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Samuel hbv lt ds 1- 2013

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  • 1. HBV PROPHYLAXIS SHOULD WE GIVE A MAXIMAL PROTECTIVETHERAPY AT THE TIME OF TRANSPLANTATION Didier SAMUEL, M.D. Professor of Hepatology CENTRE HEPATOBILIAIRE INSERM PARIS Sud UNIT 785 HOPITAL PAUL BROUSSE VILLEJUIF, FRANCE C.H.B.
  • 2. Evolution of Liver Transplantation For Viral Cirrhosis without HCC in Europe 700 600 500 400 300 200 100 0 6 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 8 19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 re Virus Delta Virus B Virus C ELTR foBe
  • 3. Evolution of Liver Transplantation For Viral Cirrhosis with HCC in Europe 500 450 400 350 300 250 200 150 100 50 0 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 re Virus Delta + HCC Virus B + HCC Virus C + HCC fo ELTRBe
  • 4. Liver Transplantation for Viral B Cirrhosis in USAKim WR Gastro 09
  • 5. Prophylaxis of HBV Infection Post-transplantation Major improvements have been made in the past 20 yrs Before transplantation – Lamivudine (2000) or adefovir – Nucleos(t)ide analogues After transplantation – Anti-hepatitis B immunoglobulins (HBIG)-1990 – Lamivudine (1997),Adefovir, or ETV monoprophylaxis(2011) – Combination HBIG + nucleos(t)ide analogue: (2000) – Combination HBIG + Nuc, then HBIG discontinuation
  • 6. Prophylaxis afterLiver Transplantation C.H.B.
  • 7. Long-Term Use of IV HBIG AimHigh doses during anhepatic phase, then during first 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
  • 8. HBV Recurrence and Survival According to HBIG ProphylaxisD. Samuel et al. NEJM 1993;329:1842-7 C.H.B.
  • 9. 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 B Roche B et al. Hepatology. 2003;38:86
  • 10. 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
  • 11. 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]
  • 12. 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=34 N=39 N=28 N=40 0 12 24 36 48 60 Time (mo)Perrillo RP et al. Hepatology. 2001;33:424
  • 13. HBV Recurrence with Lam Monoprophylaxis A Great FailureJiang WJG 2009
  • 14. Monoprophylaxis Lamivudine or Adefovir After LT Fox, Terrault J Hepatol 2012
  • 15. Entecavir Monoprophylaxis after LT 80 Patients Mean follow up 3 years Rate of HBsAg loss 86% and 91% at 1-2 years 10 patients had HBsAg reappearance At end of FU : – 18 Patients (22%) were HBsAg positive, – one was HBV DNA positiveFung Gastro 2011
  • 16. HBsAg Clearance after LT on ETV Monoprophylaxis Fung Gastro 2011
  • 17. HBsAg Relapse after LT on ETV Monoprophylaxis Fung Gastro 2011
  • 18. HBV DNA and HBsAg Used 2 Distinct Pathways Antiviral Alone not Able to Block HBsAgChan J Hepatol 2011
  • 19. Posttransplant Combination HBIG + Nucs: RationaleLower rate of escape mutation due to pressure on 2 differentregions in HBV genome– PreS/S region for HBIG– YMDD region of polymerase gene for lNucsPossible to reduce HBIG amount and overall cost
  • 20. HBV RecurrenceHBIG Monoprophylaxis vs Combined HBIG + Nucleos(t)ide Paul Brousse 1995-2005 Faria Gastroenterology 2008
  • 21. Low-Dose HBIG + Lamivudine• 147 patients• Pretransplant 0.5 - • LAM if HBV DNA (+) (80% pts) Proportion of Patients With• Posttransplant 0.4 - HBV Recurrence • LAM + HBIG IM 400–800 IU daily 7d 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 0.0 - I I I I• Factor independently associated with 2 4 6 8 HBV recurrence Time Posttransplant (yr) Number 147 124 89 56 14 • HBV DNA prior LAM at risk Gane EJ et al. Gastroenterology. 2007;132:931
  • 22. 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
  • 23. Risk Factors of HBV Reinfection Liver Transplantation C.H.B.
