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