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Management of chronic liver diseases

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  1. Management of chronic liver diseases Irinel Popescu Fundeni Institute of Digestive Diseases and Liver Transplantation

  2. HCV infection - epidemiology • Prevalence:180 million persons (3% of the population) (underestimated!)(1999-2001) • More recent data:300 million persons!(2007) • Incidence:3-4 million persons infected annually(a minority is symptomatic: 1-3 cases/one million persons/year!) Lee WM, N Engl J Med 1997; 337: 1733; Lok ASF, McMahon BJ Hepatology 2001; 34: 1225 WHO. Hepatitis C: global prevalence. Weekly Epidemiol Rec 2000; 75: 18; Anonymous. Global Surveillance and control of Hepatitis C. J Viral Hepat 1999; 6: 35 Maria Buti, Advances in the Therapy of Liver Disease, Barcelona: Ars Medica, Sept 2007: 263

  3. HCV infection - epidemiology • 70%of chronic hepatitis • 40%of liver cirrhosis • 60%of cases of hepatocarcinoma • 40-50%of LT indications • Important personal, social, economic implications and costs NIH Consensus Development Conference. Management of Hepatitis C -2002 June 10-12. Hepatology 2003

  4. <1 % 1-2,4 % 2,5-4,9 % 5-10 % > 10 % No data available Global prevalence of HCV infection EUROPE – 22 millions Central and South Est Europe 13 millions OMS. Wkly Epidemiol Rec. 2000;75:18-19.

  5. Natural history of HCV infection 15-20% Acute HCV infection 55-80% Spontaneous Cleareance Chronic Infection Chronic hepatitis 70-85% mild moderate severe Cirrhosis 10-20%/10-30 years End-stage HCC 20%/10 years 1-4%/year Recurrent infection LTx 20% HCV+ CH/5 years Death

  6. Epidemiologic projection of HCV infection 2010 2000 2020 2040 2030 HCV infection 2.940.678 2.870.391 2.681.556 2.433.709 2.177.089 Cirrhosis472.103 720.807 858.788 879.747 828.134 Decomp. cirrhosis65.294 103.117 134.743 146.408 142.732 HCC 7.271 11.185 13.183 13.390 12.528 Death13.000 27.732 36.483 39.875 39.064 Davis et al. Projecting future complications of chronic hepatitis C in the United States. Liver transplantation, 2003

  7. Mortality due to liver cirrhosis (standardized rates) Ascione, Roche Symp 2006 Poiana Brasov

  8. Prevalence of HCV infection in Romania Results of a nationwide cross-sectional survey (2006-2008) Gheorghe L, Csiki IE, Iacob S, Regep L, J Gastrointestin Liver Dis 2010 (in press) Grant Roche Romania

  9. What do we know in Romania in 2010? 99.13% genotype 1 19,6 millions1 Romanian population Moldavia Transylvania HCV chronic infection prevalence 3,23 %2 Wallachia 633,080 HCV chronic infected people • Anuarul Statistic al României(http://; 2. Gheorghe L et al,submitted

  10. Hepatitis C Treatment System in Romania • Quality of antiviral therapy delivery • State-of-the-art therapy with pegylated interferon and ribavirin is currently prescribed for HCV-infected patients for 48 weeks • Until March 2009: restricted access to therapy which prioritized advanced disease/fibrosis, younger patients, with high viral load and aminotransferases, professional exposure • From March 2009: an unrestricted access to therapy for all eligible HCV-infected patients (positive HCV RNA, at least mild hepatitis, compensated disease)

  11. Hepatitis C Treatment System in Romania • Quantity of antiviral therapy delivery • limited funds---low treatment rates------ waiting lists • The access to antiviral therapy is limited by restricted reimbursement quantity; this results in waiting lists (WL) for antiviral therapy • A certain number of treatment courses are negotiated each year by the National Health Insurance Agency (NHIA) with the pharmaceutical companies (Roche and Schering Plough/Merck)

