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EASL-ELTA Postgraduate Course Berlin, 2004

EASL-ELTA Postgraduate Course Berlin, 2004. Hepatitis C: management of recurrent disease throughout retransplantation. Xavier Forns Liver Unit Barcelona. HCV RECURRENCE AFTER O.L.T. Development of cirrhosis in the liver graft. 0,5. cumulative probability. 28%. 16%. 0,25. 8.5%.

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EASL-ELTA Postgraduate Course Berlin, 2004

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  1. EASL-ELTA Postgraduate Course Berlin, 2004 Hepatitis C: management of recurrent disease throughout retransplantation Xavier Forns Liver Unit Barcelona

  2. HCV RECURRENCE AFTER O.L.T. Development of cirrhosis in the liver graft 0,5 cumulative probability 28% 16% 0,25 8.5% 12 24 36 48 60 months after liver transplantation Prieto et al., Hepatology 1999

  3. Recurrent Hepatitis C. Possible Therapeutic Interventions • I.Pre-transplant antiviral treatment • II. Immunoprophylaxis • III. Post-trasplant antiviral treatment • (early therapy, late therapy) • IV. Changes in immunosuppression • No steroids, short-course steroids • MMF? • CyA vs TAC?

  4. I. Antiviral Therapy before LT • Stabilize and/or improve hepatic function • Suppress viral replication to reduce risk of recurrence

  5. I. Antiviral Therapy before LT • 15 patients with decompensated cirrhosis • Inclusion criteria: Platelets > 45 k, Hb >11g/dl, Status 2B, Group 0 • Treatment while on waiting list: IFN 1 MU, IFN 3 MU, IFN +RBV • Viral load decreased in 14/15. Viral clearance 5/15 • Serious adverse effects (study discontinued) (Charlton et al, 2001)

  6. I. Antiviral Therapy before LT • 102 patients with decompensated HCV-related cirrhosis (50% Child A). • 77% genotype 1 • Treatment schedule: Low-Accelerating Dose Regimen (LADR) • IFN alfa 2b 1.5 MU tiw and RBV 600 mg q.d • (1.0 to 1.2, as tolerated) (Everson et al, 2002)

  7. I. Antiviral Therapy before LT 102 patients treated 62 (60%) 19 (19%) 21 (21%) * *10 underwent LTx, no recurrence (Everson et al, 2003)

  8. I. Antiviral Therapy before LT 30 patients in waiting list for LT 57(36-66) 25(83%) 17(57%) 15/15 5,8.105(102-3,3.107) 21(70%) 25(83%) Age (years) *: Sex (M): IndicationLT (CHC): Child A/BC: Viral load pre-Tx (IU/mL) *: Low VL: Genotype 1: Treatment regimen: IFN 3x106/d and RBV 800 mg/d (Forns et al, 2003)

  9. I. Antiviral Therapy before LT Response Non response n=9 n=21 VL pre-Tx log 10 (UI/mL)a Genotype1/non 1 Child-Pugh (A/B/C) Weeks of therapy Weeks of full-dose therapy VL reduction >2 log10 (4ª week of therapy)a 2.8x105 6.4x105 6/3 19/2 4/5 9/12 12 (4-27) 15 (2-33) 8 (1-12) 4(1-21) 9/0 2/14 ap < 0.05 (Forns et al., 2003)

  10. I. Antiviral Therapy before LT (Forns et al., 2003)

  11. II. Immunoprophylaxis of HCV recurrence • Feray et al (1998) • HBIG: HCV recurrence, 45% vs 77% • Anti-HCV human IG (plasma pools from anti-HCV positve donors) • 26 HCV-RNA liver transplant recipients: no clinical nor virological beneffits (Willems 2002).

  12. III. Early post-transplant antiviral therapy No Initiation (after LT) Wks of therapy SVR Singh (1998)24 2nd wk 24 0 IFN vs placebo Sheiner (1998)71 3rd wk 48 0 IFN vs placebo Mazzaferro (2004)43 4th wk 48 13% vs 33% IFN vs IFN+RBV

  13. 1000000 100000 10000 Viral load (IU/ml) 1000 100 72 96 24 48 120 pre-OLT 4 12 reperfusion anhep. Time after OLT (hours) HCV KINETICS DURING AND AFTER LT 10000000 1000000 1000000 100000 100000 10000 10000 Viral load (IU/ml) Viral load (IU/ml) 1000 1000 100 100 72 96 24 48 24 96 48 72 120 120 4 pre-OLT 4 12 pre-OLT 12 anhep. anhep. reperfusion reperfusion Time after OLT (hours) Time after OLT (hours) 10000000 1000000 100000 10000 Viral load (IU/ml) 1000 100 96 12 24 48 72 120 pre-OLT reperf. reperfusion Time after OLT (hours) (Garcia-Retortillo, 2002)

