C.H.B.

LIVER TRANSPLANTATION

IN VIRAL HEPATITIS B

Didier SAMUEL, M.D.

Professor of Hepatology

CENTRE HEPATOBILIAIRE

INSERM PARIS XI UNIT 785

HOPITAL PAUL BROUSSE VILLEJUIF, FRANCE

Evolution of Survival After Liver Transplant for HBV-Related Liver Disease

Kim WR et al. Liver Transpl. 2004;10:968

P<0.01

Other

HBV S

urvi

val (

%)

Time (yr)

100

90

80

70

60

50 0 1 2 3 4 5

ERA 1 (1987–1991)

Sur

viva

l (%

)

100

90

80

70

60

50

0

Time (yr)

1 2 3 4 5

P=0.14

ERA 3 (1997–2002)

Other

HBV

Sur

viva

l (%

)

1

90

80

70

60

50 0

ERA 2 (1992–1996) 100

Other

HBV

P=0.19

Time (yr)

2 3 4 5

Prophylaxis of HBV Infection Posttranplantation

� Major improvements have been made in prevention of HBV infection in past 15 yr

� Before transplantation – Lamivudine or adefovir

� After transplantation – Anti-hepatitis B immunoglobulins (HBIG)

– Lamivudine monoprophylaxis

– Combination HBIG + lamivudine

Long -Term Prophylaxis of HBV Infection Posttransplantation

Questions

• Is prophylaxis still necessary at long term?

• What is optimal dosage of HBIG?

• What is optimal route of HBIG and for what duration?

• Is it possible to stop HBIG administration and in whom?

• Which antiviral to be used after 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.

HBV Recurrence According to Initial Liver Disease

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

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

HBV Recurrence According to HBV Prophylaxis

C.H.B.

Survival In Relationship with Type of HBV Prophylax is

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

Actuarial HBV Recurrence Rate Hôpital Paul Brousse : 1986−−−−2000

284 Patients

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

21.9 21.9 24.2 25.4

15.3 (205)

(177) (168) (146) (47)

100

80

60

40

20

0

Ris

k of

Rec

urre

nce

(%)

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

Time (yr)

Actuarial HBV Recurrence Rate in Relation to Initial Liver Disease

Hôpital Paul Brousse : 1986−−−−2000 284 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

56.5 54.4 49.4 49.4 HBV-C

Ris

k of

Rec

urre

nce

(%)

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

Lamivudine Monoprophylaxis Posttransplantation

Perrillo RP et al. Hepatology. 2001;33:424

HBV Reactivation Due to YMDD Variant

100

80

60

40

20

0 12 24 36 48 60

Time (mo)

% H

BsA

g (+

)

N=4

0

N=3

9

N=3

4

N=2

8

No Immunoprophylaxis (n=67)

Lamivudine (n=42)

Long-term HBIG (n=209)

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]

Adefovir Monoprophylaxis

Schiff E et al. Liver Transpl. 2007;13:349

0 (0%)

3 (13%)

2 (6%) 4 (12%)

Serum HBV DNA >1000 copies/mL � Confirmed* ‡

� Single positive test §§§§

Recurrence of HbsAg or Serum HBV DNA Following On-S tudy Liver Transplantation

0 (0%) 2 (9%)

0 (0%) 2 (6%)

HBsAg � Confirmed* � First test was only positive †

No HBIG (n=23)

Concomitant HBIG (n=34)

Marker

No short-term recurrence, no long-term data availab le

*2 consecutive positive tests †HBsAg was detected on only first test between days 4 and 67 posttransplantation. 2 patients had no further follow-up, and 2 patients had subsequent negative tests over 2 (to day 239) and 2 visits (to day 667) ‡In these 2 patients, the first 2 tests posttransplantation detected serum HBV DNA (maximum 32,084 and 29,672 copies/mL), and subsequently, serum HBV DNA was undetectable on 3 (to day 309) and 7 (to day 528) measurements §Maximum titer among 7 tests was 3055 copies/mL. 4 patients subsequently had undetectable serum HBV DNA (measured over next 25–211 days); 3 patients did not have further laboratory follow-up

Posttransplant Combination HBIG + Lamivudine : 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 lamivudine

