1. Treatment for Chronic Hepatitis B Screening for Hepatocellular Carcinoma Mindie H. Nguyen, MD, MAS Assistant Professor of Medicine Division of Gastroenterology & Hepatology Liver Transplant Program Stanford University Medical Center 9/15/2006

2. Chronic Hepatitis B Disease burden in Asian Americans Natural history: –HBV DNA levels –ALT levels Impact of treatment on disease progression Rationale for screening for hepatocellular carcinoma (HCC)

3. HBV Disease Burden in Asian-Americans

4. Hepatitis B Prevalence Low overall U.S. prevalence: 0.3% Asians: ~ 10-13% Son D, Asian Am Pac Isl J Health 2001

5. El-Serag et al, Ann Int Med 2003;139:817

6. Etiology of HCC in Asians Di Bisceglie AM, et al, Am J Gastroenterol 2003;98:2060 *Results from survey of 21 US transplant centers between 1997-1999 (n=691):

7. HCC - California California Cancer Registry, Accessed 10/2004

8. Impact of HBV DNA and ALT Levels on Disease Outcomes

9. HBV DNA Levels, Disease Progression and HCC Risk

10. Impact of Viral Load High viral load: –Liver inflammation 1 –Cirrhosis 2 –Liver failure 3 –HCC 4 –Liver-related deaths 4 Reduction in viral load: –Liver disease progression 3,5 –HCC 3 1. Mommeja-Marin H et al. Hepatology 2003. 37:1309-19. 2. Iloeje UH et al. J Hepatology 2005;42(suppl 2):180. Abstract 497. 3. Liaw YF et al. N Engl J Med. 2004;351:1521-35. 4. Chen CJ et al. JAMA 2006:295(1);65-73. 5. Marcellin P et al. N Engl J Med 2003;348:808-16.

11. HBV DNA Associated with Increased Risk of HCC Likelihood of HCC in individuals with detectable HBV DNA is 3.9 times more than those with undetectable HBV DNA –Risk associated with increasing HBV DNA levels These data support possibility of preventing long-term risk of HCC by inducing sustained suppression of HBV replication Yang HI, et al. N Engl J Med. 2002;347:168-174.

12. HBV DNA levels and Risk of Cirrhosis and HCC REVEAL-HBV Study Large population-based prospective, long-term cohort study (Taiwan) Mean follow-up: 11 years (> 40,000 person- years) Cirrhosis analysis 1,2 : n=3582  365 cases (10%) HCC analysis 3 : n=3653  164 cases (4.5%) 1. Iloeje UH et al. Gastroenterol 2006;130 (3):678-86. 2. Iloeje UH et al. J Hepatology 2005;42(suppl 2):180. Abstract 497. 3. Chen CJ et al. JAMA 2006;295(1):65-73.

13. HBV DNA Levels Predict Risk of Developing Cirrhosis Serum HBV DNA Level (copies/mL) Sample Size Person- years of follow-up Cirrhosis Cases Incidence rate (per 100,000) Adjusted relative risk * (95% CI) <300 (LOQ)86910,048.834338.8 1.0 (reference) 300–9.9x10 3 115013,259.057429.91.4 (0.9-2.2) 1.0–9.9x10 4 6287105.555774.02.5 (1.6-3.8) † 1.0–9.9x10 5 3333460.0651878.65.9 (3.9-9.0) † ≥1.0x10 6 6026164.31542498.39.8 (6.7-14.4) † *Adjusted for gender, age, cigarette smoking, and alcohol consumption † P <0.001 P <0.001 for the trend Iloeje UH et al. Gastroenterol 2006;130 (3):678-86.