  14. III. Post-transplant antiviral therapy Combination Therapy in patients with established chronic hepatitis EOT SR n n (%) n (%) TOTAL 191 48 (25) 30 (15) Bizollon 21 10 (50) 5 (20) Shakil 44 7 (16) 5 (11) De Vera 32 3 (9) 3 (9) Reuben 16 1 (6) 1 (6) Firpi 50 20 (40) 10 (20) Samuel (RCT) 28 7 (25) 6 (21)

  15. III. Post-transplant antiviral therapy Combination Therapy in patients with established chronic hepatitis • N= 28 • IFN alfa-2b 3MIU-TIW + Ribavirin 800-1200 mg/day Screening 48 weeks 24 weeks • N= 24 • Untreated control group Samuel et al 2003

  16. III. Post-transplant antiviral therapy Combination therapy in patients with established chronic hepatitis SVR: HCV-RNA negative 6 months after treatment finalization (NGI < 100 copies/mL) 60% P= 0.036 40% % Patients with SVR 21% 20% 0% 0% IFN alfa-2b + RBV Control Samuel et al 2003

  17. III. Post-transplant antiviral therapy Discontinuations Causes IFN alfa-2b + RBV Controls P value (n=28) (n=24) Anemia* 7 (25%) 0 0.016 Chronic rejection 1 0 Insomnia 1 0 Depression 1 0 Irritability 2 0 Death 0 1 (septic Shock) Progression fibrosis 0 1 Lost of follow-up 0 2 * 3 W4, 1 W8, 2 W12, 1 W28 Samuel et al 2003

  18. Samuel et al. 2003 22 Peg-interferon alfa-2b 1 μg/Kg/w plus RBV (7.5 mg/Kg/d), 12 m.* 23% Neumann et al. 2003 25 Peg-interferon alfa-2b 1.5 μg/Kg/w plus RBV (400mg-800 mg), 12 m. 36% Rdgz-Luna et al. 2004 19 Peg-interferon alfa-2b 0.5-1.5 μg/Kg/wplus RBV (400-1000mg), 12 m. 26% III. Post-transplant antiviral therapy Treatment with pegylated interferon Study N Treatment regimen SVR

  19. Influence of antiviral treatment on disease progression Worsening Worsening Worsening Worsening No change No change No change No change Improvement Improvement Improvement Improvement Necroinflamtory activity 30 30 Number of patients Number of patients 20 20 10 10 SVR NR Fibrosis stage 30 30 Number of patients Number of patients 20 20 10 10 SVR NR Alberti 2001, Firpi 2002, Bizollon 2003, Rdz-Luna 2004

  20. IV. Changes in immunosuppression Probability to develop cirrhosis Year of transplantation 1991-1996 1997-2000 (n=142) (n=137) CyA 100% 56% FK 0 44% AZT 97% 43% MMF 0 7% PDN 879 273 (days) Berenguer et al 2002

  21. Recurrent Hepatitis C after LT: Future • Individualization of immunosuppression regimens (RCT necessary) • New antiviral agents (HCV protease/polymerase inhibitors) • Prevent fibrosis progression

  22. Recurrent Hepatitis C after LT: Future Antiviral efficacy of a novel HCV protease inhibitor Treatment period BILN 2061 Rx Placebo Genotype 1a Genotype 1b Hinrichsen et al 2003

  23. Recurrent Hepatitis C after LT: Future Blockade of renin-angiotensin system and fibrosis progression • Retrospective analysis: charts of patients undergoing LT, 1988-1998 • Patients: 152, LT for HCV-related liver disease with graft survival > 6 months and periodical liver biopsies • 33 patients received ACE-i or AR-a, 119 patients did not • Both groups were comparable for donor age, type of immunosuppression, treatment with steroids, genotype and antiviral therapy. • ‘Severe fibrosis’: patients with fibrosis stage 3 or 4 (METAVIR) Rimola et al 2004

  24. Severe graft fibrosis (stages 3 - 4) in patients with liver transplantation and HCV infection recurrence, treated with ACE-i / AR-a or not 70 60 50 No ACE-i / AR-a 40 Probability of severe fibrosis (%) log rank test: p = 0.0026 30 20 ACE-i / AR-a 10 0 0 20 60 80 100 40 Months

  25. Compensated cirrhosis (HCC) and good virological profile Antiviral therapy Decompensated cirrhosis and good virological profile Offer antiviral treatment (on individual basis) HCV recurrence after LT Protocol liver biopsy Early antiviral therapy Evidence of severe HCV disease recurrence Progression of liver fibrosis Antiviral therapy No progression of liver fibrosis Follow-up, no therapy HCV-infected patients awaiting LT

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