Samuel Transplant Foie

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Samuel Transplant Foie

  1. 1. LIVER TRANSPLANTATION IN VIRAL HEPATITIS B Didier SAMUEL, M.D. Professor of Hepatology CENTRE HEPATOBILIAIRE INSERM PARIS XI UNIT 785 HOPITAL PAUL BROUSSE VILLEJUIF, FRANCE C.H.B.
  2. 2. Evolution of Survival After Liver Transplant for HBV-Related Liver Disease 100 ERA 1 (1987–1991) P<0.01 90 Survival (%) 80 Other 70 HBV 60 50 0 1 2 3 4 5 Time (yr) 100 ERA 2 (1992–1996) 100 ERA 3 (1997–2002) P=0.19 P=0.14 90 90 HBV Other Survival (%) Survival (%) 80 80 Other 70 HBV 70 60 60 50 50 0 1 2 3 4 5 0 1 2 3 4 5 Time (yr) Time (yr) Kim WR et al. Liver Transpl. 2004;10:968
  3. 3. Prophylaxis of HBV Infection Posttranplantation Major improvements have been made in prevention of HBV infection in past 15 yr Before transplantation – Lamivudine or adefovir After transplantation – Anti-hepatitis B immunoglobulins (HBIG) – Lamivudine monoprophylaxis – Combination HBIG + lamivudine
  4. 4. Long-Term Prophylaxis of HBV Infection Posttransplantation Questions • Is prophylaxis still necessary at long term? • What is optimal dosage of HBIG? • What is optimal route of HBIG and for what duration? • Is it possible to stop HBIG administration and in whom? • Which antiviral to be used after transplantation?
  5. 5. Long-Term Use of IV HBIG Aim High doses during anhepatic phase, then during first wk – Aim Make serum HBsAg negative Obtain protective anti-HBs titer – Maintain protective anti-HBs titer Effective in FHF, HDV-C Less effective in nonreplicative HBV-C - Possible low replication detected by PCR Insufficient in replicative HBV-C
  6. 6. HBV Recurrence According to Initial Liver Disease D. Samuel et al. NEJM 1993;329:1842-7 C.H.B.
  7. 7. HBV Recurrence According to HBV Prophylaxis D. Samuel et al. NEJM 1993;329:1842-7 C.H.B.
  8. 8. Survival In Relationship with Type of HBV Prophylaxis D. Samuel et al. NEJM 1993;329:1842-7 C.H.B.
  9. 9. Actuarial HBV Recurrence Rate − Hôpital Paul Brousse: 1986−2000 284 Patients 100 Risk of Recurrence (%) 80 60 40 25.4 21.9 21.9 24.2 (177) (168) (146) (47) 15.3 20 (205) 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (yr) Roche B et al. Hepatology. 2003;38:86
  10. 10. Actuarial HBV Recurrence Rate in Relation to Initial Liver Disease − Hôpital Paul Brousse: 1986−2000 100 284 Patients Risk of Recurrence (%) 80 60 56.5 54.4 49.4 49.4 HBV-C 41.8 37.5 40 FHD 25.0 25.0 25.0 25.0 20 13.5 13.5 15.3 15.3 5.8 HDV-C 0 FHB 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (yr) HBV-C = HBV cirrhosis; FHD = fulminant hepatitis B-Delta; HDV-C = HDV cirrhosis; FHB = fulminant hepatitis B Roche B et al. Hepatology. 2003;38:86
  11. 11. Lamivudine Monoprophylaxis Posttransplantation HBV Reactivation Due to YMDD Variant 100 80 No Immunoprophylaxis (n=67) % HBsAg (+) 60 Lamivudine (n=42) 40 Long-term HBIG (n=209) 20 N=28 N=39 N=34 N=40 0 12 24 36 48 60 Time (mo) Perrillo RP et al. Hepatology. 2001;33:424
  12. 12. Lamivudine Monoprophylaxis Patients remained HBsAg positive after liver transplant Progressive decline of HBsAg1 Rate of HBV reinfection – Related to HBV DNA level before liver transplant – Related to treatment duration – Increased with time posttransplant HBV reinfection due to YMDD HBV mutant Question of long-term compliance and risk of reinfection 1. Grellier L et al. Lancet. 1996;348:1212 [published correction in Lancet. 1997;349:364]
