Giovanna FATTOVICH
How to predict the outcome of chronic hepatitis B
International Hepatitis Conference
Paris, January 22 and 23, 2007
Giovanna Fattovich
Department of Gastroenterology, University of
Verona, Italy
How to predict HBeAg seroconversion *● older age● Higher ALT levels at presentation
● acute flares
of hepatitis
● HBV genotype (B > C)
severeCH
HBeAg+ anti-HBe+1500
1000
200
100
010521 years
ALT
Chu CM, J Hepatol 2005: 43: 411
* strong associationwith higher rates
Genotype B
Genotype C
years
Hsu
2002
Manno
2004
Bortolotti
2006
Fattovich 2007
• Race Asians Caucasians Caucasians Caucasians
• Clinical setting clinic Blood donors
clinic
(children)
clinic
• Number patients 189 296 80 40
• Median Follow-up (yrs) 8 29 14 23
• Histologic deterioration 0.06 nr 0 0
• HCC 0.19 0.02 a 0 0.2 b
• Liver-related death 0 0.03 c 0 0.2
• HBsAg loss 0.6 1.0 1.0 1.0
a alcohol consumption > 60g/die; b 2 pts with cirrhosis occurrence before HBeAg seroclearance; c 2 HCC, 1 alcoholic cirrhosis; nr = not reported
Morbidity and mortality in inactive HBsAg carriers
incidence per 100 person years of major events
How to predict the outcome of CHB: effect of HBsAg lossmean follow-up: 5 to 6 yrs
Eurohep, Am J Gastroenterol 1998; 93: 896-9000 2 4 6 8 10 12 14
20
40
60
A
B
A. Patients who did not clear HBsAg
B. Patients who cleared HBsAg
P = 0.0137
%Probability of HCC occurrence in cirrhosis B
0Yrs
Author Population Status at clearance
N° Pts Any liver-related complications/death
Eurohep 1998 Caucasians cirrhosis 32 22%
Chen 2002 Asians cirrhosis 29 17%
No cirrhosis 189 2.1% *
Arase 2006 Asians cirrhosis 67 3%
No cirrhosis 167 0
* only those with HCV co-infection
Risk of HCC after HBsAg loss
- cirrhosis
- HCV coinfection
Higher risk of HCC in cirrhotics
with older age at HBsAg loss
Natural history of cirrhosis type BNatural history of cirrhosis type B
Annual incidenceAnnual incidence decompensation decompensation 3-4% 3-4%
Annual incidenceAnnual incidence HCC HCC 2-3% 2-3%
EASL International Consensus Conference on Hepatitis B, 2002 EASL International Consensus Conference on Hepatitis B, 2002
5-yrs probability in compensated cirrhosis :5-yrs probability in compensated cirrhosis :80-85%80-85%
5-yrs probability after decompensation:5-yrs probability after decompensation: 15-30% 15-30%
SurvivalSurvival
0 1 2 3 4 5 6 7 8 9 100
20
40
60
80
100
%
HCC
survival
decompensation
86
68
16
30
918
Fattovich G,Am J Gastroenterol 2002
Causes of liver-related deathHCC 40 %Liver failure/VB 60 %
HOST
EXTERNAL FACTORS
VIRUS
How to predict the outcome of chronic hepatitis B
Factors influencing progression to cirrhosis, HCC and liver-related death
•Levels of HBV-DNA replication
•HBV genotype
•HBV variant
* Adjusted for age, sex, cigarette smoking, and alcohol consumption.
300 - < 104 104 - 105
HBV DNA copies/mL
105 - 106
All Participants(n = 3582)
*
RR * (95% CI)
*P < .001
6.55.6
2.51.4
0
2
4
6
8
10
12
14
> 106
*
*
HBeAg(-), Normal ALT(n = 2923)
300 - < 104 104 - 105 > 106
HBV DNA copies/mL
105 - 106
6.65.6
2.51.4
*P < .001
*
*
*
0
2
4
6
8
10
12
14
Level of HBV DNA (PCR-assays) at entry & progression to cirrhosis in population-based cohort studies
3582 HBsAg untreated asian carriersmean follow-up 11 yrs → 365 patients newly diagnosed with cirrhosis
Iloeje UH, Gastroenterology 2006; 130: 678-686
HBV-DNA viral load (> 104 cp/ml) strongest predictor of progression to cirrhosis independent of ALT and HBeAg statusHBV-DNA status only at entry, NOT at the time of diagnosis of cirrhosis
HBV-DNA levels (> 104 cp/ml) strong predictor of HCC, independent of HBeAg, ALT and cirrhosis
Entire cohort (N = 3653)
HBV-DNA (cp/ml) RR
< 3001.0-9.9 x 10 4
1.0-9.9 x 10 5
> 1.0 x 10 6
1.02.36.66.1
Subcohort (N = 2925)
HBV-DNA (cp/ml) RR
< 3001.0-9.9 x 10 4
1.0-9.9 x 10 5
> 1.0 x 10 6
1.04.5
11.317.7
• Population based cohort study of HBsAg asian carriers, mean follow-up= 11.4
Chen CJ et al JAMA 2006;295:65-73
13.5 %
7.9 %
0.9 %
0.7 %
3.1 %
>6log
5-6log
4-5log
<4log
Level of HBV DNA (PCR-assays) at entry & risk of HCC
HBeAg (), Normal ALT,No cirrhosis at entry
(n = 2925)>6log
5-6log
4-5log
<4log
14.9%
12.1%
3.5%
1.3% 1.3%
Entire cohort (n = 3653)
Persistent HBV DNA Associated With Increased HCC Risk
*Cox proportional hazards models. Risk is relative to < 104 copies/mL at entry/not tested at follow-up. Data adjusted for sex, age, cigarette smoking, and alcohol consumption.
