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D. Samuel

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    HBV_Transplantation hépatique.pdf HBV_Transplantation hépatique.pdf Presentation Transcript

    • LIVER TRANSPLANTATION IN VIRAL HEPATITIS B Didier SAMUEL, M.D. Professor of Hepatology CENTRE HEPATOBILIAIRE INSERM PARIS XI UNIT 785 HOPITAL PAUL BROUSSE VILLEJUIF, FRANCE C.H.B.
    • Evolution of Survival After Liver Transplant for HBV-Related Liver Disease 100 ERA 1 (1987–1991) P<0.01 90 Survival (%) 80 Other 70 HBV 60 50 0 1 2 3 4 5 Time (yr) 100 ERA 2 (1992–1996) 100 ERA 3 (1997–2002) P=0.19 P=0.14 90 90 HBV Other Survival (%) Survival (%) 80 80 Other 70 HBV 70 60 60 50 50 0 1 2 3 4 5 0 1 2 3 4 5 Time (yr) Time (yr) Kim WR et al. Liver Transpl. 2004;10:968
    • Prophylaxis of HBV Infection PosttranplantationMajor improvements have been made in prevention ofHBV infection in past 15 yrBefore transplantation– Lamivudine or adefovirAfter transplantation– Anti-hepatitis B immunoglobulins (HBIG)– Lamivudine monoprophylaxis– Combination HBIG + lamivudine
    • Long-Term Prophylaxis of HBV Infection Posttransplantation Questions• Is prophylaxis still necessary at long term?• What is optimal dosage of HBIG?• What is optimal route of HBIG and for what duration?• Is it possible to stop HBIG administration and in whom?• Which antiviral to be used after transplantation?
    • Long-Term Use of IV HBIG AimHigh doses during anhepatic phase, then duringfirst wk– Aim Make serum HBsAg negative Obtain protective anti-HBs titer– Maintain protective anti-HBs titer Effective in FHF, HDV-C Less effective in nonreplicative HBV-C - Possible low replication detected by PCR Insufficient in replicative HBV-C
    • HBV Recurrence According to Initial Liver DiseaseD. Samuel et al. NEJM 1993;329:1842-7 C.H.B.
    • HBV Recurrence According to HBV ProphylaxisD. Samuel et al. NEJM 1993;329:1842-7 C.H.B.
    • Survival In Relationship with Type of HBV ProphylaxisD. Samuel et al. NEJM 1993;329:1842-7 C.H.B.
    • Actuarial HBV Recurrence Rate − Hôpital Paul Brousse: 1986−2000 284 Patients 100 Risk of Recurrence (%) 80 60 40 25.4 21.9 21.9 24.2 (177) (168) (146) (47) 15.3 20 (205) 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (yr)Roche B et al. Hepatology. 2003;38:86
    • Actuarial HBV Recurrence Rate in Relation to Initial Liver Disease − Hôpital Paul Brousse: 1986−2000 100 284 Patients Risk of Recurrence (%) 80 60 56.5 54.4 49.4 49.4 HBV-C 41.8 37.5 40 FHD 25.0 25.0 25.0 25.0 20 13.5 13.5 15.3 15.3 5.8 HDV-C 0 FHB 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (yr)HBV-C = HBV cirrhosis; FHD = fulminant hepatitis B-Delta; HDV-C = HDV cirrhosis;FHB = fulminant hepatitis BRoche B et al. Hepatology. 2003;38:86
    • Lamivudine Monoprophylaxis Posttransplantation HBV Reactivation Due to YMDD Variant 100 80 No Immunoprophylaxis (n=67) % HBsAg (+) 60 Lamivudine (n=42) 40 Long-term HBIG (n=209) 20 N=28 N=39 N=34 N=40 0 12 24 36 48 60 Time (mo)Perrillo RP et al. Hepatology. 2001;33:424
    • Lamivudine MonoprophylaxisPatients remained HBsAg positive after liver transplantProgressive decline of HBsAg1Rate of HBV reinfection– Related to HBV DNA level before liver transplant– Related to treatment duration– Increased with time posttransplantHBV reinfection due to YMDD HBV mutantQuestion of long-term compliance and risk of reinfection1. Grellier L et al. Lancet. 1996;348:1212 [published correction in Lancet. 1997;349:364]
