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Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF Program Chair Leonard Miller Professor of Medicine University of Miami Scho

Introduction and Program Overview. Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF Program Chair Leonard Miller Professor of Medicine University of Miami School of Medicine Miami, Florida. Program Overview.

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Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF Program Chair Leonard Miller Professor of Medicine University of Miami Scho

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  1. Introduction and Program Overview Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF Program Chair Leonard Miller Professor of Medicine University of Miami School of Medicine Miami, Florida

  2. Program Overview Chronic hepatitis B (HBV) infection is significantly under-diagnosed and under-treated in the US Much new data has emerged, increasing our knowledge of the natural history of this disease and its treatment Effective new anti-HBV agents and novel treatment approaches for long-term management are now in use Interactive case presentations will help us review the latest developments in the understanding and treatment of the disease

  3. Educational Objectives Upon completion of this activity, participants should be able to: DESCRIBE the epidemiology and natural history of hepatitis B virus (HBV) infection IMPLEMENT an activity of screening, vaccination, and diagnosis of HBV within their clinical practices EVALUATE the risks and benefits of available agents for treating chronic HBV infection EVALUATE current data on the potential use of combination therapy for patients with chronic HBV infection

  4. Agenda The Hepatitis B Virus: A Silent Killer Whom to Treat/When to Treat Treatment Options for Chronic HBV Infection Combination Therapy: Controversies and Uncertainties

  5. Program Faculty Program Chair Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF Leonard Miller Professor of Medicine Director, Schiff Liver Institute Director, Center for Liver Diseases Division of Hepatology University of Miami School of Medicine Miami, FL Marion Peters, MD, FRACP Professor of Medicine Chief of Hepatology Research University of California, San Francisco San Francisco, CA Mark Sulkowski, MD Associate Professor of Medicine Medical Director, Viral Hepatitis Center Johns Hopkins University School of Medicine Baltimore, MD Norah A. Terrault, MD Associate Professor of Medicine Director, Viral Hepatitis Research in Liver Transplantation Dept of Medicine, Division of Gastroenterology University of California, San Francisco San Francisco, CA Tram T. Tran, MD Assistant Professor of Medicine Geffen UCLA School of Medicine Division of Gastroenterology Medical Director of Liver Transplant Comprehensive Transplant Center Cedars Sinai Medical Center Los Angeles, CA

  6. Audience Participation Audience Response System Used to pose a series of questions during the meeting At slide prompts, key in your answers on the keypads Please return your keypad at the end of the program Questions? Question cards Please jot down your questions, and staff will pick them up during the course of the meeting Microphones

  7. Accreditation Statement This activity has been planned and implemented through the joint sponsorship of the University of Kentucky College of Medicine and HealthmattersCME The University of Kentucky College of Medicine designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credits™

  8. How to Obtain CME Credit Complete this activity in its entirety After the activity, go to www.cecentral.com/getcredit Enter activity code MLN09103 Log in or register for a free account Complete activity evaluation and get credit A printable certificate will be issued

  9. Disclosure Statements Program faculty have disclosed their relevant financial relationships with commercial interests that produce health care goods and/or services consumed by, or used on patients. Written disclosures can be found within your folder.

  10. Tram T. Tran, MD Assistant Professor of Medicine Geffen School of Medicine at UCLA Medical Director of Liver Transplant Comprehensive Transplant Center Cedars-Sinai Medical Center Los Angeles, California The Hepatitis B Virus:A Silent Killer

  11. Case Presentation A 44-year-old Russian man who immigrated to the United States in 1989 is seeing you for abnormal transaminase levels. - ROS: occasional flares of diarrhea and abdominal pain, currently asymptomatic - PMH: Crohn’s disease; previously vaccinated for hepatitis B virus - Social: 1-2 drinks per week, works construction - Family Hx: Mother d. cirrhosis; was “drinker” - Meds: 5-aminosalicylic acid (5-ASA) - PE: normal

  12. Let’s Vote!

  13. Audience Response Question 0 New CDC 2008 Guidelines recommend HBV screening in immigrants from endemic areas with hepatitis B prevalence of: • > 25% • >10% • >8% • >2%

  14. Hepatitis B: Region/Country CDC.MMWR 2008

  15. Incidence* of Acute Hepatitis B, by Age Group, Sex, and Year – United States, 1990-2002 20 Males aged 0-19 yr Males aged 20-39 yr Males aged ≥40 yr Females aged 0-19 yr Females aged 20-39 yr Females aged ≥40 yr Total 16 12 Incidence 8 4 0 1990 1992 1994 1996 1998 2000 2002 Year *Per 100,000 population.

