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50 Years of HBV: What’s New?

50 Years of HBV: What’s New?. Scott K. Fung, MD, FRCPC Toronto General Hospital University of Toronto November 7, 2010. Learning Objectives. To review the epidemiology of HBV in Canada To evaluate advances in HBV in the last 10 yrs ‘Normal’ ALT Liver Biopsy HBV DNA FibroScan

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50 Years of HBV: What’s New?

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  1. 50 Years of HBV: What’s New? Scott K. Fung, MD, FRCPC Toronto General Hospital University of Toronto November 7, 2010

  2. Learning Objectives • To review the epidemiology of HBV in Canada • To evaluate advances in HBV in the last 10 yrs ‘Normal’ ALT Liver Biopsy HBV DNA FibroScan Hepatocellular carcinoma • To discuss treatment of chronic HBV Who to treat? What to use? For how long?

  3. Characteristics of a Successful Organ Array of Antiviral Therapeutics Array of Therapeutics Regenerative Potential Transplantable Easily accessible with a biopsy needle Infectable with a detectable virus

  4. Natural History and Epidemiology

  5. 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

  6. Complications of HBV Ascites Varices 6

  7. CHB Is A Dynamic Disease! HBeAg Treatment Anti-HBe Treatment HBV DNA ALT Immuneactive Inactivecarrier state Immunetolerant HBeAg-negative CHB Normal or minimal hepatitis Chronic hepatitis Normal orinactive hepatitis Progressive fibrosis Cirrhosis HCC CHB is a dynamic disease and patients can transition backwards and forwards between stages Adapted from Yim & Lok, Hepatology 2006; 43: S173

  8. Global Burden of Chronic Hepatitis B 1. WHO Report 1996 2. Lai et al, 2005 3. Lai et al, Lancet 2003; 362: 2089 4. Keeffe et al, Clin Gastroenterol Hepatol 2004; 2: 87 Worldwide • 400 million people infected • Asia accounts for 75% of cases (260–300 million) • Causes 60–80% liver cancer • Approximately 500,000–700,000 deaths each yr Canada • Overall prevalence of HBV infection in Canada is low (0.5–1.0%) • Figure rising due to immigration from endemic regions

  9. The World According to HBV ~ 2 million Asians ~ 930, 000 Europeans ~ 400,000 South Americans HBsAg Prevalence ~ 350,000 Africans > 8% - High 2-8% - Intermediate < 2% - Low Immigration numbers summed by continent from 1996-2002 Adapted from: 1. CDC. Available at: http://www.cdc.gov/hepatitis. Accessed January 31, 2006. 2. Mahoney FJ. Clin Microbiol Rev 1999;12:351-66. 3. Hepatitis B Foundation. Available at: http://www.hepb.org/hepb/statistics.org. Accessed January 31, 2006.

  10. Prevalence of HBV Infection is Higher in Immigrant Populations from SE Asia 1Guane et al, Hepatology 2005; 40(4 Suppl. 1): 716A 2Chao et al, Hepatology 2005; 40(4 Suppl. 1): 717A 3CDC, MMWR Morb Mortal Wkly Rep 2006; 55: 505 • HBsAg seroprevalence higher in adult Asian immigrant populations in North America • including Chinese, Korean and Vietnamese populations • Large metropolitan cities in the US: 10.4%1 • San Francisco: 12.3% • Los Angeles: 12.5% • Orange County: 9.3% • New York City: 15%3

  11. HBV Prevalence In Canada Leber & Sherman MD, CDDW 2009

  12. Prevalence of CHB in Canada BC 76,337 AB 37,334 QC 62,579 ON 231,494 Leber & Sherman MD, CDDW 2009

  13. Hepatocellular Carcinoma

  14. Hepatocellular Carcinoma

  15. HCC • Hepatoma is treatable and sometimes curable in 2010! • Small tumors (<3-5 cm) are associated with a better prognosis • Regular US screening detects tumors early • Milan criteria for liver transplantation: • 1 tumor less than 5 cm or • Up to 3 tumors all less than 3 cm • No extrahepatic spread or vascular invasion

  16. Treatment for HCC Radiation Sorafenib HCC Palliative Resection Surgery RFA TACE Curative Intent Transplant Recurrence Bridge Therapy

  17. Llovet et al, NEJM 2008

  18. Bruix and Sherman, Hepatology 2010

  19. Screening for HCC

  20. Nomogram for Predicting HCC Yang et al, J Clin Onc 2010

  21. Predicting HCC Risk

  22. Monitoring HBV

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

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

  25. HBV DNA Associated With Increased Risk of HCC and Cirrhosis • REVEAL: Long-term follow-up of untreatedHBsAg-positive but HBeAg-negative men in Taiwan 50 Cumulative Incidence of HCC at Year 13 Follow-up[1] (N = 3653) Cumulative Incidence of Cirrhosis at Year 13 Follow-up[2] (N = 3582) 40 36.2 30 23.5 Patients (%) 20 14.9 12.2 9.8 10 5.9 4.5 3.6 1.4 1.3 0 < 300 300- 999 1000- 9999 10,000- 99,999 ≥ 100,000 < 300 300- 9999 10,000- 99,999 100,000- 999,999 ≥ 1 million Baseline HBV DNA (copies/mL) 1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

  26. Risk of Developing Complications High in Patients with ALT 1–2 x ULN ALT >1–2 x ULN ALT >2–6 x ULN ALT 0.5–1 x ULN ALT >6 x ULN ALT <0.5 x ULN 40 Risk of complications (%) 30 20 10 0 0 30 60 90 120 150 180 Follow-up (months) p<0.0001 for ALT 0.5–1 x ULN and >1–2 x ULN and >2–6 x ULN vs ALT 0.5 x ULN Yuen et al, Gut 2005; 54: 1610

