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  1. 1. LIVER TRANSPLANTATION FOR HCV DISEASE John R. Lake, M.D Minneapolis, USA
  2. 2. LIVER TRANSPLANTATION FOR HCV DISEASE OUTLINE • The problem • Predictors of outcome • Impact of acute cellular rejection • Impact of immunosuppression • Impact of anti-viral treatment • Conclusions
  3. 3. HEPATITIS C VIRUS INFECTION Worldwide prevalence C oh en J . S c ie n c e 1 9 9 9 ;2 8 5 :2 6 .
  4. 4. Estimated incidence of HCV in the USA, 1982-1996 20 Cases per 100 000 15 10 HIV Prevention Measures 5 Decline among Decline among transfusion recipients injection-drug users 0 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 Year Centers for Disease Control and Prevention. Unpublished data.
  5. 5. Indications for adult liver transplantation, 1994-1998 Transplant Indication % Cirrhosis 68.2 Hepatitis C 22.9 Alcoholic liver disease 15.8 Cryptogenic 11.4 Autoimmune 4.9 Hepatitis B 4.0 ALD + hepatitis C 7.4 Cholestatic liver disease 16.6 Primary biliary cirrhosis 7.9 Primary sclerosing cholangitis 8.0 n = 12 908 Seaberg EC et al, 1999. Clinical Transplants 1998. Chapter 2.
  6. 6. Liver Transplantation in Europe: Indications Cirrhosis 01/1988 - 12/2001 Primary Biliary : 2952 Others : 357 13% Virus related : 9565 2% Unknown causes : 1851 42% 8% Secondary Biliary : 271 1% Autoimmune : 991 Alcoholic : 6937 4% 30%
  7. 7. Primary Indications of Liver Transplantation for Virus related Cirrhosis in Europe 01/1988 - 12/2001 Virus BCD : 79 Virus BC : 380 1% Other virus : 84 4% 1% Virus B : 2410 Virus BD : 640 25% 7% Virus C : 5972 62%
  8. 8. PREDICTORS OF OUTCOME OF TRANSPLANTATION FOR HEPATITIS C
  9. 9. LIVER TRANSPLANTATION FOR HEPATITIS C Re-infection Center n Re-infection Cleared UCSF 41 39 (95%) 2 (5%) LTD 134 131 (97%) 3 (3%) Paris 69 60 (87%) 9 (13%) Berlin 15 13 (87%) 2 (13%)
  10. 10. HCV POST TRANSPLANT:DIFFERENT PATTERNS OF RECURRENCE • Minimal liver injury • Chronic HCV • Cholestatic HCV
  11. 11. CHOLESTATIC HCV
  12. 12. CHOLESTATIC HCV • D ef in it ion – In cr ea s ed S A P ,G G T w it h b ili.>1 0 0 u m /l – >1 m on t h d u r a t ion – b a lloon in g /ch oles t a s is on b iop s y – v ir a l loa d >1 x1 0 6 – occu r r in g >1 m on t h p os t t r a n s p la n t
  13. 13. 27 89 180 299 502 572 1069 1524 Days post-transplant Pre 9 32 54 72 152 194 243 282 Days post-transplant 26 70 98 168 308 426 Non-Cholestatic Patients Days post-transplant
  14. 14. Pre 61 68 75 148 162 232 442 456 519 Days post-transplant Pre 8 13 21 27 30 72 203 632 Days post-transplant Pre 8 23 37 65 75 83 95 122 Cholestatic Patients Days post-transplant
  15. 15. Lack of HCV T cell response in severe HCV (Cholestatic) recurrence
  16. 16. NON-CHOLESTATIC CHOLESTATIC HCV persistence HCV persistence TH1 response No immune response Cell mediated Escape from immunity Immune-mediated immune tissue damage system Control of viral load Very high viral loads (no clearance) Direct tissue damage Cholestatic hepatitis Immune pressure on HCV No viral mutation viral mutation
  17. 17. HISTOLOGIC SEVERITY OF POST-OLT HEPATITIS C Center n CPH CAH Cirrhosis Norml( (%) (%) (%) %) Paris 60 18 43 1 38 London 130 54 35 8 12 Washington 45 0 74 4 22 Mayo 42 47 23 20 10 LTD (2 year) 47 57 25 12 6
  18. 18. PATIENT SURVIVAL BY DISEASE 100 Cumulative survival (%) chol 80 non B-C HCV 60 metab ALD 40 malig HBV 20 0 0 1 2 3 4 5 Time post-OLT (years)
  19. 19. LIVER TRANSPLANTATION FOR HEPATITIS C Is the Disease Becoming More Aggressive • Is HCV re-infection leading to more aggressive liver disease? • Is HCV re-infection having a greater impact on long term patient and graft survival? • What factors might be responsible for this?
