Samuel d hcv lt 2014

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Samuel d hcv lt 2014

  1. 1. HCV PRE AND POST-LIVER TRANSPLANTATION Professor Didier SAMUEL Centre Hépatobiliaire, Inserm Unit 785, Paris XI University Hopital Paul Brousse, Villejuif, France C.H.B.
  2. 2. Evolution of Liver Transplantation for Viral Cirrhosis in Europe. Without HCC With HCC 800 800 700 700 600 600 500 500 400 400 300 300 200 200 100 100 0 0 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Virus Delta Virus B Virus C 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Virus Delta Virus B Virus C www.eltr.org C.H.B.
  3. 3. Trends in Waiting List for HCV Cirrhosis in USA Kim Gastroenterology 2009
  4. 4. PATTERN OF HCV RECURRENCE POST OLTx NO HEPATITIS 20% 6 MTH ACUTE HEPATITIS 70% 6 MTH CHRONIC HEPATITIS ? 1 MTH OLT 1 MTH 1 MTH VIRAL RECURRENCE CHRONIC HEPATITIS  CHOLESTATIC HEPATITIS < 10 % Adapted From McCaughan DEATH 50% CIRRHOSIS
  5. 5. CHOLESTATIC HEPATITIS C McCaughan J Hepatol 2011
  6. 6. FIBROSING CHOLESTATIC HEPATITIS C Antonini AJT 2011
  7. 7. FCH in HCV-HIV Coinfected Patienst Impact on Survival Antonini AJT 2011
  8. 8. Pathobiology of Chronic HCV Post LT Immunosuppression - The immune response + HCV load - Inflammation + IFN- related genes IFN- response Proliferation Apoptosis Fibrosis Stimulation of the IMMUNE RESPONSE by more HCV WINS Acute Rejection Inflammation Stress Response McCaughan and Zekry J.Hepatol 2004, Samuel Easl Hepatol 2006
  9. 9. EVALUATION OF THE SEVERITY OF HCV RECURRENCE • Liver Biopsy Gold Standard, Bring additional information than fibrosis stage . HPVG Invasive, can be done with liver biopsy Not routine for many Centres . Non invasive tests Biochemical Elastometry (fibroscan) . Time post-LT as an adding variable C.H.B.
  10. 10. HPVG, Fibrosis at 1 Year Post-Transplant and Outcome Blasco Hepatology 2006; 43: 492-499
  11. 11. Fibrosis Stage at 12 months at Liver Biopsy and Survival Gallegos-Orozco Liver Transplant 2009
  12. 12. Non Invasive 3-MALG Test and Decompensation and Survival Post-Transplant Carrion Gastro 2010
  13. 13. Liver Stiffness and Severity of HCV Recurrence Carrion Hepatology 2010
  14. 14. Donor and Host Factors of HCV Recurrence C.H.B.
  15. 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. 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) C.H.B.
  17. 17. No Impact of Steroid-Free IS on Graft HCV Fibrosis Klintmalm Liver Transplant 2011
  18. 18. HCV Recurrence , Cyclosporine vs Tacrolimus • There is currently no proof of superiority of one vs another – Antiviral effect of Cyclosporine only in vitro – Better efficacy of IFN in Ciclosporine patients not confirmed – Randomized studies showed earlier reinfection with Tac but no difference in fibrosis stage, better survival with Tac? Samonakis, J Hepatol 2012 in Press, Berenguer Nat Rev Gastroenterol 2011 C.H.B.
  19. 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 C.H.B.
  20. 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 C.H.B.
  21. 21. ANTIVIRAL TREATMENT PRE-LT Authors Patients Child Treatment Virologic Response EOT SVR Post-LT Tolerance Forns (2003) 30 (Time preLT 4 mths) G1:83% A 50% B 43% C 7% INF 3M/d +RBV 800mg Mean Duration : 12 wks (2-33 wks) 9 (30%) 6/30 (20%) Decrease INF 60%, RBV 23% Stop 20% Sepsis: 2 Liver Failure: 4 51 G1:80% Meld 11 Peg 2a 180 g/wk +RBV 0,8-1g/d Mean duration: 15 Wks 10/51 (20%) infectious risk increased by Trt (NS) Carrion (2008) 51 controls Factors for response : viral laod pre-LT, Decrease viral load≥ 2 log Wk 4 15 (29%) Factors response: G non 1, RVR Wk4 Forns J Hepatol 2003, Carrion J Hepatol 2008 C.H.B.
  22. 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. 23. Antiviral Treatment in Patients Waiting for Liver Transplantation, Norfloxacin Prophylaxis Carrión JA et al. J Hepatol. 2009;50:719-28.