    • Adefovir Monoprophylaxis Recurrence of HbsAg or Serum HBV DNA Following On-Study Liver Transplantation Marker Concomitant HBIG No HBIG (n=34) (n=23) HBsAg Confirmed* 0 (0%) 0 (0%) First test was only positive† 2 (6%) 2 (9%) Serum HBV DNA >1000 copies/mL Confirmed*‡ 2 (6%) 0 (0%) Single positive test§ 4 (12%) 3 (13%) No short-term recurrence, no long-term data available*2 consecutive positive tests†HBsAg was detected on only first test between days 4 and 67 posttransplantation. 2 patients had no further follow-up,and 2 patients had subsequent negative tests over 2 (to day 239) and 2 visits (to day 667)‡In these 2 patients, the first 2 tests posttransplantation detected serum HBV DNA (maximum 32,084 and 29,672copies/mL), and subsequently, serum HBV DNA was undetectable on 3 (to day 309) and 7 (to day 528) measurements§Maximum titer among 7 tests was 3055 copies/mL. 4 patients subsequently had undetectable serum HBV DNA(measured over next 25–211 days); 3 patients did not have further laboratory follow-upSchiff E et al. Liver Transpl. 2007;13:349
    • Posttransplant Combination HBIG + Lamivudine: RationaleLower rate of escape mutation due to pressure on 2different regions in HBV genome– PreS/S region for HBIG– YMDD region of polymerase gene for lamivudinePossible to reduce HBIG amount and overall cost
    • Low-Dose HBIG + Lamivudine• 147 patients• Pretransplant • LAM if HBV DNA (+) (80% pts) 0.5 - Proportion of Patients With• Posttransplant • LAM + HBIG IM 400–800 IU daily × 7 0.4 - HBV Recurrence days 0.3 - • LAM + HBIG IM 400/800 IU monthly• HBV recurrence: 4% at 5 yr 0.2 -• 5 pts with HBV recurrence • All YMDD HBV 0.1 - • ADV in all, 1 death from liver failure• Factor independently associated with 0.0 - I I I I HBV recurrence 2 4 6 8 • HBV DNA prior LAM Time Posttransplant (yr) Number 147 124 89 56 14 at risk Gane EJ et al. Gastroenterology. 2007;132:931
    • Long-Term Anti-HBs Titers in Patients Receiving Low-Dose HBIG + Lamivudine Plasma (anti-HBs) Titers at 1, 3, and 12 mo Posttransplant (Horizontal Bars Demonstrate Median Values) 10000 – 1 mo Plasma [anti-HBs] Titer 1000 – 3 mo 12 mo 100 – 10 – 1– 1 mo 3 mo 12 mo Timepoint PosttransplantGane EJ et al. Gastroenterology. 2007;132:931
    • HBIG + Lamivudine vs Lamivudine LAM + HBIG: 114 pts LAM: 51 ptsHBV DNA >105 at LT: Recurrence 88% in the LAM group vs 28% in combined groupHBV DNA <105 at LT: Recurrence 18% in the LAM group vs 8% in combined group Zheng S et al. Liver Transplant. 2006;12:253
    • HBV Recurrence in Relation to Pretransplant PCR HBV DNA LevelLamivudine Monoprophylaxis Lamivudine + HBIG ProphylaxisMarzano A et al. Liver Transpl. 2005;11:402
    • HBV Recurrence In Patients Receiving HBIG Monoprophylaxis vs Combined HBIG + Antiviral Paul Brousse 1995-2005 Factors independently associated with HBV recurrence: HBV DNA at LT> 100 000 copies/ml HCC at LT HBIG monprophylaxis Faria Gastroenterology 2008 in press
    • HBV Recurrence In Patients with and without HCC Paul Brousse 1995-2005Faria Gastroenterology 2008 In press
    • HBV Recurrence Is Associated with HCC Recurrence Paul Brousse 1995-2005Faria Gastroenterology 2008 In press
    • Prophylaxis Protocol Place of HBIG in Combination? HBIG at start is essential – Immediately makes HBsAg negative – Protects graft from immediate reinfection IV administration important at start – Good results also with IM immediately1 – Can be replaced safely by IM administration at medium term2 High doses of HBIG – Important at start – Dose related to HBV DNA level at liver transplant3 – Lower doses can be used at medium term1. Gane EJ et al. Gastroenterology. 2007;132:931; 2. Han SH et al. Liver Transpl. 2003;9:182; 3.Dickson RC et al. Liver Transpl. 2006;12:124