  16. Hepatitis B: Disease Progression Liver Cancer (HCC) 5%-10% 2%-6% Death Liver Transplantation Acute Infection Cirrhosis Chronic Infection 10%-30% 90% in perinatal 30%-90% in children <5 years old 5% in healthy adults Higher in HIV, immunosuppressed Chronic HBV is the 6th leading cause of liver transplantation in the US Liver Failure (Decompensation) 23% within 5 years Torresi J et al. Gastroenterology. 2000;118(2 Suppl 1):S83-S103. Fattovich G et al. Hepatology. 1995;21(1):77-82. Moyer LA et al. Am J Prev Med. 1994;10(Suppl):45-55. Perrillo RP et al. Hepatology. 2001;32(2):424-432.

  17. Asian-American Age-Adjusted Liver Cancer Rates (California, 2000-2002) Incidence Mortality Male Female Male Female 54.3 35.5 33.7 Rate (per 100,000) Rate (per 100,000) 26.6 23.3 19.9 16.8 15.8 15.9 11.5 12.0 10.4 9.3 8.1 8.3 7.6 7.8 7.8 6.8 6.0 5.4 4.2 2.5 2.7 Chinese Filipino Viet- namese Korean Japanese White Chinese Filipino Viet- namese Korean Japanese White Approximately 3.7 million Asians in California. Cancer data from California Cancer Registry. McCracken M et al. CA Cancer J Clin. 2007;57:190-205.

  18. Case Presentation: Laboratory Findings CBC: WBC 5.5, Hgb 12.5, Plt 288 AST 39 IU/L, ALT 35 IU/L Bilirubin 1.0 mg/dL, INR 1.1, albumin 3.7 g/dL HBsAg: positive HBeAg: negative Anti-HBe: positive HBV DNA 1800 IU/mL HCV, HIV, HDV negative

  19. Let’s Vote!

  20. Audience Response Question 0 This patient is most likely in which stage of CHB infection? • Immune tolerant • Immunoactive/immune clearance • Inactive carrier • HBeAg CHB • Can’t tell

  21. Phases of HBV Infection Yim JY, Lok AS-F. Hepatology. 2006;43:S173-S181.

  22. Case Presentation (cont’d) Serial follow-up of his liver tests reveals - ALT fluctuation 30105 - HBV DNA 1800 IU/mL 7600 IU/mL

  23. ALT and Histology 192 patients (Boston) HBV DNA > 10,000 copies/mL Liver biopsy data Stratified by ALT - Persistently normal (< 40 IU/L), n=59 - 1-1.5 x ULN, n=26 - >1.5 x ULN, n=107 Lai M et al. J Hepatol. 2007;47(6):760-767.

  24. Grade of Inflammation by ALT Group 78% 54% 34% PNALT, persistently normal ALT. Lai M et al. J Hepatol. 2007;47(6):760-767.

  25. Stage of Fibrosis by ALT Group 62% 18% 34%

  26. Case Presentation (cont’d) Liver biopsy is performed: - Grade 2-3 inflammation - Stage 2 fibrosis

  27. HBeAg Seroconversion 298 patients with documented HBeAg seroconversion - 116 treatment induced, 182 spontaneous Reactivation in 71 patients (39%) - Older age, male gender, and higher ALT at seroconversion were risks for reactivation (all P <.006) - No difference between interferon, adefovir, lamivudine treatment Treatment-induced seroconversion less durable than spontaneous - Remission of ALT shorter (14 vs 22 months, P=.037) - More likely to have HBeAg reactivation at 48 months (38% vs 25%, P=.048) Lim G et al. 58th AASLD; 2007; Boston. Poster 937.

  28. HBeAg Seroconversion to Anti-HBe Development of cirrhosis complications and HCC - 3233 Chinese patients - Mean follow-up 46.9 months Yuen MF et al. Gut 2005;54(11):1610-1614.

  29. Incidence of Cirrhosis: HBeAg Status Taiwan and Korea Europe 50 50 HBeAg negative HBeAg positive HBeAg negative HBeAg positive 40 40 30 30 20 20 Percent Percent 10 10 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Fattovich G et al. J Hepatol. 2008;48(2):335-352.

  30. Cumulative Incidence of Hepatocellular Carcinoma (HCC) Taiwan, China, Singapore, Koreaand Japan Europe and USA 20 20 Cirrhosis Chronic hepatitis Inactive carrier Cirrhosis Chronic hepatitis Inactive carrier 15 15 10 10 5 5 Percent Percent 1 1 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Fattovich G et al. J Hepatol. 2008;48(2):335-352.

