Transcript Document

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
8.4
8
7.7
7.3
7
7
5.7
6
6.3
6
5.4
5
4.2
3.7
4
3
3.7
3.2
2.5
2.5
2.8
2.2
2
1.1
2.5
1
1.2
1.2
1.4
19811983
19841986
19871989
1.6
1.8
19901992
19931995
White
Black
Other
1
0
19751978
19781980
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)
Neither,
160
Asian (n=107)
Neither, 16
HBsAg, 24
Both
markers, 6
anti-HCV,
212
Both
markers,
14
anti-HCV,
32
Black (n=95)
Neither, 21
HBsAg, 53
Others (n=79)
HBsAg, 15
HBsAg, 15
Neither, 32
Both
markers, 8
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
Inceidence per 100,000
HCC Incidence per 100,000 Population,
California 1990-1994
17.4
20
15
10
Total
5.2
5
7
6.9
Male
3.3
Female
0
A
es
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a
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hi
W
Hi
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B
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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)
Sample
Size
Personyears of
follow-up
Cirrhosis
Cases
Incidence
rate (per
100,000)
Adjusted
relative risk*
(95% CI)
<300 (LOQ)
869
10,048.8
34
338.8
1.0
(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 <0.001
P <0.001 for the trend
Iloeje UH et al. Gastroenterol 2006;130 (3):678-86.
HBV DNA Levels Predict Risk of
Developing Cirrhosis
Cumulative Incidence of Liver
Cirrhosis
Adjusted HR of Cirrhosis Risk by HBV DNA levels
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
0.4
0.3
0.2
0.1
0
0
1
2
3
4
5
6
7
Year of Follow-up
Iloeje UH et al. Gastroenterol 2006;130 (3):678-86.
8
9
10
11
12
13
Viral Load Is the Main Predictor of
Cirrhosis Regardless of Serum ALT
Cirrhosis incidence /100,000 Person-Years of Follow-up
4500
ALT <1 x ULN, n = 3542, P < .001
ALT ≥1 x ULN, n = 232, P < .001
4000
3500
3000
2500
2000
1500
1000
500
0
<300
300 – <104
104 – <105
105 – <106
HBV DNA (copies/mL)
Iloeje UH et al. J Hepatology 2005;42(suppl 2):180. Abstract 497.
≥ 106
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 <0.001
P <0.001 for the trend
Chen CJ et al. JAMA 2006;295(1):65-73.
Dose-Response Relationship:
HBV DNA and HCC
Cumulative Incidence of HCC
(%)
100.0%
90.0%
HBeAg neg, Normal ALT, No cirrhosis at entry
Subcohort: n=2925
80.0%
70.0%
60.0%
50.0%
40.0%
30.0%
20.0%
10.0%
0.7%
0.9%
3.2%
300-9999
10,00099,999
8.0%
0.0%
<300
100,000999,999
HBV DNA (copies/mL)
Chen CJ et al. JAMA 2006;295(1):65-73.
13.5%
6
>10
HBV DNA Levels are Associated With
Clinical Outcomes (HCC)
Cumulative Incidence of HCC, %
Baseline HBV DNA Level, copies/mL
14
>1 Million
100000-999999
10000-99999
300-9999
<300
12
10
Subcohort (n = 2925)
HBeAg-negative
Normal ALT
No cirrhosis at entry
8
6
4
2
0
0
1
2
3
4
5
Chen CJ et al. JAMA 2006;295(1):65-73.
6
7
Year of Follow-up
8
9
10
11
12
13
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
Disease Progression
(% patients)
25
ITT population
P = .001
20
Placebo
(n=215)
15
10
Lamivudine
(n=436)
5
0
6
12
Liaw YF et al. N Engl J Med 2004;351:152135.
16
24
30
36
Diagnosis of HCC (%)
HBV DNA Suppression Reduces
HCC Incidence Rate
10
7.4%
Placebo
P = .047
Placebo (n= 215)
3.9%
LVD (n= 436)
Lamivudine
0
0
6
12
18
24
Time to diagnosis of HCC (months)
Liaw YF, et al. N Engl J Med 2004;351:1521-1531.
30
36
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
– Hepatoma-specific isoforms of alphafetoprotein
Range of AFP levels
10
108
106
104
5
102
1
log AFP (ng/mL)
0
Malignant Benign
HCC
Normal
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
DCP (PIVKA II)
Des-carboxy prothrombin (prothrombin induced by Vitamin K
absence II)
DCP vs. AFP for HCC Diagnosis
Percent
100
Tanaka (68/106)
80
60
Mita (57/91)
40
20
Ishii (594/29)
Takikawa
(253/116)
P
Marrero (53/14)
DC
DC
P
Se
ns
i
tiv
ity
Sp
ec
AF
ific
P
ity
Se
ns
AF
itiv
P
ity
Sp
ec
ific
ity
0
Takikawa, J Gastroenterol hepatol 1992;Ishii, A, J Gastroentrol 2000;
Mita, Cancer 1998; Tanaka, Hepatogastroenterol 1999; Marrero, Hepatology 2003.
Screening
US Sensitivity and Specificity
Study
Sensitivity Specificity
Okazaki, 1984
Maringhini, 1988
Tremolda, 1989
Dodd, 1992
Pateron, 1994
Zhang, 1999
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
McMahon, 2000, Alaska, US
Wong, 2000, Hawaii, US
Yuen, 2000, Hong Kong
Bolondi, 2001, Italy
Chen 2002, Taiwan
Yes
Yes
Yes
Yes
Yes
None 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
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%
**P<0.01
Stage II
13.9%
37.3%
Stage III
25.6%
62.7%
Small HCC
45.3%
0
Zhang BH et al, J Cancer Res Clin Oncol 2004;130:417-22
Treatment
Screening
N=86
Control
N=67
Resection
46.5%
7.5%
TACE/PEI
32.6%
41.8%
Supportive
20.9%
50.7%
Zhang BH et al, J Cancer Res Clin Oncol 2004;130:417-22
Survival (%)
1-year
Screening
N=86
Control
N=67
65.9
31.2
**P<0.01
2-year
59.9
7.2
3-year
52.6
7.2
4-year
52.6
0
5-year
46.4
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$/US
HCC Screening: Cost-effectiveness Analysis
(AFP/US every 6 months)
Study
Patients
CE ratio
(< 50,000$/QALY)
Sarasin, 1996
Child A
No OLT
No
Everson, 2000
(abbreviated)
OLT/LDLT
Yes
Sarasin, 2001
OLT/LDLT
Patel, 2002
(abstract)
HCV cirrhosis
OLT/LDLT
Lin, 2004
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.