  13. 13. Adefovir Monoprophylaxis Recurrence of HbsAg or Serum HBV DNA Following On-Study Liver Transplantation Marker Concomitant HBIG No HBIG (n=34) (n=23) HBsAg Confirmed* 0 (0%) 0 (0%) First test was only positive† 2 (6%) 2 (9%) Serum HBV DNA >1000 copies/mL Confirmed*‡ 2 (6%) 0 (0%) Single positive test§ 4 (12%) 3 (13%) No short-term recurrence, no long-term data available *2 consecutive positive tests †HBsAg was detected on only first test between days 4 and 67 posttransplantation. 2 patients had no further follow-up, and 2 patients had subsequent negative tests over 2 (to day 239) and 2 visits (to day 667) ‡In these 2 patients, the first 2 tests posttransplantation detected serum HBV DNA (maximum 32,084 and 29,672 copies/mL), and subsequently, serum HBV DNA was undetectable on 3 (to day 309) and 7 (to day 528) measurements §Maximum titer among 7 tests was 3055 copies/mL. 4 patients subsequently had undetectable serum HBV DNA (measured over next 25–211 days); 3 patients did not have further laboratory follow-up Schiff E et al. Liver Transpl. 2007;13:349
  14. 14. Posttransplant Combination HBIG + Lamivudine: Rationale Lower rate of escape mutation due to pressure on 2 different regions in HBV genome – PreS/S region for HBIG – YMDD region of polymerase gene for lamivudine Possible to reduce HBIG amount and overall cost
  15. 15. Low-Dose HBIG + Lamivudine • 147 patients • Pretransplant • LAM if HBV DNA (+) (80% pts) 0.5 - Proportion of Patients With • Posttransplant • LAM + HBIG IM 400–800 IU daily × 7 0.4 - HBV Recurrence days 0.3 - • LAM + HBIG IM 400/800 IU monthly • HBV recurrence: 4% at 5 yr 0.2 - • 5 pts with HBV recurrence • All YMDD HBV 0.1 - • ADV in all, 1 death from liver failure • Factor independently associated with 0.0 - I I I I HBV recurrence 2 4 6 8 • HBV DNA prior LAM Time Posttransplant (yr) Number 147 124 89 56 14 at risk Gane EJ et al. Gastroenterology. 2007;132:931
  16. 16. Long-Term Anti-HBs Titers in Patients Receiving Low-Dose HBIG + Lamivudine Plasma (anti-HBs) Titers at 1, 3, and 12 mo Posttransplant (Horizontal Bars Demonstrate Median Values) 10000 – 1 mo Plasma [anti-HBs] Titer 1000 – 3 mo 12 mo 100 – 10 – 1– 1 mo 3 mo 12 mo Timepoint Posttransplant Gane EJ et al. Gastroenterology. 2007;132:931
  17. 17. HBIG + Lamivudine vs Lamivudine LAM + HBIG: 114 pts LAM: 51 pts HBV DNA >105 at LT: Recurrence 88% in the LAM group vs 28% in combined group HBV DNA <105 at LT: Recurrence 18% in the LAM group vs 8% in combined group Zheng S et al. Liver Transplant. 2006;12:253
  18. 18. HBV Recurrence in Relation to Pretransplant PCR HBV DNA Level Lamivudine Monoprophylaxis Lamivudine + HBIG Prophylaxis Marzano A et al. Liver Transpl. 2005;11:402
  19. 19. HBV Recurrence In Patients Receiving HBIG Monoprophylaxis vs Combined HBIG + Antiviral Paul Brousse 1995-2005 Factors independently associated with HBV recurrence: HBV DNA at LT> 100 000 copies/ml HCC at LT HBIG monprophylaxis Faria Gastroenterology 2008 in press
  20. 20. HBV Recurrence In Patients with and without HCC Paul Brousse 1995-2005 Faria Gastroenterology 2008 In press
  21. 21. HBV Recurrence Is Associated with HCC Recurrence Paul Brousse 1995-2005 Faria Gastroenterology 2008 In press