  • 24. HBIG, Peak Anti-HBs and Viral Replicative Status at LTDickson Liver Transplant 2005; 12: 124-133 C.H.B.
  • 25. HBV RECURRENCE IN RELATION WITH PRE-LT PCR HBV DNA LEVELMarzano Liver Transplant 2004
  • 26. HBV Recurrence in Relation to Pretransplant PCR HBV DNA LevelLamivudine Monoprophylaxis Lamivudine + HBIG ProphylaxisMarzano A et al. Liver Transpl. 2005;11:402
  • 27. HBV Recurrence Is Associated with HBV DNA at LT USADegertekin AJT 2010
  • 28. HBV RecurrenceHBIG Monoprophylaxis vs Combined HBIG + Nucleos(t)ide Paul Brousse 1995-2005 Factors independently associated with HBV recurrence: • HBV DNA at LT> 105 copies/ml • HCC at LT • HBIG monoprophylaxis Faria Gastroenterology 2008
  • 29. HBV Recurrence In Patients with and without HCC Paul Brousse 1995-2005Faria L. Gastroenterology 2008
  • 30. HBV Recurrence Is Associated with HCC Recurrence Paul Brousse 1995-2005Faria L. Gastroenterology 2008
  • 31. HBV Recurrence Is Associated with HCC RecurrenceSaab LT 2009
  • 32. HBV DNA Detection In HIV-HBV LT PatientsCoffin AJT 2010
  • 33. HBV DNA Detection in HIV-HBV LT PatientsCoffin AJT 2010
  • 34. Prophylaxis Protocol Place of HBIG in Combination? HBIG at start is essential – Immediately makes HBsAg negative – Protects graft from immediate reinfection High doses of HBIG – Important at start – Dose related to HBV DNA level at liver transplant3 – Lower doses can be used at medium term – Ant-HBsAb Level of 50-100 IU protective – IM or SC HBIG can be used1. 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, 4. Faria Gastroenterology 2008
  • 35. 3 Specifics IssuesDefinition of HBV reinfection– HBsAg Reappearance Classical definition (Used in HBIG prophylaxis)– HBV DNA breakthrough Used now in some series on NucsHBV Reinfection no more severe?– True if well monitored, but reinfection is lifelong– Untrue if monitoring inaccurate, severe HBV reactivationNucs alone vs HBIG + Nucs?– At best, it will be a non-inferiority comparison– Nucs alone less protective than combination HBIG +Nucs
  • 36. Strategies for Prevention of HBV Recurrence 40% 36 36Recurrence Rate 30% 33 33 Overall HBV 20% 18 18 10% 65 0% Lamivudine Low-Dose High-Dose Nucs (mono) HBIG HBIG + HBIG Adapted from Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120
  • 37. Patient Survival after Liver Transplantation For Viral Cirrhosis in Europe From 13/11/1973 to 30/06/2009 Without HCC With HCC 1 92% 1 88% 87% 85% 82% 77%Survie Cum. ,8 ,8 84% 71% Survie Cum. 73% 81% 67% 82% 68% ,6 60% ,6 67% 59% ,4 55% ,4 Virus D (n=1148) 46% Virus D (n=288) Virus B (n=3398) Virus B (n=1810) ,2 ,2 Virus C (n=8545) Virus C (n=4882) 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
  • 38. Patient survival according to the year of LT HBV Cirrhosis ELTR update of December 2007 >= 2005 : 419 2000 to 2005 : 973 95 to 2000 : 831 100 91% 90% 90 to 95 : 653 85 to 90 : 175 80 <1985 : 12 60% Survival 40 20 0 0 1 2 3 4 5 6 7 8 9 10 Years
  • 39. Factors Influencing the Choice of HBV Prophylaxis after LTFox, Terrault J Hepatol 2012
  • 40. ConclusionBefore LT– Viral replication should be treated– If possible HBV DNA <105 copies/ml– The importance of HBsAg quantification before LT is debatedAfter LT– At the start, HBIG + Nuc superior to HBIG or Nuc alone– Nuc alone: some patients remained HBsAg +ve– Reappearance of HBsAg frequentPost-op high dose HBIG should be given to high risk Patients : HBV DNA >105 copies/ml, HCC,HIV coinfection

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