� Possible to reduce HBIG amount and overall cost

Low -Dose HBIG + Lamivudine • 147 patients

• Pretransplant • LAM if HBV DNA (+) (80% pts)

• Posttransplant • LAM + HBIG IM 400–800 IU daily ×××× 7

days • 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 - I 2

I 4

I 6

I 8

Pro

port

ion

of P

atie

nts

With

H

BV

Rec

urre

nce

Number at risk 147 124 89 56 14

Time Posttransplant (yr)

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

10000 –

1000 –

100 –

10 –

1 –

Pla

sma

[ant

i-HB

s] T

iter

1 mo 3 mo 12 mo

1 mo 3 mo 12 mo

Timepoint Posttransplant

Plasma (anti-HBs) Titers at 1, 3, and 12 mo Posttra nsplant (Horizontal Bars Demonstrate Median Values)

Long -Term Anti-HBs Titers in Patients Receiving Low -Dose HBIG + Lamivudine

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

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 In Patients Receiving HBIG Monoproph ylaxis vs Combined HBIG + Antiviral

Paul Brousse 1995-2005

Faria Gastroenterology 2008 in press

Factors independently associated with HBV recurrence:

HBV DNA at LT> 100 000 copies/ml

HCC at LT

HBIG monprophylaxis

HBV Recurrence In Patients with and without HCC Paul Brousse 1995-2005

Faria Gastroenterology 2008 In press

HBV Recurrence Is Associated with HCC Recurrence Paul Brousse 1995-2005

Faria Gastroenterology 2008 In press

Prophylaxis Protocol Place of HBIG in Combination ?

� HBIG at start is essential – Immediately makes HBsAg negative – Protects graft from immediate reinfection

� IV administration important at start – Good results also with IM immediately1 – Can be replaced safely by IM administration at medium term2

� High doses of HBIG – Important at start – Dose related to HBV DNA level at liver transplant3

– Lower doses can be used at medium term

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

Prophylaxis Protocol: Which Antiviral in Combination ?

� Almost all studies have used lamivudine � In cases of pretransplant, HBV strain resistant to lamivudine

– Cases of severe recurrence despite HBIG + LAM1,2

– Adefovir should be added to HBIG � Adefovir can be used in first line3

– Risk of escape mutation lower – Doses to be adapted in case of impaired renal clearance

� No reported experience with entecavir

1. Rosenau J et al. J Hepatol. 2001;34:895; 2. Roche B et al. Hepatology. 2003;38:86; 3. Schiff E et al. Liver Transpl. 2007;13:349

Discontinuation of HBIG ? � Arguments for discontinuation

– High cost – Constraining, high degree of compliance – Few cases of HBV reinfection after 3 yr posttransplant

� Arguments against discontinuation – Cases of long-term recurrence after discontinuation – Residual HBV DNA in >50% of patients at 10 yr1,2 – Difficult to identify patients who have cleared virus

� Open questions – Who to select? – When to stop?

� Probable consensus – Maintain prophylaxis (antiviral, vaccine)

Roche B et al. Hepatology. 2003;38:86; Hussain M et al. Liver Transpl. 2007;13:1137

Discontinuation of HBIG Replacement by Lamivudine

Buti M et al. Transplantation. 2007;84;650

LT Recipients 29 Patients Total

HBIG + LAM for 1 month Randomization

HBIG + LAM N=15

LAM N=14

HBIG + LAM N=15

LAM N=14

HBIG + LAM (N=9) HBV Recurrent (N=1)

LAM (N=14 ) HBV Recurrence (N=1)

LAM (N=6) HBV Recurrence (N=2)

N=6

18 mos

83 mos 83 mos 83 mos

Discontinuation of HBIG Replacement by Lamivudine

Wong SN et al. Liver Transplant. 2007;13:374

� 21 patients stopped HBIG – 18 patients stopped after 11 months – 3 patients stopped after 15 days

� All on lamivudine � 2 recurrence (actuarial rate of 3 year HBV recurrence 9% after HBIG

withdrawal), one following lamivudine discontinuation � Both recurrence YMDD � 3 additional patients with transient HBV DNA

17% Ab response Angelico M et al. Hepatology. 2002;35:176

62% Ab response Sanchez-Fueyo A et al. Hepatology. 2000;31:496

HBV Vaccination After Discontinuation of HBIG or LA M

80% Ab response Bienzle U et al. Hepatology. 2003;38:811

4/50 Responders Lo CM et al. J Hepatol. 2005;43:283

Lo CM et al. Am J Transplant. 2007;7:434

Efficacy of Pre S Vaccine in HBV Transplant

Patients on Lamivudine Prophylaxis

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

1000 -

100 -

10 -

1 -

Ant

i-HB

s T

iter

(mIU

/mL)

vaccination vaccination

Time (mo)

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Vaccine After Transplantation

� Great discordance in results – Results of Berlin not confirmed by others and in

larger series

– Poor tolerance to Berlin vaccine

– Durability of response?

