1 / 35

From Hepatitis Viral Infection to Hepatocellular Carcinoma: a Perspective of Clinical Managemen t

1. 1. 1st Central China International Forum on on Liver Disease and Infection, Wuhan (2012-9-23). From Hepatitis Viral Infection to Hepatocellular Carcinoma: a Perspective of Clinical Managemen t. Chien -Jen Chen Genomics Research Center , Academia Sinica Taipei, Taiwan.

inari
Download Presentation

From Hepatitis Viral Infection to Hepatocellular Carcinoma: a Perspective of Clinical Managemen t

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 1 1 1st Central China International Forum on on Liver Disease and Infection, Wuhan(2012-9-23) From Hepatitis Viral Infection to Hepatocellular Carcinoma: a Perspective of Clinical Management Chien-Jen Chen Genomics Research Center, Academia Sinica Taipei, Taiwan

  2. Hepatocellular Carcinoma (HCC)

  3. Liver Cancer Incidence in the World

  4. Disease Deaths per Year Lower respiratory tract infections ~ 3.5 million HIV/AIDS ~ 3.0 million Diarrheal diseases ~ 2.2 million Tuberculosis ~ 2.0 million Malaria ~ 1-3 million Measles ~ 888,000 Hepatitis B ~ 500,000-750,000 Pertussis ~ 355,000 Neonatal tetanus ~ 300,000 Hepatitis C ~ 250,000 Ten Leading Causes of Infectious Disease Deaths Worldwide (2000) WHO. Hepatitis B. 2002. Maynard JE, et al. In: Viral Hepatitis and Liver Disease. New York: Alan R. Liss, Inc. 1988. CDC. Epidemiology & prevention of vaccine-preventable diseases. The Pink Book. 8th ed. CDC. MMWR. 2001;50:RR-11.

  5. Chronic Hepatitis B 1 350-400 million chronic carriers worldwide Leads to liver cirrhosis and hepatocellular carcinoma Levanchy, 2004

  6. Chronic Hepatitis C 1 170-200 million chronic carriers worldwide Leads to liver cirrhosis and hepatocellular carcinoma Source: WHO

  7. Global Impact of Chronic Hepatitis B • Due to its high incidence and risk of Liver injury, CHB constitutes a significant health and economic burden within this region2 2 billion with evidence of 25–40% die of cirrhosis or liver cancer HBV infection 75% of infections are in the Asian Pacific Region1 350–400 million with World population chronic HBV1 6 billion 1. WHO and CDC fact sheets, available at www.who.int and www.cdc.gov 2. Rosmawati et al. J. Gastroenterol. Hepatol. 2004; 19:958–969

  8. Host Factors • Androgen level • Xenobiotic metabolism enzymes • DNA repair enzymes • Hormone receptors • Oncogenes • Tumor suppressor genes • HLA • T-cell receptors • Cytokines • Chemokines Chronic infection Self-limited infection Precancerous lesions Cancers DNA damage Chromosomal ab. Viral DNA integration Cell proliferation/ Chromosomal instability Loss of cellular growth control Inflammation • Alcohol drinking • Cigarette smoking • Carcinogen exposure • Antioxidant vitamins • Selenium • Viral load • Genotypes • Mutants Virus Factors Environment Factors

  9. Chronic Hepatitis B:Risk Predictors for Disease Progression Age (Increasing risk with age) Elevated viral load (Biological risk gradient with increasing HBV DNA) Family History HBeAg status (Increases risk of HCC) Gender (M > F) Presence of hepatic inflammation / fibrosis (Increases risk of HCC) HBV Genotype (Genotype C > B in Asians) Alcohol consumption (Increases risk of HCC) Fattovich G. Semin Liver Dis 2003;23:47-58; Chen CJ, et al. JAMA 2006;295:65-73; Iloeje UH, et al. Gastroenterology 2006;130:678-86; Chen CJ J.Gastroenterol Hepatol 1997;12:S294-S308; Yang HI et al. NEJM 2002;347:168-174; Yang HI et al. JNCI 2008;100:1134-43

  10. HCC Risk Nomogram (REVEAL-HBV Study) Yang HI et al., J Clin Oncol 2009; 28:2437-2444.

  11. Risk Calculator Validation: REACH-B Study Development Community-based REVEAL-HBV cohort Validation Hospital-based composite international cohort 23820 cohort members recruited in Taiwan CUHK cohort 426 patients (46 HCC cases) Yonsei U cohort 259 patients (25 HCC cases) UHK cohort 820 patients (40 HCC cases) 4155 HBsAg-seropositive 3851 tested serum HBV DNA on enrollment sample (REVEAL-HBV cohort) 3653 anti-HCV-seronegative subjects Risk scores and predicted HCC risk for external validation 3584 free of liver cirrhosis at study entry (131 developed HCC during follow-up) 1505 CHB patients for validation (111 developed HCC during follow-up) Yang et al., Lancet Oncol, 2011; 12:568-574

  12. Model Development using Multivariate Cox Proportional Hazards Model Yang et al., Lancet Oncol, 2011

  13. Assignment of REACH-B Score Yang et al., Lancet Oncol, 2011

  14. Projected HCC Risk by Cumulative REACH-B Scores Yang et al., Lancet Oncol, 2011

  15. National Hepatitis B Immunization Program in Taiwan Chen et al., J. Am. Med. Assoc., 1987

  16. Reduction in Liver Cancer Incidence after National HBV Vaccination Program Chang et al., N. Engl. J. Med., 1997

  17. National HBV Vaccination and Childhood (6-9 years) HCC Incidence Birth year Incidence Relative Risk (per 100,000) 1974-1984 0.521 1.00 (referent) 1984-1986 0.132 0.25 (P<0.001) Chang et al., New Engl J Med 1997;336:1855-1859