  24. 24. PegIFN + RBV Before LT • Treatment PegIFN+RBV until LT – 47 G1/4/6 patients » 30 treated » 17 not treated • 32 G2/3 patients treated » 29 treated » 3 not treated Everson Hepatology 2012 C.H.B.
  25. 25. PegIFN + RBV Treatment Before LT Meld score: 12, CTP score : 7 Serious Infection rate: 7/59 (12) pts vs 0% control Death pre-LT: 5/59 vs 2/20 (NS) Everson Hepatology 2012 C.H.B.
  26. 26. Antiviral Treatment Before Transplantation Roche, Samuel Liver Int 2012
  27. 27. Direct Antiviral Agents Before LT A New Challenge • Data In cirrhotic patients are lacking • Therapies with IFN will remain poorly tolerated • Increase possibility to achieve SVR or on treatment virologic response • Increase risk of virologic breakthrough • Duration, safety issues to be analysed • Therapies without IFN awaited C.H.B.
  28. 28. Study ANRS HC29 BOCEPRETRANSPLANT Pilot study of Efficacy and Tolerablity of Boceprevir in combination with Peginterferon alpha-2b and Ribavirin in patients infected with HCV genotype 1, naive or non responders with cirrhosis awaiting liver transplantation Promoteur : ANRS Coordinating investigator : Didier Samuel Co-investigators : JC Duclos-Vallée, H Fontaine, B Roche C.H.B.
  29. 29. Inclusion criteria • Age > 18 years • Chronic HCV infection proved with a positive HCV PCR during 6 months or more • Genotype 1 • Patient with cirrhosis and registered for LT • MELD score ≤ 18 • With or without hepatocellular carcinoma • Naïve or non responders C.H.B.
  30. 30. Pre-Transplant Sofosbuvir + RBV Until LT Patient Demographics SOF + RBV (n=61) Male, n (%) Median age, y (range) 49 (80) 59 (46–73) White, n (%) 55 (90) BMI < 30 kg/m2, n (%) 43 (70) HCV RNA > 6 log10 IU/mL, n (%) 41 (67) Genotype, n (%) 1a 1b 2 3a 4 24 (39) 21 (34) 8 (13) 7 (12) 1 (2) Non-CC allele, n (%) 47/60 (78) CTP score, n (%) 5 6 7 8 26 (43) 18 (30) 14 (23) 3 (5) Median MELD score, (range) 8 (6–14) Prior HCV treatment, n (%) Curry AASLD 2013. Washington, DC. Oral #213 46 (75) C.H.B.
  31. 31. Pre-Transplant Sofosbuvir + RBV Until LT Pre-Transplant Virologic Response Post-Transplant Virologic Response Viral Response Rate (%) 100 93 80 64 60 40 20 41/44* 25/39*† Transplant 0 PTVR 12 SOF + RBV was safe and effective in patients with well compensated cirrhosis, and prevented post-transplant HCV recurrence in 64% of patients who had HCV RNA < 25 IU/mL prior to transplant Curry AASLD 2013. Washington, DC. Oral #213 C.H.B.
  32. 32. Pre-Transplant Sofosbuvir + RBV Until LT Impact of Duration of Treatment on HCV Recurrence No Recurrence (n=28) Recurrence (n=10) Median days TND No recurrence 95 Recurrence 5.5 p <0.001 0 50 100 150 200 250 300 350 Days with HCV RNA Continuously TND Prior to Liver Transplant *3 patients with recurrent HCV had 0 consecutive days TND before transplant. Curry MP, et al. AASLD 2013. C.H.B.
  33. 33. Strategies Before and After Transplantation Feray J Hepatol 2011
  34. 34. Mechanism of HCV Entry Zeisel J Hepatol 2011
  35. 35. Antiviral Treatment Immediately after Transplantation Roche, Samuel Liver Transplant 2010
  36. 36. Antiviral Therapy PegINF+ RBV Post-Transplantation Authors Studie s Patients Years ETVR SVR Tolerance AR Factors linked with SVR Wang 21 (1RCT) 587 1980-05 42% (30-37) 27% (2331) Reduction 66% (61-70%) Stop: 26% ( 20-32) 5% (3-7) No prior antiviral tt post-LT Non-1 G Berenguer 19 (2RCT) 611 2004-07 42% (17-68) 30% G1: 28% G2: 71100% G3:41% (30-77%) Reduction:68% Stop 28% 6.4% EVR G2 Adherence Baseline viremia Xirouchakis 6 RCT 264 2005-07 - 30% G1: 29% G2: 71100% G3: 41% ( 30-77) - 5% Roche, Samuel Liver Int 2012, Wang AJT 2006, Berenguer J Hepatol 2008 , Xirouchakis J Viral Hep 2008 C.H.B.