    • Prophylaxis Protocol: Which Antiviral in Combination? Almost all studies have used lamivudine In cases of pretransplant, HBV strain resistant to lamivudine – Cases of severe recurrence despite HBIG + LAM1,2 – Adefovir should be added to HBIG Adefovir can be used in first line3 – Risk of escape mutation lower – Doses to be adapted in case of impaired renal clearance No reported experience with entecavir1. Rosenau J et al. J Hepatol. 2001;34:895; 2. Roche B et al. Hepatology. 2003;38:86;3. Schiff E et al. Liver Transpl. 2007;13:349
    • Discontinuation of HBIG? Arguments for discontinuation – High cost – Constraining, high degree of compliance – Few cases of HBV reinfection after 3 yr posttransplant Arguments against discontinuation – Cases of long-term recurrence after discontinuation – Residual HBV DNA in >50% of patients at 10 yr1,2 – Difficult to identify patients who have cleared virus Open questions – Who to select? – When to stop? Probable consensus – Maintain prophylaxis (antiviral, vaccine)Roche B et al. Hepatology. 2003;38:86; Hussain M et al. Liver Transpl. 2007;13:1137
    • Discontinuation of HBIG Replacement by Lamivudine LT Recipients 29 Patients Total HBIG + LAM for 1 month Randomization HBIG + LAM LAM N=15 N=14 18 mos N=6 HBIG + LAM LAM N=15 N=14 83 mos 83 mos 83 mos HBIG + LAM (N=9) LAM (N=6) LAM (N=14 ) HBV Recurrent (N=1) HBV Recurrence (N=2) HBV Recurrence (N=1)Buti M et al. Transplantation. 2007;84;650
    • Discontinuation of HBIG Replacement by Lamivudine 21 patients stopped HBIG – 18 patients stopped after 11 months – 3 patients stopped after 15 days All on lamivudine 2 recurrence (actuarial rate of 3 year HBV recurrence 9% after HBIG withdrawal), one following lamivudine discontinuation Both recurrence YMDD 3 additional patients with transient HBV DNAWong SN et al. Liver Transplant. 2007;13:374
    • HBV Vaccination After Discontinuation of HBIG or LAM62% Ab response 80% Ab responseSanchez-Fueyo A et al. Hepatology. 2000;31:496 Bienzle U et al. Hepatology. 2003;38:811 17% Ab response Angelico M et al. Hepatology. 2002;35:176 4/50 Responders Lo CM et al. J Hepatol. 2005;43:283
    • Efficacy of Pre S Vaccine in HBV Transplant Patients on Lamivudine Prophylaxis 1000 - Anti-HBs Titer (mIU/mL) 100 - 10 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 1- 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 vaccination vaccination Time (mo)Lo CM et al. Am J Transplant. 2007;7:434
    • Vaccine After TransplantationGreat discordance in results– Results of Berlin not confirmed by others and in larger series– Poor tolerance to Berlin vaccine– Durability of response?– Response probably more frequent in FHB patients (spontaneous seroconversion boosted by vaccine?)How to identify patients susceptible to respond to vaccine?
    • Strategies for Prevention of HBV Recurrence 40% 36 36Recurrence Rate 30% 33 33 Overall HBV 20% 18 18 10% 66 0% Lamivudine Low-Dose High-Dose Lamivudine (mono) HBIG HBIG + HBIG Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120
    • Future Strategies for Prevention of HBV Recurrence HBIG + LAM/ADV HBIG IM + LAM/ADVHBIG + LAM/ADV HBIG + LAM Vaccination Nucleoside monoprophylaxis Nucleotide monoprophylaxis Nucleoside + nucleotideHBIGInductionNucleoside ± nucleotideLiver Transplant 0.5–2 yr Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120
    • ConclusionMajor improvement with Combination HBIG + antiviralQuestions :– Dose of HBIG taking into account viral parameters– Ideal antiviral:Good tolerance, low resistance profiles– Antiviral combination alone?– Long-term prophylaxis mandatory Possibibility to stop HBIG ? Yes in selected groups but not mandatory; best long-term concept: low dose HBIG + antiviral
    • NEW STRATEGIES IN PREVENTION AND TREATMENT TO MINIMIZEPOST-TRANSPLANT HCV RECURRENCE Professor Didier SAMUEL Centre Hépatobiliaire, Inserm Unit 785, Paris XI University Hopital Paul Brousse, Villejuif, France C.H.B.
