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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

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)

HBV Disease Burden in Asian-Americans

Hepatitis B Prevalence
‡ Low overall U.S. prevalence: 0.3% ‡ Asians: ~ 10-13%
Laotians Vietnamese Korean Japanese Filippino Chinese 0% 2% 4% 6% 8% 10% 12% 14%

Son D, Asian Am Pac Isl J Health 2001

Age-Adjusted HCC Incidence Rate per 100,000 Patients
9 8
7 7.3 7.7 8.4

7 6 5 4 3 2
1.1 1 2.5 2.5 2.8 2.5 5.7 6 5.4

6.3

4.2 3.7 3.2 2.2 1.2 1.2 1.4 1.6 1.8 3.7

White Black Other

1 0 19751978 19781980 19811983 19841986 19871989 19901992 19931995 19961998

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

51 Both markers. 6 anti-HCV. et al. 15 anti-HCV. 15 Neither. Am J Gastroenterol 2003. 8 HBsAg. 16 Neither. 24 Both markers. 160 HBsAg.Etiology of HCC in Asians *Results from survey of 21 US transplant centers between 1997-1999 (n=691): White (n=410) Asian (n=107) Neither. 53 Both markers. 212 HBsAg. 21 Both markers. 32 HBsAg. 14 anti-HCV. 32 Black (n=95) Others (n=79) Neither.98:2060 . 5 anti-HCV. 27 Di Bisceglie AM.

California California Cancer Registry.9 17. Accessed 10/2004 HCC Incidence per 100.2 7 3.000 20 15 10 5 0 5.000 Population.HCC .4 Total Male Female Hi sp an ic W hi te As ia n/ O th er s Al lr ac es Bl ac k .3 6. California 1990-1994 Inceidence per 100.

Impact of HBV DNA and ALT Levels on Disease Outcomes .

HBV DNA Levels. Disease Progression and HCC Risk .

Abstract 497.5 ± HCC3 . Marcellin P et al. 2. Iloeje UH et al. Chen CJ et al. 5. J Hepatology 2005. 4. Hepatology 2003. Liaw YF et al.Impact of Viral Load ‡ High viral load: ± Liver inflammation1 ± Cirrhosis2 ± Liver failure3 ± HCC4 ± Liver-related deaths4 1. 3. N Engl J Med.351:1521-35. 2004. ‡ Reduction in viral load: ± Liver disease progression3.65-73. Mommeja-Marin H et al. N Engl J Med 2003.42(suppl 2):180.348:808-16. JAMA 2006:295(1). 37:1309-19.

N Engl J Med.HBV DNA Associated with Increased Risk of HCC ‡ Likelihood of HCC in individuals with detectable HBV DNA is 3.347:168-174. .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. 2002.

. long-term cohort study (Taiwan) ‡ Mean follow-up: 11 years (> 40. Iloeje UH et al.000 personyears) ‡ Cirrhosis analysis1. Chen CJ et al.295(1):65-73.2: n=3582 365 cases (10%) ‡ HCC analysis3: n=3653 164 cases (4. J Hepatology 2005.42(suppl 2):180.130 (3):678-86. 3.HBV DNA levels and Risk of Cirrhosis and HCC REVEAL-HBV Study ‡ Large population-based prospective. Abstract 497. 2. Iloeje UH et al.5%) 1. Gastroenterol 2006. JAMA 2006.

0±9.000) 338.001 for the trend Iloeje UH et al.9-9.0x106 Sample Size 869 1150 628 333 602 Personyears of follow-up 10.9x105 •1. .130 (3):678-86.HBV DNA Levels Predict Risk of Developing Cirrhosis Serum HBV DNA Level (copies/mL) <300 (LOQ) 300±9.7-14.4)‚ *Adjusted for gender.0)‚ 9.5 (1.9x103 1. age.6 2498.8 (6.0 7105.0 1878. cigarette smoking.0 (reference) 1.0 6164.9x104 1.001 P <0.8)‚ 5.8 13.9 (3.9-2.048.5 3460.8 429.3 Cirrhosis Cases 34 57 55 65 154 Incidence rate (per 100. Gastroenterol 2006.4 (0.9 774.259.3 Adjusted relative risk* (95% CI) 1.0±9.2) 2.6-3. and alcohol consumption ‚P <0.

