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

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

Pou

rcen

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of

Live

rtr

ansp

lan

tati

on

Alc-C

HCC

HCV-C

HBV-C

Liver Transplantation for Viral B Cirrhosis in USA

Kim WR Gastro 09

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

C.H.B.

Patients with HBV Decompensated Cirrhosisin 2014

• 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 20143 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 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]

Monoprophylaxis With Nuc

Lamivudine: unsufficient

Jiang WJG 2009

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

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 LAM

Gane EJ et al. Gastroenterology. 2007;132:931

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Number

at risk147 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 Reinfection

Liver Transplantation

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

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 Recurrence

Paul 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 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

Remaining Questions in 2014

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 + 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%)

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 reactivationafter 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