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Evolution of Liver Transplantation for Viral Cirrhosis in Europe.

HCV PRE AND POST-LIVER TRANSPLANTATION Professor Didier SAMUEL Centre Hépatobiliaire, Inserm Unit 785, Paris XI University Hopital Paul Brousse, Villejuif, France. Evolution of Liver Transplantation for Viral Cirrhosis in Europe. Without HCC. With HCC. www.eltr.org.

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Evolution of Liver Transplantation for Viral Cirrhosis in Europe.

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  1. HCV PRE AND POST-LIVER TRANSPLANTATIONProfessor Didier SAMUELCentre Hépatobiliaire, Inserm Unit 785, Paris XI UniversityHopital Paul Brousse, Villejuif, France

  2. Evolution of Liver Transplantation for Viral Cirrhosis in Europe. Without HCC With HCC www.eltr.org

  3. Trends in Waiting List for HCV Cirrhosis in USA Kim Gastroenterology 2009

  4. PATTERN OF HCV RECURRENCE POST OLTx NO HEPATITIS 20% CHRONIC HEPATITIS 6 MTH ? 1 MTH ACUTE HEPATITIS 70% OLT CIRRHOSIS CHRONIC HEPATITIS 6 MTH 1 MTH  1 MTH CHOLESTATIC HEPATITIS < 10 % VIRAL RECURRENCE DEATH 50% Adapted From McCaughan

  5. CHOLESTATIC HEPATITIS C McCaughan J Hepatol 2011

  6. FIBROSING CHOLESTATIC HEPATITIS C Antonini AJT 2011

  7. FCH in HCV-HIV CoinfectedPatienst Impact on Survival Antonini AJT 2011

  8. Pathobiology of Chronic HCV Post LT The immune response - + HCV load Inflammation + IFN- related genes - IFN- response Proliferation Apoptosis Fibrosis Acute Rejection Inflammation Stress Response Immunosuppression Stimulation of the IMMUNE RESPONSE by more HCV WINS McCaughan and Zekry J.Hepatol 2004, Samuel Easl Hepatol 2006

  9. EVALUATION OF THE SEVERITY OF HCV RECURRENCE LiverBiopsy Gold Standard, Bringadditional information thanfibrosis stage. HPVG Invasive, canbedonewithliverbiopsy Not routine for many Centres. Non invasive testsBiochemicalElastometry (fibroscan). Time post-LT as an adding variable

  10. HPVG, Fibrosis at 1 Year Post-Transplant and Outcome Blasco Hepatology 2006; 43: 492-499

  11. Fibrosis Stage at 12 months at Liver Biopsy and Survival Gallegos-Orozco Liver Transplant 2009

  12. Non Invasive 3-MALG Test and Decompensation and Survival Post-Transplant Carrion Gastro 2010

  13. Liver Stiffness and Severity of HCV Recurrence Carrion Hepatology 2010

  14. Donor and Host Factorsof HCV Recurrence

  15. Fibrosis on the Graft In HCV+ve Liver Transplant Patients According to Donor Age and Gender Risk of Fibrosis: Stable over years, Higher in women receiving old donors Belli Liver Transplant 2007; 13: 733-740

  16. STEROIDS AND HCV • Controversial role • Increase viral load (Fong Gastro 1994, Gane Gastro 1996) • Increase viral hepatocyte entry (Gastro 2010) • Boluses of steroids deleterious (Berenguer J Hepatol 2000) • Rapid withdrawal deleterious (Berenguer Hepatology 2003, McCaughan J Hepatol 2004, Vivarelli J Hepatol 2007) • Immune rebound? • Immunosuppression without steroids: not yet proven beneficial (Klintmaln Liver Transplant 2007)

  17. No Impact of Steroid-Free IS on Graft HCV Fibrosis KlintmalmLiver Transplant 2011

  18. HCV Recurrence , Cyclosporine vs Tacrolimus • There iscurrently no proof of superiority of one vs another • Antiviral effect of Cyclosporine only in vitro • Betterefficacy of IFN in Ciclosporine patients not confirmed • Randomizedstudiesshowedearlierreinfectionwith Tac but no difference in fibrosis stage, bettersurvivalwith Tac? Samonakis, J Hepatol 2012 in Press, Berenguer Nat Rev Gastroenterol 2011

  19. ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION • Difficult to manage in decompensated cirrhotic patients • Risk of deterioration of liver function • Risk of sepsis, severe neutropenia, and anemia • Poor antiviral effect at this stage • However, some patients candidates to LT: • Have preserved liver function (those with HCC) • Have a long expected waiting time for LT • Have never been treated or are ”false” non responders

  20. ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION • 124 patients • 56 Child A, 45 Child B, 23 Child C • 86 Genotype 1, 16 Genotype 2, 17 Genotype 3 • SVR: • 50% in genotype non-1, • 13% in genotype 1 • 22 complications in 15 patients ( 21 in Child B and C), 4 died • No HCV recurrence in sustained responders. • Everson Hepatology 2005

  21. ANTIVIRAL TREATMENT PRE-LT Forns J Hepatol 2003, Carrion J Hepatol 2008

  22. Antiviral Treatment in Patients Waiting for Liver Transplantation, Risk of Sepsis Related to CPT Carrión JA et al. J Hepatol. 2009;50:719-28.

