1. Can One Pill A Day Keep Hepatitis B Away? Scott K. Fung, MD, FRCPC Toronto General Hospital University of Toronto November 30, 2009 TGH

2. Learning Objectives To discuss new ‘normal’ values for ALT and define significant HBV DNA levels To briefly review antiviral treatment options for chronic HBV infection in 2009 To illustrate indications for treatment of chronic hepatitis B and monitoring strategies using case studies

3. Quiz 1 23 4 A.Wilson disease B.Hereditary hemochromatosis C.Chronic hepatitis B and HCC D.Fatty liver

4. Liver Disease in Canada HBV HCV NAFLD Alcohol Others

5. Age-Standardized Mortality Cause of Death2001*2003*2005* Chronic liver disease/ cirrhosis6.56.46.1 Renal failure8.38.58.3 Diabetes mellitus19.320.519.1 Heart disease143.1133.3121.5 Malignant neoplasm178.7175.6170.3 *Rate per 100,000 population, both sexes

6. Hepatitis B and HCC in Canada Rate of HCC is rising in Canada and most Western countries Related to immigration from HBV endemic parts of the world No accurate data on overall prevalence of HBV and HCC in Canada Estimated 1981-2005 using 2006 National census

7. Hepatitis B and HCC in Canada Between 1981-2005, Canada accepted 4 million new immigrants 90% from HBV endemic areas (>3-7%) HBsAg+ immigrants = 209,401 individuals HBsAg+ nonimmigrants = 182,000 indiv. Overall prevalance in Canadian pop =1.3 % Limited impact of HBV vaccine ~500 immigrants will develop HCC per yr (0.22/100,000/yr) Leber et al, Can J Gastro 2009

8. All HBV Carriers are Potential Treatment Candidates Slow down Observe closely May need Rx later Stop Rx not indicated Go ahead with Rx

9. Stages of Chronic Hepatitis B Infection Lok, Gastroenterology 2007

10. HBeAg-negative CHB Viral Load >3–4 log IU/mL HBeAg-negative –pre-core / core promoter mutant ALT intermittently abnormal Biopsy –inflammation intermittent –fibrosis progression Risk of complications (cirrhosis/ HCC) higher Adapted from Yim & Lok, Hepatology 2006; 43: S173

11. Disease Progression Chronic hepatitis Cirrhosis Liver Failure Death or OLTx 20% 15-40% HCC 10-20% EASL Consensus Guidelines. J Hepatol 2003 Lok et al, Hepatology 2004 Age40 50 60 Years

12. 12 Complications of HBV Ascites Varices HCC

13. Danger Signs: Time To Worry Cirrhosis  INR  Bilirubin  Albumin  Platelets  Confusion  Jaundice  GI bleeding  Ascites

14. HBV DNA New unit of measurement for HBV DNA = logs IU/ml

15. HBV Viral load in Log Scale Log scales simplify large numeric differences in HBV DNA values Error of the test = 0.5 log IU Tripling of viral load = within the error of the test Following trends in HBV DNA important If in doubt, repeat testing to confirm

16. How High Can You Go? 1 = 10 0 = 1E0 10 = 10 1 = 1E1 100 = 10 2 = 1E2 1,000 = 10 3 = 1E3 10,000 = 10 4 = 1E4 100,000 = 10 5 = 1E5 1,000,000 = 10 6 = 1E6 10,000,000 = 10 7 = 1E7 100,000,000 = 10 8 = 1E8 1,000,000,000 = 10 9 = 1E9 10,000,000,000 = 10 10 =1E10 Low Medium High HBeAg-neg HBeAg-pos

17. REVEAL HBV Iloeje et al, JAMA 2006 Chen et al, Gastroenterology 2006 Cirrhosis HCC HCC in HBeAg-negative patients with normal ALT

18. HBV DNA

19. HBV DNA Report 4.3 E+7 43,000,000 7.4 log

20. 20 “Normal” ALT Levels Yuen et al, Gut 2005 Upper Limit of Normal Male 53 U/L Female 31 U/L

21. ALT and Liver Mortality Tai et al, Hepatology 2009

22. ALT Normal Values Current upper limit of normal too high New standard for ALT –Male <30 U/L –Female <19 U/L Normal ALT does not exclude significant liver disease Patients should not be denied antiviral treatment based on normal ALT Sherman et al, Can J Gastro 2007

23. Histology in HBeAg-positive CHB Yang et al, Chinese J Dig Dis 2002; 3: 150 Note: This study population consisted of males over the age of 30

24. Beware ‘Normal’ ALT Nguyen et al, Am J Gastro 2009 Predictors of Sig. Fibrosis: Older Age Fluct. ALT

25. HBeAg-positive Patients Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C HBeAg-positive No treatment. Monitor every 3 months with ALT and HBV DNA Rule out other causes of liver disease Monitor ALT every 3 months. Consider biopsy if age >35–40 years, and treat if significant disease Treat ALT normal ALT elevated for 3–6 months HBV DNA >20,000 IU/mL (>105,200 copies/mL) HBV DNA <20,000 IU/mL (<105,200 copies/mL) Based on a conversion factor of 1 IU/mL = 5.26 copies/mL