14. HBV DNA Levels Predict Risk of Developing Cirrhosis Iloeje UH et al. Gastroenterol 2006;130 (3):678-86. HBV DNA levels:

15. Viral Load Is the Main Predictor of Cirrhosis Regardless of Serum ALT Iloeje UH et al. J Hepatology 2005;42(suppl 2):180. Abstract 497. <300300 – <10 4 10 4 – <10 5 10 5 – <10 6 ≥ 10 6 HBV DNA (copies/mL) Cirrhosis incidence /100,000 Person-Years of Follow-up ALT <1 x ULN, n = 3542, P <.001 ALT ≥1 x ULN, n = 232, P <.001

16. HBV DNA Levels Predict Risk of Developing HCC Serum level of HBV DNA (copies/mL) Cohort member number Person-year of follow-up Number of subjects with HCC Incidence rate (per 100,000) Adjusted HR * (95% CI) <300 (LOQ)87310,154111081.0 (reference) 300–9.9x10 3 116113,518151111.1 (0.5–2.3) 1.0–9.9x10 4 6437404222972.3 (1.1–4.9) † 1.0–9.9x10 5 3493845379626.6 (3.3-13.1) ‡ ≥1.0x10 6 62768587911526.1 (2.9-12.7) ‡ *Adjusted for gender, age, habits of cigarette smoking and alcohol consumption † P =0.02 ‡ P <0.001 P <0.001 for the trend Chen CJ et al. JAMA 2006;295(1):65-73.

17. Dose-Response Relationship: HBV DNA and HCC Chen CJ et al. JAMA 2006;295(1):65-73.

18. HBV DNA Levels are Associated With Clinical Outcomes (HCC) 14 12 10 8 6 4 2 0 0123456789 111213 Year of Follow-up Cumulative Incidence of HCC, % Baseline HBV DNA Level, copies/mL >1 Million 100000-999999 10000-99999 300-9999 <300 Chen CJ et al. JAMA 2006;295(1):65-73. Subcohort (n = 2925) HBeAg-negative Normal ALT No cirrhosis at entry

19. REVEAL-HBV Study: Cirrhosis Analysis Conclusions HBV DNA level ≥ 10 4 copies/mL is associated with significant risk for progression to cirrhosis - regardless of HBeAg status or serum ALT level 1,2 Elevated serum HBV DNA is a strong predictor of cirrhosis in HBV-infected patients 1,2 According to a prediction model, HBV DNA is the most significant modifiable risk factor 3 1. Iloeje UH et al. Gastroenterol 2006;130 (3):678-86. 2. Iloeje UH et al. J Hepatology 2005;42(suppl 2):180. Abstract 497. 3. Chen CJ et al. DDW 2006. Abstract T1842.

20. REVEAL-HBV Study: HCC Analysis Conclusions HBV DNA level ≥ 10 4 copies/mL is a strong and significant predictor of HCC – independent of HBeAg status, serum ALT level, and presence of cirrhosis 1 According to a prediction model, HBV DNA is the most significant modifiable risk factor 2 Patients with persistently elevated serum HBV DNA levels were at highest risk for development of HCC 1 1. Chen CJ et al. JAMA 2006;295(1):65-73. 2. Chen CJ et al. DDW 2006. Abstract T1842.

21. REVEAL-HBV Study: HCC Analysis Conclusions (continued) Potent antiviral agents that can decrease HBV DNA to undetectable levels (regardless of HBeAg status and ALT levels) may reduce the risk for HCC HBeAg negative patients with normal ALT and elevated HBV DNA, representing an increasing majority of CHB patients, should be further studied Chen CJ et al. JAMA 2006;:295(1):65-73.

22. Impact of Treatment on Disease Progression

23. Primary Goal of Treatment Rapid and sustained suppression of HBV to the lowest possible level 1,2 Outcomes –Delay in progression to cirrhosis and HCC 3 –Improved survival 4 –Reduction in the development of resistance 5 –Increased rate of seroconversion 6,7 –Improvement in liver histology 6 –Normalization of ALT levels 6 Rapid and Profound HBV Suppression: an Important Therapeutic Goal 1. Keeffe EB et al. Clin Gastroenterol Hepatol 2004;2:87-106. 2. Liaw YF et al. Liver Int 2005;25:472-89. 3. Liaw YF et al. N Engl J Med 2004;351:1521-35. 4. Niederau C et al. N Engl J Med 1996;334:1422-7. 5. Yuen MF et al. Hepatology 2001;34(4 part 1):785-91. 6. Marcellin P et al. N Engl J Med 2003;348:808-16. 7. Gauthier J et al. J Infect Dis 1999;180:1757-62.

