Samuel hcv lt

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Samuel hcv lt

  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 HCC800 800700 700600 600500 500400 400300 300200 200100 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 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 Virus Delta Virus B Virus C www.eltr.org C.H.B.
  3. 3. Trends in Waiting List for HCV Cirrhosis in USAKim Gastroenterology 2009
  4. 4. 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 HEPATITISRECURRENCE < 10 % DEATH Adapted From McCaughan 50%
  5. 5. CHOLESTATIC HEPATITIS C McCaughan J Hepatol 2011
  6. 6. FIBROSING CHOLESTATIC HEPATITIS CAntonini AJT 2011
  7. 7. FCH in HCV-HIV Coinfected Patienst Impact on SurvivalAntonini AJT 2011
  8. 8. Pathobiology of Chronic HCV Post LTImmunosuppression - The immune response + HCV load - Inflammation + IFN- related genes IFN- response Stimulation of the IMMUNE RESPONSE by more HCV WINS Proliferation Acute Rejection Apoptosis Inflammation Fibrosis 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 OutcomeBlasco Hepatology 2006; 43: 492-499
  11. 11. Fibrosis Stage at 12 months at Liver Biopsy and SurvivalGallegos-Orozco Liver Transplant 2009
  12. 12. Non Invasive 3-MALG Test and Decompensation and Survival Post-TransplantCarrion Gastro 2010
  13. 13. Liver Stiffness and Severity of HCV RecurrenceCarrion 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 GenderRisk 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 FibrosisKlintmalm 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-LTAuthors Patients Child Treatment Virologic SVR Tolerance Response EOT Post-LTForns 30 A 50% INF 3M/d 9 (30%) 6/30 Decrease INF(2003) (Time pre- B 43% +RBV (20%) 60%, RBV LT 4 800mg 23% C 7% Factors for mths) Mean response : viral Stop 20% G1:83% Duration : laod pre-LT, Sepsis: 2 12 wks Decrease viral Liver Failure: (2-33 wks) load≥ 2 log Wk 4 4Carrion 51 Meld Peg 2a 15 (29%) 10/51 infectious(2008) G1:80% 11 180 g/wk (20%) risk +RBV increased by Factors response: Trt (NS) 51 0,8-1g/d G non 1, controls Mean RVR Wk4 duration: 15 Wks Forns J Hepatol 2003, Carrion J Hepatol 2008 C.H.B.
  22. 22. Antiviral Treatment in Patients Waitingfor Liver Transplantation, Risk of Sepsis Related to CPTCarrión JA et al. J Hepatol. 2009;50:719-28.
  23. 23. Antiviral Treatment in Patients Waiting for Liver Transplantation, Norfloxacin ProphylaxisCarrión 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 treatedEverson Hepatology 2012 C.H.B.
  25. 25. PegIFN + RBV Treatment Before LTMeld score: 12, CTP score : 7Serious Infection rate: 7/59 (12) pts vs 0% controlDeath pre-LT: 5/59 vs 2/20 (NS) Everson Hepatology 2012 C.H.B.
  26. 26. Antiviral Treatment Before TransplantationRoche, 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 combinationwith 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. Strategies Before and After TransplantationFeray J Hepatol 2011
  31. 31. Mechanism of HCV EntryZeisel J Hepatol 2011
  32. 32. Antiviral Treatment Immediately after TransplantationRoche, Samuel Liver Transplant 2010
  33. 33. Antiviral Therapy PegINF+ RBV Post-TransplantationAuthors Studie Patients Years ETVR SVR Tolerance AR Factors s linked with SVRWang 21 587 1980-05 42% 27% (23- Reduction 66% 5% No prior (1RCT) (30-37) 31) (61-70%) (3-7) antiviral tt Stop: 26% ( post-LT 20-32) Non-1 GBerenguer 19 611 2004-07 42% 30% Reduction:68% 6.4% EVR (2RCT) (17-68) G1: 28% Stop 28% G2 G2: 71- Adherence 100% Baseline G3:41% viremia (30-77%)Xirouchakis 6 RCT 264 2005-07 - 30% - 5% G1: 29% G2: 71- 100% G3: 41% ( 30-77) Roche, Samuel Liver Int 2012, Wang AJT 2006, Berenguer J Hepatol 2008 , Xirouchakis J Viral Hep 2008 C.H.B.
  34. 34. Auto(Allo)immune Hepatitis and IFNSharma Liver Transplant 2007
  35. 35. 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 ( RocheLiver transplant 2008) C.H.B.
  36. 36. SVR and IL28 in all Genotype Transplant PatientsLange J Hepatol 11 C.H.B.
  37. 37. SVR According to IL 28CharltonHepatology 2011 C.H.B.
  38. 38. Survival (Death and Graft Loss) According to IL 28 IL 28 Recipient IL 28 DonorCharlton Hepatology 2011 C.H.B.