26. Selection of Specific Agents for HBeAg-positive CHB Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C Standard interferon Pegylated interferon Adefovir Entecavir* Tenofovir* † Entecavir* Tenofovir* † HBV DNA <20 million IU/mL (<105.2 million copies/mL) HBV DNA >20 million IU/mL (>105.2 million copies/mL) HBeAg-positive *If Entecavir or Tenofovir not available, use Telbivudine or Lamivudine † Approved since publication of the guidelines Based on a conversion factor of 1 IU/mL = 5.26 copies/mL

27. HBeAg-negative Patients Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C Based on a conversion factor of 1 IU/mL = 5.26 copies/mL HBeAg-negative No treatment. Monitor every 3 months for 1–2 years with ALT and HBV DNA Rule out other causes of liver disease Monitor ALT every 3 months, or consider biopsy, since ALT often fluctuates. Treat if significant disease. Long-term treatment required (oral agents) Treat. Long-term treatment required (oral agents) ALT normal ALT elevated HBV DNA >2,000 IU/mL (>10,520 copies/mL) HBV DNA <2,000 IU/mL (<10,520 copies/mL)

28. Selection of Specific Agents for HBeAg-negative CHB Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C Pegylated interferon Adefovir Entecavir* Tenofovir* † Entecavir* Tenofovir* † HBV DNA <20 million IU/mL (<105.2 million copies/mL) HBV DNA >20 million IU/mL (>105.2 million copies/mL) HBeAg-negative *If Entecavir or Tenofovir not available, use Telbivudine or Lamivudine † Approved since publication of the guidelines Based on a conversion factor of 1 IU/mL = 5.26 copies/mL

29. Comparison of Oral Therapy for Chronic Hepatitis B LamivudineAdefovirEntecavir*TelbivudineTenofovir* Relative Antiviral Potency ++ +++++++++++ ResistanceHighLowVery lowIntermediateVery low * Recommended as first-line therapy for HBV

30. HBV Treatment in Ontario in 2009 Public FormularyPrivate Formulary Treatment-Naive (1 st Line) Tenofovir* Entecavir* Lamivudine Standard IFN-α Adefovir Tenofovir Tenofovir + FTC Telbivudine PEG-IFN Standard IFN Lamivudine Treatment-Experienced (2 nd Line) Adefovir** Tenofovir**├ Entecavir Tenofovir Tenofovir + FTC Telbivudine PEG-IFN Standard IFN Lamivudine * Cirrhosis with DNA > 6 log IU/ml ** LAM virologic breakthrough and F3/F4 fibrosis or LAM-resistant HBV ├ Suboptimal response to LAM after 6 months

31. On Treatment Monitoring* Frequency can be decreased once stable on treatment (HBV DNA undetectable)

32. Patterns of Response Lok et al. Hepatology. 2007;45:507-539. 1 log Change in HBV DNA (log 10 IU/mL) 0 -2.0 -3.0 -4.0 1.0 Nadir Virologic breakthrough Antiviral Drug Mos 601218 Primary nonresponse Suboptimal response

33. HBV Resistance Pathways R LAM-R 180/204 Pathway S LdT-R 236 Pathway ADV-R R ETV-R Pre-existing resistant mutants LAM ADV 184/202/250 Pathway 181 Pathway

34. Endpoints of Therapy HBsAg Clearance HBV DNA Suppression HBeAg Loss

35. Regression of Fibrosis Pre-Tx Post-Tx Adefovir

36. Antiviral Therapy for Advanced Liver Disease Liaw et al, NEJM 2004

37. True Goals of Therapy Lower Mortality Prevent HCC and Cirrhosis Decrease Liver Transplant

38. New Kid on the Block: Tenofovir

39. RANDOMIZATION 2:1 Tenofovir 300 mg Adefovir 10 mg Open-label 8 Years Week 240 Liver Biopsy Week 48 Liver Biopsy Pre-treatment Liver Biopsy Double Blind Week 72 Tenofovir 300 mg Marcellin P et al., NEJM 2008 Study 102 N=250 Study 103 N=176 Study 102 N=125 Study 103 N=90 Tenofovir for Chronic Hepatitis B

40. % Patients with HBV DNA <400 c/mL 89% 91% [P=0.672] One patient was <400 copies/mL on FTC + TDF at Week 96. Long Term Evaluation ITT Analysis: Patients who discontinued for administrative reasons with HBV DNA <400 copies/mL excluded (N= 7) Randomized Double Blind Open Label Marcellin P, et al., AASLD 2009; Oral # 146. HBeAg (-) Study 102 99% 100% [P=0.166] On-Treatment Analysis ~ 89% Patient Retention

41. 78% [P=0.801] Five patients were <400 copies/mL at Week 96 on FTC + TDF. Long Term Evaluation: Patients who discontinued for administrative reasons with HBV DNA <400 copies/mL had their data excluded for visits after discontinuation (N = 8.) % Patients with HBV DNA <400 c/mL Randomized Double Blind Open Label HBeAg (+) Study 103 Heathcote J, et al., AASLD 2009; Oral # 153. 89% 85% [P=0.374] On-Treatment Analysis ~ 86% Patient Retention