9 x 10 < 300 0.0 .3 0.0 x 10 1.0 .HBV DNA Levels Predict Risk of Developing Cirrhosis Adjusted HR of Cirrhosis Risk by HBV DNA levels Cumulative Incidence of Liver Cirrhosis 0. Gastroenterol 2006.9 x 10 300 .9.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Year of Follow-up Iloeje UH et al.130 (3):678-86.4 HBV DNA levels: • 1.2 0.9. .9 x 10 1.9.

Viral Load Is the Main Predictor of Cirrhosis Regardless of Serum ALT Cirrhosis incidence /100.000 Person-Years of Follow-up 4500 4000 3500 3000 2500 2000 1500 1000 500 0 ALT <1 x ULN. n = 3542.001 <300 300 ² <104 104 ² <105 105 ² <106 • 106 HBV DNA (copies/mL) Iloeje UH et al. . Abstract 497.001 ALT •1 x ULN. n = 232. J Hepatology 2005. P < . P < .42(suppl 2):180.

1±4.7)Á 10.9-12.001 P <0.1)Á 6.9x105 •1.9x104 1.3-13.02 ÁP <0.9)‚ 6. habits of cigarette smoking and alcohol consumption ‚P =0.0±9.1 (0.295(1):65-73.000) 108 111 297 962 1152 Adjusted HR* (95% CI) 1.518 7404 3845 6858 *Adjusted for gender.HBV DNA Levels Predict Risk of Developing HCC Serum level of HBV DNA (copies/mL) <300 (LOQ) 300±9.5±2. .0±9. JAMA 2006.3) 2.0 (reference) 1.154 13.6 (3.9x103 1. age.1 (2.3 (1.0x106 Cohort member number 873 1161 643 349 627 Person-year of follow-up Number of subjects with HCC 11 15 22 37 79 Incidence rate (per 100.001 for the trend Chen CJ et al.

0% 13.999 100.0% <300 300-9999 10. No cirrhosis at entry Subcohort: n=2925 >10 6 HBV DNA (copies/mL) Chen CJ et al.0% 10.5% HBeAg neg.0% Cumulative Incidence of HCC (%) 90.0% 20.0% 40.0% 60.9% 3.7% 0.0% 30.0% 70.000999.999 0. .0% 0.2% 8.0% 50. Normal ALT.00099. JAMA 2006.Dose-Response Relationship: HBV DNA and HCC 100.0% 80.295(1):65-73.

JAMA 2006. % Subcohort (n = 2925) HBeAg-negative Normal ALT No cirrhosis at entry 12 10 8 6 4 2 0 0 1 2 3 4 5 6 7 Year of Follow-up 8 9 10 11 12 13 Chen CJ et al. . copies/mL >1 Million 100000-999999 10000-99999 300-9999 <300 Cumulative Incidence of HCC.HBV DNA Levels are Associated With Clinical Outcomes (HCC) 14 Baseline HBV DNA Level.295(1):65-73.

42(suppl 2):180. 2. J Hepatology 2005. 3. Abstract T1842. DDW 2006.REVEAL-HBV Study: Cirrhosis Analysis Conclusions ‡ HBV DNA level • 104 copies/mL is associated with significant risk for progression to cirrhosis regardless of HBeAg status or serum ALT level1. HBV DNA is the most significant modifiable risk factor3 1. . Chen CJ et al. Gastroenterol 2006.130 (3):678-86.2 ‡ Elevated serum HBV DNA is a strong predictor of cirrhosis in HBV-infected patients1. Iloeje UH et al.2 ‡ According to a prediction model. Iloeje UH et al. Abstract 497.