  22. 22. Prophylaxis Protocol Place of HBIG in Combination? HBIG at start is essential – Immediately makes HBsAg negative – Protects graft from immediate reinfection IV administration important at start – Good results also with IM immediately1 – Can be replaced safely by IM administration at medium term2 High doses of HBIG – Important at start – Dose related to HBV DNA level at liver transplant3 – Lower doses can be used at medium term 1. Gane EJ et al. Gastroenterology. 2007;132:931; 2. Han SH et al. Liver Transpl. 2003;9:182; 3. Dickson RC et al. Liver Transpl. 2006;12:124
  23. 23. Prophylaxis Protocol: Which Antiviral in Combination? Almost all studies have used lamivudine In cases of pretransplant, HBV strain resistant to lamivudine – Cases of severe recurrence despite HBIG + LAM1,2 – Adefovir should be added to HBIG Adefovir can be used in first line3 – Risk of escape mutation lower – Doses to be adapted in case of impaired renal clearance No reported experience with entecavir 1. Rosenau J et al. J Hepatol. 2001;34:895; 2. Roche B et al. Hepatology. 2003;38:86; 3. Schiff E et al. Liver Transpl. 2007;13:349
  24. 24. Discontinuation of HBIG? Arguments for discontinuation – High cost – Constraining, high degree of compliance – Few cases of HBV reinfection after 3 yr posttransplant Arguments against discontinuation – Cases of long-term recurrence after discontinuation – Residual HBV DNA in >50% of patients at 10 yr1,2 – Difficult to identify patients who have cleared virus Open questions – Who to select? – When to stop? Probable consensus – Maintain prophylaxis (antiviral, vaccine) Roche B et al. Hepatology. 2003;38:86; Hussain M et al. Liver Transpl. 2007;13:1137
  25. 25. Discontinuation of HBIG Replacement by Lamivudine LT Recipients 29 Patients Total HBIG + LAM for 1 month Randomization HBIG + LAM LAM N=15 N=14 18 mos N=6 HBIG + LAM LAM N=15 N=14 83 mos 83 mos 83 mos HBIG + LAM (N=9) LAM (N=6) LAM (N=14 ) HBV Recurrent (N=1) HBV Recurrence (N=2) HBV Recurrence (N=1) Buti M et al. Transplantation. 2007;84;650
  26. 26. Discontinuation of HBIG Replacement by Lamivudine 21 patients stopped HBIG – 18 patients stopped after 11 months – 3 patients stopped after 15 days All on lamivudine 2 recurrence (actuarial rate of 3 year HBV recurrence 9% after HBIG withdrawal), one following lamivudine discontinuation Both recurrence YMDD 3 additional patients with transient HBV DNA Wong SN et al. Liver Transplant. 2007;13:374
  27. 27. HBV Vaccination After Discontinuation of HBIG or LAM 62% Ab response 80% Ab response Sanchez-Fueyo A et al. Hepatology. 2000;31:496 Bienzle U et al. Hepatology. 2003;38:811 17% Ab response Angelico M et al. Hepatology. 2002;35:176 4/50 Responders Lo CM et al. J Hepatol. 2005;43:283
  28. 28. Efficacy of Pre S Vaccine in HBV Transplant Patients on Lamivudine Prophylaxis 1000 - Anti-HBs Titer (mIU/mL) 100 - 10 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 1- 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 vaccination vaccination Time (mo) Lo CM et al. Am J Transplant. 2007;7:434
  29. 29. Vaccine After Transplantation Great discordance in results – Results of Berlin not confirmed by others and in larger series – Poor tolerance to Berlin vaccine – Durability of response? – Response probably more frequent in FHB patients (spontaneous seroconversion boosted by vaccine?) How to identify patients susceptible to respond to vaccine?