    • 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 VIRALRECURRENCE HEPATITIS < 10 % DEATH Adapted From McCaughan Adapted From McCaughan 50%
    • Cumulative probability of developing HCV-graft cirrhosis 50% Berenguer,2002 Sanchez-Fueyo,2002Prevalence of Cirrhosis 40% Prieto,1999 Gane,1996 30% Feray,1999 Neumann,2002 20% Neumann, 2004 10% IC patient Poynard,1997 0% 0 1 2 3 4 5 Years Posttransplant Adapted from Gane , Berenguer
    • Late-onset severe Early exponential increase HCV-liver disease followed by stabilization N=57 with initial benign (n=183) evolution (F0-1 in first bx) Late onset F: 20/57 (34%) 3 4 2,5Fibrosis Stage 2 3 0.08 1,5 0.25 2 1 1.2 0,5 1 0 1 3 5 7 10 0 1 3 5 7 Duration of infection (years) Duration of infection (years) Neumann, J hepatol 2004 Berenguer et al, Liver transpl 2003
    • PATIENT SURVIVAL IN LIVER TRANSPLANT PATIENTS WITH HCV CIRRHOSIS ON THE GRAFT Patients Survival After Cirrhosis Patient Survival After Graft Cirrhosis on the Graft First DecompensationM Berenguer et al. Hepatology 2000; 32:852 C.H.B.
    • PATHOBIOLOGY of CHOLESTATIC HCV Immune responseImmunosuppression •Absent CD4 responses •Stable quasispecies (High level) TH-2 like cytokine HCV load response (IL-10 & IL-4) Cytopathic allograft damage IMMUNOSUPPRESSION MARKEDLY INHIBITING THE IMMUNE RESPONSE WINS McCaughan and Zekry J Hepatol 2004; Samuel EASL report J Hepatol 2006
    • Pathobiology of Chronic HCV Post LTImmunosuppression - The immune response + - HCV load Inflammation + γ IFN-γ related genes α IFN-α response Stimulation of the IMMUNE RESPONSE by more HCV WINS Proliferation Acute Rejection Apoptosis Inflammation Fibrosis Stress Response McCaughan and Zekry J.Hepatol 2004, EASL Report J Hepatol 2006
    • DYNAMIC OF HCV REPLICATION IN THE FIRST HOURS AFTER LT Garcia-Retortillo Hepatology 2002: 35: 680 C.H.B.
    • Cholestatic HCV : Intrahepatic Viral Load ( X106 m-RNA copies / ug RNA) Intrahepatic viral load 1.4 * * P = 0.005 Chol vs AR, CHI & CHC 1.2 1.0 0.8 0.6 0.4 0.2 0 Chol AR CHI CHCChol = Cholestatic HCV post transplantAR = Acute rejection + HCVCHI = HCV post transplantCHC = HCV pre transplant Zekry et al. Liver Transplant 2002;8:292
    • Relation Between Histology and Liver HCV RNA HCV RNA Log (CU) CU) p < 0.03HCV RNA (CU) CU) ** p=0.01 1000 220 • ** 200 • 180 100 • • • • • • 160 • • 140 • • • • • 120 2 7 10 • • 15 • • 100 8 • • • • 80 • 60 34 1 • 40 • 20 0 .1 lobular CAH cholestasis Normal Acute hepatitis CAH hepatitis Decrease of HCV RNA with progression to CAH High HCV RNA at time of acute hepatitis High initial HCV RNA related with more severe CAH Di Martino et al. Hepatology 1997 C.H.B.
