1. C.H.B. Didier SAMUEL

2. C.H.B. TREATMENT OF HEPATITIS C BEFORE AND AFTER LIVER TRANSPLANTATION Professor Didier SAMUEL Centre Hépatobiliaire, Inserm Unit 785, Paris XI University Hopital Paul Brousse, Villejuif, France

3. C.H.B. COURSE OF HCV INFECTION AFTER TRANSPLANTATION 95-100 % of patients HCV RNA + before transplantation will develop recurrence post-transplant Almost all patients will develop chronic hepatitis <10% patients will develop cholestatic hepatitis 10-40 % will develop cirrhosis at 5 years

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

5. 0% 10% 20% 30% 40% 50% 012345 Years Posttransplant Prevalence of Cirrhosis Cumulative probability of developing HCV-graft cirrhosis Adapted from Gane, Berenguer Berenguer,2002 Sanchez-Fueyo,2002 Prieto,1999 Gane,1996 Feray,1999 Neumann,2002 Poynard,1997 IC patient Neumann, 2004

6. C.H.B. PATIENT SURVIVAL IN LIVER TRANSPLANT PATIENTS WITH HCV CIRRHOSIS ON THE GRAFT Patient Survival After Graft Cirrhosis First Decompensation M Berenguer et al. Hepatology 2000; 32:852 Patients Survival After Cirrhosis on the Graft

7. C.H.B. Gane Gastroenterology 1996 SERUM HCV RNA LEVEL BEFORE AND AFTER LT

8. C.H.B. DYNAMIC OF HCV REPLICATION IN THE FIRST HOURS AFTER LT Garcia-Retortillo Hepatology 2002: 35: 680

9. Cholestatic HCV : Intrahepatic Viral Load ( X10 6 m-RNA copies / ug RNA) Chol = Cholestatic HCV post transplant AR = Acute rejection + HCV CHI = HCV post transplant CHC = HCV pre transplant Intrahepatic viral load 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Chol AR CHI CHC * Zekry et al. Liver Transplant 2002;8:292 * P = 0.005 Chol vs AR, CHI & CHC

10. C.H.B. Relation Between Histology and Liver HCV RNA HCV RNA (CU) Normal cholestasisCAH lobular hepatitis 220 200 180 160 140 120 100 80 60 40 20 0 ** p=0.01 34 2828 7 15 ** Di Martino et al. Hepatology 1997 High HCV RNA at time of acute hepatitis Decrease of HCV RNA with progression to CAH High initial HCV RNA related with more severe CAH

11. 0 1 2 3 4 5 6 7 8 9 10 11 Survival (%) 100 50 0 Neumann et al, J Hepatol 04 F at one year: 0 (n=68) 1-2 (n=76) 3-4 (n=39) Prediction of survival based on first year fibrosis

12. Blasco Hepatology 2006; 43: 492-499 HPVG, Fibrosis Stage 1 Year in HCV +ve Transplant Patients and 0utcome

13. C.H.B. 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 »Never been treated or are ”false” non responders

14. Kuo, Terrault AJT 2006; 6: 449-458 Antiviral Treatment In HCV+ve Cirrhotic Patients Before Liver Transplantation

15. C.H.B. 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 »Low increase therapy IFN (1.5MU X3/wk to 3MU after wk 2) + ribavirin (600 mg/d to 800mg/d after wk 4) »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

16. C.H.B. ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION Interferon + Ribavirin before LT –30 HCV Cirrhotic pts; Child A: 15, Child BC: 15; Genotype 1b: 25 »IFN 3MU/day + Ribavirin 800 mg/day until LT »9 (30%) virologic response »11 patients required filgrastim and 8 required EPO »No change in LFTs »Factors of response: low viral load, low ALT, non-1 genotype »After LT: 6/9 responders remained HCV RNA Neg after LT, 3 relapsed Forns et al J Hepatol 2003

17. C.H.B. ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION Treatment should be envisaged in Child A patients waiting for LT –Group of patients with HCC on Child A cirrhosis –Child B patients There is a place for the treatment with the increased waiting time However: –Is it possible to delay LT to achieve SVR? –Balance between the aim to achieve SVR and the risk of hepatic deterioration or HCC growth

18. C.H.B. ANTIVIRAL TREATMENT DURING LIVER TRANSPLANTATION HCIG Polyclonal HCIG (Davis Liver Transplant 2005) –RCT: »HCIG 75 mg/kg 17 infusions on 14 weeks »HCIG 200 mg/Kg 17 Infusions on 14 weeks »Placebo Decrease of ALT, No effect on HCV RNA –Monoclonal HCV Ab XTL 68 (Schiano Liver Transplant 2006) »- 2.4 log HCV RNA decrease in 240 mg (high doses) group vs - 1.5 log in placebo at day 2, no difference at day 7 »Significant increase of anti-E2 at day 7 in 240 mg group

19. C.H.B. TREATMENT OF HCV RECURENCE AFTER TRANSPLANTATION When to treat ? –Immediately after LT (within 3 first weeks) –At time of recurrence (acute hepatitis)? –At time of chronic hepatitis? –Only in case of severe hepatitis on the graft? »Fibrosing cholestatic hepatitis »Rapidly evolving hepatitis (routine biopsies) –Who should be treated? –All patients? –Only those with severe hepatitis?

