VIRUS DE L’HEPATITE B
ET TRANSPLANTATION HEPATIQUE

Professeur Didier SAMUEL

Centre Hépatobiliaire
Unité de Recherche Ins...
Indications for LT among HBV Patients

Burra P J Hepatol 2013
Prophylaxis after
Liver Transplantation

C.H.B.
Prophylaxis of HBV Infection Post-transplantation
Major improvements have been made in the past 20 yrs

Before transplanta...
HBV Recurrence and Survival
According to HBIG Prophylaxis

D. Samuel et al. NEJM 1993;329:1842-7

C.H.B.
Long-Term Use of IV HBIG
Aim
High doses during anhepatic phase, then during first wk
– Aim

Make serum HBsAg negative
Obta...
Actuarial HBV Recurrence Rate
Hôpital Paul Brousse: 19862000
284 Patients
Risk of Recurrence (%)

100

80
60
40

15.3
(20...
Lamivudine Monoprophylaxis
Patients remained HBsAg positive after liver transplant
Progressive decline of HBsAg1
Rate of H...
Lamivudine Monoprophylaxis
Posttransplantation
HBV Reactivation Due to YMDD Variant
100

No Immunoprophylaxis (n=67)

% HB...
HBV Recurrence with Lam Monoprophylaxis
A Great Failure

Jiang WJG 2009
Entecavir Monoprophylaxis after LT
80 Patients
Mean follow up 3 years
Rate of HBsAg loss 86% and 91% at 1-2 years

10 pati...
HBsAg Relapse after LT on ETV Monoprophylaxis

Fung Gastro 2011
HBV DNA and HBsAg Used 2 Distinct Pathways
Antiviral Alone not Able to Block HBsAg

Chan J Hepatol 2011
Posttransplant Combination
HBIG + Nucs: Rationale
Lower rate of escape mutation due to pressure on 2 different
regions in ...
Studies on HBV Prophylaxis after LT

Cholongitas E AJT 2013
HBV Recurrence
HBIG Monoprophylaxis vs Combined HBIG + Nucleos(t)ide
Paul Brousse 1995-2005

Faria Gastroenterology 2008
Low-Dose HBIG + Lamivudine
0.5 Proportion of Patients With
HBV Recurrence

• 147 patients
• Pretransplant
• LAM if HBV DNA...
Risk Factors of HBV Reinfection
Liver Transplantation

C.H.B.
HBV RECURRENCE IN RELATION
WITH PRE-LT PCR HBV DNA LEVEL

Marzano Liver Transplant 2004
HBV Recurrence
HBIG Monoprophylaxis vs Combined HBIG + Nucleos(t)ide
Paul Brousse 1995-2005

Factors independently associa...
HBV Recurrence Is Associated with HCC Recurrence
Paul Brousse 1995-2005

Faria L. Gastroenterology 2008
Survival After Liver Transplantation in HBV Patients
(ELTR)According to HBV DNA Status

HBV Cirrhosis
Burra J Hepatol 2013...
Prophylaxis Protocol
Place of HBIG in Combination?
HBIG at start is essential
– Immediately makes HBsAg negative
– Protect...
3 Specifics Issues
Definition of HBV reinfection
– HBsAg Reappearance

Classical definition (Used in HBIG prophylaxis)
– H...
Discontinuation of HBIG
Replacement by Lamivudine
21 pts stopped HBIG (Wong SN et al. Liver Transplant. 2007)
All on lamiv...
Discontinuation of HBIG after 12 Months HBIG + Lam
and Replacement by ADV/Lam

Positive HBsAg

Detectable HBV DNA

ADV/Lam...
Vaccine After Transplantation
Great discordance in results
– Good Results dependent of the adjuvant or Pre S vaccine
( non...
Discontinuation of all Prophylaxis after LT:
End of a Dogma ?