  30. 30. Strategies for Prevention of HBV Recurrence 40% 36 36 Recurrence Rate 30% 33 33 Overall HBV 20% 18 18 10% 66 0% Lamivudine Low-Dose High-Dose Lamivudine (mono) HBIG HBIG + HBIG Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120
  31. 31. Future Strategies for Prevention of HBV Recurrence HBIG + LAM/ADV HBIG IM + LAM/ADV HBIG + LAM/ADV HBIG + LAM Vaccination Nucleoside monoprophylaxis Nucleotide monoprophylaxis Nucleoside + nucleotide HBIG Induction Nucleoside ± nucleotide Liver Transplant 0.5–2 yr Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120
  32. 32. Conclusion Major improvement with Combination HBIG + antiviral Questions : – Dose of HBIG taking into account viral parameters – Ideal antiviral:Good tolerance, low resistance profiles – Antiviral combination alone? – Long-term prophylaxis mandatory Possibibility to stop HBIG ? Yes in selected groups but not mandatory; best long-term concept: low dose HBIG + antiviral
  33. 33. NEW STRATEGIES IN PREVENTION AND TREATMENT TO MINIMIZE POST-TRANSPLANT HCV RECURRENCE Professor Didier SAMUEL Centre Hépatobiliaire, Inserm Unit 785, Paris XI University Hopital Paul Brousse, Villejuif, France C.H.B.
  34. 34. PATTERN OF HCV RECURRENCE POST OLTx NO HEPATITIS CHRONIC HEPATITIS 20% 6 MTH ? 1 MTH ACUTE HEPATITIS OLT 70% 6 MTH CHRONIC HEPATITIS CIRRHOSIS 1 MTH 1 MTH CHOLESTATIC VIRAL RECURRENCE HEPATITIS < 10 % DEATH Adapted From McCaughan Adapted From McCaughan 50%
  35. 35. Cumulative probability of developing HCV-graft cirrhosis 50% Berenguer,2002 Sanchez-Fueyo,2002 Prevalence of Cirrhosis 40% Prieto,1999 Gane,1996 30% Feray,1999 Neumann,2002 20% Neumann, 2004 10% IC patient Poynard,1997 0% 0 1 2 3 4 5 Years Posttransplant Adapted from Gane , Berenguer
  36. 36. Late-onset severe Early exponential increase HCV-liver disease followed by stabilization N=57 with initial benign (n=183) evolution (F0-1 in first bx) Late onset F: 20/57 (34%) 3 4 2,5 Fibrosis Stage 2 3 0.08 1,5 0.25 2 1 1.2 0,5 1 0 1 3 5 7 10 0 1 3 5 7 Duration of infection (years) Duration of infection (years) Neumann, J hepatol 2004 Berenguer et al, Liver transpl 2003
  37. 37. PATIENT SURVIVAL IN LIVER TRANSPLANT PATIENTS WITH HCV CIRRHOSIS ON THE GRAFT Patients Survival After Cirrhosis Patient Survival After Graft Cirrhosis on the Graft First Decompensation M Berenguer et al. Hepatology 2000; 32:852 C.H.B.
  38. 38. PATHOBIOLOGY of CHOLESTATIC HCV Immune response Immunosuppression •Absent CD4 responses •Stable quasispecies (High level) TH-2 like cytokine HCV load response (IL-10 & IL-4) Cytopathic allograft damage IMMUNOSUPPRESSION MARKEDLY INHIBITING THE IMMUNE RESPONSE WINS McCaughan and Zekry J Hepatol 2004; Samuel EASL report J Hepatol 2006
  39. 39. Pathobiology of Chronic HCV Post LT Immunosuppression - The immune response + - HCV load Inflammation + γ IFN-γ related genes α IFN-α response Stimulation of the IMMUNE RESPONSE by more HCV WINS Proliferation Acute Rejection Apoptosis Inflammation Fibrosis Stress Response McCaughan and Zekry J.Hepatol 2004, EASL Report J Hepatol 2006
  40. 40. DYNAMIC OF HCV REPLICATION IN THE FIRST HOURS AFTER LT Garcia-Retortillo Hepatology 2002: 35: 680 C.H.B.
