1. Giovanna FATTOVICH

2. 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

3. How to predict HBeAg seroconversion * older age Higher ALT levels at presentation acute flares of hepatitis HBV genotype (B > C) severe CH HBeAg+anti-HBe+ 1500 1000 200 100 0 10521 years ALT Chu CM, J Hepatol 2005: 43: 411 * strong association with higher rates Genotype B Genotype C years

4. Hsu 2002 Manno 2004 Bortolotti 2006 Fattovich 2007 RaceAsiansCaucasians Clinical settingclinicBlood donors clinic (children) clinic Number patients 1892968040 Median Follow-up (yrs) 8291423 Histologic deterioration 0.06nr00 HCC 0.190.02 a 00.2 b Liver-related death 00.03 c 00.2 HBsAg loss 0.61.0 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

5. How to predict the outcome of CHB: effect of HBsAg loss mean follow-up: 5 to 6 yrs Eurohep, Am J Gastroenterol 1998; 93: 896-900 024681012 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 0 Yrs AuthorPopulationStatus at clearance N° PtsAny liver-related complications/death Eurohep 1998Caucasianscirrhosis3222% Chen 2002Asianscirrhosis2917% No cirrhosis1892.1% * Arase 2006Asianscirrhosis673% No cirrhosis1670 * 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

7. Natural history of cirrhosis type B Annual incidence decompensation 3-4% Annual incidence HCC 2-3% EASL International Consensus Conference on Hepatitis B, 2002 5-yrs probability in compensated cirrhosis :80-85% 5-yrs probability in compensated cirrhosis :80-85% 5-yrs probability after decompensation: 15-30% 5-yrs probability after decompensation: 15-30% Survival 012345678910 0 20 40 60 80 100 % HCC survival decompensation 86 68 16 30 9 18 Fattovich G, Am J Gastroenterol 2002 Causes of liver-related death HCC 40 % Liver failure/VB60 %

8. 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

9. * Adjusted for age, sex, cigarette smoking, and alcohol consumption. 300 - < 10 4 10 4 - 10 5 HBV DNA copies/mL 10 5 - 10 6 All Participants (n = 3582) * RR * (95% CI) *P <.001 6.5 5.6 2.5 1.4 0 2 4 6 8 10 12 14 > 10 6 * * HBeAg(-), Normal ALT (n = 2923) 300 - < 10 4 10 4 - 10 5 > 10 6 HBV DNA copies/mL 10 5 - 10 6 6.6 5.6 2.5 1.4 *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 carriers mean follow-up 11 yrs 365 patients newly diagnosed with cirrhosis Iloeje UH, Gastroenterology 2006; 130: 678-686 HBV-DNA viral load (> 10 4 cp/ml) strongest predictor of progression to cirrhosis independent of ALT and HBeAg status HBV-DNA status only at entry, NOT at the time of diagnosis of cirrhosis

10. HBV-DNA levels (> 10 4 cp/ml) strong predictor of HCC, independent of HBeAg, ALT and cirrhosis Entire cohort (N = 3653) HBV-DNA (cp/ml)RR < 300 1.0-9.9 x 10 4 1.0-9.9 x 10 5 > 1.0 x 10 6 1.0 2.3 6.6 6.1 Subcohort (N = 2925) HBV-DNA (cp/ml)RR < 300 1.0-9.9 x 10 4 1.0-9.9 x 10 5 > 1.0 x 10 6 1.0 4.5 11.3 17.7 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% Entire cohort (n = 3653)

11. Persistent HBV DNA Associated With Increased HCC Risk *Cox proportional hazards models. Risk is relative to < 10 4 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 < 10 4 Mid 10 4 - 10 5 High 10 5 HBV DNA (copies/mL) High 10 5 DNA at entry: DNA at follow-up: 10.1 7.3 3.8 0 4 8 12 16 n = 146120 537 Chen CJ, et al. JAMA. 2006;295:65-73.

12. Compensated cirrhosis type B independent 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

13. VariableRR Cirrhosis Genotype C (vs B) 10.24 2.84 HBV genotype & risk of HCC Increased 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) CH genotype > 50 yrs B B C C B C B C cirrhosis< 50 HCC % * p=0.03 * * Chan, Gut 2004 Yu, J Natl Cancer Inst 2005 Mahmood, Liver Int 2005 Kao, Gastroenterology 2000 Ni, Gastroenterology 2004 Chen CH, Hepatogastroenterology 2004 Cirrhosis + genotype C Cirrhosis + genotype B

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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