  31. AASLD Guidelines: Periodic Screening for HCC At-risk hepatitis B carriers - Asian males >40 years of age - Asian females >50 years of age - All cirrhotic hepatitis B carriers - Family history of hepatocellular carcinoma - Africans >20 years of age - Those with high HBV DNA levels and those with ongoing hepatic inflammatory activity remain at risk for hepatocellular carcinoma Liver ultrasound every 6 to 12 months Bruix J et al. Hepatology. 2007;42:1208-1236.

  32. Case Presentation (cont’d) Patient’s Crohn’s disease flares; consideration is made for steroids and possibly anti-tumor necrosis factor (TNF) therapy

  33. Let’s Vote!

  34. Audience Response Question 0 Is it necessary to screen patients for HBV before anti-TNF therapy? • Yes, screen all patients • Yes, but only those with risk factors for HBV • No, just monitor • No, never

  35. Screening: New CDC Guidelines CDC Guidelines 2006 - Persons born endemic areas >8% prevalence - Pregnant women, infants - Sexual, household contacts of HBV+ - HIV - Needlestick/assault - Hemodialysis patients - Blood donors CDC Guidelines 2008 - Persons born endemic areas >2% prevalence - US-born children of immigrants from high- risk areas - Injection drug users - MSM - Immunosuppressive Rx GI, rheumatologic, oncologic, tx - ALT/AST elevation Centers for Disease Control; MMWR Sept 19 2008

  36. Case Presentation (cont’d) Patient started on antiviral therapy prior to anti-TNF treatment HBV DNA becomes undetectable ALT remains persistently normal

  37. Summary HBV burden is significant, some groups disproportionately affected New CDC guidelines have broadened screening recommendations Disease progression may be independent of biochemical and serological markers

  38. Norah Terrault, MD, MPH Associate Professor of MedicineDirector of Viral Hepatitis Research in Liver TransplantationUniversity of California, San FranciscoSan Francisco, California Whom to TreatWhen to Treat

  39. Goals of Treatment Improvedsurvival Improvedhistology Anti-HBs+ Loss of HBsAg Anti-HBe+ Loss of HBeAg Loss of HBV DNA HBV is controlled not eradicated TIME

  40. Decision to Treat: Balancing Benefits and Risks Costs Side EffectsDrug Resistance Risk of Liver Complications

  41. Factors Associated With Disease Progression in Patients With CHB Host Factors >40 years of age Male Immune status Virus Factors High serum HBV DNA concentrations Prolonged time to HBeAg seroconversion Development of HBeAg(-) chronic hepatitis Core promoter HBV variant Genotype C Environmental Factors • Concurrent infection (HCV, HDV, HIV) • Alcohol consumption • Diabetes mellitus • Obesity Yim HJ, Lok ASF. Hepatology. 2006;43:S173-S181.

  42. Persistent Elevated HBV DNA and Cumulative Incidence of HCC P<.001 12 67% ≥40 yrs and 62% male 10.1 (6.3-16.2) P<.001 10 7.3 8 (3.5-15.3) Adjusted HR for HCC (95% CI) P<.001 6 3.8 (1.7-8.4) 4 P= NS 2 1 10/120 55/537 26/2034 8/146 0 ≥105 → 104 -<105 ≥105 <104 ≥105 ≥105 <104 Not Tested HBV DNA : Baseline Follow-up (copies/mL) Chen CJ et al. JAMA. 2006;295(1):65-73.

  43. Case Presentation A 37-year-old Asian woman is referred for HBsAg-positive status. Discovered when mother was diagnosed with HCC at age 65 Asymptomatic, recently married, husband vaccinated, no children No medications other than oral contraceptives Initial lab results: - HBeAg+, HBV DNA 2.5 million IU/mL - ALT 30 IU/L, AST 27 IU/L, total bilirubin 0.6 mg/dL, albumin 4.0, g/dL, INR 1.0, platelets 300K

  44. Case Presentation (cont’d) Ultrasound findings: - Normal-appearing liver with normal echotexture, no splenomegaly or collaterals Repeat labs: - 3 months: ALT 35 IU/L - 6 months: ALT 31 IU/L, HBV DNA 1.3 million IU/mL

  45. Let’s Vote!

  46. Audience Response Question 0 What do you recommend at this point? • Continue monitoring ALT every 3-6 months and treat if ALT increases to ≥2 X ULN • Obtain HBV genotype and treat if genotype A • Start treatment, regardless of HBV genotype • Obtain liver biopsy and treat if significant inflammation or fibrosis

  47. Recommendations: Whom to Treat AASLD Guidelines 2007 Treatment indicated for ‘active’ disease: - ALT ≥2 ULN - HBV DNA ≥20,000 IU/mL Or if - ALT 1-2 ULN and ≥age 40, consider biopsy and treat if significant fibrosis or necroinflammation is present

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