2. Chen CJ et al. serum ALT level. .295(1):65-73. JAMA 2006. HBV DNA is the most significant modifiable risk factor2 ‡ Patients with persistently elevated serum HBV DNA levels were at highest risk for development of HCC1 1. Chen CJ et al. DDW 2006. and presence of cirrhosis1 ‡ According to a prediction model.REVEAL-HBV Study: HCC Analysis Conclusions ‡ HBV DNA level • 104 copies/mL is a strong and significant predictor of HCC ± independent of HBeAg status. Abstract T1842.

should be further studied Chen CJ et al.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. .:295(1):65-73. JAMA 2006.

Impact of Treatment on Disease Progression .

5. Niederau C et al. Yuen MF et al.7 Outcomes ± Improvement in liver histology6 ± Normalization of ALT levels6 1.34(4 part 1):785-91.Suppression: an Important Therapeutic Goal Primary Goal of Treatment Rapid and sustained suppression of HBV to the lowest possible level1. 3. Hepatology 2001. N Engl J Med 2003.348:808-16.351:1521-35. N Engl J Med 1996. N Engl J Med 2004.180:1757-62. 2. Keeffe EB et al. 4. Liaw YF et al. Marcellin P et al. Gauthier J et al.2:87-106.334:1422-7. Liaw YF et al.25:472-89. 6. 7. . J Infect Dis 1999. Clin Gastroenterol Hepatol 2004. Liver Int 2005.2 ± Delay in progression to cirrhosis and HCC3 ± Improved survival4 ± Reduction in the development of resistance5 ± Increased rate of seroconversion6.

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

001 Placebo (n=215) Lamivudine (n=436) Liaw YF et al. N Engl J Med 2004.HBV DNA Suppression Reduces Cirrhosis Progression 25 Disease Progression (% patients) 20 15 10 5 0 6 12 16 24 30 36 ITT population P = .351:1521-35. .

047 3. . N Engl J Med 2004. et al.4% P = .HBV DNA Suppression Reduces HCC Incidence Rate Diagnosis of HCC (%) 10 Placebo Placebo (n= 215) LVD (n= 436) Lamivudine 7.9% 0 0 6 12 18 24 30 36 Time to diagnosis of HCC (months) Liaw YF.351:1521-1531.

N Engl J Med 2004. but did not negate it Liaw YF et al.351:1521-35. .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.

‡ Emerging potent antiviral therapies provide the potential for more effective treatment response and prevention of complications of CHB .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.

Screening for Hepatocellular Carcinoma .

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

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 Des-gamma± Hepatoma-specific isoforms of alphaHepatomaalphafetoprotein .

340:145-159 . Clinics in Liver Disease 2001.Range of AFP levels 108 106 104 102 1 10 5 log AFP (ng/mL) Malignant Benign HCC Normal 0 Range of 10-500 ng/mL does not allow clear distinction between HCC and benign chronic liver disease Johnson.

4 56.Changes in sensitivity and specificity of AFP for diagnosis of HCC using various cut-offs Diagnostic criteria AFP > 615 ng/mL AFP > 530 ng/mL AFP > 445 ng/mL AFP > 100 ng/mL AFP > 20 ng/mL Sensitivity (%) 56.5 94.5 70.6 87.4 72.9 Johnson. Clin Liver Disease 2001 .4 94.1 Specificity (%) 96.9 30.4 56.

J Gastroentrol 2000.Des-carboxy prothrombin (prothrombin induced by Vitamin K absence II) DCP (PIVKA II) DCP vs. A. Tanaka. Cancer 1998. Marrero. AFP for HCC Diagnosis 100 Percent 80 60 40 20 0 Tanaka (68/106) Mita (57/91) Ishii (594/29) ity Se ns AF iti v it P y Sp ec ifi c it y en si pe ci Takikawa (253/116) Marrero (53/14) ity S S DC P tiv DC P Takikawa. AF P fic . Hepatogastroenterol 1999. Mita. Hepatology 2003. J Gastroenterol hepatol 1992.Ishii.