Adjusted Hazard Ratio* for HCC (95% CI)
Low < 104 Mid 104 - 105 High ≥ 105
HBV DNA (copies/mL)
High ≥ 105 High ≥ 105 High ≥ 105DNA at entry:
DNA at follow-up:
10.1
7.3
3.8
0
4
8
12
16
n = 146 120 537
Chen CJ, et al. JAMA. 2006;295:65-73.
Compensated cirrhosis type Bindependent factors affecting liver-related
mortality
• Age
• Albumin
• Bilirubin
• Platelets
• Splenomegaly
• HBeAg
Factors
Realdi, J Hepatol 1994
• Age
• AST/ALT ratio
• Viral status
adjusted RR= 5.9
in HBV DNA+ vs
HBV DNA-
Factors
Fattovich, Am J Gastroenterol 2002
Variable RR
CirrhosisGenotype C (vs B)
10.242.84
HBV genotype & risk of HCCIncreased HCC risk among Chinese patients with genotype C vs genotype B
Genotype B more common than genotype C in younger non-cirrhotic pts with HCC (Taiwan)41
55
30
80
14
32
6051
0
100
CH
genotype
> 50 yrs
BB
BB
CCCC
BB
CC
BB
CC
cirrhosis < 50HCC
% * p=0.03*
*
Chan, Gut 2004Yu, J Natl Cancer Inst 2005Mahmood, Liver Int 2005
Kao, Gastroenterology 2000Ni, Gastroenterology 2004Chen CH, Hepatogastroenterology 2004
Cirrhosis + genotype C
Cirrhosis + genotype B
VIRUS
HOST
EXTERNAL FACTORS
VIRUS
• Older age at diagnosis•, Older age at anti-HBe seroconversion• Male gender• Recurrent flares of hepatitis HCC • Presence of cirrhosis• Family history of HCC • Race (Asian, African)
How to predict the outcome of chronic hepatitis B
Factors influencing disease progression
VIRUS HOST
EXTERNAL FACTORS
VIRUS
How to predict the outcome of chronic hepatitis B
Factors influencing disease progression
• Concurrent infections (HCV, HDV, HIV)• Alcohol consumption • Comorbidities (diabetes, obesity ….)• Aflatoxin • Smoking
The association between diabetes and HCC
El Serag, Clinical Gastroenterol Hepatol 2006; 4: 369-80
• Pooled risk estimates and 95% CIs of studies grouped according to study design, geographic location, and control group selection
• Not all studies controlled for confounding risk factors adequately (eg, HBV, HCV, alcohol, obesity ….)
• Unclear whether diabetes preceded the underlying chronic liver disease
• The association between diabetes and HCC requires more research
● Some population-based cohort studies from Europe and USA found that obesity is associated with a 2-4 fold increased HCC risk, however these studies …..
did not control for confounding risk factors (eg. HBV, HCV, alcohol, diabetes) (Moller, 1994)
Or controlled only for alcoholism and diabetes (Calle, 2003; Samanic, 2004)
Or found no increased risk when excluding pts with diabetes (Wolk, 2001)
● A USA cohort study of OLT candidates found that obesity was an independent risk factor for HCC in alcoholic cirrhosis (OR 3) and cryptogenic cirrhosis (OR 11), but not in HBV and HCV-related cirrhosis (Nair, 2002)
•The association between obesity and HCC
● No definitive conclusion can be drawn as to the role of obesity as a risk factor for HCC per se or as a cofactor in chronic hepatitis B
Adapted from Donato & Fattovich, Oncogene 2006 ; 25: 3756-70
● Persistent high level of HBV replication and long duration of active hepatitis are the best predictors of adverse clinical outcome (cirrhosis, HCC and liver-related mortality)
● Sustained suppression of HBV replication (inactive carrier state) before the onset of cirrhosis confers favorable prognosis (with similar survival compared to uninfected individuals in caucasians)
● Sustained suppression of HBV replication in cirrhotic patients lowers the risk of HCC
How to predict the outcome of CHB: conclusions
● Older age, male gender, multiple ALT flares, severity of compensated cirrhosis at diagnosis, concurrent viral infections and alcohol abuse are additional predictors of disease progression
● Growing evidence suggest that HBV genotypes may influence different clinical outcomes, but their role in HBV-related liver disease needs to better defined
● Further studies are needed to investigate other viral factors (eg HBV mutant) and preventable or treatable comorbidities (eg diabetes, obesity) in the prognosis of chronic hepatitis B
● This scenario suggests that an efficient treatment of chronic hepatitis B should shorten the highly replicative phase and counseling could prevent comorbidity
How to predict the outcome of CHB: conclusions