  41. 41. Cholestatic HCV : Intrahepatic Viral Load ( X106 m-RNA copies / ug RNA) Intrahepatic viral load 1.4 * * P = 0.005 Chol vs AR, CHI & CHC 1.2 1.0 0.8 0.6 0.4 0.2 0 Chol AR CHI CHC Chol = Cholestatic HCV post transplant AR = Acute rejection + HCV CHI = HCV post transplant CHC = HCV pre transplant Zekry et al. Liver Transplant 2002;8:292
  42. 42. Relation Between Histology and Liver HCV RNA HCV RNA Log (CU) CU) p < 0.03 HCV RNA (CU) CU) ** p=0.01 1000 220 • ** 200 • 180 100 • • • • • • 160 • • 140 • • • • • 120 2 7 10 • • 15 • • 100 8 • • • • 80 • 60 34 1 • 40 • 20 0 .1 lobular CAH cholestasis Normal Acute hepatitis CAH hepatitis Decrease of HCV RNA with progression to CAH High HCV RNA at time of acute hepatitis High initial HCV RNA related with more severe CAH Di Martino et al. Hepatology 1997 C.H.B.
  43. 43. Prediction of survival based on first year fibrosis Survival (%) 100 50 F at one year: 0 (n=68) 0 1-2 (n=76) 3-4 (n=39) 0 1 2 3 4 5 6 7 8 9 10 11 Neumann et al, J Hepatol 04
  44. 44. HPVG, Fibrosis Stage 1 Year in HCV +ve Transplant Patients and 0utcome Blasco Hepatology 2006; 43: 492-499
  45. 45. HPVG and Fibrosis Stage (Ishak) in HCV +ve Transplant Patients Samonakis Liver Transplant 2007; 13: 1305-1311
  46. 46. Donor and Host Factors of HCV Recurrence C.H.B.
  47. 47. EFFECT OF DONOR AGE ON THE DEVELOPMENT OF HCV GRAFT FIBROSIS AND CIRRHOSIS Cirrhosis and donor age Fibrosis and donor age Wali et al. Gut 2002; 51: 248-252 C.H.B. Berenguer Hepatology 2002; 36: 202-210
  48. 48. Relation Donor Age, HCV and Graft Fibrosis Rifai J Hepatol 2004 C.H.B.
  49. 49. 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
  50. 50. Graft Survival According to Donor Age in HCV and ALD Patients Mutimer Transplantation 2006; 81: 7-14
  51. 51. HCV RECURRENCE IN LIVING DONOR TRANSPLANTATION Donor Age: 47 ( 13-86) in CDLT vs 31 ( 19-58) LDLT p<0.01 Cya : 59% in CDLT vs 14% LDLT p<0.01 Biliary Complications: 22% in CDLT vs 72% in LDLT p<0.01 Garcia Retortillo Hepatology 2004; 40: 699-707 C.H.B.
  52. 52. HCV Recurrence in Split, CDLT and LDLT Histologic recurrence LDLT Grade and stage of hepatitis C LDLT Humar AJT 2005; 5: 399-405
  53. 53. Patient Survival after LDLT in HCV Patients Takada Transplantation 2006; 81: 350-354
  54. 54. Impact of Immunosuppression on HCV Recurrence C.H.B.
  55. 55. STEROIDS AND HCV • Controversial role – Increase viral load (Fong Gastro 1994, Gane Gastro 1996) – Boluses of steroids deleterious (Berenguer J Hepatol 2000) – But rapid withdrawal deleterious (Berenguer Hepatology 2003, McCaughan J Hepatol 2004) » Immune rebound? – Immunosuppression without steroids: not yet proven beneficial C.H.B.
