Treatment for Chronic Hepatitis B Screening for Hepatocellular Carcinoma Mindie H. Nguyen, MD, MAS Assistant Professor of Medicine Division of Gastroenterology

Treatment for Chronic Hepatitis BScreening 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%

0% 2% 4% 6% 8% 10% 12% 14%

Chinese

Filippino

Japanese

Korean

Vietnamese

Laotians

Son D, Asian Am Pac Isl J Health 2001

1.1

2.5

5.7

1

2.5

5.4

1.2

2.8

6

1.2

2.5

6.3

1.4

3.2

7

1.6

3.7

7.3

1.8

3.7

7.7

2.2

4.2

8.4

0

1

2

3

4

5

6

7

8

9

1975-1978

1978-1980

1981-1983

1984-1986

1987-1989

1990-1992

1993-1995

1996-1998

Age-Adjusted HCC Incidence Rate per 100,000 Patients

White

Black

Other

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

Etiology of HCC in Asians

White (n=410)

HBsAg, 24

anti-HCV, 212Both

markers, 14

Neither, 160

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

Asian (n=107)

HBsAg, 53

Neither, 16Both

markers, 6

anti-HCV, 32

Black (n=95)

HBsAg, 15

anti-HCV, 51

Both markers, 8

Neither, 21

Others (n=79)

HBsAg, 15

anti-HCV, 27

Both markers, 5

Neither, 32

*Results from survey of 21 US transplant centers between 1997-1999 (n=691):

HCC - California

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

5.23.3

7 6.9

17.4

0

5

10

15

20

All race

s

White

Hispan

ic

Black

Asian/O

ther

sInce

iden

ce p

er 1

00,0

00

Total

Male

Female

California Cancer Registry, Accessed 10/2004

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

• Reduction in viral load:– Liver disease

progression3,5

– HCC3

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.

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 person-

years)• 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)

Sample

Size

Person-years of follow-up

Cirrhosis

Cases

Incidence rate (per 100,000)

Adjusted relative risk*

(95% CI)

<300 (LOQ) 869 10,048.8 34 338.81.0

(reference)

300–9.9x103 1150 13,259.0 57 429.9 1.4 (0.9-2.2)

1.0–9.9x104 628 7105.5 55 774.0 2.5 (1.6-3.8)†

1.0–9.9x105 333 3460.0 65 1878.6 5.9 (3.9-9.0)†

≥1.0x106 602 6164.3 154 2498.3 9.8 (6.7-14.4)†

*Adjusted for gender, age, cigarette smoking, and alcohol consumption†P <0.001P <0.001 for the trend

Iloeje UH et al. Gastroenterol 2006;130 (3):678-86.

HBV DNA Levels Predict Risk of Developing Cirrhosis

Iloeje UH et al. Gastroenterol 2006;130 (3):678-86.

Adjusted HR of Cirrhosis Risk by HBV DNA levels

0

0.1

0.2

0.3

0.4

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Year of Follow-up

Cu

mu

lati

ve

In

cid

en

ce

of

Liv

er

Cir

rho

sis

≥ 1.0 x 101.0 - 9.9 x 101.0 - 9.9 x 10300 - 9.9 x 10< 300

HBV DNA levels:

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.

0

500

1000

1500

2000

2500

3000

3500

4000

4500

<300 300 – <104 104 – <105 105 – <106 ≥ 106

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

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) 873 10,154 11 108 1.0 (reference)

300–9.9x103 1161 13,518 15 111 1.1 (0.5–2.3)

1.0–9.9x104 643 7404 22 297 2.3 (1.1–4.9)†

1.0–9.9x105 349 3845 37 962 6.6 (3.3-13.1)‡

≥1.0x106 627 6858 79 1152 6.1 (2.9-12.7)‡

*Adjusted for gender, age, habits of cigarette smoking and alcohol consumption†P =0.02‡P <0.001P <0.001 for the trend

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

Dose-Response Relationship: HBV DNA and HCC

0.7% 0.9% 3.2%8.0%

13.5%

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

90.0%

100.0%

Cu

mu

lati

ve

In

cid

en

ce

of

HC

C

(%)

<300 300-9999 10,000-99,999

100,000-999,999

>10

HBV DNA (copies/mL)

HBeAg neg, Normal ALT, No cirrhosis at entrySubcohort: n=2925

6

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

HBV DNA Levels are Associated With Clinical Outcomes (HCC)

14

12

10

8

6

4

2

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Year of Follow-up

Cu

mu

lati

ve I

nci

de

nce

of

HC

C,

%

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

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

Primary Goalof Treatment

Rapid and sustained suppression of HBV to the lowest possible level1,2

Outcomes

– Delay in progression to cirrhosis and HCC3

– Improved survival4

– Reduction in the development of resistance5

– Increased rate of seroconversion6,7

– Improvement in liver histology6

– Normalization of ALT levels6

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.

