C.H.B.

HBV PROPHYLAXIS

SHOULD WE GIVE A MAXIMAL PROTECTIVE

THERAPY AT THE TIME OF TRANSPLANTATION

Didier SAMUEL, M.D.

Professor of Hepatology

CENTRE HEPATOBILIAIRE

INSERM PARIS Sud UNIT 785HOPITAL PAUL BROUSSE

VILLEJUIF, FRANCE

Evolution of Liver TransplantationFor Viral Cirrhosis without HCC in Europe

ELTR

Evolution of Liver TransplantationFor Viral Cirrhosis with HCC in Europe

ELTR

Liver Transplantation for Viral B Cirrhosis in USA

Kim WR Gastro 09

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.

Prophylaxis after

Liver Transplantation

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

C.H.B.D. Samuel et al. NEJM 1993;329:1842-7

HBV Recurrence and Survival According to HBIG Prophylaxis

Actuarial HBV Recurrence Rate in Relation to Initial Liver Disease

Hôpital Paul Brousse: 19862000284 Patients

HDV-C

FHD

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

41.8

25.0 25.0 25.0 25.0

5.8

13.5 13.5 15.3

Time (yr)

15.3

37.5

56.554.449.449.4 HBV-C

Ris

k o

f R

ecu

rren

ce (

%)

FHB

Roche B et al. Hepatology. 2003;38:86

HBV-C = HBV cirrhosis; FHD = fulminant hepatitis B-Delta; HDV-C = HDV cirrhosis; FHB = fulminant hepatitis B

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

Fox, Terrault J Hepatol 2012

Monoprophylaxis Lamivudine or Adefovir After LT

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 Clearance after LT on ETV Monoprophylaxis

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

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)

HBIG + Lamivudine vs Lamivudine

Zheng S et al. Liver Transplant. 2006;12:253

LAM + HBIG: 114 pts

LAM: 51 pts

HBV DNA >105 at LT: Recurrence 88% in the LAM group vs 28% in combined group

HBV DNA <105 at LT: Recurrence 18% in the LAM group vs 8% in combined group

C.H.B.

Risk Factors of HBV Reinfection

Liver Transplantation

C.H.B.Dickson Liver Transplant 2005; 12: 124-133

HBIG, Peak Anti-HBs and Viral Replicative Status at LT

Marzano Liver Transplant 2004

HBV RECURRENCE IN RELATION WITH PRE-LT PCR HBV DNA LEVEL

HBV Recurrence in Relation to Pretransplant PCR HBV DNA Level

Lamivudine Monoprophylaxis Lamivudine + HBIG Prophylaxis

Marzano A et al. Liver Transpl. 2005;11:402

HBV Recurrence Is Associated with HBV DNA at LTUSA

Degertekin AJT 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 In Patients with and without HCCPaul Brousse 1995-2005

Faria L. Gastroenterology 2008

HBV Recurrence Is Associated with HCC RecurrencePaul Brousse 1995-2005

Faria L. Gastroenterology 2008

HBV Recurrence Is Associated with HCC Recurrence

Saab LT 2009

HBV DNA Detection In HIV-HBV LT Patients

Coffin AJT 2010

HBV DNA Detection in HIV-HBV LT Patients

Coffin AJT 2010

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 Gastroenterology 2008

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

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

Virus D (n=1148)

Virus C (n=8545)Virus B (n=3398)

0

,2

,4

,6

,8

1

Su

rvie

Cu

m.

0 1 2 3 4 5 6 7 8 9 10Years

82%73%

67%81%

67%

55%

92%88%

85%

0

,2

,4

,6

,8

1

Su

rvie

Cu

m.

0 1 2 3 4 5 6 7 8 9 10Years

Virus D (n=288)

Virus C (n=4882)Virus B (n=1810)

84%68%

60%82%

59%

46%

87%77%

71%

Patient Survival after Liver TransplantationFor Viral Cirrhosis in Europe

From 13/11/1973 to 30/06/2009

With HCCWithout HCC

Patient survival according to the year of LTHBV Cirrhosis

ELTR update of December 2007

2000 to 2005 : 973

<1985 : 12

95 to 2000 : 831

90 to 95 : 653

85 to 90 : 175

>= 2005 : 419

0 1 2 3 4 5 6 7 8 9 10

Years

0

20

40

60

80

100

% S

urv

ival

91% 90%

Fox, Terrault J Hepatol 2012

Factors Influencing the Choice of HBV Prophylaxis after LT

Conclusion

Before LT

– Viral replication should be treated

– If possible HBV DNA <105 copies/ml

– The importance of HBsAg quantification before LT is debated

After LT

– At the start, HBIG + Nuc superior to HBIG or Nuc alone

– Nuc alone:

some patients remained HBsAg +ve

– Reappearance of HBsAg frequent

Post-op high dose HBIG should be given to high risk Patients :

HBV DNA >105 copies/ml, HCC,HIV coinfection