  20. 20. HCV IN ORGAN TRANSPLANT RECIPIENTS Rates of Fibrogenesis • Berenguer, et al analyzed the change in fibrosis score (fibrosis progression/year) post-transplantation as an indicator of disease progression • There was a linear association between change in fibrosis score and time from transplantation, with a median rate of fibrosis progression per year of 0.3 (0.004-2.19/year) • Variables independently associated with post- transplantation progression included year of transplantation (p=0.0001), race (p=0.02), number of methyl-prednisolone boluses(p=0.03), and HCV RNA levels at transplantation (p=0.01)
  21. 21. Pre-OLT characteristics associated with increased mortality and graft loss in HCV- infected recipients Characteristic Patient survival Graft survival RR 95% CI p RR 95% CI p HCV RNA ≥ 1x106 4.3 2.1-8.5 0.0001 3.6 2.0-6.6 0.0001 vEq/ml Non-Caucasian 4.1 1.0-4.3 0.04 2.8 1.5-5.1 0.001 recipient Recipient age (per 1.05 1.02-1.09 0.004 1.05 1.02-1.08 0.004 year) Recip pre-LT ugh 2.0 1.0-4.0 0.04 score > 10
  22. 22. FACTORS ASSOCIATED WITH INCREASED RATE OF FIBROSIS IN HCV RECIPIENTS p value • D on or a ge > 5 0 y ea r s 0.009 • B olu s S t er oid s - r eject ion 0.04 • OK T 3 u s e 0.002 • In d u ct ion w it h 0.002 m y cop h en olic a cid • S h or t d u r a t ion p r ed n is on e 0.0001 • P a s t in t er f er on f a ilu r e 0.001 Berenguer, et al. Hepatology 2001;34:407A.
  23. 23. PATIENT SURVIVAL BY PRE-LT HCV RNA LEVEL 10 0 C m lativ su v al (%) 90 80 e r iv 70 60 50 40 30 u u 20 RA 02 N <. RA . - . 9 N 0204 10 RA . - . 9 N 0509 RA 1 N> 0 0 1 2 3 4 5 T epstOT yas) i o L ( er m
  24. 24. IMPACT OF ACUTE CELLULAR REJECTION ON OUTCOME
  25. 25. INCIDENCE OF ACUTE HEPATIC ALLOGRAFT REJECTION 80 R ) 70 I cid ce of A (% 60 50 Tt l oa 40 Ery al 30 n en 20 10 0 HV C Nn C o HV
  26. 26. IMPACT OF ACUTE REJECTION ON PATIENT SURVIVAL Relative risk of Mortality death Non HCV 0.5 p < 0.007 (steroids) HCV (steroids) 2.9 p < 0.03 HCV (OKT3) 5.4 p < 0.003
  27. 27. Rejection and HCV Recurrence in TAC-Treated Patients HCV Recurrence No HCV Recurrence 100 80 % 60 40 20 0 Overall No Rejection 1 Rejection >1 Rejection Recurrence Episodes Episode Episodes Singh N, et al. Surgery. 1996;119:452-456.
  28. 28. OKT3 Administration as a Predictor of HCV Recurrence 100 No HCV Recurrence 90 HCV Recurrence 80 70 60 % 50 40 30 20 10 0 OKT3 No OKT3* 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.
  29. 29. FACTORS ASSOCIATED WITH INCREASED RATE OF FIBROSIS IN HCV RECIPIENTS p value • Donor age > 50 years 0.009 • Bolus Steroids - rejection 0.04 • OKT3 0.002 • Induction with mycophenolic acid 0.002 • Short duration prednisone • Past interferon failure 0.0001 0.001 Berenguer, et al. Hepatology 2001;34:407A.
  30. 30. CORTICOSTEROID TREATMENT • Steroid bolus therapy is associated with an 4 to100-fold increase of HCV RNA • Steroid bolus therapy is associated an increased frequency of acute hepatitis and earlier time to recurrence • Higher HCV RNA levels are associated with increased histological severity of graft injury/hepatitis Gane EJ. Gastroenterology 1996; 110:167.
  31. 31. IMPACT OF IMMUNOSUPPRESSIVE AGENTS
  32. 32. IMMUNOSUPPRESSIVE AGENTS MOST COMMONLY USED Maintenance Therapy 2001 • Calcineurin inhibitor – Tacrolimus (83%) – Cyclosporine (12%) • Corticosteroids (89%) • Adjunct agents – Azathioprine (3.1%) – Mycophenylate mofetil (48%) – Sirolimus (10%)
  33. 33. IMPACT OF SPECIFIC IMMUNOSUPPRESSIVE AGENTS • Tacrolimus • Cyclosporine • Corticosteroids • Mycophenylate mofetil
  34. 34. US Multicenter Study 5-Year Patient Survival by Baseline HCV Status HCV Positive 100 90 80 n = 57 70 % 60 n = 56 50 40 P = 0.041 30 0 0 6 12 18 24 30 36 42 48 54 Months TAC CyA Wiesner RH. Transplantation. 1998;66:493-499.
