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    6 6 Presentation Transcript

    • LIVER TRANSPLANTATION FOR HCV DISEASE John R. Lake, M.D Minneapolis, USA
    • 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
    • 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 .
    • 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 Unpublished data.
    • 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.
    • 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%
    • 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%
    • PREDICTORS OF OUTCOME OF TRANSPLANTATION FOR HEPATITIS C
    • 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%)
    • HCV POST TRANSPLANT:DIFFERENT PATTERNS OF RECURRENCE • Minimal liver injury • Chronic HCV • Cholestatic HCV
    • CHOLESTATIC HCV
    • 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
    • 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
    • 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
    • Lack of HCV T cell response in severe HCV (Cholestatic) recurrence
    • 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
    • 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
    • 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)
    • 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?
    • 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)
    • 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
    • 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.
    • 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
    • IMPACT OF ACUTE CELLULAR REJECTION ON OUTCOME
    • 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
    • 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
    • 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.
    • 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.
    • 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.
    • 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.
    • IMPACT OF IMMUNOSUPPRESSIVE AGENTS
    • 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%)
    • IMPACT OF SPECIFIC IMMUNOSUPPRESSIVE AGENTS • Tacrolimus • Cyclosporine • Corticosteroids • Mycophenylate mofetil
    • 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.
    • 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.
    • IMPACT OF SPECIFIC IMMUNOSUPPRESSIVE AGENTS • Tacrolimus • Cyclosporine • Corticosteroids • Mycophenylate mofetil
    • OPTIMAL IMMUNOSUPPRESSION Steroid Withdrawal • Timing? • Withdrawal (when), minimization, avoidance • Assess benefits for the individual patient • One “size” does not fit all
    • 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
    • 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.
    • IMPACT OF SPECIFIC IMMUNOSUPPRESSIVE AGENTS • Tacrolimus • Cyclosporine • Corticosteroids • Mycophenylate mofetil
    • 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.
    • 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
    • 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.
    • 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)
    • 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)
    • LIVER TRANSPLANTATION FOR HCV DISEASE Agents on the Horizon • Everolimus • FTY • FK 778 • New antibodies • Tolerance induction
    • 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
    • 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
    • ANTI-VIRAL THERAPY OF POST- TRANSPLANT HEPATITIS C
    • TREATMENT STATEGIES • Observation • Preemptive Treatment • Treatment of Recurrence – Acute – Chronic
    • 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
    • PREEMPTIVE INTERFERON 180 160 140 120 Sheiner 100 Control 80 Singh 60 Control 40 20 0 HCV RNA Recurrence Survival Rejection
    • 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
    • 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)
    • 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).
    • 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).
    • 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
    • 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
    • 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
    • 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
    • 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