1982-1984.On staff at Toronto General Hospital since 1984, currently Associate Professorof Medicine at University of Toronto.Chairman Canadian Viral Hepatitis Network, President of Canadian Association for Studyof the Liver.Dr. Emmet Keeffe is Professor of Medicine, Chief of Hepatology and Co-Director of theLiver Transplant Program at Stanford University Medical Centre. He obtained his MD degreefrom Creighton University and completed postgraduate training at the Oregon Health & ScienceUniversity and University of California, San Francisco. He is a past-president of the American GastroenterologicalAssociation and the American Society for Gastrointestinal Endoscopy, and servesas a member of the Subspecialty Board on Gastroenterology for the American Board of InternalMedicine. He is a Master of the American College of Physicians and a Fellow of the American GastroenterologicalAssociation, the American Society for Gastrointestinal Endoscopy, the AmericanCollege of Gastroenterology, and the Royal College of Physicians of Ireland. His research interestsinclude antiviral therapy of chronic hepatitis B and C, use of hepatitis vaccines, and liver transplantselection criteria and outcomes. He has published more than 500 papers, book chapters andmiscellaneous publications, and lectures widely at national and international scientific meetings,postgraduate courses, and miscellaneous educational programs.Interests in viral hepatitis and hepatocellular carcinoma.The following faculty has indicated that he does have a significant financial interest and that the content of his presentationmay/will include discussion of investigative use or off-label application of medicines, medical devices, or procedures:Faculty: Morris Sherman Applicable Date: February 18Comment: Advisory Board: Bristol-Myers Squibb, Gilead, Hoffmann-La Roche, NovartisResearch Support: Hoffmann-La Roche Speaker’s Bureau: Bristol-Myers Squibb, Gilead, Hoffmann-La RocheThe following faculty has indicated that he does have a significant financial interest and that the content of his presentationwill not include discussion of investigative use or off-label application of medicines, medical devices, or procedures:Faculty: Emmet Keefe Applicable Date: February 18Comment: Advisory Board/Consultant: Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Hoffmann-La Roche,Idenix-Novartis Research Support: Hoffmann-La Roche Speaker’s Bureau: Bristol-Myers Squibb, Gilead,GlaxoSmithKline, Hoffmann-La Roche, Idenix-NovartisPage 4 canadian association for the study of the liversymposia: hbv and its therapyPage 5

SpeakerAbstractDr. Mel Krajden md, frcp(c)Dr. Morris Sherman, mdAs Associate Director, BCCDC Laboratory Services Dr. Krajden’s research focus involvesthe molecular diagnosis of viruses, the assessment of correlates between infection and clinicaldisease, using molecular markers to monitor anti-viral efficacy in vivo, and the use of moleculartechniques (pathogen fingerprinting) to track microbial agents for epidemiological purposes. Hehas particular expertise in quantitative nucleic acid testing of cytomegalovirus, hepatitis B and Cviruses and inter-assay evaluation. He has also published in the fields of nucleic acid based detectionof both hepatitis B and C viruses. Since Jan 2001, he has served as the Director, HepatitisServices. This provincial program is focused on the integration of hepatitis prevention and careservices in BC. In partnership with Canadian Blood Services, the Provincial Blood CoordinatingOffice and the BCCDC, Dr. Krajden has also been instrumental in initiating an Anonymized DataLinkage Project: Application of Privacy Enhancing Technologies to Enhance Public Health andBlood Safety.There have been major changes in the understanding of the natural history of chronic hepatitis B over thelast 2-3 years. In addition, several new antiviral agents have become available that are able to suppress viral replicationmore potently and with less resistance than lamivudine. As a result, the approach to the management of hepatitis B haschanged dramatically and fairly suddenly. In order to determine best practices the Canadian Association for Study ofthe Liver held a consensus conference in January 2007. A consensus document is being prepared. This represents a draftversion of the consensus document. This abstract will only highlight some of the recommendations.1. Normal ALT is not a reason to deny patients treatment if the viral load is high and a biopsy showsevidence of significant disease.2. HBV DNA is the main (but not the only) determinant of treatment, not ALT.3. HBeAg seroconversion cannot be taken as evidence of permanent inactivation of disease. All patientswho have undergone HBeAg seroconversion must continue to be followed regularly.4. Lamivudine remains a treatment option. Although all the other agents have advantages over lamivudinein terms of potency and lower rates of resistance, lamivudine remains an acceptable alternative simplybecause of cost.5. To minimize the possibility of resistance developing patients with high viral loads should be treatedwith more potent agents. Patients receiving lamivudine, adefovir or telbivudine should have treatmentregimens changed if suppression of virus is inadequate by 24-52 weeks.6. Lamivudine resistance should be detected early by following patients at 3 monthly intervals with HBVDNA. A rise in viral load precedes a rise in ALT. By the time that ALT rises the viral load is usually high,reducing the efficacy of the second line agent.7. Lamivudine resistance should be treated by addition of adefovir.The following faculty has indicated that he does have a significant financial interest:Additional recommendations will be discussed during the presentation.Faculty: Mel Krajden Applicable Date: February 18Comment: Advisory Board: Gilead, Hoffmann-La Roche Educational Support: Hoffmann-La Roche, ScheringResearch Support: Hoffmann-La Roche, ScheringPage 6 canadian association for the study of the liversymposia: hbv and its therapyPage 7