• Inclusion criteria:

• > 5 years post-LT treated with HBI...
Results
30 patients stop HBIg

1 patient
HBs+
4 week after HBIg discontinuation

cccDNA 2nd biopsy
négative 29 patients

2...
Discontinuation of HBV Prophylaxis after LT

Lenci I. J Hepatol 2011
Strategies for Prevention
of HBV Recurrence
Overall HBV
Recurrence Rate

40%

36
30%

36

33
33

20%

18
18
10%

6
5
0%
La...
HBV reinfection According to Prophylaxis

Cholongitas E AJT 2013
Factors Influencing the Choice of HBV Prophylaxis after
LT

Fox, Terrault J Hepatol 2012
Survival After Liver Transplantation in HBV Patients (ELTR)

HBV vs other
Burra J Hepatol 2013

HBV per period
Conclusion

Before LT
– Viral replication should be treated
– If possible HBV DNA <105 copies/ml

– The importance of HBsA...
Conclusion
HBIG + Nuc the Best combination at the start
At mid-term
– Low dose HBIG + Nucs extremely effective

– HBIG can...
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Samuel d hbv lt 2014

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Samuel d hbv lt 2014

  1. 1. VIRUS DE L’HEPATITE B ET TRANSPLANTATION HEPATIQUE Professeur Didier SAMUEL Centre Hépatobiliaire Unité de Recherche Inserm-Paris Sud 785 Hopital Paul Brousse Villejuif, France C.H.B.
  2. 2. Indications for LT among HBV Patients Burra P J Hepatol 2013
  3. 3. Prophylaxis after Liver Transplantation C.H.B.
  4. 4. 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
  5. 5. HBV Recurrence and Survival According to HBIG Prophylaxis D. Samuel et al. NEJM 1993;329:1842-7 C.H.B.
  6. 6. Long-Term Use of IV HBIG Aim High 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
  7. 7. Actuarial HBV Recurrence Rate Hôpital Paul Brousse: 19862000 284 Patients Risk of Recurrence (%) 100 80 60 40 15.3 (205) 20 25.4 (47) 24.2 (146) 21.9 21.9 (177) (168) 0 0 1 2 3 4 5 6 7 8 Time (yr) Roche B et al. Hepatology. 2003;38:86 9 10 11 12 13 14
  8. 8. Lamivudine Monoprophylaxis Patients remained HBsAg positive after liver transplant Progressive decline of HBsAg1 Rate of HBV reinfection – Related to HBV DNA level before liver transplant – Related to treatment duration – Increased with time posttransplant HBV reinfection due to YMDD HBV mutant Question of long-term compliance and risk of reinfection 1. Grellier L et al. Lancet. 1996;348:1212 [published correction in Lancet. 1997;349:364]
  9. 9. Lamivudine Monoprophylaxis Posttransplantation HBV Reactivation Due to YMDD Variant 100 No Immunoprophylaxis (n=67) % HBsAg (+) 80 60 Lamivudine (n=42) 40 Long-term HBIG (n=209) 0 12 24 Time (mo) Perrillo RP et al. Hepatology. 2001;33:424 N=28 N=34 N=39 N=40 20 36 48 60
  10. 10. HBV Recurrence with Lam Monoprophylaxis A Great Failure Jiang WJG 2009
  11. 11. 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 positive Fung Gastro 2011
  12. 12. HBsAg Relapse after LT on ETV Monoprophylaxis Fung Gastro 2011
  13. 13. HBV DNA and HBsAg Used 2 Distinct Pathways Antiviral Alone not Able to Block HBsAg Chan J Hepatol 2011
  14. 14. Posttransplant Combination HBIG + Nucs: Rationale Lower rate of escape mutation due to pressure on 2 different regions in HBV genome – PreS/S region for HBIG – YMDD region of polymerase gene for lNucs Possible to reduce HBIG amount and overall cost
  15. 15. Studies on HBV Prophylaxis after LT Cholongitas E AJT 2013
  16. 16. HBV Recurrence HBIG Monoprophylaxis vs Combined HBIG + Nucleos(t)ide Paul Brousse 1995-2005 Faria Gastroenterology 2008
  17. 17. Low-Dose HBIG + Lamivudine 0.5 Proportion of Patients With HBV Recurrence • 147 patients • Pretransplant • LAM if HBV DNA (+) (80% pts) • Posttransplant • LAM + HBIG IM 400–800 IU daily 7d • LAM + HBIG IM 400/800 IU monthly • HBV recurrence: 4% at 5 yr • 5 pts with HBV recurrence • All YMDD HBV • ADV in all, 1 death from liver failure • Factor independently associated with HBV recurrence • HBV DNA prior LAM Gane EJ et al. Gastroenterology. 2007;132:931 0.4 0.3 0.2 0.1 0.0 - Number 147 at risk I 2 124 I I 4 6 Time Posttransplant (yr) 89 56 I 8 14