  35. 35. US Multicenter Study 5-Year Patient Survival by Baseline HCV Status HCV Negative 100 90 80 n = 206 70 % n = 210 60 50 40 P = 0.862 30 0 0 6 12 18 24 30 36 42 48 54 Months TAC CyA Wiesner RH. Transplantation. 1998;66:493-499.
  36. 36. IMPACT OF SPECIFIC IMMUNOSUPPRESSIVE AGENTS • Tacrolimus • Cyclosporine • Corticosteroids • Mycophenylate mofetil
  37. 37. OPTIMAL IMMUNOSUPPRESSION Steroid Withdrawal • Timing? • Withdrawal (when), minimization, avoidance • Assess benefits for the individual patient • One “size” does not fit all
  38. 38. HCV: STEROID AVOIDANCE Thymo+TCR+MMF TCR+MMF+CS (n=60) (n=59) p 2-yr Surv 82% 83% NS Rejection 23% 31% NS Hep C 62%(29) 73%(33)NS Stage 3-4 10% 21% NS Eason et al Liver Transplantation 7:693, 2001
  39. 39. FACTORS ASSOCIATED WITH INCREASED RATE OF FIBROSIS IN HCV RECIPIENTS p value • Donor age > 50 years 0.009 • Bolus Steroids - rejection 0.04 • OKT3 0.002 • Induction with mycophenolic 0.002 acid • Short duration prednisone 0.0001 • Past interferon failure 0.001 Berenguer, et al. Hepatology 2001;34:407A.
  40. 40. IMPACT OF SPECIFIC IMMUNOSUPPRESSIVE AGENTS • Tacrolimus • Cyclosporine • Corticosteroids • Mycophenylate mofetil
  41. 41. MMF AND HEPATITIS C: SALVE ON A WOUND OR GASOLINE ON FIRE ? (Charlton 2002) • Only two large controlled randomized trials in HCV positive patients • No effect on the incidence of rejection, survival and severity of HCV recurrence Wiesner et al. Liver Transplant 7:442, 2001. Jain et al. Liver Transplant 8: 40, 2002.
  42. 42. MMF AND HCV RECURRENCE MMF AZA (n=108) (n=110) p- value Rej or Graft loss 30.6 41.4 0.04 Graft Loss 9.4 16.1 NS Hepatitis C (6 mo) 18.5 29.1 NS Rejction 30.6 41.4 NS
  43. 43. FACTORS ASSOCIATED WITH INCREASED RATE OF FIBROSIS IN HCV RECIPIENTS p value • Donor age > 50 years 0.009 • Bolus Steroids - rejection 0.04 • OKT3 0.002 • Induction with mycophenolic acid 0.002 • Short duration prednisone • Past interferon failure 0.0001 0.001 Berenguer, et al. Hepatology 2001;34:407A.
  44. 44. EFFECTIVENESS OF MMF IN THE LONG-TERM IN HCV POSITIVE PATIENTS AFTER OLT Berlin, 40 patients, follow-up 24 months Histological course HCV-RNA blood levels: No changes in viral load measured 1,6 by PCR during MMF treatment 1,4 In fla m m a tio n 1,2 1 F ib ro s is Treatment of side effects: Stage 0,8 Reduction of nephrotoxic side 0,6 effects (n=3) with normalization 0,4 of creatinine/ BUN 0,2 0 Switch from FK506 to MMF due prior MMF after MMF (24 months) to neurotoxic side-effects with improved symptoms (n=1)
  45. 45. MMF OUTCOMES No MMF Low-dose MMF High-Dose MMF ACR RS ACR RS (96) (%) (8) (3) (13) (5) P Grade None (0) (22) (0) (33) (0) (40) Inter (1-2) (54) (50) (33) (92) (60) .07 Sever(3-4) (22) (50) (33) (8) (0) Stage No fib(0) (43) (0) (33) (23) (80) Inter (1-2) (33) (63) (67) (77) (20) .01 Sever(3-4) (24) (37) (0) (0) (0)
  46. 46. LIVER TRANSPLANTATION FOR HCV DISEASE Agents on the Horizon • Everolimus • FTY • FK 778 • New antibodies • Tolerance induction
  47. 47. IMMUNOSUPPRESSION FOR HCV- INFECTED RECIPIENTS Revised paradigms • Recurrent hepatitis C is an increasing problem post- transplant • It is difficult to determine if allo-immunity is also playing a role in post-tx hepatitis C • Change in the degree of immunosuppression is “bad” for HCV-infected recipients • Cortico-steroid “boluses” are “bad” for HCV- infected recipients
