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