  12. Hepatitis C Treatment System in Romania • The antiviral therapy is fully reimbursed:NHIAreimbursed 100% of PegIFN costs and 25% of RIBA costs (the companies are currently supporting 75% of RIBA costs). There are no bureaucratic hurdles in the reimbursement process excepting the WLs • Patients receive reimbursed treatment on the following criteria: • Time spent on the WL • Severity of the disease, professional exposure, age (children and adolescents), oncologic co-morbidities requiring chemotherapy • Retreatment is reimbursed for a limited % of relapsers and not reimbursed for non-responders since 2010

  13. Hepatitis C Treatment System in Romania • The diagnosis, recommendation, and follow-up is performed by specialists(gastroenterologists/infectious diseases specialists) • Patients are referred monthly from the local WL,according to the above mentioned criteria for national validation and access to therapy • A central NIHA database allows to registry and follow-up the patients ever receiving reimbursed antiviral therapy in Romania • Within the National Program for Therapy in Chronic Diseases, chronic hepatitis compete with other chronic diseases (psychiatric, rheumatologic, or dermatologic) for the same category of NHIA funds

  14. European treatment rates specific to each country indicating the number of treated patients with PegInterferon for 100 prevalent cases of HCV 2008 2005 <1% Lettmeier B, Muhlberger N. et al, J Hepatol 2008; 49: 528–536

  15. First National Awareness and Prevention Campaign on Hepatitis C (Find about C = Find out why) • Articles in press: > 150, since April 2007 • TV advertise • More than 10 million people have seen the ad at least once • In total, the ad was seen 44 million times • TV news: 15 • 12 pages of references on “hepatita C” / “afla de C” on Google in Romanian language • More than 27,000 people visited • More than 1,000 people called the toll-free number

  16. Ministry of Health and NHIA actions • Screening program for chronic diseases initiated by the Ministry of Health in 2007: large numbers of patients with increased ALT have been discovered and further referred to a specialist for HCV & HBV screening • Screening programs inhigh risk’s groups • 100% increase of the CHC reimbursed therapy courses in 2008 vs 2006 (5,200 vs 2,600)

  17. Efficiency of Peg-IFN2a/2b+ribavirin in Romanian patients with chronic hepatitis C – Clinical Practice Gheorghe L, Iacob S, et al. J Gastrointestin Liver Dis 2007 Gheorghe L, Grigorescu M, Iacob S et al. Rom J Gastroenterol 2005

  18. Evolution of chronic hepatitis C treatment Discovery of hep C PegIFN alfa 2b plus RIBA Protease inhibitors IFN alfa 2a IFN alfa 2b plus RIBA PegIFN alfa 2a plus RIBA IFN alfa 2b 1989 1991 1992 1998 2001 2002 2010 2011

  19. Evaluation of preventable liver-related deaths, including HCC due to antiviral therapy (estimated according to Romanian program of antiviral therapy approval) Yet unpublishet data

  20. HBV infection - epidemiology • 350 million people around the world are chronically infected with HBV • 75% of them reside in the Asia-Pacific region • increased risk of developing hepatic decompensation, cirrhosis and HCC • main indication for LT in Asia • 15–25% deaths due to HBV-related liver disease Liaw Y, J Hepatol 2009

  21. HBV infection - epidemiology • universal HBV vaccination in newborns in Asian countries since 1984 • universal HBV vaccination in newborns in Romania since 1995

  22. Global prevalence of HBV infection Dienstag JL, NEJM 2008

  23. Decreasing HBV prevalence and acute incidence due to HBV vaccination • HBsAg prevalence in children < 15years  from 9.8% in 1984 to 0.7% in 1999 and 0.5% in 2004 in Asia • China reduced HBsAg prevalence to <1% among children <5 years and has prevented an estimated 16-20 million HBV carriers through hepatitis B vaccination of infants • In order for the HBV carrier rate to approximate zero, universal vaccination programs need to continue for at least 21 years Liaw Y, J Hepatol 2009; Liang X, Vaccine 2009; Su FH, Chang Gung Med J. 2007

  24. Prevalence of HBV infection in Romania Results of a nationwide cross-sectional survey (2006-2008) Gheorghe L, Csiki IE, Iacob S, Regep L (not published yet) Grant Roche Romania