  48. 48. OPTIMAL IMMUNOSUPPRESSION HEPATITIS C • Don’t make major changes! • Steroids: either avoid or do not taper • MMF: use or don’t use • Avoid antibody induction • Avoid treating rejection with steroid boluses; avoid antibody therapy
  49. 49. ANTI-VIRAL THERAPY OF POST- TRANSPLANT HEPATITIS C
  50. 50. TREATMENT STATEGIES • Observation • Preemptive Treatment • Treatment of Recurrence – Acute – Chronic
  51. 51. INTERFERON FOR ESTABLISHED DISEASE 50 40 36 30 28 ETR 20 20 SVR 13 12 10 2.5 0 0 0 0 0 Wright n=18 Feray n=16 Gane n=28 Cotler n=12 Shakil n=40
  52. 52. PREEMPTIVE INTERFERON 180 160 140 120 Sheiner 100 Control 80 Singh 60 Control 40 20 0 HCV RNA Recurrence Survival Rejection
  53. 53. POST-TRANSPLANT HEPATITIS C Interferon and ribavirin 60 50 40 30 ETR SVR 20 10 0 Bizzilion Bellati Zamboni Ahmad Davis Alberti Samuel n=20 n=122 n=45 n=20 n=54 n=18 n=28
  54. 54. 40-kDa branched PEG-IFN: Interferon 3 MIU TIW Sustained therapeutic 14 M T W T F S S serum concentrations over IFN (U/mL) 12 10 a one-week period 8 6 4 Nieforth et al, Clin Pharmacol Ther 1996; 2 59:636-46. 0 Xu J et al, Hepatology 1998; 25 50 75 100 125 150 Time (hours over one week) 5-kDa linear PEG-IFN α-2a 40-kDa branched PEG-IFN α-2a once weekly once weekly 1.8 1.6 M T W T F S S 1.4 PEG-IFN (ng/ml) 25 M T W T F S S 1.2 20 1 15 0.8 0.6 10 0.4 5 0.2 0 0 0 25 50 75 100 125 150 0 25 50 75 100 125 150 Time (hours over one week) Time (hours over one week)
  55. 55. PEG-IFN α-2a Recurrent HCV post-OLT 60 HCV RNA 2-log drop only HCV RNA Negative 50% Response (%) 50 41% 40 37% 41% 30 31% 20 10 16% 0 Week 4 Week 12 Week 24 Riely C et al, Am J Transplant 2001; 1 (Suppl 1):158 (A89).
  56. 56. PEG-IFN α-2a Recurrent HCV post-OLT Adverse event PEG-IFN α-2a Untreated Fatigue 45 14 Nausea 30 24 Diarrhea 20 14 Pyrexia 30 5 Abd pain 15 14 Headache 25 5 Riely C et al, Am J Transplant 2001; 1 (Suppl 1):158 (A89).
  57. 57. SUSTAINED VIROLOGIC RESPONSE & GENOTYPE PEG-IFN α-2a + ribavirin PEG-IFN α-2a + placebo PEG-IFN α-2a + RBV IFN α-2b + RBV p = 0.001 p = 0.001 p = 0.054 p = 0.008 80 p = 0.001 p = 0.016 76% Patients (%) 70 60 61% 50 46% 45% 40 37% n = 140 30 n = 145 21% n = 298 20 n = 285 n = 69 10 n = 145 0 Genotype 1 Genotype 2, 3 Fried MW et al, NEJM, 2002
  58. 58. POST-TRANSPLANT HEPATITIS C Pegylated interferon and ribavirin 100 90 80 70 60 50 40 30 HCV RNA (-) 20 10 0 Chicago Mayo Miami Omaha n=10 Scott n=33 n=31 n=23
  59. 59. HCV IN ORGAN TRANSPLANT RECIPIENTS HCV Treatment • Using standard dose interferon, sustained response rates are poor, significant risk of rejection in non-liver recipients • Pre-emptive treatment is difficult but may yield the best chance to impact post-transplant liver disease • Newer regimens, i.e. with pegylated interferons and/or ribavirin will likely lead to better results
  60. 60. TREATMENT OF RECURRENT HCV POST-OLT • Sustained virologic and histologic data with pegylated IFN are forthcoming • Studies of PEG-IFN + ribavirin represent the future • True anti-viral agents are sorely needed
  61. 61. CHRONIC HEPATITIS C Advances in therapy 100 ? S u s t a in ed v ir ologic r es p on s e r a t e ( %) ? P eg in t er f er on + r ib a v ir in 50 IF N + r ib a v ir in eg in t er f er on P ( 1 2 m on t h s ) ( 1 2 m on t h s ) ? IF N ( 1 2 m on t h s ) ? IF N ( 6 m on t h s ) N o t r ea t m en t 1991 1998 2000

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