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

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, 16
Neither, 160 HBsAg, 24

Both markers, 6
anti-HCV, 212

HBsAg, 53

Both markers, 14

anti-HCV, 32

Black (n=95)

Others (n=79)

Neither, 21 Both markers, 8

HBsAg, 15 Neither, 32

HBsAg, 15

anti-HCV, 51

Both markers, 5

anti-HCV, 27

Di Bisceglie AM, et al, Am J Gastroenterol 2003;98:2060

HCC - California
California Cancer Registry, Accessed 10/2004

HCC Incidence per 100,000 Population, California 1990-1994

Inceidence per 100,000 20 15 10 5 0 5.2 7 3.3 6.9 17.4
Total Male Female

Hi sp an ic

W hi te

As ia n/ O th er s

Al lr ac es

Bl ac k

Impact of HBV DNA and ALT Levels on Disease Outcomes

HBV DNA Levels, Disease Progression and HCC Risk

Impact of Viral Load

High viral load:
Liver inflammation1 Cirrhosis2 Liver failure3 HCC4 Liver-related deaths4
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.

Reduction in viral load:

Liver disease progression3,5 HCC3

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.

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 personyears) Cirrhosis analysis1,2: n=3582 365 cases (10%) HCC analysis3: 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.

HBV DNA Levels Predict Risk of Developing Cirrhosis

Serum HBV DNA Level (copies/mL) <300 (LOQ) 3009.9x103 1.09.9x104 1.09.9x105 1.0x106 Sample Size 869 1150 628 333 602 Personyears of follow-up 10,048.8 13,259.0 7105.5 3460.0 6164.3 Cirrhosis Cases 34 57 55 65 154 Incidence rate (per 100,000) 338.8 429.9 774.0 1878.6 2498.3 Adjusted relative risk* (95% CI) 1.0 (reference) 1.4 (0.9-2.2) 2.5 (1.6-3.8) 5.9 (3.9-9.0) 9.8 (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.

HBV DNA Levels Predict Risk of Developing Cirrhosis

Adjusted HR of Cirrhosis Risk by HBV DNA levels
Cumulative Incidence of Liver Cirrhosis 0.4
HBV DNA levels: 1.0 x 10 1.0 - 9.9 x 10 1.0 - 9.9 x 10 300 - 9.9 x 10 < 300

0.3

0.2

0.1

0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Year of Follow-up
Iloeje UH et al. Gastroenterol 2006;130 (3):678-86.

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, P < .001 ALT 1 x ULN, n = 232, P < .001

<300

300 <104

104 <105

105 <106

106

HBV DNA (copies/mL)

Iloeje UH et al. J Hepatology 2005;42(suppl 2):180. Abstract 497.

HBV DNA Levels Predict Risk of Developing HCC

Serum level of HBV DNA (copies/mL) <300 (LOQ) 3009.9x103 1.09.9x104 1.09.9x105 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 100,000) 108 111 297 962 1152 Adjusted HR* (95% CI) 1.0 (reference) 1.1 (0.52.3) 2.3 (1.14.9) 6.6 (3.3-13.1) 6.1 (2.9-12.7)

10,154 13,518 7404 3845 6858

*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.

Dose-Response Relationship: HBV DNA and HCC

100.0% Cumulative Incidence of HCC (%) 90.0% 80.0% 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% <300 300-9999 10,00099,999 100,000999,999 0.7% 0.9% 3.2% 8.0% 13.5% HBeAg neg, Normal ALT, No cirrhosis at entry Subcohort: n=2925

>10

HBV DNA (copies/mL)

Chen CJ et al. JAMA 2006;295(1):65-73.

HBV DNA Levels are Associated With Clinical Outcomes (HCC)

14 Baseline HBV DNA Level, copies/mL >1 Million 100000-999999 10000-99999 300-9999 <300

Cumulative Incidence of HCC, %

Subcohort (n = 2925) HBeAg-negative Normal ALT No cirrhosis at entry

12 10 8 6 4 2 0 0 1

6 7 Year of Follow-up

10

11

12

13

Chen CJ et al. JAMA 2006;295(1):65-73.

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 level1,2 Elevated serum HBV DNA is a strong predictor of cirrhosis in HBV-infected patients1,2 According to a prediction model, HBV DNA is the most significant modifiable risk factor3
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.