  39. 39. IL 28 In the Donor should be determined on GraftReperfusion Biopsy or PBMC, not on follow-up BiopsiesCoto-Llorena J Hepatol 2012 C.H.B.
  40. 40. SVR According to IL 28 in Recipient, Donor, and FU BiopsyCoto-Llorena J Hepatol 2012 C.H.B.
  41. 41. Histological Outcome in Relation withVirological Response to PEGIFN+ Ribavirine Variables associated with Histological improvement: EVR, BR, SVRCarrion Gastroenterology 2007 C.H.B.
  42. 42. Impact of SVR on Suvival in Transplant HCV + PatientsPiciotto J Hepatol 2007 Berenguer M AJT 2008
  43. 43. 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.
  44. 44. 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 XGarg Hepatology 2011
  45. 45. Treatment After LT with Protease Inhibitors One limitation: drug-drug interactionsHealthy volunteers Liver transplant patients • CNI, cyclosporine or tacrolimus 100 12 10 Clairance orale (L/h) 80 • PI: CYP 3A4 potent inhibitors 60 8 6 • AUC increase 40 4 20 2 0 0 Alone Boce Alone Boce Boceprevir Telaprevir Cyclosporine TacrolimusCyclosporine 2.7 4.6 • Boceprevir in 5 transplant patients: the estimated oral clearanceTacrolimus 9.9 70 decreased Garg, Hepatology, 2011 • Cyclosporine (n=3): 50% Hulskotte, Hepatology, 2012 • Tacrolimus (n=2): up to 80% • Everolimus (n=1): 55% Coilly, AAC, 2012
  46. 46. 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
  47. 47. Patients and Methods PEG-IFN/RBV PEG-IFN/RBV+Boceprevir (800mg tid) n=18 n=8 PEG-IFN/RBV PEG-IFN/RBV+Telaprevir (750mg tid) PEG-IFN/RBV+Telaprevir (750mg tid) n=11 W48Week -4 Week 0 Week 4 Week 12
  48. 48. DAA Post-Transplantation Practical IssuesCoilly Liver Int 2013 C.H.B.
  49. 49. Virological response EVR at Week 12 ETVR at Week 48p=ns p=ns 89% 89% 75% 67% 64% 63% 50% ITT PP ITT PP ITT PP ITT PP ITT PP Boceprevir Bocéprévir (n=18) Telaprevir Télaprévir (n=19) Boceprevir Bocéprévir (n=13) t n=18 n=19 n=13
  50. 50. Boceprevir group, n=18 9 Mean treatment duration: 42 ± 8.7 weeks 8 7  End of treatment with undetectable viral load, n=7 6  On going, n=7 5HCV viral load (log10 Treatment discontinuation 4  Null response, n=1  Virological breakthrough , n=1IU/mL) 3  Adverse events, n=2 2 1 0 S-4 S2 S4 S8 S12 S16 S20 S24 S28 S32 S36 S40 S44 S48 Treatment duration
  51. 51. Telaprevir group, n=19 9 Mean treatment duration: 33 ± 10.2 weeks 8 7  On going, n=10 6 5HCV viral load (log10 Treatment discontinuation 4  Null response, n=4  Virological breakthrough , n=2 3IU/mL)  Adverse events, n=2 2 1 0 S-4 S0 S4 S8 S12 S16 S20 S24 S28 S32 S36 S40 S44 S48 Treatment duration
  52. 52. Adverse events Boceprevir Telaprevir p (n = 18) (n = 19)Death – n°(%) 1 (5 %) 1 (5 %) nsInfections – n° (%) 3 (17 %) 4 (21 %) nsHematotoxicity – n° (%) Anemia < 10 g/dL 18 (100 %) 16 (84 %) ns < 8 g/dL 7 (39 %) 3 (15 %) Neutropenia (<1 G/L) 11 (61 %) 4 (21 %) Thrombopenia (< 50 G/L) 5 (28 %) 3 (15 %)Dermatological toxicity –n° (%) 1 (5 %) 1 (5 %) nsRenal failure – n° (%) 0 2 (9 %) nsDiabetes mellitus – n° (%) 2 (10 %) 0 (26%) ns
  53. 53. 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
  54. 54. Evolution of Liver Transplantation for Viral Cirrhosis in Europe. Without HCC With HCC www.eltr.org C.H.B.
  55. 55. Evolution of Patient Survival after LT for Virus CCirrhosis without HCC in Europe (ELTR: 1988-2010) www.eltr.org C.H.B.
  56. 56. DAA Post-Transplantation The future PossibilitiesMc Caughan J Hepatol 2012 C.H.B.
  57. 57. DAA Post-Transplantation The Hope of Non-IFN Based TherapiesMc Caughan J Hepatol 2012 C.H.B.
  58. 58. PegIFN +RBV+Daclatasvir for FCH after LTFontana Liver Transpant 2012 C.H.B.
  59. 59. 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.
  60. 60. 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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