– Response probably more frequent in FHB patients (spontaneous seroconversion boosted by vaccine?)

� How to identify patients susceptible to respond to vaccine?

36 33

18

6 0%

10%

20%

30%

40%

Ove

rall

HB

V

Rec

urre

nce

Rat

e

Lamivudine (mono)

Low-Dose HBIG

High-Dose HBIG

Lamivudine + HBIG

Strategies for Prevention of HBV Recurrence

Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120

36 33

18

6

HBIG + LAM /ADV HBIG IM + LAM /ADV HBIG + LAM /ADV HBIG + LAM Vaccination Nucleoside monoprophylaxis Nucleotide monoprophylaxis Nucleoside + nucleotide HBIG Induction Nucleoside ± nucleotide

Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120

Future Strategies for Prevention of HBV Recurrence

Liver Transplant 0.5–2 yr

Conclusion

� Major improvement with Combination HBIG + antiviral

� Questions :

– Dose of HBIG taking into account viral parameters

– Ideal antiviral:Good tolerance, low resistance profiles

– Antiviral combination alone?

– Long-term prophylaxis mandatory

� Possibibility to stop HBIG ?

� Yes in selected groups but not mandatory; best long-term concept: low

dose HBIG + antiviral

C.H.B.

NEW STRATEGIES

IN PREVENTION AND TREATMENT

TO MINIMIZE

POST-TRANSPLANT HCV RECURRENCE

Professor Didier SAMUEL

Centre H épatobiliaire ,

Inserm Unit 785 , Paris XI University

Hopital Paul Brousse , Villejuif, France

PATTERN OF HCV RECURRENCE POST OLTx

OLT

DEATH 50%

NO HEPATITIS 20%

CHRONIC HEPATITIS

ACUTE HEPATITIS 70%

CHOLESTATIC HEPATITIS

< 10 %

VIRAL RECURRENCE

1 MTH

6 MTH

CHRONIC HEPATITIS CIRRHOSIS

?

6 MTH 1 MTH

1 MTH ����

Adapted From McCaughan Adapted From McCaughan

0%

10%

20%

30%

40%

50%

0 1 2 3 4 5 Years Posttransplant

Prevalence of Cirrhosis

Cumulative probability of developing HCV-graft cirrhosis

Adapted from Gane , Berenguer

Berenguer,2002

Sanchez-Fueyo,2002

Prieto,1999

Gane,1996

Feray,1999

Neumann,2002

Poynard,1997

IC patientIC patient

Neumann, 2004

Early exponential increase followed by stabilization

(n=183)

Neumann, J hepatol 2004

0

0,5

1

1,5

2

2,5

3

1 3 5 7 10

1.2

0.25

0.08

Duration of infection (years)

Fi brosis Stage

Late-onset severe HCV-liver disease

Berenguer et al, Liver transpl 2003

N=57 with initial benign evolution (F0-1 in first bx) Late onset F: 20/57 (34%)

0

1

2

3

4

1 3 5 7 Duration of infection (years)

C.H.B.

PATIENT SURVIVAL IN LIVER TRANSPLANT PATIENTS WITH HCV CIRRHOSIS ON THE GRAFT

Patient Survival After Graft Cirrhosis First Decompensation

M Berenguer et al. Hepatology 2000; 32:852

Patients Survival After Cirrhosis on the Graft

Immunosuppression

(High level)

TH-2 like cytokine response (IL-10 & IL-4)

Immune response •Absent CD4 responses

•Stable quasispecies

HCV load

Cytopathic allograft damage

PATHOBIOLOGY of CHOLESTATIC HCV

McCaughan and Zekry J Hepatol 2004; Samuel EASL report J Hepatol 2006

IMMUNOSUPPRESSION MARKEDLY INHIBITING THE IMMUNE RESPONSE WINS

Immunosuppression

ProliferationProliferation

ApoptosisApoptosis

FibrosisFibrosis

HCV load Inflammation + IFN-γγγγ related genes

IFN-αααα response

-

Acute Rejection

Inflammation

Stress Response

The immune response

-

+

Pathobiology of Chronic HCV Post LT

McCaughan and Zekry J.Hepatol 2004, EASL Report J Hepatol 2006

Stimulation of the IMMUNE RESPONSE by more HCV WINS

C.H.B.