  23. Antiviral Treatment in Patients Waiting for Liver Transplantation, Norfloxacin Prophylaxis Carrión JA et al. J Hepatol. 2009;50:719-28.

  24. Antiviral Treatment Before Transplantation Roche, Samuel Liver Int 2012

  25. Direct Antiviral Agents Before LTA New Challenge • Data In cirrhotic patients are lacking • Therapieswith IFN willremainpoorlytolerated • Increasepossibility to achieve SVR or on treatmentvirologicresponse • Increaserisk of virologicbreakthrough • Duration, safety issues to beanalysed • Therapieswithout IFN awaited

  26. Mechanism of HCV Entry Zeisel J Hepatol 2011

  27. Strategies Before and After Transplantation Feray J Hepatol 2011

  28. Antiviral Treatment Immediately after Transplantation Roche, Samuel Liver Transplant 2010

  29. Antiviral TherapyPegINF+ RBV Post-Transplantation Roche, Samuel Liver Int 2012, Wang AJT 2006, Berenguer J Hepatol 2008 , Xirouchakis J Viral Hep 2008

  30. Auto(Allo)immune Hepatitis and IFN Sharma Liver Transplant 2007

  31. Treatment with PEG IFN + RBV After LTSVR Dependent of Fibrosis stage • 27 Pts mildHepatitis C (F1-F2): SVR 48% • 27 Pts severehepatitis C (F3-F4), CholestaticHepatitis: SVR 18% • F3-4: 4/15 • Cholestatichepatitis, 1/12 (Carrion Gastro 2007) • 20% F3-F4 vs 1% F1 Patients died or wereretransplanted( Roche Liver transplant 2008)

  32. SVR and IL28 in all Genotype Transplant Patients Lange J Hepatol 11

  33. SVR According to IL 28 Charlton Hepatology 2011

  34. Survival (Death and GraftLoss) According to IL 28 IL 28 Recipient IL 28 Donor Charlton Hepatology 2011

  35. IL 28 In the Donorshouldbedetermined on GraftReperfusionBiopsy or PBMC, not on follow-up Biopsies Coto-Llorena J Hepatol 2012

  36. SVR According to IL 28 in Recipient, Donor, and FU Biopsy Coto-Llorena J Hepatol 2012

  37. Histological Outcome in Relation with Virological Response to PEGIFN+ Ribavirine Variables associated with Histological improvement: EVR, BR, SVR Carrion Gastroenterology 2007

  38. Impact of SVR on Suvival in Transplant HCV + Patients Berenguer M AJT 2008 Piciotto J Hepatol 2007

  39. Direct Antiviral Agents After LTA New Challenge • Increase possibility to achieve SVR or on treatment virologic response • Interaction between anti NS3 protease and calcineurin inhibitors • Duration, safety issues to be analysed • Therapies without IFN awaited

  40. Telaprevir and Cyclosprine and Tacrolimus Interactions Cmax increased by 1.4X AUC Increased by 4.1-4.6X T1/2 increased by 4 X Cmax increased by 9.3X AUC Increased by 70X T1/2 increased by 5 X GargHepatology 2011

  41. Evolution of Liver Transplantation for Viral Cirrhosis in Europe. Without HCC With HCC www.eltr.org

  42. Evolution of Patient Survivalafter LT for Virus C Cirrhosiswithout HCC in Europe (ELTR: 1988-2010) www.eltr.org

  43. CONCLUSION • Survival still affected by HCV recurrence • Monitoring combining liver biopsy and non invasive methods • Treatment before Transplantation poorly effective • SVR before LT , no recurrence post-LT • HCVRNA negativity at LT, Risk of post transplant recurrence reduced by 70% • Treatment after transplantation : • Effective at time of Chronic hepatitis before the F3 stage • 30-40% SVR in G1 Patients • 70% SVR in G2-G3 Patients

  44. CONCLUSION • Advent of Direct antiviral agents will open a new era • Before LT: Presence of IFN in the treatment arm will remain a limitating factor • After LT: new strategies will arise • Viral breakthrough, tolerance, interaction with calcineurin inhibitors, treatment duration: • Open questions for the close future

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