    • Prediction of survival based on first year fibrosis Survival (%)10050 F at one year: 0 (n=68)0 1-2 (n=76) 3-4 (n=39) 0 1 2 3 4 5 6 7 8 9 10 11 Neumann et al, J Hepatol 04
    • HPVG, Fibrosis Stage 1 Year in HCV +ve Transplant Patients and 0utcomeBlasco Hepatology 2006; 43: 492-499
    • HPVG and Fibrosis Stage (Ishak) in HCV +ve Transplant PatientsSamonakis Liver Transplant 2007; 13: 1305-1311
    • Donor and Host Factors of HCV Recurrence C.H.B.
    • EFFECT OF DONOR AGE ON THE DEVELOPMENT OF HCV GRAFT FIBROSIS AND CIRRHOSIS Cirrhosis and donor age Fibrosis and donor age Wali et al. Gut 2002; 51: 248-252 C.H.B.Berenguer Hepatology 2002; 36: 202-210
    • Relation Donor Age, HCV and Graft FibrosisRifai J Hepatol 2004 C.H.B.
    • 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
    • Graft Survival According to Donor Age in HCV and ALD Patients Mutimer Transplantation 2006; 81: 7-14
    • HCV RECURRENCE IN LIVING DONOR TRANSPLANTATIONDonor Age: 47 ( 13-86) in CDLT vs 31 ( 19-58) LDLT p<0.01Cya : 59% in CDLT vs 14% LDLT p<0.01Biliary Complications: 22% in CDLT vs 72% in LDLT p<0.01 Garcia Retortillo Hepatology 2004; 40: 699-707 C.H.B.
    • HCV Recurrence in Split, CDLT and LDLT Histologic recurrenceLDLT Grade and stage of hepatitis C LDLT Humar AJT 2005; 5: 399-405
    • Patient Survival after LDLT in HCV PatientsTakada Transplantation 2006; 81: 350-354
    • Impact of Immunosuppression on HCV Recurrence C.H.B.
    • STEROIDS AND HCV• Controversial role – Increase viral load (Fong Gastro 1994, Gane Gastro 1996) – Boluses of steroids deleterious (Berenguer J Hepatol 2000) – But rapid withdrawal deleterious (Berenguer Hepatology 2003, McCaughan J Hepatol 2004) » Immune rebound? – Immunosuppression without steroids: not yet proven beneficial C.H.B.
    • HCV Recurrence in Patients Without Steroids No différence in Patient and graft survival at 1 year Waiting for histological analysis long-termKlintmalm Liver Transplant 2007
    • Rapid Steroid Withdrawal Deleterious for Hep C Recurrence Group A: Rapid Steroid Withdrawal D91 Group B: Slow Decrease in steroids, Stop at M25 % patients without severe FibrosisVivarelli J Hepatol 2007
    • HCV Recurrence , Cyclosporine, Tacrolimus• Controversial Role of Tacrolimus and Cyclosporine• Tacrolimus Deleterious? Not proven: – Absence of CyA independently associated with severe fibrosis (Berenguer Hepatology 2003) – More rapid reinfection with tacrolimus (Levy Transplantation 2004, Samuel ATC 2005, Berenguer 2006) – Better efficacy of IFN in patients treated with CyA ( Calmus AASLD 2007) – Antiviral effect of de la CyA in replicon system (Watashi Hepatology 2003; 38: 1282-1288). C.H.B.
    • HCV and Calcineurine InhibitorsBerenguer Liver Transplant 2006
    • MMF and HEPC• Induction with MMF associated with more severe recurrence? (Berenguer J Hepatol 2000, M Berenguer Hepatology 2003; 38:34 - 41)• What is sure – No antiviral action – Deleterious or favourable impact unknown C.H.B.
    • MMF And Hep C Decrease of CNI And introduction of MMF: • Increase viral load • Decrease fibrosis • Decrease ALTBahra AJT 2005; 5: 406-411
    • Overall Role of IS 1999-2000 2001-2003 PDuration Pred (d) 249 350 <.0001Bolus MP 21 4.5 .002 Berenguer> Is double (%) 25 10 .001 J Hepatol 2006IFN preTH (%) 9 30 .006Donor age (yr) 51 57 .07
    • 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.
    • ANTIVIRAL TREATMENT PRIOR LT LTTreatment 48 Wks Follow-up Follow up Treatment Follow-up 12-16 week C.H.B
    • Antiviral Treatment In HCV+ve Cirrhotic Patients Before Liver TransplantationKuo, Terrault AJT 2006; 6: 449-458
    • 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 » Low increase therapy • IFN (1.5MU X3/wk to 3MU after wk 2) + ribavirin (600 mg/d to 800mg/d after wk 4) » 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.