  37. 37. Auto(Allo)immune Hepatitis and IFN Sharma Liver Transplant 2007
  38. 38. Treatment with PEG IFN + RBV After LT SVR Dependent of Fibrosis stage • 27 Pts mild Hepatitis C (F1-F2): SVR 48% • 27 Pts severe hepatitis C (F3-F4), Cholestatic Hepatitis: SVR 18% • F3-4: 4/15 • Cholestatic hepatitis, 1/12 (Carrion Gastro 2007) • 20% F3-F4 vs 1% F1 Patients died or were retransplanted ( Roche Liver transplant 2008) C.H.B.
  39. 39. SVR and IL28 in all Genotype Transplant Patients Lange J Hepatol 11 C.H.B.
  40. 40. SVR According to IL 28 Charlton Hepatology 2011 C.H.B.
  41. 41. Survival (Death and Graft Loss) According to IL 28 IL 28 Recipient Charlton Hepatology 2011 IL 28 Donor C.H.B.
  42. 42. IL 28 In the Donor should be determined on Graft Reperfusion Biopsy or PBMC, not on follow-up Biopsies Coto-Llorena J Hepatol 2012 C.H.B.
  43. 43. SVR According to IL 28 in Recipient, Donor, and FU Biopsy Coto-Llorena J Hepatol 2012 C.H.B.
  44. 44. Histological Outcome in Relation with Virological Response to PEGIFN+ Ribavirine Variables associated with Histological improvement: EVR, BR, SVR Carrion Gastroenterology 2007 C.H.B.
  45. 45. Impact of SVR on Suvival in Transplant HCV + Patients Piciotto J Hepatol 2007 Berenguer M AJT 2008
  46. 46. Direct Antiviral Agents After LT A 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 C.H.B.
  47. 47. Telaprevir and Cyclosprine and Tacrolimus Interactions Cmax increased by 1.4X Cmax increased by 9.3X AUC Increased by 4.1-4.6X AUC Increased by 70X T1/2 increased by 4 X T1/2 increased by 5 X Garg Hepatology 2011
  48. 48. Treatment After LT with Protease Inhibitors One limitation: drug-drug interactions Liver transplant patients • CNI, cyclosporine or tacrolimus • PI: CYP 3A4 potent inhibitors • AUC increase 100 Clairance orale (L/h) Healthy volunteers 12 80 10 8 60 6 40 4 20 2 0 0 Alone Boceprevir Telaprevir Cyclosporine 2.7 4.6 Tacrolimus 9.9 70 Garg, Hepatology, 2011 Hulskotte, Hepatology, 2012 Boce Cyclosporine Alone Boce Tacrolimus • Boceprevir in 5 transplant patients: the estimated oral clearance decreased • Cyclosporine (n=3): 50% • Tacrolimus (n=2): up to 80% • Everolimus (n=1): 55% Coilly, AAC, 2012
  49. 49. French Collaborative study • Cohort study, N=37 • 5 transplant centers in France Villejuif, Lyon, Grenoble, Marseille, Montpellier • Inclusion criteria: • • • • Active genotype 1 HCV chronic hepatitis HCV recurrence, ≥ F2 or cholestatic hepatitis Steady-state of immunosuppressive regimen No contraindication for protease inhibitors, PEG-IFN/RBV
  50. 50. Patients and Methods PEG-IFN/RBV+Boceprevir (800mg tid) PEG-IFN/RBV PEG-IFN/RBV+Telaprevir (750mg tid) PEG-IFN/RBV PEG-IFN/RBV+Telaprevir (750mg tid) n=18 n=8 n=11 W48 Week -4 Week 0 Week 4 Week 12
  51. 51. DAA Post-Transplantation Practical Issues Coilly Liver Int 2013 C.H.B.