24. Lamivudine and Disease Progression and HCC incidence in Advanced HBV (stage III/IV) Prospective, multicenter, randomized, double-blind, placebo-controlled, parallel group study HBeAg+ or HBeAg- Lamivudine 100 mg qd (n=436) vs. placebo (n=215) Designed to be ≤ 5 year study; terminated at 2nd interim analysis due to lamivudine superiority Liaw YF et al. N Engl J Med 2004;351:1521-35.

25. HBV DNA Suppression Reduces Cirrhosis Progression Liaw YF et al. N Engl J Med 2004;351:1521- 35. Disease Progression (% patients) Placebo (n=215) Lamivudine (n=436) 0 5 10 15 20 25 36302416126 ITT population P =.001

26. Liaw YF, et al. N Engl J Med 2004;351:1521-1531. Lamivudine Placebo Diagnosis of HCC (%) 601218243036 Time to diagnosis of HCC (months) P =.047 7.4% 3.9% Placebo (n= 215) LVD (n= 436) 10 0 HBV DNA Suppression Reduces HCC Incidence Rate

27. Conclusions Lamivudine reduces risk of liver complications for patients with CHB and cirrhosis or advanced fibrosis by about 50% over 32 months Lamivudine also reduces HCC incidence rate by almost 50% YMDD mutations reduced benefit of lamivudine, but did not negate it Liaw YF et al. N Engl J Med 2004;351:1521-35.

28. Summary HBV DNA is an essential marker for predicting risk for complications Viral suppression is associated with improved treatment outcomes in patients with advanced fibrosis. Emerging potent antiviral therapies provide the potential for more effective treatment response and prevention of complications of CHB

29. Screening for Hepatocellular Carcinoma

30. Screening for HCC Consensus Recommendations 1 Anchorage, Alaska: AFP and US –Yearly: HBsAg carriers age >35 years or FH of HCC –Every 6 months: chronic hepatitis B with cirrhosis 2 Milan, Italy: AFP and US every 6 months –Cirrhosis of any cause 3 Barcelona, Italy: AFP and US every6 months –Cirrhotic patients who are eligible to available treatments 1 McMahon, J Natl Cancer Inst 1991 2 Colombo. J Hepatol 1992 3 Bruix, J Hepatol 2001

31. HCC: Screening Tests Imaging studies –Ultrasound* –Computed tomography –No significant differences between spiral CT and MRI Stoker J, Gut 2002 Blood tests –Alpha-fetoprotein* –Des-gamma-carboxy prothrombin –Hepatoma-specific isoforms of alpha- fetoprotein

32. Range of AFP levels 10 8 10 6 10 4 10 2 1 Range of 10-500 ng/mL does not allow clear distinction between HCC and benign chronic liver disease Johnson, Clinics in Liver Disease 2001;340:145-159

33. Changes in sensitivity and specificity of AFP for diagnosis of HCC using various cut-offs Johnson, Clin Liver Disease 2001

34. DCP (PIVKA II) Des-carboxy prothrombin (prothrombin induced by Vitamin K absence II) Takikawa, J Gastroenterol hepatol 1992;Ishii, A, J Gastroentrol 2000; Mita, Cancer 1998; Tanaka, Hepatogastroenterol 1999; Marrero, Hepatology 2003.