REVEAL-HBV Study: HCC Analysis Conclusions

HBV DNA level 104 copies/mL is a strong and significant predictor of HCC independent of HBeAg status, serum ALT level, and presence of cirrhosis1 According to a prediction model, 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. JAMA 2006;295(1):65-73. 2. Chen CJ et al. DDW 2006. Abstract T1842.

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.

Impact of Treatment on Disease Progression

Suppression: an Important Therapeutic Goal

Primary Goal of Treatment Rapid and sustained suppression of HBV to the lowest possible level1,2
Delay in progression to cirrhosis and HCC3 Improved survival4 Reduction in the development of resistance5 Increased rate of seroconversion6,7

Outcomes

Improvement in liver histology6 Normalization of ALT levels6

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.

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.

HBV DNA Suppression Reduces Cirrhosis Progression

25 Disease Progression (% patients) 20 15 10 5 0 6 12 16 24 30 36 ITT population P = .001

Placebo (n=215)

Lamivudine (n=436)

Liaw YF et al. N Engl J Med 2004;351:1521-35.

HBV DNA Suppression Reduces HCC Incidence Rate

Diagnosis of HCC (%)

10
Placebo Placebo (n= 215) LVD (n= 436) Lamivudine

7.4%
P = .047

3.9%

0 0 6 12 18 24 30 36

Time to diagnosis of HCC (months)

Liaw YF, et al. N Engl J Med 2004;351:1521-1531.

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.

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

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, Italy: AFP and US every 6 months

Cirrhosis of any cause

3Barcelona, Italy: AFP and US every6 months

Cirrhotic patients who are eligible to available treatments
1McMahon,

J Natl Cancer Inst 1991 2Colombo. J Hepatol 1992 3Bruix, J Hepatol 2001

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

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, Clinics in Liver Disease 2001;340:145-159

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 (%) 56.4 56.4 56.4 72.6 87.1

Specificity (%) 96.4 94.5 94.5 70.9 30.9

Johnson, Clin Liver Disease 2001

Des-carboxy prothrombin (prothrombin induced by Vitamin K absence II)

DCP (PIVKA II)

DCP vs. 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, J Gastroenterol hepatol 1992;Ishii, A, J Gastroentrol 2000; Mita, Cancer 1998; Tanaka, Hepatogastroenterol 1999; Marrero, Hepatology 2003.

AF P

fic

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

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

WHO Principles of Screening

Screening improves survival Cost of screening is acceptable

HCC Screening: clinical studies

Study, year, location Improved survival Yes Yes Yes Yes Yes

McMahon, 2000, Alaska, US Wong, 2000, Hawaii, US Yuen, 2000, Hong Kong Bolondi, 2001, Italy Chen 2002, Taiwan

None were randomized controlled studies

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

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

Zhang BH et al, J Cancer Res Clin Oncol 2004;130:417-22

Stage Stage I Stage II Stage III Small HCC

Screening N=86 60.5% 13.9% 25.6% 45.3%

Control N=67 0%
**P<0.01

37.3% 62.7% 0

Zhang BH et al, J Cancer Res Clin Oncol 2004;130:417-22

Treatment Resection TACE/PEI Supportive

Screening N=86 46.5% 32.6% 20.9%

Control N=67 7.5% 41.8% 50.7%

Zhang BH et al, J Cancer Res Clin Oncol 2004;130:417-22

Survival (%) 1-year 2-year 3-year 4-year 5-year

Screening N=86 65.9 59.9 52.6 52.6 46.4

Control N=67 31.2

**P<0.01

7.2 7.2 0 0

Cost-Effectiveness of Screening: Other Cancers

Others year saved Pap smear Colonoscopy Flexible sigmoidoscopy Fecal occult blood testing Mammography 100,000

$/life-

15,000 30,000 28,143 74,032 81,678 30,000

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

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

HCC Screening: Cost-effectiveness Analysis (AFP/US every 6 months)

Study Patients CE ratio (< 50,000$/QALY) No

Sarasin, 1996

Child A No OLT OLT/LDLT

Everson, 2000 (abbreviated) Sarasin, 2001 Patel, 2002 (abstract) Lin, 2004

Yes

OLT/LDLT HCV cirrhosis OLT/LDLT HCV cirrhosis

Yes *OLT > LDLT after 3.5 months Yes *Main cost burden is cost of OLT and not with screening cost No *Yes if US q12 months only

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 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.