1. HBV PROPHYLAXIS
SHOULD WE GIVE A MAXIMAL PROTECTIVE
THERAPY 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
fo
Be

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
ELTR
Be

4. Liver Transplantation for Viral B Cirrhosis in USA
Kim 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 after
Liver Transplantation
C.H.B.

7. 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

8. HBV Recurrence and Survival
According to HBIG Prophylaxis
D. 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 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]

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 Failure
Jiang 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 positive
Fung 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 HBsAg
Chan J Hepatol 2011

19. 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

20. HBV Recurrence
HBIG 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 pts
HBV DNA >105 at LT: Recurrence 88% in the LAM group vs 28% in combined group
HBV 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 LT
Dickson Liver Transplant 2005; 12: 124-133 C.H.B.

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

26. HBV Recurrence in Relation to
Pretransplant PCR HBV DNA Level
Lamivudine Monoprophylaxis Lamivudine + HBIG
Prophylaxis
Marzano A et al. Liver Transpl. 2005;11:402

27. HBV Recurrence Is Associated with HBV DNA at LT
USA
Degertekin AJT 2010

28. 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

29. HBV Recurrence In Patients with and without HCC
Paul Brousse 1995-2005
Faria L. Gastroenterology 2008

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

31. HBV Recurrence Is Associated with HCC Recurrence
Saab LT 2009

32. HBV DNA Detection In HIV-HBV LT Patients
Coffin AJT 2010

33. HBV DNA Detection in HIV-HBV LT Patients
Coffin 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 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 Gastroenterology 2008

35. 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

36. Strategies for Prevention
of HBV Recurrence
40%
36
36
Recurrence 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
LT
Fox, Terrault J Hepatol 2012

40. Conclusion
Before LT
– Viral replication should be treated
– If possible HBV DNA <105 copies/ml
– The importance of HBsAg quantification before LT is debated
After LT
– At the start, HBIG + Nuc superior to HBIG or Nuc alone
– Nuc alone:
some patients remained HBsAg +ve
– Reappearance of HBsAg frequent
Post-op high dose HBIG should be given to high risk Patients :
HBV DNA >105 copies/ml, HCC,HIV coinfection