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HEPATITIS C:EFFECTS OF PRE-TRANSPLANT CHARACTERISTICS, ORGAN MATCHING AND IMMUNOSUPPRESSION

HEPATITIS C:EFFECTS OF PRE-TRANSPLANT CHARACTERISTICS, ORGAN MATCHING AND IMMUNOSUPPRESSION. John Lake, MD University of Minnesota Medical School Minneapolis, Minnesota, USA. The liver is not the kidney!. Kidney Acute rejection leads to shorter graft half-lives

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HEPATITIS C:EFFECTS OF PRE-TRANSPLANT CHARACTERISTICS, ORGAN MATCHING AND IMMUNOSUPPRESSION

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  1. HEPATITIS C:EFFECTS OFPRE-TRANSPLANT CHARACTERISTICS, ORGAN MATCHING AND IMMUNOSUPPRESSION John Lake, MD University of Minnesota Medical School Minneapolis, Minnesota, USA

  2. The liver is not the kidney!

  3. Kidney Acute rejection leads to shorter graft half-lives Chronic allograft nephropathy predicts long-term outcome High CNI levels associated with better outcomes Liver Acute rejection not associated with worse outcomes Chronic rejection rare Higher CNI levels not associated with better outcomes Consequences of Rejection

  4. Impact of Acute Cellular Rejection on Outcome in HCV- Recipients

  5. Impact of Acute Rejection on Patient Survival 0.828 0.749 Relative risk (rej/no rej) = 0.71; P = 0.047.

  6. Impact of Acute Rejection on Patient Survival

  7. US Multicenter Study: 5-Year Patient Survival by Baseline HCV Status HCV- TAC n = 206 n = 210 CyA % P = 0.862 0 Wiesner RH. Transplantation. 1998;66:493-499.

  8. Diagnosis of Rejection in HCV+ Recipients

  9. Consequences of Rejection: Current Paradigms • Recurrent hepatitis C an increasing problem post-tx • Post-tx hepatitis C difficult to differentiate from acute cellular rejection

  10. Consequences of Rejection: Revised Paradigms • Recurrent hepatitis C an increasing problem post-tx • Difficult to determine if alloimmunity is also playing role in post-tx hepatitis C

  11. Incidence of Acute Hepatic Allograft Rejection

  12. 100 Other diagnoses Hepatitis B Hepatitis C 90 Event-Free Survival (%)* 80 70 0 1 2 3 4 Years From Transplant Date Event- Free Rate (%) No. at Risk Cumulative No. of Events Drug Group Yr 0 Yr 1 Yr 2 Yr 3 Yr 4 Yr 0 Yr 1 Yr 2 Yr 3 Yr 4 Yr 0 Yr 1 Yr 2 Yr 3 Yr 4 Hepatitis B 100.0% 85.8 82.6 77.6 75.6 778 639 529 315 200 0 109 132 160 167 Hepatitis C 100.0% 85.8 80.4 76. 6 72.2 3463 2871 2223 1478 815 0 486 660 751 818 Other diagnosis 100.0% 86.0 82.1 78.6 75.7 7429 6234 5215 3812 2567 0 1037 1312 1507 1624 Graft Survival by Pretransplantation Diagnosis *Hepatitis B vs hepatitis C, P = 0.1148; hepatitis C vs other diagnosis, P = 0.0043; hepatitis B vs other diagnosis, P = 0.9206.

  13. Impact of Acute Rejection on Patient Survival

  14. Corticosteroid Treatment • Steroid bolus therapy is associated with a 4- to100-fold increase of HCV RNA • Steroid bolus therapy associated with increased frequency of acute hepatitis and earlier time to recurrence • Higher HCV RNA levels associated with increased histological severity of graft injury/hepatitis Gane EJ. Gastroenterology. 1996;110:167.

  15. Mortality and Steroids

  16. Factors Associated With Increased Rate of Fibrosis in HCV Recipients P Value • Donor age >50 years • Bolus steroids – rejection • OKT3 • Induction with mycophenolic acid • Short duration prednisone • Past interferon failure 0.009 0.04 0.002 0.002 0.0001 0.001 Berenguer et al. Hepatology. 2001;34:407A.

  17. OKT3 Administration as a Predictor of HCV Recurrence % P <0.01 *No episodes of steroid-resistant rejection or no episodes prior to diagnosis of recurrence. Sheiner PA et al. Hepatology. 1995;21:30-34.

  18. US Multicenter Study: 5-Year Patient Survival by Baseline HCV Status HCV+ TAC n = 57 CyA % n = 56 P = 0.041 0 Wiesner RH. Transplantation. 1998;66:493-499.

  19. Immunosuppression for HCV+ Recipients

  20. Consequences of Rejection: Optimizing Immunosuppression Infection, side effects, high cost Over Optimal Under Rejection

  21. Consequences of Rejection: Risk Factors for Rejection • Young age 50 years • Diagnosis of FHF, autoimmune liver disease • Cold ischemic time >15 hours • Normal renal function • Donor/recipient race mismatch • Cyclosporine-based compared to tacrolimus-based immunosuppression

  22. Most Commonly Used Immunosuppressive Agents Maintenance therapy, 2002 • Calcineurin inhibitors • Tacrolimus (87%) • Cyclosporine (10%) • Corticosteroids (90%) • Adjunct agents • Azathioprine (3.6%) • Mycophenolate mofetil (48%) • Sirolimus (7%)

  23. Immunosuppression For HCV- Infected Recipients: Current Paradigms • More immunosuppression “bad” for HCV-infected recipients • Corticosteroids “bad” for HCV-infected recipients

  24. Immunosuppression For HCV- Infected Recipients: Current Paradigms • Change in degree of immunosuppression “bad” for HCV-infected recipients • Corticosteroid “boluses” “bad” for HCV-infected recipients

  25. Consequences of Rejection: Immunosuppression in Liver Donor Recipients LRD 0.15 0.141 0.141 CAD 0.138 0.14 0.129 0.13 0.123 0.123 0.12 0.12 * * 0.11 0.11 0.099 * 0.097 0.097 0.1 0.092 0.091 0.086 0.09 * 0.08 Tacrolimus * 0.07 0.063 Dose 0.057 0.06 0.052 (mg/kg/d) 0.05 0.043 0.04 0.03 0.02 0.01 0 Wk 1 Wk 2 Wk 3 Wk 4 Mo 2 Mo 3 Mo 4 Mo 5 Mo 6 Posttransplant Time Period *P <0.05.

  26. The liver is not the kidney!

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