  18. National HBV Vaccination and Childhood (6-14 years) HCC Incidence Birth year Incidence Relative Risk (per 100,000) (95% confidence interval) 1966-1984 0.539 1.00 (referent) 1984-1994 0.196 0.36 (0.26-0.52) Chang et al., Clin Cancer Res 2005; 11:7953-7957

  19. National HBV Vaccination and Childhood (6-19 years) HCC Incidence Birth year Incidence Relative Risk (per 100,000) (95% confidence interval) 1963-1984 0.566 1.00 (referent) 1984-1998 0.170 0.31 (0.24-0.41) Chang et al., J. Natl. Cancer Inst. 2009 (in press)

  20. Primary Goal of Hepatitis B Therapy: Preventing Cirrhosis, HCC, and Death Durable Suppression of HBV Replication Impact of viral suppression on liver disease outcomes • Prolonged viral suppression is associated with • Reduction in necroinflammation, fibrosis, and cirrhosis • Reduction in decompensation • Reduction in rates of HCC • Reduction in mortality

  21. Evolution of Approved HBV Therapy Peginterferon alfa-2a Entecavir Lamivudine Tenofovir 1990 2006 1998 2002 2005 2008 Interferon alfa-2b Telbivudine Adefovir

  22. 22 Dienstag, 2008

  23. Effect of LAM on Disease Progression in Chronic Hepatitis B with Advanced Fibrosis 25 Placebo 20 P = .001 15 Disease Progression (%) 10 Lamivudine 5 0 0 6 12 18 24 30 36 Time to Disease Progression (months) Placebo (n = 215) Lamivudine (n = 436) Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.

  24. Female, young age at infection  30 years Cirrhosis develops in 20% Risk of carcinoma, 1-4% per year Normal liver Acute infection Chronic infection develops in 80% Chronic hepatitis  20 years Alcohol use, coinfection Natural History of HCV Infection: Individual Variability Slow Rate of progression Fast Lauer and Walker, 2001

  25. Hepatitis C Seromarkers for Long-term Prediction of Long-term Risk of Hepatocellular Carcinoma Lee et al., J. Clin. Oncol, 2010

  26. HCC Risk Point for HCV Seromarkers

  27. Projected HCC Risk by a Patient’s Risk Profile … Lee MH et al. In submission

  28. Aim of CHC Treatment is to Prevent HCC Chronic inflammation and increasing liver damage over time X Aim of therapy: Prevent progression to cirrhosis, end-stage liver disease, HCC and death WHO 2003.

  29. 70 60 50 40 30 20 10 0 Improved CHC Treatment Outcomes 1998 2004 2011 66% 10-fold increase 41% Sustained virologic response (%) 13% 6% IFN 24 weeks1 IFN 48 weeks1 IFN + RBV 48 weeks1,2 Peg-IFN-2a + RBV 48 weeks3 1. McHutchison et al. N Engl J Med 1998;339:1485; 2. Poynard et al. Lancet 1998;352:1426; 3. Zeuzem et al. J Hepatol 2005;43:250.

  30. Caucasian Asian 100 80 60 40 20 0 Higher Successful Treatment Outcomes in Asian vs. Caucasian Patients Genotype 148 weeks’ Peg-IFN-2a 180 µg/week + RBV 1,000–1,200 mg/day 83% 79% 68% 61% 52% SVR (%) Hadziyannis et al2004 Kuboki et al2007 Lee et al2008 Yu et al2008 Chen et al2010 Hadziyannis et al. Ann Intern Med 2004;140:346; Kuboki et al. J Gastroenterol Hepatol 2007;22:645;Lee et al. Korean J Hepatol 2008;14:46; Yu et al. Hepatology 2008;47:1884; Chen et al. Chin J Hepatol 2010;18:585.

  31. p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 Milestones in CHC Treatment in Asia Undetectable HCV (%) TT TT TT TT TT TC TC TC TC TC CC CC CC CC CC RVR n=1091 cEVR n=1,089 EOT n=998 Relapse n=687 SVR n=1,171 • Host IL28B genotype determined by SNP (rs12979860) • Determines activity of IFN l-3 (innate immunity) • T (unfavorable) and C (favorable) alleles Thompson et al. Gastroenterology 2010;139:120.

  32. IL28BGenotype is Predominantly the Favorable C allele in East Asia Thomas et al. Nature 2009;461:798.

  33. Milestones in CHC in Asia Over the past 18 years there has been a dramatic improvement in treatment results for CHC in Asia SVR (%) IFN 3 MU 24 wks IFN 6 MU 24 wks IFN+RBV 24 wks Peg+RBV 24 wks Peg+RBV 48/24 wks Peg+RBV RVR +ve Yu et al. J Gastroenterol Hepatol 2011;24:336.

  34. Summary CHB and CHC are associated with a major health burden both globally and in the Asia Pacific region HCC risk calculators based on age, gender serum ALT (AST) level, and viral load and genotype have been developed for the triage and clinical management of CHB and CHC patients. Both vaccination and anti-viral therapy may be used to decrease the CHB burden, while anti-viral therapy may be used eliminate CHC burden.

  35. 35 Thank You!

More Related