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
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%
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]
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
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)
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
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