  25. Significantly increased prevalence of HBsAg in persons aged 40-60 years Gheorghe L, Csiki IE, Iacob S, Regep L (not published yet) Grant Roche Romania

  26. Significantly increased prevalence of HBcAb in persons aged >30 years Gheorghe L, Csiki IE, Iacob S, Regep L (not published yet) Grant Roche Romania

  27. Choosing therapies in chronic hepatitis BA chronic hepatitis B patient might be a life long patient! Treatment of chronic HBV infection is a complex task that requires individualized assessment! Start therapy in the right patients at the right time so that the response endpoint can be achieved earlier hence, shortening the duration of therapy!

  28. Worldwide costs studies in treating HBV patients Lee TA, J Clin Gastroenterol 2004;Zhiqiang G, J Clin Gastroenterol 2004; Butler JR, J Clin Gastroenterol 2004; Hsieh CR, J Clin Gastroenterol 2004; Brown RE, J Clin Gastroenterol 2004

  29. National Transplant Agency • A national transplant network • Established the protocol of diagnosis and declaration of the brain death • Established the conditions for the removal of the organs from the deceased donor • Mass-media campaign to explain the brain death and to promote organ and tissue donation

  30. National Program of Organs, Tissues and Cells Transplantation • Immunologic and virusologic testing of potential donors and recipients • Coordination of transplant activities • Maintaining in physiologic conditions the brain dead donors • Transplant procedures • Providing medication for posttransplant status • Management of the National Transplant Registry

  31. Liver transplant indications USA 1992-2007 Korea

  32. LT indications in Romania – 200 patients (adults and children)April 2000- October 2009 Popescu I et al, Chirurgia 2010

  33. Characteristics of 372 adult patients with cirrhosis on WL for LT Iacob S,……Popescu I. Chirurgia 2009

  34. Frequency of cirrhosis complications in 372 patients on WL Iacob S,……Popescu I. Chirurgia 2009

  35. Management of cirrhosis complications Hepato-renal syndrome Spontaneous bacterial peritonitis 1-2mg/4h terlipressin + Albumin 1g/kgbw first day followed by albumin 20-40g/day, 15 days Cefotaxime+ Albumin 1.5g/kgbw first day followed by albumin 1g/kgbw, day 3 Refractory ascites – repeated paracentesis Albumin 6-8g/liter of fluid removed Ortega R, Hepatology 2002 Sort P, NEJM 1999 Runyon A, Hepatology 2004

  36. Estimated costs for treatment of these complications on WL in Romania • 50 ml albumin 20% (10g albumin)  40Eur • 1mg terlipressin  24Eur Hepato-renal syndrome Refractory ascites  47 patients  85 patients 2160Eur for terlipressin 15 days 5 paracentesis/month +  3 bottles of albumin/paracentesis 1400Eur for albumin 15 days  600Eur/month

  37. Waiting list mortality in Romania (adults) Global rate of mortality while on WL (2001-1 June 2010):44.7% Median survival = 43.4 months 5 years mortality = 60.8% 2 years mortality = 36.7% 1 year mortality = 25.3% 6 months mortality = 13.9%

  38. Survival following LT in Romanian Program 1 year post-LT median survival 84.2% 2 years post-LT median survival 82.3% 5 years post-LT median survival 75%

  39. Estimated liver-related deaths (including HCC) that can be prevented by LT in Romania Yet unpublishet data

  40. Conclusions • Recent epidemiologic data are valuable for a better understanding of the burden of the disease and developing appropriate preventive strategies and programs to control the spread and consequences of HCV/HBV infection in Romania • Strategies to increase the number of treated patients: limited funding → campaigns to bring to knowledge → improving detection → increase of the prescribed therapy → positive pressure on authorities → increase of the reimbursed therapies/year

  41. Conclusions • Need for improved access to antiviral therapy for patients with chronic hepatitis C/B in order to decrease the number of related cirrhosis and its complications • decrease of costs and liver related mortality • Need for strategies to increase the donors number for LT in order to decrease liver related mortality (organ donation card)