This document discusses optimal strategies for preventing hepatitis B virus (HBV) recurrence after liver transplantation. It reviews evidence that combination prophylaxis with hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogues (NUCs) is most effective at preventing early HBV reinfection. For long-term prophylaxis, low-dose HBIG or HBIG discontinuation combined with lifelong NUC therapy may be sufficient for patients at low risk of recurrence. Factors such as HBV DNA level pre-transplant, hepatocellular carcinoma, and HBV/HIV coinfection increase risk of recurrence and require continued HBIG plus NUC prophylaxis.

1. C.H.B.
OPTIMAL PREVENTION
OF
POST–TRANSPLANTATION HBV RECURRENCE
Professor Didier SAMUEL
Centre Hépatobiliaire
Inserm Research Unit-Paris Sud 785
Hopital Paul Brousse
Université Paris Sud
Villejuif, France

2. Evolution of Main Indications of Liver Transplantation,
Without Emergencies and Retransplantation
2007- 2012, France
Source: http://www.agence-biomedecine.fr
27.3
9
23.8
7.9
0
5
10
15
20
25
30
2007 2008 2009 2010 2011 2012
Cirrhose alcoolique
Cirrhose post-hépatite C
Cirrhose post-hépatite B ou B+D
Carcinome hépatocellulaire
Autre tumeur maligne
Pathologie biliaire
Pathologie métabolique
Cirrhose auto-immune
Autre cause de cirrhose
Autre pathologie
PourcentageofLivertransplantation
Alc-C
HCC
HCV-C
HBV-C

3. Liver Transplantation for Viral B Cirrhosis in USA
Kim WR Gastro 09

4. 0.0% 0.1% 0.2% 0.1% 0.2% 0.6% 0.8% 1.0% 1.2% 1.0%
1.9%
5%
6% 5%
4%
5% 5% 5% 5% 5% 5% 6%
7% 7% 6%
7% 7% 6% 6%
7%
6% 6% 6%
12% 13% 13% 12%
10% 9% 9%
8% 8% 8% 8%
19%
20% 20%
19%
18% 18% 18%
17% 16%
17% 17%
19% 19%
20%
23%
26% 26%
29% 28%
27%
27%
25%
37%
35% 35%
34%
35% 35%
33%
34%
36% 36%
37%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Evolution of Indications of LT in Europe
ELTR 2003-2013
NASH : 345 VHB : 2874 HF : 3815 VHC : 5705 ALC : 10320 CHC : 14057 AUTRES : 19970

6. C.H.B.
Patients with HBV Decompensated Cirrhosis
in 2016
• Naive cirrhotic patients
• HBV reactivation due to:
• Discontinuation of nucleos(t)ide analogue treatment
• Virological Resistance to nucleos(t)ide analogue treatment
• Chemotherapy, Immunosuppression

7. C.H.B.
HBV Decompensated Cirrhosis in 2016
3 Main Issues
• Therapeutic emergency
• Nucleos(t) ide analogue:
• Entecavir or Tenofovir
• Combination?
• Determine Prognosis and the need for liver transplantation:
• Meld ; Delta-Meld ?
• Bilirubin, INR, creatinin?
• HBV DNA level ?
• Virological objective for post transplant prophylaxis
• Decrease HBV DNA below 105 copies/ml

8. Dramatic Change in the Prophylaxis of HBV
Infection Post-transplantation
 Before transplantation
– Lamivudine (2000) or adefovir
– Nucleos(t)ide analogues
 After transplantation
– Anti-hepatitis B immunoglobulins (HBIG)-1990
– Nucs first generation monoprophylaxis (2000)
– Combination HBIG + Nucs
– Combination HBIG + Nuc, then HBIG discontinuation
– Nucs Second generation alone

9. Burra J Hepatol 2013
Survival After Liver Transplantation in HBV Patients (ELTR)
HBV vs otherHBV per period
HBV-HDV
HBV
HCV