    • ANTIVIRAL TREATMENT BEFORE TRANSPLANTATION• Interferon + Ribavirin before LT – 30 HCV Cirrhotic pts; Child A: 15, Child BC: 15; Genotype 1b: 25 » IFN 3MU/day + Ribavirin 800 mg/day until LT » 9 (30%) virologic response » 11 patients required filgrastim and 8 required EPO » No change in LFTs » Factors of response: low viral load, low ALT, non-1 genotype » After LT: • 6/9 responders remained HCV RNA Neg after LT, • 3 relapsed Forns et al J Hepatol 2003 C.H.B.
    • TREATMENT PRE-LTauteurs Patients Child treatment Virologic Response SVR Tolérance during trt Post-LTForns 30 A 50% INF 3M/j 9 (30%) 6/30 Baisse INF(2003) (Délai pré- B 43% +RBV 800 (20%) 60%, riba TH 4 mois) 23% C 7% Durée Facteurs réponse: G1:83% moyenne: charge virale pré- Arrêt 20% Pts exclus 12 sem trt, Sepsis: 2 40% (2-33 sem) Diminution charge Insuf virale de 2 log sem 4 hépatique: 4Carrion 51 Meld α Pegα2a 15 (29%) 10/51 Risque (2008) G1:80% 11 µ 180µg/sem (20%) infectieux +RBV augmenté par Factors response: G trt (NS) 51 0,8-1g/j non 1, contrôles Durée response virologic at moyenne: wk4 15 sem C.H.B
    • ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION• Treatment in Child A patients waiting for LT – Group of patients with HCC on Child A cirrhosis – Child B patients• There is place for treatment with the increased waiting time• However: – Is it possible to delay LT to achieve SVR? – Balance between the aim to achieve SVR and the risk of hepatic deterioration or HCC growth – Treatment until LT with virologic response without waiting for SVR? C.H.B.
    • ANTIVIRAL TREATMENT DURING TRANSPLANTATION HYPERIMMUNE ANTI-HCV INMUNOGLOBULINS (HCIG)• Polyclonal HCIG (Davis Liver Transplant 2005) – RCT: » HCIG 75 mg/kg 17 infusions on 14 weeks » HCIG 200 mg/Kg 17 Infusions on 14 weeks » Placebo • Decrease of ALT, No effect on HCV RNA – Monoclonal HCV AbXTL 68 (Schiano Liver Transplant 2006) » - 2.4 log HCV RNA decrease in 240 mg group vs - 1.5 log in placebo at d 2, no difference at d 7 » Significant increase of anti-E2 at d 7 in 240 mg group C.H.B.
    • PRE-EMPTIVE TREATMENT OF HCV RECURENCE AFTER TRANSPLANTATION– In the first post-transplant weeks: » Low viral load » Risk of rejection high • Frequent presence of acute rejection and hepatitis on the same liver biopsy during the first month » High level of Immunosuppressive treatment » Risk of poor hematological tolerance +++: • Severe anemia, leucopenia and thrombocytopenia • Patients are anemic before treatment » Septic and surgical complications frequent C.H.B.