20. C.H.B. PRE-EMPTIVE TREATMENT OF HCV RECURENCE AFTER TRANSPLANTATION –In the first post-transplant weeks: »Low viral load »Risk of rejection high Frequent presence of acute rejection and hepatitis on the same liver biopsy during the first month »High level of Immunosuppressive treatment »Risk of poor hematological tolerance +++: Severe anemia, leucopenia and thrombocytopenia Patients are anemic before treatment »Septic and surgical complications frequent

21. Terrault, Berenguer Liver Transplant 2006 Preemptive Treatment In HCV+ve Liver Transplant Patients

22. Kuo, Terrault AJT 2006; 6: 449-458 Preemptive Antiviral Treatment In HCV+ve Liver Transplant Patients

23. MEAN HCV VIRAL LOAD IN LIVER TRANSPLANT PATIENTS TREATED PREEMPTIVELY WITH PEGIFN ALPHA 2A Chalasani Hepatology 2005; 41: 289-298 SVR: 8%

24. Shergill AJT 2005; 5: 118-124 PREEMPTIVE TREATMENT IN IN HCV LIVER TRANSPLANT PATIENTS Adherence to TreatmentETVR and SVR 51/124 Patients eligible, 44 Received one dose of treatment 6/124 (5%) achieved SVR

25. MEAN HCV VIRAL LOAD IN LIVER TRANSPLANT PATIENTS TREATED WITH PEGIFN ALPHA 2A Chalasani Hepatology 2005; 41: 289-298 SVR : 8%

26. TREATMENT INTERFERON-RIBAVIRINE AFTER TRANSPLANTATION AuthorsTreatment Pts (N) Bioch response (%) HCV RNA Neg SVR Bizollon Hepatology 1997 IFN 3MU x 3 / week + Ribavirine(6 M) then Ribavirine (6 M) 21100% 48 % 24% ND Samuel Gastro 2003 INF 3MU x 3 / weeks + Ribavirine(12 M) 28ND32%21.4% Gopal Liver Transp 01 INF 3MU x 3 / weeks + Ribavirine(1-17 M) 1275%50%8.3% Lavezzo J Hepatol 2002 IFN 3MUX3/weeks + Ribavirin (6 vs 12 Mths) 57ND 33% 23% 22% (6M) 17%(12M) Menon Liver Transp 2002 IFN 3MUX3/weeks + ribavirin (1 year) 2642%35%30% Shakil Hepatol 02 IFN 3MUX3/weeks+ RBV ( 1 year) 3818%NA5%

27. C.H.B. Treatment with PEG Interferon + Ribavirine 20 patients treated With Peg IFN (0.5µg/Kg to 1 µg/Kg) + Ribavirin 400 to 800 mg/d) 80% infected with genotype 1 4 withdrawn 13 required doses reduction of ribavirin due to anemia End of treatment virologic response 65% SVR: 9/20: 45% Dumortier J Hepatol 2004

28. C.H.B. Treatment with PEG Interferon + Ribavirine Transpeg Study: –100 patients –Peg IFN alpha 90 µg/wk + Ribavirin 600 mg/d then increased to PegIFN 180 µg/wk + Ribavirin 100 mg/d for one year –Randomisation at one year placebo vs ribavirin maintainance At Week 52, 60/97 (62%) patients had a virologic response by ITT;75 % by per-protocol (PP). At week 78, SVR: 34% Genotype 1-4, 75% Genotype 2-3 37% Use of EPO Calmus, Samuel AASLD 2006

29. Castells J Hepatol 2005; 43: 53-59 KINETIC OF HCV RNA ACCORDING TO VIROLOGIC RESPONSE IN HCV POSITIVE TRANSPLANT PATIENTS

30. C.H.B. Predictive Factors for Response To IFN in Genotype 1 Transplant Patients 67 Patients EOT virological response: 45 % SVR: 33% Predictive factors of response: –At baseline and on treatment: »Peg IFN vs standard IFN »Early virological response »EPO use Berenguer Liver Transplant 2006

31. HCV RNA Kinetic During the First days of Antiviral Treatment In HCV+ve Liver Transplant Patients Heydtman AJT 2006; 6: 825-833 Gen 3 SVR Gen 3 NR Gen 1b RR Gen 3 RR