  56. 56. HCV Recurrence in Patients Without Steroids No différence in Patient and graft survival at 1 year Waiting for histological analysis long-term Klintmalm Liver Transplant 2007
  57. 57. Rapid Steroid Withdrawal Deleterious for Hep C Recurrence Group A: Rapid Steroid Withdrawal D91 Group B: Slow Decrease in steroids, Stop at M25 % patients without severe Fibrosis Vivarelli J Hepatol 2007
  58. 58. HCV Recurrence , Cyclosporine, Tacrolimus • Controversial Role of Tacrolimus and Cyclosporine • Tacrolimus Deleterious? Not proven: – Absence of CyA independently associated with severe fibrosis (Berenguer Hepatology 2003) – More rapid reinfection with tacrolimus (Levy Transplantation 2004, Samuel ATC 2005, Berenguer 2006) – Better efficacy of IFN in patients treated with CyA ( Calmus AASLD 2007) – Antiviral effect of de la CyA in replicon system (Watashi Hepatology 2003; 38: 1282-1288). C.H.B.
  59. 59. HCV and Calcineurine Inhibitors Berenguer Liver Transplant 2006
  60. 60. MMF and HEPC • Induction with MMF associated with more severe recurrence? (Berenguer J Hepatol 2000, M Berenguer Hepatology 2003; 38:34 - 41) • What is sure – No antiviral action – Deleterious or favourable impact unknown C.H.B.
  61. 61. MMF And Hep C Decrease of CNI And introduction of MMF: • Increase viral load • Decrease fibrosis • Decrease ALT Bahra AJT 2005; 5: 406-411
  62. 62. Overall Role of IS 1999-2000 2001-2003 P Duration Pred (d) 249 350 <.0001 Bolus MP 21 4.5 .002 Berenguer > Is double (%) 25 10 .001 J Hepatol 2006 IFN preTH (%) 9 30 .006 Donor age (yr) 51 57 .07
  63. 63. 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 C.H.B.
  64. 64. ANTIVIRAL TREATMENT PRIOR LT LT Treatment 48 Wks Follow-up Follow up Treatment Follow-up 12-16 week C.H.B
  65. 65. Antiviral Treatment In HCV+ve Cirrhotic Patients Before Liver Transplantation Kuo, Terrault AJT 2006; 6: 449-458
  66. 66. 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 C.H.B.
  67. 67. ANTIVIRAL TREATMENT BEFORE 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 C.H.B.
  68. 68. TREATMENT PRE-LT auteurs Patients Child treatment Virologic Response SVR Tolérance during trt Post-LT Forns 30 A 50% INF 3M/j 9 (30%) 6/30 Baisse INF (2003) (Délai pré- B 43% +RBV 800 (20%) 60%, riba TH 4 mois) 23% C 7% Durée Facteurs réponse: G1:83% moyenne: charge virale pré- Arrêt 20% Pts exclus 12 sem trt, Sepsis: 2 40% (2-33 sem) Diminution charge Insuf virale de 2 log sem 4 hépatique: 4 Carrion 51 Meld α Pegα2a 15 (29%) 10/51 Risque (2008) G1:80% 11 µ 180µg/sem (20%) infectieux +RBV augmenté par Factors response: G trt (NS) 51 0,8-1g/j non 1, contrôles Durée response virologic at moyenne: wk4 15 sem C.H.B
  69. 69. ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION • Treatment in Child A patients waiting for LT – Group of patients with HCC on Child A cirrhosis – Child B patients • There is place for 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 – Treatment until LT with virologic response without waiting for SVR? C.H.B.
  70. 70. ANTIVIRAL TREATMENT DURING TRANSPLANTATION HYPERIMMUNE ANTI-HCV INMUNOGLOBULINS (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 AbXTL 68 (Schiano Liver Transplant 2006) » - 2.4 log HCV RNA decrease in 240 mg group vs - 1.5 log in placebo at d 2, no difference at d 7 » Significant increase of anti-E2 at d 7 in 240 mg group C.H.B.