  27. ALT: The New Normal • Current upper limit of normal is too high • Men: 0.75 x current ULN (previously 40 U/L, now 30 U/L) • Women: 0.50 x current ULN (previously 40 U/L, now 20 U/L) • Patients should not be denied treatment on the basis of a normal ALT Adapted from Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C

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

  29. Fibrosis Stage and ALT % Patients Fung et al, Can J Gastro 2010

  30. Quantitative HBsAg

  31. A Day in the Life of a Biopsy

  32. What Every HBV Patient Should Know About Liver Biopsy Liver biopsy is not a surgery An adult must accompany you home You don’t need to be admitted to hospital We can’t do your biopsy on Saturday or Sunday Only 1 biopsy is needed for a very long time It can be painful without adequate local anaesthetic Your hepatologist won’t feel a thing If you don’t poke, you won’t know

  33. Complications Might Occur Ghent, Can J Gastro 2006

  34. Bystander Organs

  35. Rockey et al, Hepatology 2009

  36. Transient Elastography (FibroScan) • Rapid U/S-based test • Elastic wave through liver • Measures liver stiffness • Correlates with liver fibrosis

  37. N = 453 HBeAg+ patients Predictive factors for advanced fibrosis • Age > 35 years • ALT > 0.5 ULN FibroScan in HBV Wong et al, Clin Gastro Hep 2009

  38. Treatment Options

  39. Progress in HBV Treatment Peginterferon alfa-2a Entecavir Tenofovir Lamivudine 1990 1998 2002 2005 2006 2008 Interferon alfa-2b Telbivudine Adefovir

  40. Selection of HBeAg-Positive Patients for Treatment HBeAg-positive HBV DNA > 4 log IU/ml HBV DNA < 4 log IU/ml ALT normal ALT elevated ALT elevated for 3-6 months ALT normal • Monitor every3 months • Consider biopsy if > 35-40 years • Treat if significant disease TREAT • Rule out other causes of liver disease • No treatment • Monitor every3 months with ALT and HBV DNA Adapted from CASL Consensus Guidelines. Sherman M, et al. Can J Gastroenterol 2007;21(Suppl C):5C-24C.

  41. Selection of HBeAg-negative Patients for Treatment HBeAg negative HBV DNA > 3 log IU/ml HBV DNA < 3 log IU/ml ALT normal ALT elevated ALT normal ALT elevated • Monitor ALT every3 months, or • Consider biopsy because ALT fluctuates • Treat if significant disease • Long-term treatment required (oral agents) • Rule out other causes of liver disease TREAT Long-term treatment required • No treatment • Monitor every3 months for 1-2 years with ALT and HBV DNA Adapted from CASL Consensus Guidelines. Sherman M, et al. Can J Gastroenterol 2007;21(Suppl C):5C-24C.

  42. Who Needs Treatment? Treatment decision ALT abnormal ALT normal Inactive carrierHBeAg-negative HBV DNA <2 x 103 IU/mL Monitor Active diseaseHBV DNA >2 x 103 IU/mLTreat HBV Immune tolerant HBeAg-positive HBV DNA >107 IU/mL Monitor Suspected cirrhosis US/ Biopsy/ FibroScan Detectable HBV DNA Treat HBV

  43. Selection of Specific Antiviral Agents HBeAg (+) High viral load HBV DNA > 7 log IU/ml Low viral load HBV DNA < 7 log IU/ml • Entecavir • Tenofovir • Standard interferon • Pegylated interferon • Lamivudine • Adefovir • Entecavir • Telbivudine • Tenofovir Adapted from CASL Consensus Guidelines. Sherman M, et al. Can J Gastroenterol 2007;21(Suppl C):5C-24C.

  44. Cumulative Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients Not head-to-head trials; different patient populations and trial designs Yr 6 Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Drug Generation 1st LAM 24% 49% 67% 38% 70% ADV 29% 0% 3% 11% 18% 2nd TBV 4% 17% ETV 0.2% 0.5% 1.2% 1.2% 1.2% 1.2% 3rd 0% TDF 0% 0% 0% EASL HBV Guidelines. J Hepatol. 2009;50:227-242. Tenny DJ, et al. EASL 2009. Abstract 20. Marcellin P, et al. AASLD 2009. Abstract 481. Heathcote E, et al. Abstract 483.

  45. HBV Treatment in Ontario in 2010 * Cirrhosis and HBV DNA > 6 log IU/ml ** LAM breakthrough and cirrhosis or LAM-resistant HBV ├ Suboptimal response to LAM after 6 months

  46. Goals of Treatment Prevent HCC and Cirrhosis 防止肝 癌和肝硬化 Decrease Liver Transplant 減少肝臟移植 Lower Mortality 降低死亡率

  47. Treatment Goals

  48. Regression of Fibrosis: The Great Hope of Hepatology Pre-Tx Antiviral Rx Post-Tx

  49. GP Management of HBV • Management of hepatitis B is complex and should only be undertaken by those familiar with the disease and its treatment • Clinical management of HBV is rapidly changing and managing patients requires a commitment to continuing education on the subject • Access to regular HBV DNA and antiviral resistance testing is essential

  50. Monitoring Oral Antiviral Agents 1Currently the Taqman assay. Use of less sensitive assays is not recommended Adapted from Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C

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