    • Preemptive Antiviral Treatment In HCV+ve Liver Transplant PatientsKuo, Terrault AJT 2006; 6: 449-458
    • MEAN HCV VIRAL LOAD IN LIVER TRANSPLANT PATIENTS TREATED PREEMPTIVELY WITH PEGIFN ALPHA 2A SVR: 8%Chalasani Hepatology 2005; 41: 289-298
    • PREEMPTIVE TREATMENT IN IN HCV LIVER TRANSPLANT PATIENTS51/124 Patients eligible, 44 Received one dose of treatment 6/124 (5%) achieved SVR Adherence to Treatment ETVR and SVRShergill AJT 2005; 5: 118-124
    • MEAN HCV VIRAL LOAD IN LIVER TRANSPLANT PATIENTS TREATED WITH PEGIFN ALPHA 2A SVR : 8%Chalasani Hepatology 2005; 41: 289-298
    • TREATMENT INTERFERON-RIBAVIRINE AFTER TRANSPLANTATION Pts Bioch HCV Authors Treatment response RNA SVR (N) (%) Neg IFN 3MU x 3 / week + 48 % Bizollon Ribavirine(6 M) 21 100% NDHepatology 1997 then Rbv(6 M) 24% Samuel INF 3MU x 3 / wks + Ribavirine(12 M) 28 ND 32% 21.4% Gastro 2003 Gopal INF 3MU x 3 / wks + Ribavirine(1-17 M) 12 75% 50% 8.3%Liver Transp 01 Lavezzo IFN 3MUX3/wks + Rbv 33% 22% (6M) (6 vs 12 Mths) 57 ND J Hepatol 02 23% 17%(12M Menon IFN 3MUX3/weeks + rbv (1 year) 26 42% 35% 30%Liver Transp 02 Shakil IFN 3MUX3/weeks+ RBV ( 1 year) 38 18% NA 5% Hepatol 02
    • KINETIC OF HCV RNA ACCORDING TO VIROLOGIC RESPONSE IN HCV POSITIVE TRANSPLANT PATIENTSCastells J Hepatol 2005; 43: 53-59
    • Treatment with PEG Interferon + Ribavirine • 20 patients treated With Peg IFN (0.5µg/Kg to 1 µg/Kg) + Ribavirin 400 to 800 mg/d) • 80% infected with genotype 1 • 4 withdrawn • 13 required doses reduction of ribavirin due to anemia • End of treatment virologic response 65% • SVR: 9/20: 45% Dumortier J Hepatol 2004 C.H.B.
    • Treatment with PEG Interferon + Ribavirine27 patients mild Hepatitis C (F1-F2): SVR: 48%27 Patients with severe hepatitis C(F3-F4) , cholestatic hepatitis C: SVR: 18%(1/12 Cholestatic hepatitis, 4/15 F3-4 Carrion Gastroenterology 2007 C.H.B.
    • Histological Outcome in Relation withVirological Response to PEGIFN+ Ribavirine Variables associated with Histological improvement: EVR, BR, SVRCarrion Gastroenterology 2007 C.H.B.
    • Histological Outcome and HPVG ChangeCarrion Gastroenterology 2007 C.H.B.
    • Adverse Events During PegIFN + RBVCarrion Gastroenterology 2007 C.H.B.
    • Treatment with PEG Interferon + Ribavirine• Transpeg Study: – 100 patients – Peg IFN alpha 90 µg/wk + Ribavirin 600 mg/d then increased to PegIFN 180 µg/wk + Ribavirin 100 mg/d for one year – Randomisation at M12 placebo vs RBV maintainance• At Week 52, 60/97 (62%) patients had a virologic response by ITT;75 % by per-protocol (PP).• At week 78, SVR: 34% Genotype 1- 4, 75% Genotype 2-3• 37% Use of EPO Calmus, Samuel AASLD 2006 C.H.B.
    • FACTEURS PREDICTIFS DE REPONSE AU TRAITEMENT Facteurs significatifs en analyse univariée, non significatifs En analyse multivariée. Sharma P, et al. liver Transpl 2007;13:1100-1108 C.H.B
    • 1 Year and Long Term Histological Outcome after Treatment In Relation With Initial Stage of Fibrosis20% of F3-F4 patients died or were retransplanted after treatment vs 1% of F1-F2Roche Liver Transplantation 2008 In Press C.H.B
    • Predictive Factors for Response To IFN in Genotype 1 Transplant Patients • 67 Patients • EOT virological response: 45 % • SVR: 33% • Predictive factors of response: – At baseline and on treatment: » Peg IFN vs standard IFN » Early virological response » EPO useBerenguer Liver Transplant 2006 C.H.B.
    • Tolerance to Treatment• The tolerance is poor• 40-80% rate of doses reduction• 40-50% discontinuation rate• Anaemia++ is the first cause of discontinuation• EPO is required in many cases C.H.B.
