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Giovanna FATTOVICH

Giovanna FATTOVICH. International Hepatitis Conference Paris, January 22 and 23, 2007. How to predict the outcome of chronic hepatitis B. Giovanna Fattovich Department of Gastroenterology, University of Verona, Italy. older age Higher ALT levels at presentation.

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Giovanna FATTOVICH

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  1. Giovanna FATTOVICH

  2. International Hepatitis Conference Paris, January 22 and 23, 2007 How to predict the outcome of chronic hepatitis B Giovanna Fattovich Department of Gastroenterology, University of Verona, Italy

  3. older age • Higher ALT levels at presentation How to predict HBeAg seroconversion * HBeAg+ anti-HBe+ • acute flares of hepatitis 1500 severe CH 1000 200 ALT 100 0 years 1 2 5 10 • HBV genotype (B > C) Genotype B Genotype C * strong associationwith higher rates years Chu CM, J Hepatol 2005: 43: 411

  4. Morbidity and mortality in inactive HBsAg carriersincidence per 100 person years of major events a alcohol consumption > 60g/die; b 2 pts with cirrhosis occurrence before HBeAg seroclearance;c 2 HCC, 1 alcoholic cirrhosis; nr = not reported

  5. How to predict the outcome of CHB: effect of HBsAg lossmean follow-up: 5 to 6 yrs * 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 60 Probability of HCC occurrence in cirrhosis B % • Patients who did not clear HBsAg • Patients who cleared HBsAg A 40 20 P = 0.0137 B 0 Yrs 0 2 4 6 8 10 12 14 Eurohep, Am J Gastroenterol 1998; 93: 896-900

  6. Natural history of cirrhosis type B EASL International Consensus Conference on Hepatitis B, 2002 Annual incidence decompensation  3-4% Annual incidence HCC  2-3% Survival 5-yrs probability in compensated cirrhosis : 80-85% 5-yrs probability after decompensation: 15-30% 100 % survival 80 86 Causes of liver-related death HCC 40 % Liver failure/VB 60 % 68 60 Fattovich G, Am J Gastroenterol 2002 40 decompensation 30 16 20 18 HCC 9 0 0 1 2 3 4 5 6 7 8 9 10

  7. How to predict the outcome of chronic hepatitis B Factors influencing progression to cirrhosis, HCC and liver-related death VIRUS • Levels of HBV-DNA replication • HBV genotype • HBV variant HOST EXTERNAL FACTORS

  8. 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 All Participants (n = 3582) HBeAg(-), Normal ALT (n = 2923) 14 14 *P < .001 *P < .001 12 12 RR * (95% CI) * * 10 10 * * 8 8 6.6 6.5 5.6 5.6 6 6 * * 4 4 2.5 2.5 1.4 1.4 2 2 0 0 > 106 300 - < 104 104 - 105 105 - 106 300 - < 104 104 - 105 105 - 106 > 106 HBV DNA copies/mL HBV DNA copies/mL * Adjusted for age, sex, cigarette smoking, and alcohol consumption. HBV-DNA status only at entry, NOT at the time of diagnosis of cirrhosis HBV-DNA viral load (> 104 cp/ml) strongest predictor of progression to cirrhosis independent of ALT and HBeAg status Iloeje UH, Gastroenterology 2006; 130: 678-686

  9. Level of HBV DNA (PCR-assays) at entry & risk of HCC • Population based cohort study of HBsAg asian carriers, mean follow-up= 11.4 Entire cohort (n = 3653) HBeAg (), Normal ALT, No cirrhosis at entry (n = 2925) 14.9% 13.5 % 12.1% >6log 7.9 % 5-6log >6log 3.1 % 3.5% 5-6log 4-5log 4-5log <4log 0.9 % 1.3% <4log 1.3% 0.7 % HBV-DNA levels (> 104 cp/ml) strong predictor of HCC, independent of HBeAg, ALT and cirrhosis Chen CJ et al JAMA 2006;295:65-73

  10. Persistent HBV DNA Associated With Increased HCC Risk 16 12 10.1 Adjusted Hazard Ratio* for HCC (95% CI) 8 7.3 3.8 4 537 146 120 n = 0 DNA at entry: DNA at follow-up: High ≥ 105 High ≥ 105 High ≥ 105 Low < 104 Mid 104 - 105 High ≥ 105 HBV DNA (copies/mL) *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. Chen CJ, et al. JAMA. 2006;295:65-73.

  11. Compensated cirrhosis type Bindependent factors affecting liver-related mortality Factors Factors • Age • Albumin • Bilirubin • Platelets • Splenomegaly • HBeAg • Age • AST/ALT ratio • Viral status adjusted RR= 5.9 in HBV DNA+ vs HBV DNA- Realdi, J Hepatol 1994 Fattovich, Am J Gastroenterol 2002

  12. HBV genotype & risk of HCC Increased HCC risk among Chinese patients with genotype C vs genotype B Cirrhosis + genotypeC Cirrhosis + genotype B Chan, Gut 2004 Yu, J Natl Cancer Inst 2005 Mahmood, Liver Int 2005 * genotype Genotype B more common than genotype C in younger non-cirrhotic pts with HCC (Taiwan) % * p=0.03 B C B C C * Kao, Gastroenterology 2000 Ni, Gastroenterology 2004 Chen CH, Hepatogastroenterology 2004 C B B CH cirrhosis < 50 > 50 yrs HCC

  13. How to predict the outcome of chronic hepatitis B Factors influencing disease progression HOST 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) VIRUS EXTERNAL FACTORS

  14. How to predict the outcome of chronic hepatitis B Factors influencing disease progression VIRUS HOST VIRUS EXTERNAL FACTORS • Concurrent infections (HCV, HDV, HIV) • Alcohol consumption • Comorbidities (diabetes, obesity ….) • Aflatoxin • Smoking

  15. The association between diabetes and HCC • Pooled risk estimates and 95% CIs of studies grouped according to study design, geographic location, and control group selection El Serag, Clinical Gastroenterol Hepatol 2006; 4: 369-80 • 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

  16. The association between obesity and HCC • 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) • 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 ….. • 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) • 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

  17. How to predict the outcome of CHB: conclusions • 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

  18. 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

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