  18. 18. Risk Factors of HBV Reinfection Liver Transplantation C.H.B.
  19. 19. HBV RECURRENCE IN RELATION WITH PRE-LT PCR HBV DNA LEVEL Marzano Liver Transplant 2004
  20. 20. HBV Recurrence HBIG 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
  21. 21. HBV Recurrence Is Associated with HCC Recurrence Paul Brousse 1995-2005 Faria L. Gastroenterology 2008
  22. 22. Survival After Liver Transplantation in HBV Patients (ELTR)According to HBV DNA Status HBV Cirrhosis Burra J Hepatol 2013 HCC
  23. 23. 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 used 1. 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 L Gastroenterology 2008, 5. Di Costanzo GG AJT 2013; 13: 348
  24. 24. 3 Specifics Issues Definition of HBV reinfection – HBsAg Reappearance Classical definition (Used in HBIG prophylaxis) – HBV DNA breakthrough Used now in some series on Nucs HBV Reinfection no more severe? – True if well monitored, but reinfection is lifelong – Untrue if monitoring inaccurate, severe HBV reactivation Nucs alone vs HBIG + Nucs? – At best, it will be a non-inferiority comparison – Nucs alone less protective than combination HBIG +Nucs
  25. 25. Discontinuation of HBIG Replacement by Lamivudine 21 pts stopped HBIG (Wong SN et al. Liver Transplant. 2007) All on lamivudine 2 recurrence (actuarial rate of 3 year HBV recurrence 9% after HBIG withdrawal), both recurrence YMDD, 3 additional patients with transient HBV DNA 20 Pts stopped HBIG replaced by Lam: HBV reinfection 3/20 at 5 years (Buti Transplantation 2007) HBV recurrence Increase with Follow-up
  26. 26. Discontinuation of HBIG after 12 Months HBIG + Lam and Replacement by ADV/Lam Positive HBsAg Detectable HBV DNA ADV/Lam 1/15 (6%) 0/18 (0%) HBIG/Lam 0/15 (0%) 0/18 (0%) 13 718 $ VS 8 289 $ Angus Hepatology 2008
  27. 27. Vaccine After Transplantation Great discordance in results – Good Results dependent of the adjuvant or Pre S vaccine ( none commercialised) – Durability of response? – Tolerance and reproducibility of results – Response probably more frequent in FHB patients (spontaneous seroconversion boosted by vaccine?) How to identify patients susceptible to respond to vaccine? NOT READY TO REPLACE HBIG
  28. 28. Discontinuation of all Prophylaxis after LT: End of a Dogma ? • Inclusion criteria: • > 5 years post-LT treated with HBIG ±Nuc • Serum HBV DNA negative • HBV DNA and cccDNA negative in liver biopsy 1 Lenci I. J Hepatol 2011
  29. 29. Results 30 patients stop HBIg 1 patient HBs+ 4 week after HBIg discontinuation cccDNA 2nd biopsy négative 29 patients 29 patients stop NUC 25 patients no HBV reactivation after 24 months 4 patients became HBsAg + after 8-32 wks discontinuation NUCs 1 patient HBV DNA > 50 in 4 weeks cccDNA pos on third biopsy Lenci I. J Hepatol 2011 3 patients HBV DNA neg seroconversion HBs after 18 week. (16-24)
  30. 30. Discontinuation of HBV Prophylaxis after LT Lenci I. J Hepatol 2011
  31. 31. Strategies for Prevention of HBV Recurrence Overall HBV Recurrence Rate 40% 36 30% 36 33 33 20% 18 18 10% 6 5 0% Lamivudine (mono) Low-Dose HBIG High-Dose HBIG Adapted from Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120 Nucs + HBIG
  32. 32. HBV reinfection According to Prophylaxis Cholongitas E AJT 2013
  33. 33. Factors Influencing the Choice of HBV Prophylaxis after LT Fox, Terrault J Hepatol 2012
  34. 34. Survival After Liver Transplantation in HBV Patients (ELTR) HBV vs other Burra J Hepatol 2013 HBV per period
  35. 35. Conclusion Before LT – Viral replication should be treated – If possible HBV DNA <105 copies/ml – The importance of HBsAg quantification before LT is debated
  36. 36. Conclusion HBIG + Nuc the Best combination at the start At mid-term – Low dose HBIG + Nucs extremely effective – HBIG can be stopped in patients with low risk recurrence Spontaneous HBV DNA negative at LT FHF If Nucs are maintained+++ – In high risk Patients: HBV DNA +ve at LT, HCC, HIV coinfection Low dose HBIg + Nuc remain the best combination

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