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. Indications for LT among HBV Patients
Burra P J Hepatol 2013

3. Prophylaxis after
Liver Transplantation
C.H.B.

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. HBV Recurrence and Survival
According to HBIG Prophylaxis
D. Samuel et al. NEJM 1993;329:1842-7
C.H.B.

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. 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. 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. 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. HBV Recurrence with Lam Monoprophylaxis
A Great Failure
Jiang WJG 2009

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. HBsAg Relapse after LT on ETV Monoprophylaxis
Fung Gastro 2011

13. HBV DNA and HBsAg Used 2 Distinct Pathways
Antiviral Alone not Able to Block HBsAg
Chan J Hepatol 2011

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. Studies on HBV Prophylaxis after LT
Cholongitas E AJT 2013

16. HBV Recurrence
HBIG Monoprophylaxis vs Combined HBIG + Nucleos(t)ide
Paul Brousse 1995-2005
Faria Gastroenterology 2008

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. Risk Factors of HBV Reinfection
Liver Transplantation
C.H.B.

19. HBV RECURRENCE IN RELATION
WITH PRE-LT PCR HBV DNA LEVEL
Marzano Liver Transplant 2004

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. HBV Recurrence Is Associated with HCC Recurrence
Paul Brousse 1995-2005
Faria L. Gastroenterology 2008

22. Survival After Liver Transplantation in HBV Patients
(ELTR)According to HBV DNA Status
HBV Cirrhosis
Burra J Hepatol 2013
HCC

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. 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. 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. 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. 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. 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. 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. Discontinuation of HBV Prophylaxis after LT
Lenci I. J Hepatol 2011

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. HBV reinfection According to Prophylaxis
Cholongitas E AJT 2013

33. Factors Influencing the Choice of HBV Prophylaxis after
LT
Fox, Terrault J Hepatol 2012

34. Survival After Liver Transplantation in HBV Patients (ELTR)
HBV vs other
Burra J Hepatol 2013
HBV per period

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. 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