    • Tolerance to Treatment: Risk of Rejection• Risk of Rejection controversial: 0-35% after IFN alone (Gane Hepatology 98, Wright Hepatology 94, Feray Hepatology 95)• 5% in 2 randomized studies(4%) (Samuel Gastro 03, Chalasani Hepatol 05 )• 25-35% in non randomized studie, in patients treated with IFN, PEG IFN alone or with Ribavirine (Saab Liver Transpl04, Stravitz Liver Transplant 04, Dumortier J Hepatol 04)• Risk of rejection not dependent of HCV RNA persistence• Differences may be due to: – Underdiagnosed in NR patients with high LFTs – Different type and level of immunosuppression – Different risk by using IFN, Peg IFN ± Ribavirin C.H.B.
    • Auto(Allo)immune Hepatitis and IFNKontorinis Liver Transplant 2006
    • Auto(Allo)immune Hepatitis and IFNSharma Liver Transplant 2007
    • Telaprevir (VX-950) + pegIFN: antiviral effect in treatment-naïve patients with HCV G1HCV RNA 1medianchange from 0 Baselinebaseline(log10 IU/mL) -1 PegIFN + placebo -2 -3 -4 Telaprevir -5 Telaprevir + pegIFN -6 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Treatment day Reesink HW et al. EASL 2006
    • FUTURE TREATMENT OF HCV RECURENCE AFTER TRANSPLANTATION ? Antiprotease BILN 2061Hinrichsen Gastroenterology 2004; 127:1347-1355 C.H.B.
    • Histological Outcome in SVR Transplant Patients Necroinflammatory score reduction, Fibrosis Score StabilityBizollon Gut 2003, 52, 283-287 C.H.B.
    • Graft Histology In HCV+ve Liver Transplant Patients With or Without SVR Median Follow-up : 57 Months in NR and 52 months in SVRBizollon AJT 2005; 6: 449-458
    • Survival Without Cirrhosis In HCV+ve Liver Transplant Patients With or Without SVR Bizollon AJT 2005; 6: 449-458
    • Long-Term Histology in SVR HCV Liver Transplant Patients Inflammatory Score Fibrosis Score Abdelmalek Liver Transplant 2004; 10: 199-207
    • Role of SVR After LT in HCV + PatientsPiciotto J Hepatol 2007; 46:459-465
    • EFFET DU TRAITEMENT ANTIVIRAL C SUR LA SURVIEBerenguer M AJT 2008 C.H.B
    • EFFECT OF ANTIVIRAL TREATMENT ON SURVIVALBerenguer M AJT 2008 C.H.B
    • Role of SVR After LT in HCV + PatientsPiciotto J Hepatol 2007; 46:459-465
    • Improved Survival In HCV+ve Liver Transplant Patients Italian Multicenter StudyBelli Liver Transplant 2007; 13: 733-740
    • Patient (A) and Graft (B) Survival of HCV+ve vs HCV Neg Liver Transplant PatientsTuluvath Liver Transplant 2007;
    • HCV Recurrence After LT Deceased vs living donorsSchmeding Liver Transplant 2007;
    • Survival of Liver Transplant Patients Over Years in USATuluvath Liver Transplant 2007;
    • Survival of Liver Transplant Patients Over Years in USA Lower graft Survival and no Improvement in HCV +ve PatientsHCV PositiveHCV Negative Tuluvath Liver Transplant 2007;
    • Survival of HCV+ve Liver Transplant Patients in USADonor HCV- vs HCV + Deceased vs LDLT Tuluvath Liver Transplant 2007;
    • Patient Survival after Liver Transplantation in Europe ELTR- 01/1988 - 12/2004(%)100 93 87 87 85 85 85 HDV 81 7880 74 81 73 70 68 72 65 HBV60 66 60 55 HCV Virus BD : 88340 PBC : 3578 Alcoholic : 1009320 Virus B : 3162 Virus C : 8061 0 0 1 2 3 4 5 6 7 8 9 10 Yrs
    • Patient survival according to the year of LT HBV and HCV Cirrhosis >=2000 : 1410 ELTR update of December 2004 >=2000 : 3194 95 to 2000 : 1196 1995 to 2000 : 2705 90 to 95 : 915 1990 to 1995 : 1357 85 to 90 : 287 1985 to 1990 : 127 <1985 : 10 <1985 : 6 1 1 91% 86% 84% 83% 72%% Survival .8 .8 67% % Survival .6 .6 .4 .4 .2 .2 0 0 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Years Years HBV HCV