samuel d hbv lt 2014
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C.H.B.
VIRUS DE L’HEPATITE B
ET TRANSPLANTATION HEPATIQUE
Professeur Didier SAMUEL
Centre Hépatobiliaire
Unité de Recherche Inserm-Paris Sud 785Hopital Paul Brousse
Villejuif, France
Indications for LT among HBV Patients
Burra P J Hepatol 2013
C.H.B.
Prophylaxis after
Liver Transplantation
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
C.H.B.D. Samuel et al. NEJM 1993;329:1842-7
HBV Recurrence and Survival According to HBIG Prophylaxis
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
Actuarial HBV Recurrence Rate Hôpital Paul Brousse: 19862000
284 Patients
Roche B et al. Hepatology. 2003;38:86
21.921.9 24.2 25.4
15.3(205)
(177) (168) (146) (47)
100
80
60
40
20
0
Ris
k o
f R
ecu
rren
ce (
%)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time (yr)
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]
Lamivudine Monoprophylaxis Posttransplantation
Perrillo RP et al. Hepatology. 2001;33:424
HBV Reactivation Due to YMDD Variant100
80
60
40
20
0 12 24 36 48 60
Time (mo)
% H
BsA
g (
+)
N=
40
N=
39
N=
34
N=
28
No Immunoprophylaxis (n=67)
Lamivudine (n=42)
Long-term HBIG (n=209)
HBV Recurrence with Lam MonoprophylaxisA 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 patients had HBsAg reappearance
At end of FU :
– 18 Patients (22%) were HBsAg positive,
– one was HBV DNA positive
Fung Gastro 2011
Fung Gastro 2011
HBsAg Relapse after LT on ETV Monoprophylaxis
HBV DNA and HBsAg Used 2 Distinct PathwaysAntiviral 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 HBV genome
– PreS/S region for HBIG
– YMDD region of polymerase gene for lNucs
Possible to reduce HBIG amount and overall cost
Cholongitas E AJT 2013
Studies on HBV Prophylaxis after LT
HBV Recurrence HBIG Monoprophylaxis vs Combined HBIG + Nucleos(t)ide
Paul Brousse 1995-2005
Faria Gastroenterology 2008
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 - I2
I4
I6
I8
Pro
po
rtio
n o
f P
atie
nts
Wit
hH
BV
Rec
urr
ence
Numberat risk 147 124 89 56 14
Time Posttransplant (yr)
C.H.B.
Risk Factors of HBV Reinfection
Liver Transplantation
Marzano Liver Transplant 2004
HBV RECURRENCE IN RELATION WITH PRE-LT PCR HBV DNA LEVEL
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
HBV Recurrence Is Associated with HCC RecurrencePaul Brousse 1995-2005
Faria L. Gastroenterology 2008
Burra J Hepatol 2013
Survival After Liver Transplantation in HBV Patients (ELTR)According to HBV DNA Status
HBV Cirrhosis HCC
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
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
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
Discontinuation of HBIG after 12 Months HBIG + Lamand 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%)
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
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
Results
30 patients stop HBIg
cccDNA 2nd biopsynégative 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 weekscccDNA pos on third biopsy
3 patients HBV DNA negseroconversion HBsafter 18 week. (16-24)
Lenci I. J Hepatol 2011
Lenci I. J Hepatol 2011
Discontinuation of HBV Prophylaxis after LT
3633
18
60%
10%
20%
30%
40%
Ove
rall
HB
V R
ecu
rren
ce R
ate
Lamivudine(mono)
Low-DoseHBIG
High-DoseHBIG
Nucs+ HBIG
Strategies for Prevention of HBV Recurrence
Adapted from Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120
3633
18
5
Cholongitas E AJT 2013
HBV reinfection According to Prophylaxis
Fox, Terrault J Hepatol 2012
Factors Influencing the Choice of HBV Prophylaxis after LT
Burra J Hepatol 2013
Survival After Liver Transplantation in HBV Patients (ELTR)
HBV vs other HBV per period
Conclusion
Before LT
– Viral replication should be treated
– If possible HBV DNA <105 copies/ml
– The importance of HBsAg quantification before LT is debated
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