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


Dis

ease

Pro

gre

ssio

n

(% p

atie

nts

)

Placebo (n=215)

Lamivudine(n=436)

0

5

10

15

20

25

36302416126

ITT populationP = .001

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

Lamivudine

Placebo

Dia

gnos

is o

f HC

C (

%)

60 12 18 24 30 36

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

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


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 HCCConsensus 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

treatments1McMahon, J Natl Cancer Inst 1991

2Colombo. J Hepatol 19923Bruix, J Hepatol 2001

HCC: Screening Tests

• Imaging studies– Ultrasound*– Computed tomography Computed tomography – No significant differences between spiral CT No significant differences between spiral CT

and MRI and MRI Stoker J, Gut 2002Stoker J, Gut 2002

• Blood tests– Alpha-fetoprotein*– Des-gamma-carboxy prothrombin Des-gamma-carboxy prothrombin – Hepatoma-specific isoforms of alpha-Hepatoma-specific isoforms of alpha-

fetoproteinfetoprotein

Range of AFP levels

0

5

10

MalignantHCC

Benign Normal

log AFP (ng/mL)

108

106

104

102

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

Changes in sensitivity and specificity of AFP

for diagnosis of HCC using various cut-offs

Sensitivity SpecificityDiagnostic criteria (%) (%)AFP > 615 ng/mL 56.4 96.4AFP > 530 ng/mL 56.4 94.5AFP > 445 ng/mL 56.4 94.5AFP > 100 ng/mL 72.6 70.9AFP > 20 ng/mL 87.1 30.9

Johnson, Clin Liver Disease 2001

DCP (PIVKA II)Des-carboxy prothrombin (prothrombin induced by Vitamin K

absence II)

DCP vs. AFP for HCC Diagnosis

0

20

40

60

80

100

DCP Sen

sitivi

ty

DCP Spe

cifici

ty

AFP Sen

sitivi

ty

AFP Spe

cifici

ty

Per

cen

t

Tanaka (68/106)

Mita (57/91)

Ishii (594/29)

Takikawa(253/116)

Marrero (53/14)

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

ScreeningUS Sensitivity and Specificity

Study Sensitivity Specificity

Okazaki, 1984 86% 99%

Maringhini, 1988 90% 93%

Tremolda, 1989 85% 50%

Dodd, 1992 50% 98%

Pateron, 1994 78% 93%

Zhang, 1999 84% 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

McMahon, 2000, Alaska, US YesWong, 2000, Hawaii, US YesYuen, 2000, Hong Kong YesBolondi, 2001, Italy YesChen 2002, Taiwan Yes

None were randomized controlled studiesNone were randomized controlled studies

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


Stage Screening

N=86

Control

N=67

Stage I 60.5% 0%

Stage II 13.9% 37.3%

Stage III 25.6% 62.7%

Small HCC 45.3% 0

**P<0.01


Treatment Screening

N=86

Control

N=67

Resection 46.5% 7.5%

TACE/PEI 32.6% 41.8%

Supportive 20.9% 50.7%


Survival (%) Screening

N=86

Control

N=67

1-year 65.9 31.2

2-year 59.9 7.2

3-year 52.6 7.2

4-year 52.6 0

5-year 46.4 0

**P<0.01

Cost-Effectiveness of Screening: Other Cancers

Others $/life-year saved

Pap smear 15,000 – 30,000

Colonoscopy 28,143

Flexible sigmoidoscopy 74,032

Fecal occult blood testing 81,678

Mammography 30,000 – 100,000

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

Study Patients CE ratio (< 50,000$/QALY)

Sarasin, 1996 Child A No No OLT

Everson, 2000 OLT/LDLT Yes(abbreviated)

Sarasin, 2001 OLT/LDLT Yes*OLT > LDLT after 3.5 months

Patel, 2002 HCV cirrhosis Yes (abstract) OLT/LDLT *Main cost burden is cost of OLT and not with

screening costLin, 2004 HCV cirrhosis 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 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.

Documents

Treatment for Chronic Hepatitis B Screening for Hepatocellular Carcinoma Mindie H. Nguyen, MD, MAS Assistant Professor of Medicine Division of Gastroenterology