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Can One Pill A Day Keep Hepatitis B Away? PowerPoint Presentation
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Can One Pill A Day Keep Hepatitis B Away?

Can One Pill A Day Keep Hepatitis B Away?

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Can One Pill A Day Keep Hepatitis B Away?

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  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 2 3 4 • Wilson disease • Hereditary hemochromatosis • Chronic hepatitis B and HCC • Fatty liver

  4. Liver Disease in Canada HBV Others Alcohol NAFLD HCV

  5. Age-Standardized Mortality *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 = 182,000indiv. • 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 Stop Rx not indicated Slow down Observe closely May need Rx later 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 HCC 10-20% Cirrhosis Liver Failure 15-40% Death or OLTx 20% Age 40 50 60 Years EASL Consensus Guidelines. J Hepatol 2003 Lok et al, Hepatology 2004

  12. Complications of HBV HCC Ascites Varices

  13. Danger Signs: Time To Worry • INR • Bilirubin Albumin Platelets Cirrhosis • 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 = 100 = 1E0 10 = 101 = 1E1 100 = 102 = 1E2 1,000 = 103 = 1E3 10,000 = 104 = 1E4 100,000 = 105 = 1E5 1,000,000 = 106 = 1E6 10,000,000 = 107 = 1E7 100,000,000 = 108 = 1E8 1,000,000,000 = 109 = 1E9 10,000,000,000 = 1010=1E10 Low HBeAg-neg Medium HBeAg-pos High

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

  18. HBV DNA

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

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

  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 Note: This study population consisted of males over the age of 30 Yang et al, Chinese J Dig Dis 2002; 3: 150

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

  25. HBeAg-positive Patients HBeAg-positive HBV DNA <20,000 IU/mL(<105,200 copies/mL) HBV DNA >20,000 IU/mL(>105,200 copies/mL) ALT normal ALT elevated for 3–6 months ALT normal ALT elevated for 3–6 months 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 treatif significant disease Treat Based on a conversion factor of 1 IU/mL = 5.26 copies/mL Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C

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

  27. HBeAg-negative Patients HBeAg-negative HBV DNA <2,000 IU/mL(<10,520 copies/mL) HBV DNA >2,000 IU/mL(>10,520 copies/mL) ALT normal ALT elevated ALT normal ALT elevated 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) Based on a conversion factor of 1 IU/mL = 5.26 copies/mL Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C

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

  29. Comparison of Oral Therapy for Chronic Hepatitis B * Recommended as first-line therapy for HBV

  30. HBV Treatment in Ontario in 2009 * 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 Antiviral Drug 1.0 0 Primary nonresponse Virologic breakthrough -1.0 Change in HBV DNA (log10 IU/mL) Suboptimal response -2.0 -3.0 1 log Nadir -4.0 0 6 12 18 Mos Lok et al. Hepatology. 2007;45:507-539.

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

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

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

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

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

  38. New Kid on the Block: Tenofovir

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

  40. HBeAg (-) Study 102 % Patients with HBV DNA <400 c/mL Randomized Double Blind Open Label 91% [P=0.672] 89% On-Treatment Analysis 99% [P=0.166] 100% ~ 89% Patient Retention 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) Marcellin P, et al., AASLD 2009; Oral # 146.

  41. HBeAg (+) Study 103 % Patients with HBV DNA <400 c/mL Open Label Randomized Double Blind 78% 78% [P=0.801] On-Treatment Analysis 89% 85% [P=0.374] ~ 86% Patient Retention 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.) Heathcote J, et al., AASLD 2009; Oral # 153.

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

  43. P = N S P = N S P = N S 2 7 % P = N S 3 0 3 0 2 6 % 2 5 2 5 2 1 % 2 2 % 2 1 % 2 1 % 1 8 % 2 0 2 0 % Patients % Patients 1 8 % 5 1 5 1 0 1 0 5 5 0 0 Week 48 Week 64 Week 48 Week 64 HBeAg Loss & Seroconversion TDF (Wk 48); TDF-TDF (Wk 64) ADV (Wk 48); ADV-TDF (Wk 64) HBeAg Seroconversion HBeAg Loss

  44. Cumulative Probability* of HBsAg Loss in HBeAg (+) Patients 0.10 Switch to Open label TDF 6% TDF-TDF 6% ADV-TDF Cumulative Probability Function Estimate 0.05 0.00 0 12 24 36 48 64 80 96 Weeks on Study *Kaplan-Meier 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 AST Hb ALP ALT INR WBC Platelets Albumin Total bilirubin

  49. Baseline Bloodwork 40 148 97 35 0.89 9.7 138 42 12

  50. HBV Testing