  52. 52. Virological response EVR at Week 12 ETVR at Week 48 p=ns p=ns 89% 89% 75% 64% 63% 67% 50% ITT PP Boceprevir n=18 Bocéprévir (n=18) ITT PP Telaprevir n=19 Télaprévir (n=19) ITT PP ITT PP ITT Boceprevir n=13 Bocéprévir (n=13) PP t
  53. 53. Boceprevir group, n=18 9 Mean treatment duration: 42 ± 8.7 weeks 8  End of treatment with viral load, n=7 7 HCV viral load (log10 IU/mL) 6  undetectable On going, n=7 5 Treatment discontinuation  Null response, n=1  Virological breakthrough  Adverse events, n=2 4 3 , n=1 2 1 0 S-4 S2 S4 S8 S12 S16 S20 S24 S28 S32 S36 S40 S44 S48 Treatment duration
  54. 54. Telaprevir group, n=19 9 Mean treatment duration: 33 ± 10.2 weeks 8 7  HCV viral load (log10 IU/mL) 6 On going, n=10 5 Treatment discontinuation  Null response, n=4  Virological breakthrough  Adverse events, n=2 4 3 , n=2 2 1 0 S-4 S0 S4 S8 S12 S16 S20 S24 S28 S32 S36 S40 S44 S48 Treatment duration
  55. 55. Adverse events Boceprevir (n = 18) Telaprevir (n = 19) p Death – n°(%) 1 (5 %) 1 (5 %) ns Infections – n° (%) 3 (17 %) 4 (21 %) ns Hematotoxicity – n° (%) Anemia < 10 g/dL < 8 g/dL Neutropenia (<1 G/L) Thrombopenia (< 50 G/L) 18 (100 %) 7 (39 %) 11 (61 %) 5 (28 %) 16 (84 %) 3 (15 %) 4 (21 %) 3 (15 %) Dermatological toxicity –n° (%) 1 (5 %) 1 (5 %) ns 0 2 (9 %) ns 2 (10 %) 0 (26%) ns Renal failure – n° (%) Diabetes mellitus – n° (%) ns
  56. 56. CNI-PI interactions Boceprevir Telaprevir CNI dose reduction Cyclosporine  1.8  3.4 Tacrolimus  5.2  23.8 • • • Dose reduction of CNI constantly required No overdose No biopsy-proven acute rejection
  57. 57. First Generation Protease inhibitors Telaprevir, Boceprevir 60% 51% 43% 47% 41% 27% EOT RVS 12 Tela Coilly AASLD 2013 Boce RVS 24
  58. 58. The Advent of Second Generation DAAs After Liver Transplantation C.H.B.
  59. 59. PegIFN +RBV+Daclatasvir for FCH after LT Fontana Liver Transpant 2012 C.H.B.
  60. 60. Sofosbuvir+Daclatasvir for FCH after LT Fontana Am J Transplant 2013 C.H.B.
  61. 61. Sofosbuvir + Ribavirin After Transplantation SOF 400 mg + RBV 400‒1200 mg (N=40) SVR12 • Patients with recurrent HCV post-liver transplant – Liver transplant ≥6 and ≤150 months prior to enrollment – Any HCV genotype – Naïve or treatment-experienced – CTP ≤7 and MELD ≤17 • Low, ascending-dose RBV regimen starting at 400 mg/day, escalated based on hemoglobin levels Charlton AASLD 2013 C.H.B.
  62. 62. Sofosbuvir + Ribavirin After Transplantation SOF + RBV (N=40) Male, n (%) Median age, y (range) 31 (78) 59 (49-75) White, n (%) 34 (85) BMI <30 kg/m2, n (%) 30 (75) Mean HCV RNA log10 IU/mL (range) 6.55 (4.49-7.59) Genotype, n (%) 1a 1b 2 3 4 22 (55) 11( 28) 0 6 (15) 1 (3) IL28B, n (%) CC CT TT 13 (33) 16 (40) 11 (28) Metavir-equivalent fibrosis stage, n (%) None or minimal (F0) Portal Fibrosis (F1-F2) Bridging Fibrosis (F3) Cirrhosis (F4) 1 (3) 14 (35) 9 (23) 16 (40) Prior HCV Treatment, n (%) Median years since liver transplantation (range) Charlton AASLD 2013 Yes 35 (88) 4.3 (1.02-10.6) C.H.B.
  63. 63. Sofosbuvir + Ribavirin After Transplantation 100 100 100 77 80 60 40 20 39/39 0 Week 4 Charlton AASLD 2013 EOT* SVR 4 C.H.B.
  64. 64. Sofosbuvir + Ribavirin After Transplantation Tolerance 15 1.2 14 1.1 Hb 13 1.0 Creatinin 12 0.9 11 10 0 1 2 3 4 8 12 16 20 24 0.8 FU-2 FU-4 20% Received EPO Charlton AASLD 2013 C.H.B.
  65. 65. Evolution of Liver Transplantation for Viral Cirrhosis in Europe. Without HCC With HCC www.eltr.org C.H.B.
  66. 66. Evolution of Patient Survival after LT for Virus C Cirrhosis without HCC in Europe (ELTR: 1988-2010) www.eltr.org C.H.B.
  67. 67. 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 C.H.B.
  68. 68. CONCLUSION • Triple antiviral therapies with IFN in cirrhotics remains difficult – Increase in SVR expected – High rate of anemia , risk of sepsis and death – Strategies to improve tolerance are necessary – Treatment without IFN are strongly awaited • First results of triple therapies after LT are encouraging – Increased virologic response – Acceptable tolerance and drug-drug interactions manageable – Treatment without IFN awaited but IFN might remain necessary in some patients C.H.B.

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