DYNAMIC OF HCV REPLICATION IN THE FIRST HOURS AFTER LT

Garcia-Retortillo Hepatology 2002: 35: 680

Cholestatic HCV : Intrahepatic Viral Load

(

X10

6 m

-RN

A c

opie

s / u

g R

NA

)

Chol = Cholestatic HCV post transplant AR = Acute rejection + HCV CHI = HCV post transplant CHC = HCV pre transplant

Intr

ahep

atic

vira

l loa

d

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Chol AR CHI CHC

*

Zekry et al. Liver Transplant 2002;8:292

* P = 0.005 Chol vs AR, CHI & CHC

C.H.B.

Relation Relation Between Histology and Liver Between Histology and Liver HCV RNAHCV RNA

HCV RNA HCV RNA ((CUCU))

NormalNormal cholestasischolestasis CAHCAH lobular lobular hepatitishepatitis

220220 200200 180180 160160 140140 120120 100100 8080 6060 4040 2020 00

** ** pp==0.010.01

3434

28

7 15

****

Di Martino et al. Hepatology 1997

CAHCAH AcuteAcute hepatitis hepatitis

••

••

•• ••

•• •• •• •• ••

••

•• ••

•• ••

••

••

10001000

100100

1010

11

..11

••

••

•• ••

••

••

•• ••

••

••

••

•• ••

••

••

••

••

HCV RNA Log HCV RNA Log ((CUCU))

••

p p < < 0.030.03

High HCV RNA at time of acute hepatitis Decrease of HCV RNA with progression to CAH High initial HCV RNA related with more severe CAH

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

Survival (%)

100

50

0

Neumann et al, J Hepatol 04

F at one year: 0 (n=68)

1-2 (n=76)

3-4 (n=39)

Prediction of survival based on

first year fibrosis

Blasco Hepatology 2006; 43: 492-499

HPVG, Fibrosis Stage 1 Year in HCV +ve Transplant P atients and 0utcome

Samonakis Liver Transplant 2007; 13: 1305-1311

HPVG and Fibrosis Stage (Ishak) in HCV +ve Transpla nt Patients

C.H.B.

Donor and Host Factors of

HCV Recurrence

C.H.B. Berenguer Hepatology 2002; 36: 202-210

EFFECT OF DONOR AGE ON THE DEVELOPMENT OF HCV GRAFT FIBROSIS AND CIRRH OSIS

Wali et al. Gut 2002; 51: 248-252

Cirrhosis and donor age

Fibrosis and donor age

C.H.B.

Relation Donor Age, HCV and Graft Fibrosis

Rifai J Hepatol 2004

Belli Liver Transplant 2007; 13: 733-740

Fibrosis on the Graft In HCV +ve Liver Transplant Patients

According to Donor Age and Gender

Risk of Fibrosis: Stable over years, Higher in women receiving old donors

Mutimer Transplantation 2006; 81: 7-14

Graft Survival According to Donor Age in HCV and AL D Patients

C.H.B.

HCV RECURRENCE IN LIVING DONOR TRANSPLANTATION

Garcia Retortillo Hepatology 2004; 40: 699-707

Donor Age: 47 ( 13-86) in CDLT vs 31 ( 19-58) LDL T p<0.01 Cya : 59% in CDLT vs 14% LDLT p<0.01 Biliary Complications: 22% in CDLT vs 72% in LDLT p<0.01

Humar AJT 2005; 5: 399-405

HCV Recurrence in Split, CDLT and LDLT

Histologic recurrence

Grade and stage of hepatitis C LDLT

LDLT

Takada Transplantation 2006; 81: 350-354

Patient Survival after LDLT in HCV Patients

C.H.B.