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

11. Long-Term Use of IV HBIG Monoprophyalxis
 High doses during anhepatic phase, then during first wk
– Aim
 Clear HBsAg from serum
 Achieve protective anti-HBs titer
– Maintain protective anti-HBs titer
 FHF, HDV-C: recurrence 0-20%
 Non-replicative HBV-C (<105-6 cps/ml): recurrence 30 -35%
 Replicative HBV-C (>105-6 cps/ml): recurrence 50-90%

12. C.H.B.Dickson Liver Transplant 2005; 12: 124-133
HBIG, Peak Anti-HBs and Viral Replicative Status at LT

13. Monoprophylaxis With Nuc
Lamivudine
 Some 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
– Increase with time post-transplant
 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]

14. Monoprophylaxis With Nuc
Lamivudine: unsufficient
Jiang WJG 2009

15. Monoprophylaxis With Nuc
Entecavir
 80 Patients, mean follow up 3 years
 91% HBsAg loss at 2 years
 HBsAg reappearance: in 10 pts
 At end of FU :
– 18 Pts (22%) HBsAg positive,
– One Pt HBV DNA positive
Fung Gastro 2011
HBs Ag Relapse

16. Fung Am J Gastro 2013
HBV DNA Detection on Lam or ETV monoprophylaxis

17. Fung Am J Gastro 2013
Outcome of Patients with Virological Rebound
on Nucs Monoprophylaxis

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

19. Prophylaxis using Lamivudine + adefovir
- with IM HBIG 800 IU/day 7 days, 20 patients
- without HBIG, 28 patients
No HBV recurrence
Prophylaxis with Lamivudine and Adefovir
Gane EJ et al. Liver Transpl 2013;19:268-274

20. Posttransplant Combination
HBIG + Nuc: 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 Nucs
 Possible to reduce HBIG amount and overall cost

21. HBV Recurrence
HBIG Monoprophylaxis vs Combined HBIG + Nuc
Paul Brousse 1995-2005
Faria Gastroenterology 2008

22. Low-Dose HBIG + Lamivudine
• 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
0.5 -
0.4 -
0.3 -
0.2 -
0.1 -
0.0 - I
2
I
4
I
6
I
8ProportionofPatientsWith
HBVRecurrence
Number
at risk
147 124 89 56 14
Time Posttransplant (yr)

23. PROPHYLAXIS HBIG+LAM VS HBIG
Loomba R, Clin Gastroenterol Hepatol 2008;6:696

24. PROPHYLAXIS HBIG+LAM VS LAM
KATZ LH, Transpl Infect Dis 2010;12:292

25. HBIG + Entecavir Prophylaxis
Perrillo R et al. Liver Transpl 2013;19:887-895

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

27. Marzano Liver Transplant 2004
HBV RECURRENCE IN RELATION WITH PRE-LT PCR HBV DNA
105 Copies /ml as Cut Off
Degertekin B, Am J Transpl 2010

28. HBV Recurrence
HBIG Monoprophylaxis vs Combined HBIG + Nucleos(t)ide
Paul Brousse 1995-2005
Faria Gastroenterology 2008
Factors independently associated
with HBV recurrence:
• HBV DNA at LT> 105 copies/ml
• HCC at LT
• HBIG monoprophylaxis

29. HBV Recurrence Is Linked with HCC and HCC Recurrence
Paul Brousse 1995-2005
Faria L. Gastroenterology 2008

30. HCC Recurrence and High HBV DNA, Factors of HBV
Recurrence In Patients with Lam+HBIG, Korean Experience
Chun, LT 2010
Overall HBV recurrence
HBV recurrence in HCC

31. HCC Recurrence and High HBV DNA, Factors of HBV
Recurrence In Patients with Lam+HBIG, Korean Experience
Overall HBV Recurrence HBV Recurrence HBIG VS HBIG + Nuc
Hwang S. LT 2008