Screening US Sensitivity and Specificity Study Okazaki. 1988 Tremolda. 1999 Sensitivity Specificity 86% 90% 85% 50% 78% 84% 99% 93% 50% 98% 93% 97% . 1994 Zhang. 1989 Dodd. 1984 Maringhini. 1992 Pateron.

‡ Rationale for 6-month screening interval ± Doubling time: median = 6 mo .S.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.

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

2000. US Wong. Hong Kong Bolondi. 2000. year. Taiwan None were randomized controlled studies . Italy Chen 2002. Hawaii. 2000. US Yuen. Alaska. 2001.HCC Screening: clinical studies Study. location Improved survival Yes Yes Yes Yes Yes McMahon.

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

Length/Prevalence Bias Diagnosis Tumor Detectable Tumor Begins Symptoms Death TIME Length Time .

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

816 persons.130:417-22 .12/95 ‡ Screening: ended 12/97 ‡ End of follow-up: 12/98 (38.250 or 92%) ‡ Male: Female ratios ~ 1.7 for both groups ‡ Screening group = 9373---AFP. "usual care and continued to use the health care facilities" ‡ Recruitment: 1/93 . US every 6 months ‡ Control group = 9443---No screening.444 person-years) Zhang BH et al.RCT for HCC Screening ‡ N = 18. in Shanghai ‡ History of chronic hepatitis (HBsAg+ in 17. aged 35-59. J Cancer Res Clin Oncol 2004.

Zhang BH et al.9% 25.3% 62.130:417-22 Stage Stage I Stage II Stage III Small HCC Screening N=86 60.6% 45.3% Control N=67 0% **P<0.5% 13.7% 0 . J Cancer Res Clin Oncol 2004.01 37.

J Cancer Res Clin Oncol 2004.6% 20.9% Control N=67 7.5% 32.130:417-22 Treatment Resection TACE/PEI Supportive Screening N=86 46.5% 41.7% .8% 50.Zhang BH et al.

2 **P<0.2 7.9 59.2 0 0 . J Cancer Res Clin Oncol 2004.6 46.01 7.6 52.Zhang BH et al.9 52.130:417-22 Survival (%) 1-year 2-year 3-year 4-year 5-year Screening N=86 65.4 Control N=67 31.

000 $/life- 15.000 ± 30.678 30.143 74.Cost-Effectiveness of Screening: Other Cancers Others year saved Pap smear Colonoscopy Flexible sigmoidoscopy Fecal occult blood testing Mammography 100.000 ± .000 28.032 81.

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.934 per treatable HCC $112. AFP/US q 6 mo Study period: 1989-1997 $17. 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 . Gut 2001 ± ± ± ± ± Child-Pugh A and B.Cost-Effectiveness of HCC Screening Real-life studies with cost information: Bolondi.

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 .

5 months Yes *Main cost burden is cost of OLT and not with screening cost No *Yes if US q12 months only . 2002 (abstract) Lin. 2000 (abbreviated) Sarasin. 2001 Patel.000$/QALY) No Sarasin.HCC Screening: Cost-effectiveness Analysis (AFP/US every 6 months) Study Patients CE ratio (< 50. 1996 Child A No OLT OLT/LDLT Everson. 2004 Yes OLT/LDLT HCV cirrhosis OLT/LDLT HCV cirrhosis Yes *OLT > LDLT after 3.

. ‡ Several observational studies and decision analysis modeling suggest that screening for HCC in highrisk patients who are eligible for treatment is costeffective. ‡ Screening for HCC is currently recommended for selected patients with chronic liver disease including patients with chronic hepatitis B.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.