NotesAbstractDr. Morris Sherman, mdDr. Emmet B. Keeffe, md, macp. Chronic hepatitis B is diagnosed in patients with elevated alanine aminotransferase (ALT) levels, highHBV DNA levels (defined below), and necroinflammation on liver biopsy.. The natural history of HBV infection can be divided into 4 phases: immune tolerant, immune clearance(HBeAg-positive chronic hepatitis B), non-replicative (inactive HBsAg carrier), and reactivation. (HBeAg-negative chronic hepatitis B).Treatment is currently recommended for patients in the immune clearance and reactivation phasesthose. with HBeAg-positive or HBeAg-negative chronic hepatitis B.ALT criteria used for determining the indications for therapy should be the revised upper limits of. normal, i.e., 19 U/L in women and 30 U/L in men.The primary goal of therapy for chronic hepatitis B is long-term suppression of serum HBV DNA,. which will likely reduce progression to cirrhosis and HCC.The FDA-approved therapies for chronic hepatitis B include interferon alfa-2b (1991), lamivudine. (1998), adefovir (2002), entecavir (2005), peginterferon alfa-2a (2005), and telbivudine (2006).The currently preferred treatments include adefovir, entecavir, telbivudine, and peginterferon alfa-2a;standard interferon alfa-2b has been replaced by peginterferon alfa-2a, and lamivudine is not a preferred. first-line drug due to high rates of resistance.HBeAg-positive chronic hepatitis B patients should receive treatment when serum HBV DNA levels are. ≥ 20,000 IU/mL and ALT levels are elevated, particularly ≥2-fold.HBeAg-negative chronic hepatitis B patients should receive treatment when serum HBV DNA levels. are ≥ 2,000 IU/mL and ALT levels are elevated.Patients considering peginterferon alfa-2a therapy should be tested for HBV genotype; genotype Aresponds much better than genotype D (both common in Caucasians), and genotype B responds somewhatbetter than genotype C (both common in Asians).. All patients with chronic hepatitis B and cirrhosis with HBV DNA levels ≥ 2,000 IU/mL should betreated. There is increasing evidence supporting the use of combination nucleoside/nucleotide agentsin these patients, and therapy should probably be long-term for both HBeAg-positive and HBeAg-negative patients.Page 8 canadian association for the study of the liversymposia: hbv and its therapyPage 9

AbstractNotesContinuedDr. Emmet B. Keeffe, md, macp. The rates of resistance with long-term therapy are high with lamivudine (65-70% at 4-5 years),intermediate with adefovir (29% at 5 years of therapy) and telbivudine (21.6% in HBeAg-positive and8.6% in HBeAg-negative patients), and low with entecavir in the absence of prior lamivudine resistance(1.1% after 4 years of therapy). Patients with lamivudine resistance have a 32% rate of novel mutationsafter 3 years of entecavir therapy. Resistance does not occur with interferon or peginterferon therapy.. Serum HBV DNA should be monitored every 3 to 6 months to confirm initial response to treatment(>1 log10 copies/mL decreases from baseline) at week 12, ensure adequate suppression after 24 weeksof therapy (1 log10 copies/mL from nadir value on treatment) during long-term treatment.. On-treatment monitoring strategies to define early virologic responses that are predictive of betteroutcomes and a reduced risk of viral resistance have been recently proposed (roadmap concept).Measurement of the absolute level of HBV DNA level at week 24 is considered essential in the roadmapconcept, and virologic responses at this time point are categorized as complete, partial, or inadequate.Complete virologic response is defined as negative HBV DNA (

NotesDr. Mel Krajden md, frcp(c)Page 12canadian association for the study of the liver

This program has been submitted for Category 1 accreditation under the Royal Collegeof Physicians and Surgeons of Canada Maintenance of Certification Program by the Canadian Association of Gastroenterology.Sponsored by an Educational Grant from Hoffmann-La Roche Limited