35. Screening US Sensitivity and Specificity StudySensitivitySpecificity Okazaki, 198486%99% Maringhini, 198890%93% Tremolda, 198985%50% Dodd, 199250%98% Pateron, 199478%93% Zhang, 199984%97%

36. HCC: Screening Strategies and Frequency US q 6-12 months and AFP q 6 months is the most commonly used strategy in Asia and U.S. Rationale for 6-month screening interval –Doubling time: median = 6 mo

37. WHO Principles of Screening Screening improves survival Cost of screening is acceptable

38. HCC Screening: clinical studies Study, year, locationImproved survival McMahon, 2000, Alaska, USYes Wong, 2000, Hawaii, USYes Yuen, 2000, Hong KongYes Bolondi, 2001, ItalyYes Chen 2002, TaiwanYes None were randomized controlled studies

39. Lead-Time Bias TIME Symptoms Death Diagnosis Lead Time Tumor Detectable Tumor Begins Diagnosis by screening Diagnosis by symptoms

40. Length/Prevalence Bias TIME SymptomsDeath Diagnosis Length Time Tumor Detectable Tumor Begins

41. Pseudo-Disease TIME Symptoms Cancer Death Cardiac Death Diagnosis Tumor Detectable Tumor Begins

42. RCT for HCC Screening N = 18,816 persons, aged 35-59, in Shanghai History of chronic hepatitis (HBsAg+ in 17,250 or 92%) Male: Female ratios ~ 1.7 for both groups Screening group = 9373---AFP, US every 6 months Control group = 9443---No screening, "usual care and continued to use the health care facilities" Recruitment: 1/93 - 12/95 Screening: ended 12/97 End of follow-up: 12/98 (38,444 person-years) Zhang BH et al, J Cancer Res Clin Oncol 2004;130:417-22

43. StageScreening N=86 Control N=67 Stage I60.5%0% Stage II13.9%37.3% Stage III25.6%62.7% Small HCC45.3%0 **P<0.01

44. Zhang BH et al, J Cancer Res Clin Oncol 2004;130:417-22 TreatmentScreening N=86 Control N=67 Resection46.5%7.5% TACE/PEI32.6%41.8% Supportive20.9%50.7%

45. Zhang BH et al, J Cancer Res Clin Oncol 2004;130:417-22 Survival (%)Screening N=86 Control N=67 1-year65.931.2 2-year59.97.2 3-year52.67.2 4-year52.60 5-year46.40 **P<0.01

46. Cost-Effectiveness of Screening: Other Cancers Others$/life- year saved Pap smear15,000 – 30,000 Colonoscopy28,143 Flexible sigmoidoscopy74,032 Fecal occult blood testing81,678 Mammography 30,000 – 100,000

47. Cost-Effectiveness of HCC Screening Real-life studies with cost information: Bolondi, Gut 2001 –Child-Pugh A and B; AFP/US q 6 mo –Study period: 1989-1997 –$17,934 per treatable HCC –$112,993 per QALY gained –Results may not be generalizable to US patients: cost not based on actutal cost and no OLT for age > 60. Yuen, Hepatology 2000 –$1,167 annually to detect 1 HCC –$1,667 annually to detect 1 treatable HCC –Mostly hepatitis B patients –Cost based on 25$/AFP and 100$/US

48. HCC Screening Role of Cost-effectiveness Analysis/ Decision Analysis RCT is not feasible due to ethical issues Observational or cohort studies require an extremely long follow-up period and affected by: –Lead-time bias –Length-bias –Pseudo-disease phenomenon

49. HCC Screening: Cost-effectiveness Analysis (AFP/US every 6 months) StudyPatientsCE ratio (< 50,000$/QALY) Sarasin, 1996Child ANo No OLT Everson, 2000OLT/LDLTYes (abbreviated) Sarasin, 2001OLT/LDLTYes *OLT > LDLT after 3.5 months Patel, 2002 HCV cirrhosisYes (abstract)OLT/LDLT *Main cost burden is cost of OLT and not with screening cost Lin, 2004HCV cirrhosisNo *Yes if US q12 months only

50. Screening for HCC: Summary HCC is an important cause of mortality in patients with HBV and in Asians. One randomized controlled trial suggests that screening leads to early diagnosis and improved survival. Several observational studies and decision analysis modeling suggest that screening for HCC in high- risk patients who are eligible for treatment is cost- effective. Screening for HCC is currently recommended for selected patients with chronic liver disease including patients with chronic hepatitis B.