  71. 71. 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 C.H.B.
  72. 72. Preemptive Antiviral Treatment In HCV+ve Liver Transplant Patients Kuo, Terrault AJT 2006; 6: 449-458
  73. 73. MEAN HCV VIRAL LOAD IN LIVER TRANSPLANT PATIENTS TREATED PREEMPTIVELY WITH PEGIFN ALPHA 2A SVR: 8% Chalasani Hepatology 2005; 41: 289-298
  74. 74. PREEMPTIVE TREATMENT IN IN HCV LIVER TRANSPLANT PATIENTS 51/124 Patients eligible, 44 Received one dose of treatment 6/124 (5%) achieved SVR Adherence to Treatment ETVR and SVR Shergill AJT 2005; 5: 118-124
  75. 75. MEAN HCV VIRAL LOAD IN LIVER TRANSPLANT PATIENTS TREATED WITH PEGIFN ALPHA 2A SVR : 8% Chalasani Hepatology 2005; 41: 289-298
  76. 76. TREATMENT INTERFERON-RIBAVIRINE AFTER TRANSPLANTATION Pts Bioch HCV Authors Treatment response RNA SVR (N) (%) Neg IFN 3MU x 3 / week + 48 % Bizollon Ribavirine(6 M) 21 100% ND Hepatology 1997 then Rbv(6 M) 24% Samuel INF 3MU x 3 / wks + Ribavirine(12 M) 28 ND 32% 21.4% Gastro 2003 Gopal INF 3MU x 3 / wks + Ribavirine(1-17 M) 12 75% 50% 8.3% Liver Transp 01 Lavezzo IFN 3MUX3/wks + Rbv 33% 22% (6M) (6 vs 12 Mths) 57 ND J Hepatol 02 23% 17%(12M Menon IFN 3MUX3/weeks + rbv (1 year) 26 42% 35% 30% Liver Transp 02 Shakil IFN 3MUX3/weeks+ RBV ( 1 year) 38 18% NA 5% Hepatol 02
  77. 77. KINETIC OF HCV RNA ACCORDING TO VIROLOGIC RESPONSE IN HCV POSITIVE TRANSPLANT PATIENTS Castells J Hepatol 2005; 43: 53-59
  78. 78. 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 C.H.B.
  79. 79. Treatment with PEG Interferon + Ribavirine 27 patients mild Hepatitis C (F1-F2): SVR: 48% 27 Patients with severe hepatitis C (F3-F4) , cholestatic hepatitis C: SVR: 18% (1/12 Cholestatic hepatitis, 4/15 F3-4 Carrion Gastroenterology 2007 C.H.B.
  80. 80. Histological Outcome in Relation with Virological Response to PEGIFN+ Ribavirine Variables associated with Histological improvement: EVR, BR, SVR Carrion Gastroenterology 2007 C.H.B.
  81. 81. Histological Outcome and HPVG Change Carrion Gastroenterology 2007 C.H.B.
  82. 82. Adverse Events During PegIFN + RBV Carrion Gastroenterology 2007 C.H.B.
  83. 83. 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 M12 placebo vs RBV 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 C.H.B.
  84. 84. FACTEURS PREDICTIFS DE REPONSE AU TRAITEMENT Facteurs significatifs en analyse univariée, non significatifs En analyse multivariée. Sharma P, et al. liver Transpl 2007;13:1100-1108 C.H.B
  85. 85. 1 Year and Long Term Histological Outcome after Treatment In Relation With Initial Stage of Fibrosis 20% of F3-F4 patients died or were retransplanted after treatment vs 1% of F1-F2 Roche Liver Transplantation 2008 In Press C.H.B
  86. 86. 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 C.H.B.
  87. 87. 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 C.H.B.
  88. 88. 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 high LFTs – Different type and level of immunosuppression – Different risk by using IFN, Peg IFN ± Ribavirin C.H.B.