32. Place of HBIG in Combination Protocol?
 HBIG at start is essential
– Immediately makes HBsAg negative
– Protects graft from immediate reinfection
– Dose related to HBV DNA level at liver transplant
 At Medium term
 Lower doses can be used
 Anti-HBsAb Level of 50-100 IU protective
 IM monthly or SC/week HBIG as effective
 Possibility of discontinuation in favourable cases

33. Efficacy of Subcutaneous HBIG
135 patients
HBIG: 500 to 1000 IU weekly
All patients able to SC self-injection
Di Costanzo G et al. Am J Transpl 2013;13:348-352

34. Remaining Questions in 2016
 Definition of HBV reinfection
– HBsAg Reappearance
 Classical definition (Used in HBIG prophylaxis)
– HBV DNA breakthrough
 Used in some series on Nucs
 Severity of HBV Reinfection?
– Much less than before the advent of nucs
– Severe HBV reactivation if patient not followed or not compliant
 Nucs alone vs HBIG + Nucs?
– Minimal or no difference on HBV DNA recurrence
– Cases of HBsAg reappearance in Nucs monoprophylaxis
 HBIg discontinuation? In whom?

35. Discontinuation of HBIG
Replacement by Lamivudine
 21 pts stopped HBIG (Wong SN et al. Liver Transplant. 2007)
– 2 recurrence (3 year HBV recurrence 9%), 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

36. Discontinuation of HBIG after 12 Months HBIG + Lam
and Replacement by ADV/Lam
Angus Hepatology 2008
13 718 $ VS 8 289 $
Positive HBsAg Detectable HBV DNA
ADV/Lam 1/15 (6%) 0/18 (0%)
HBIG/Lam 0/15 (0%) 0/18 (0%)

37. Discontinuation of HBIG
Replacement by TDF+FTC
 40 Pts on HBIG + FTC for 12 months
 37 randomized for HBIG+TDF+FTC (19) or TDF+FTC (18)
 1 transient recurrence (HBsAg and HBV DNA) in the group
without HBIG
Teperman Liver Transplant 2013

38. 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

39. Lenci I. J Hepatol 2011
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

40. Discontinuation of all Prophylaxis after LT
30 patients stop HBIg
cccDNA 2nd biopsy
négative 29 patients
29 patients stop NUC
1 patient
HBs+
4 week after HBIg discontinuation
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
3 patients HBV DNA neg
seroconversion HBs
after 18 week. (16-24)
Lenci I. J Hepatol 2011

41. Residual Infection after LT Close to Occult HBV Infection
Pollicino , Raimondo J Hepatol 2014
Residual HBV DNA in > 50% -70%
of patients at 10 yr after LT
Roche Hepatology 2003 ;
Hussain Liver Transpl. 2007

42. Cholongitas E AJT 2013
HBV Reinfection According to Prophylaxis

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

44. Conclusion
 Dramatic improvement in LT for HBV
– In survival
– In reducing Rate of HBV recurrence to less than 5%
– Due to effective anti-HBV prophylaxis
 Before LT
– Viral replication should be treated
– If possible HBV DNA <105 copies/ml
– The importance of HBsAg quantification before LT is debated

45. Conclusion
 HBIG + Nuc the Best combination at the start
– The goal is the clearance of HBsAg and appearance of anti-HBs Ab
– HBV DNA Positive patients might require high doses
 At mid-term
– Low dose HBIG, HBIG IM or SC + Nucs extremely effective
– HBIG can be stopped in patients with low risk recurrence
 Spontaneous HBV DNA negative at LT, FHF
 If second generation Nucs are maintained+++
– In high risk Patients (HBV DNA +ve at LT, HCC, HIV coinfection):
 Low dose HBIg + Nuc remain the best combination
 In Delta Patients
– HBIG should never be stopped, risk of Delta reactivation