samuel1 hbv lt du16
TRANSCRIPT
C.H.B.
OPTIMAL PREVENTION OF
POST–TRANSPLANTATION HBV RECURRENCE
Professor Didier SAMUEL
Centre Hépatobiliaire
Inserm Research Unit-Paris Sud 785Hopital Paul BrousseUniversité Paris Sud
Villejuif, France
Evolution of Main Indications of Liver Transplantation, Without Emergencies and Retransplantation
2007- 2012, France
Source: http://www.agence-biomedecine.fr
2007 2008 2009 2010 2011 20120
5
10
15
20
25
30
27.3
9
23.8
7.9
Cirrhose alcooliqueCirrhose post-hépatite CCirrhose post-hépatite B ou B+DCarcinome hépatocellulaireAutre tumeur malignePathologie biliairePathologie métaboliqueCirrhose auto-immuneAutre cause de cirrhoseAutre pathologie
Pour
cent
age
of L
iver
tra
nspl
anta
tion
Alc-C
HCC
HCV-C
HBV-C
Liver Transplantation for Viral B Cirrhosis in USA
Kim WR Gastro 09
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 20130.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
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%
Evolution of Indications of LT in Europe ELTR 2003-2013
NASH : 345 VHB : 2874 HF : 3815 VHC : 5705 ALC : 10320 CHC : 14057 AUTRES : 19970
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
C.H.B.
HBV Decompensated Cirrhosis in 20163 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
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
Burra J Hepatol 2013
Survival After Liver Transplantation in HBV Patients (ELTR)
HBV vs otherHBV per period
HBV-HDV
HBV
HCV
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 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%
C.H.B.Dickson Liver Transplant 2005; 12: 124-133
HBIG, Peak Anti-HBs and Viral Replicative Status at LT
Monoprophylaxis With NucLamivudine
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]
Monoprophylaxis With NucLamivudine: unsufficient
Jiang WJG 2009
Monoprophylaxis With NucEntecavir
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
Fung Am J Gastro 2013
HBV DNA Detection on Lam or ETV monoprophylaxis
Fung Am J Gastro 2013
Outcome of Patients with Virological Rebound on Nucs Monoprophylaxis
HBV DNA and HBsAg Used 2 Distinct PathwaysNucs Alone not Able to Block HBsAg
Chan J Hepatol 2011
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
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
HBV Recurrence HBIG Monoprophylaxis vs Combined HBIG + Nuc
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 LAMGane EJ et al. Gastroenterology. 2007;132:931
0.5 -
0.4 -
0.3 -
0.2 -
0.1 -
0.0 - I2
I4
I6
I8
Prop
ortio
n of
Pat
ient
s W
ithH
BV
Rec
urre
nce
Numberat risk 147 124 89 56 14
Time Posttransplant (yr)
PROPHYLAXIS HBIG+LAM VS HBIG
Loomba R, Clin Gastroenterol Hepatol 2008;6:696
PROPHYLAXIS HBIG+LAM VS LAM
KATZ LH, Transpl Infect Dis 2010;12:292
HBIG + Entecavir Prophylaxis
Perrillo R et al. Liver Transpl 2013;19:887-895
C.H.B.
Risk Factors of HBV ReinfectionLiver Transplantation
Marzano Liver Transplant 2004
HBV RECURRENCE IN RELATION WITH PRE-LT PCR HBV DNA105 Copies /ml as Cut Off
Degertekin B, Am J Transpl 2010
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 Linked with HCC and HCC RecurrencePaul Brousse 1995-2005
Faria L. Gastroenterology 2008
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
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
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
Efficacy of Subcutaneous HBIG
135 patientsHBIG: 500 to 1000 IU weeklyAll patients able to SC self-injection
Di Costanzo G et al. Am J Transpl 2013;13:348-352
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?
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
Discontinuation of HBIG after 12 Months HBIG + Lamand Replacement by ADV/Lam
Angus Hepatology 2008
13 718 $ VS 8 289 $
Positive HBsAg Detectable HBV DNAADV/Lam 1/15 (6%) 0/18 (0%)
HBIG/Lam 0/15 (0%) 0/18 (0%)
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
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
Discontinuation of all Prophylaxis after LT
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
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
Cholongitas E AJT 2013
HBV Reinfection According to Prophylaxis
Fox, Terrault J Hepatol 2012
Factors Influencing the Choice of HBV Prophylaxis after LT
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
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