  89. 89. Auto(Allo)immune Hepatitis and IFN Kontorinis Liver Transplant 2006
  90. 90. Auto(Allo)immune Hepatitis and IFN Sharma Liver Transplant 2007
  91. 91. Telaprevir (VX-950) + pegIFN: antiviral effect in treatment-naïve patients with HCV G1 HCV RNA 1 median change from 0 Baseline baseline (log10 IU/mL) -1 PegIFN + placebo -2 -3 -4 Telaprevir -5 Telaprevir + pegIFN -6 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Treatment day Reesink HW et al. EASL 2006
  92. 92. FUTURE TREATMENT OF HCV RECURENCE AFTER TRANSPLANTATION ? Antiprotease BILN 2061 Hinrichsen Gastroenterology 2004; 127:1347-1355 C.H.B.
  93. 93. Histological Outcome in SVR Transplant Patients Necroinflammatory score reduction, Fibrosis Score Stability Bizollon Gut 2003, 52, 283-287 C.H.B.
  94. 94. Graft Histology In HCV+ve Liver Transplant Patients With or Without SVR Median Follow-up : 57 Months in NR and 52 months in SVR Bizollon AJT 2005; 6: 449-458
  95. 95. Survival Without Cirrhosis In HCV+ve Liver Transplant Patients With or Without SVR Bizollon AJT 2005; 6: 449-458
  96. 96. Long-Term Histology in SVR HCV Liver Transplant Patients Inflammatory Score Fibrosis Score Abdelmalek Liver Transplant 2004; 10: 199-207
  97. 97. Role of SVR After LT in HCV + Patients Piciotto J Hepatol 2007; 46:459-465
  98. 98. EFFET DU TRAITEMENT ANTIVIRAL C SUR LA SURVIE Berenguer M AJT 2008 C.H.B
  99. 99. EFFECT OF ANTIVIRAL TREATMENT ON SURVIVAL Berenguer M AJT 2008 C.H.B
  100. 100. Role of SVR After LT in HCV + Patients Piciotto J Hepatol 2007; 46:459-465
  101. 101. Improved Survival In HCV+ve Liver Transplant Patients Italian Multicenter Study Belli Liver Transplant 2007; 13: 733-740
  102. 102. Patient (A) and Graft (B) Survival of HCV+ve vs HCV Neg Liver Transplant Patients Tuluvath Liver Transplant 2007;
  103. 103. HCV Recurrence After LT Deceased vs living donors Schmeding Liver Transplant 2007;
  104. 104. Survival of Liver Transplant Patients Over Years in USA Tuluvath Liver Transplant 2007;
  105. 105. Survival of Liver Transplant Patients Over Years in USA Lower graft Survival and no Improvement in HCV +ve Patients HCV Positive HCV Negative Tuluvath Liver Transplant 2007;
  106. 106. Survival of HCV+ve Liver Transplant Patients in USA Donor HCV- vs HCV + Deceased vs LDLT Tuluvath Liver Transplant 2007;
  107. 107. Patient Survival after Liver Transplantation in Europe ELTR- 01/1988 - 12/2004 (%) 100 93 87 87 85 85 85 HDV 81 78 80 74 81 73 70 68 72 65 HBV 60 66 60 55 HCV Virus BD : 883 40 PBC : 3578 Alcoholic : 10093 20 Virus B : 3162 Virus C : 8061 0 0 1 2 3 4 5 6 7 8 9 10 Yrs
  108. 108. Patient survival according to the year of LT HBV and HCV Cirrhosis >=2000 : 1410 ELTR update of December 2004 >=2000 : 3194 95 to 2000 : 1196 1995 to 2000 : 2705 90 to 95 : 915 1990 to 1995 : 1357 85 to 90 : 287 1985 to 1990 : 127 <1985 : 10 <1985 : 6 1 1 91% 86% 84% 83% 72% % Survival .8 .8 67% % Survival .6 .6 .4 .4 .2 .2 0 0 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Years Years HBV HCV

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