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