32. C.H.B. Tolerance to Treatment The tolerance is poor 40-80% rate of doses reduction 40-50% discontinuation rate Anaemia++ is the first cause of discontinuation EPO is required in many cases

33. C.H.B. Tolerance to Treatment: Risk of Rejection Risk of Rejection controversial: 0-35% after IFN alone (Gane Hepatology 98, Wright Hepatology 94, Feray Hepatology 95) 5% in 2 randomized studies(4%) (Samuel Gastro 03, Chalasani Hepatol 05 ) 25-35% in non randomized studie, in patients treated with IFN, PEG IFN alone or with Ribavirine (Saab Liver Transpl04, Stravitz Liver Transplant 04, Dumortier J Hepatol 04) Risk of rejection not dependent of HCV RNA persistence Differences may be due to: –Underdiagnosed in NR patients with persistent high LFTs –Different type and level of immunosuppression –Different risk by using IFN, Peg IFN ± Ribavirin

34. Auto(Allo)immune Hepatitis and IFN Kontorinis Liver Transplant 2006

35. C.H.B. Tolerance to Treatment Rejection does exist –Rate: variable –Type: variable: acute, chronic “Allo or autoimmune“ hepatitis –During or after end of treatment Viral load rebound and deterioration of LFTs –At the end of treatment –More severe in F3-F4 patients Fatal liver failure observed in F3-F4 patients (personal communication)

36. C.H.B. How to Improve the Efficacy of Treatment Avoid reduction or discontinuation of IFN or RBV –Adapt dosage of Ribavirin to renal clearance –Use of EPO ++( 40% of patients) –Maintain treatment >6 months after serum HCV RNA clearance Duration to be adapted to the kinetic of HCV RNA level decline New drugs: Viramidine, Albuferon, Protease, polymerase inhibitors…?

37. C.H.B. Bizollon Gut 2003, 52, 283-287 Histological Outcome in SVR Transplant Patients Necroinflammatory score reduction, Fibrosis Score Stability

38. Abdelmalek Liver Transplant 2004; 10: 199-207 Long-Term Histology in SVR HCV Liver Transplant Patients Inflammatory Score Fibrosis Score

39. Bizollon AJT 2005; 6: 449-458 Graft Histology In HCV+ve Liver Transplant Patients With or Without SVR Median Follow-up : 57 Months in NR and 52 months in SVR

40. Bizollon AJT 2005; 6: 449-458 Survival Without Cirrhosis In HCV+ve Liver Transplant Patients With or Without SVR

41. C.H.B. FUTURE TREATMENT OF HCV RECURENCE AFTER TRANSPLANTATION ? Antiprotease BILN 2061 Hinrichsen Gastroenterology 2004; 127:1347-1355

42. Patient Survival after Liver Transplantation in Europe ELTR- 01/1988 - 12/2004 72 87 85 93 0 20 40 60 80 100 012345678910 Virus B : 3162 Virus BD : 883 Virus C : 8061 Alcoholic : 10093 Yrs (%) 81 65 66 60 55 85 81 78 74 70 PBC : 3578 68 73 HDV HBV HCV

43. >=2000 : 1410 <1985 : 10 95 to 2000 : 1196 90 to 95 : 915 85 to 90 : 287 0.2.4.6.8 1 % Survival 012345678910 Years 91% 86% 84% Patient survival according to the year of LT HBV and HCV Cirrhosis ELTR update of December 2004 0.2.4.6.8 1 % Survival 012345678910 Years 83% 72% 67% HBVHCV >=2000 : 3194 <1985 : 6 1995 to 2000 : 2705 1990 to 1995 : 1357 1985 to 1990 : 127

44. C.H.B. CONCLUSION AND PERSPECTIVES Rate of HCV reinfection high No improvement in survival in the past years HCV fibrosis more rapid and severe than in non-transplant patients Improvement in antiviral treatment. –SVR in treated patients: 30-40% genotype 1, 60-70% Genotype 3 –But not all patients can be treated –EPO necessary in 40% of patients

45. C.H.B. CONCLUSION AND PERSPECTIVES Better understanding of mechanisms of fibrosis progression Better evaluation of fibrosis progression –Routine liver biopsy ++ –Non invasive fibrosis monitoring »Fibroscan (elastometry) »Fibrotest

46. C.H.B. CONCLUSION AND PERSPECTIVES Timing for antiviral treatment to be determined: –Preemptive treatment difficult or imposible in most cases –At time of acute hepatitis? –At time of chronic hepatitis? Yes, but when? »Not too late (before 2 years in most cases) Results better in F1-F2 patients (to be confirmed) Complications more severe in F3-F4 patients Prevention of severe fibrosis Fibrosis slowly or not reversible Improvement of efficacy and tolerance of antiviral treatments Non-antiviral treatments: antifibrotics