42. 77% 61% P= 0.014 Randomized Double Blind Open Label TDF ALT Normalization

43. HBeAg Loss & Seroconversion HBeAg Loss HBeAg Seroconversion TDF (Wk 48); TDF-TDF (Wk 64) ADV (Wk 48); ADV-TDF (Wk 64) 0 5 10 5 20 25 30 22% 18% P=NS 27% 21% P=NS Week 48Week 64 % Patients 0 5 10 15 20 25 30 26% 21% P=NS 21% 18% P=NS Week 48Week 64 % Patients

44. Cumulative Probability* of HBsAg Loss in HBeAg (+) Patients Cumulative Probability Function Estimate 0.00 0.05 0.10 Weeks on Study 012243648648096 *Kaplan-Meier 6% TDF-TDF 6% ADV-TDF Switch to Open label TDF Heathcote, et al., EASL 2009; Poster #909.

45. Resistance Surveillance Loss of viral response in 2 patients between Weeks 48 and 72 related to non-adherence documented in both patients Viremic patients received combo TDF + FTC Neither patient developed genotypic changes associated with AVR No genotypic changes associated with AVR were detected up to 72 weeks

46. Case 1: To Be or Not To Be

47. Mr. W. 48 year old Chinese male patient Known to be HBV ‘carrier’ Otherwise healthy History of liver CA in older brother On no prescription medications or herbals Routine diagnosis of HBV in China No previous ‘Western’ medication for HBV

48. Labs ALT Total bilirubin AST INR Albumin ALP Hb WBCPlatelets

49. Baseline Bloodwork 35 12 40 0.89 42 97 148 9.7138

50. HBV Testing

51. 3 Months Later 75 11 55 1.07 35 99 133 4.0132

52. Assessment of Fibrosis Liver Biopsy: A1F4 Abdominal U/S: Coarse liver Spleen sl. enlarged FibroScan: 16 kPa

53. Clinical Course on TDF MonthALTASTALPTotal BRAlbuminINR 075559911351.07 3103869015381.06 668439510400.96 945318711390.9 1219218512430.9

54. Clinical Course HBsAg+ HBeAg- Tenofovir 300 mg po od Months on treatment

55. Case 2: To Treat Now or Later?

56. Miss L. 27 year old teacher born in Canada Family history of HBV (mother) Healthy, seasonal allergies Meds:Claritin tabs occasionally Married but no children Contemplating pregnancy in 1-2 years

57. Baseline Bloodwork 25 5 20 0.91 40 68 122 8.7267

58. HBV Testing HBsAg+ HBeAg+ Anti-HBe- HBV DNA3.5 E+9 IU/ml 3,500,000,000 IU/ml

59. 3 Months Later 20 7 18 0.89 39 68 119 7.6253

60. Assessment of Fibrosis Liver Biopsy: A1F0 Abdominal U/S: Hemangioma segment 6 FibroTest: 0.35

61. 6 Months Later 78 7 16 0.91 40 65 126 6.5237

62. Question She is wondering about treatment prior to starting a family. What would you suggest? 1.Standard IFN-alpha x 20 weeks 2.Long-term lamivudine monotherapy 3.Entecavir x 1 year 4.Pegylated IFN-alpha x 6-12 months 5.Adefovir 10 mg po od

63. Course on PEG-IFN PEG-IFN HBeAg + + Anti-HBe - -

64. Question HBeAg seroconversion was not achieved. What would you suggest now? 1.Observe off therapy for the next 6 months 2.Start oral antiviral therapy before pregnancy 3.Repeat a liver biopsy to assess response 4.Retreat with a different PEG-IFN 5.Start combination oral agents

65. 10 Months Post PEG 22 9 16 0.91 35 100 120 6.5226 Miss L is pregnant, 12 weeks GA HBeAg +HBV DNA 8.6 E+8 IU/ml

66. Question How can you manage HBV infection during pregnancy? 1.Consult high-risk obstetrician 2.Start entecavir in 1 st trimester 3.Start adefovir in 2 nd trimester 4.Treat if HBV DNA > 7 logs in 3 rd trimester 5.Check HBV DNA only post-partum

67. Question Which of the agents can be considered for use during pregnancy? 1.Entecavir 2.Tenofovir 3.Clevudine 4.Telbivudine 5.Lamivudine

68. Summary HBV DNA quantitation is the new standard of care for chronic hepatitis B Disease progression Risk of cirrhosis and HCC Beware ‘normal’ ALT Does not exclude progressive liver damage Low platelet count is a clue Antiviral treatment reduces complications –Use potent agents with low rates of resistance –Long term therapy is required

69. Questions?

70. Can One Pill A Day Keep Hepatitis B Away? Scott K. Fung, MD, FRCPC Toronto General Hospital University of Toronto November 30, 2009 TGH