Impact of Immunosuppression on

HCV Recurrence

C.H.B.

STEROIDS AND HCV

• Controversial role

– Increase viral load (Fong Gastro 1994, Gane Gastro 1996)

– Boluses of steroids deleterious (Berenguer J Hepatol 2000)

– But rapid withdrawal deleterious (Berenguer Hepatology 2003, McCaughan J Hepatol 2004)

» Immune rebound?

– Immunosuppression without steroids: not yet proven beneficial

Klintmalm Liver Transplant 2007

HCV Recurrence in Patients Without Steroids

No différence in Patient and graft survival at 1 y ear Waiting for histological analysis long-term

Vivarelli J Hepatol 2007

Rapid Steroid Withdrawal Deleterious for Hep C Recu rrence

Group A: Rapid Steroid Withdrawal D91 Group B: Slow Decrease in steroids, Stop at M25

% patients without severe Fibrosis

C.H.B.

HCV Recurrence , Cyclosporine, Tacrolimus

• Controversial Role of Tacrolimus and Cyclosporine

• Tacrolimus Deleterious? Not proven:

– Absence of CyA independently associated with severe fibrosis (Berenguer Hepatology 2003)

– More rapid reinfection with tacrolimus (Levy Transplantation 2004, Samuel ATC 2005, Berenguer 2006)

– Better efficacy of IFN in patients treated with CyA ( Calmus AASLD 2007)

– Antiviral effect of de la CyA in replicon system (Watashi Hepatology 2003; 38: 1282-1288).

Berenguer Liver Transplant 2006

HCV and Calcineurine Inhibitors

C.H.B.

MMF and HEPC

• Induction with MMF associated with more severe recu rrence ? (Berenguer J Hepatol 2000, M Berenguer Hepatology 2003; 38:34 - 41)

• What is sure

– No antiviral action

– Deleterious or favourable impact unknown

Bahra AJT 2005; 5: 406-411

MMF And Hep C

Decrease of CNI And introduction of MMF: • Increase viral load • Decrease fibrosis • Decrease ALT

Overall Role of IS

.001 10 25 > Is double (%)

.006

.07

30

57

9

51

IFN preTH (%)

Donor age (yr)

<.0001

.002

350

4.5

249

21

Duration Pred (d)

Bolus MP

P 2001-2003 1999-2000

Berenguer J Hepatol 2006

C.H.B.

ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION

– Difficult to manage in decompensated cirrhotic pati ents

– Risk of deterioration of liver function

– Risk of sepsis, severe neutropenia, and anemia

– Poor antiviral effect at this stage

– However, some patients candidates to LT:

» Have preserved liver function (those with HCC )

» Have a long expected waiting time for LT

» Have never been treated or are ”false” non responde rs

C.H.B

ANTIVIRAL TREATMENT PRIOR LT

Treatment 48 Wks

Treatment 12-16 week

Follow-up Follow up

Follow-up

LT

Kuo, Terrault AJT 2006; 6: 449-458

Antiviral Treatment In HCV +ve Cirrhotic Patients

Before Liver Transplantation

C.H.B.

ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION

» 124 patients

• 56 Child A , 45 Child B , 23 Child C • 86 Genotype 1, 16 Genotype 2, 17 Genotype 3

» Low increase therapy • IFN (1.5MU X3/wk to 3MU after wk 2) + ribavirin (60 0 mg/d

to 800mg/d after wk 4) » SVR:

• 50% in genotype non-1, • 13% in genotype 1

» 22 complications in 15 patients ( 21 in Child B and C), 4 died » No HCV recurrence in sustained responders.

Everson Hepatology 2005

C.H.B.

ANTIVIRAL TREATMENT BEFORE TRANSPLANTATION

• Interferon + Ribavirin before LT – 30 HCV Cirrhotic pts; Child A : 15, Child BC : 15; Genotype 1b: 25

» IFN 3MU/day + Ribavirin 800 mg/day until LT » 9 (30%) virologic response » 11 patients required filgrastim and 8 required EPO » No change in LFTs » Factors of response: low viral load, low ALT, non-1 genotype » After LT:

• 6/9 responders remained HCV RNA Neg after LT, • 3 relapsed

Forns et al J Hepatol 2003

C.H.B

Risque infectieux

augmenté par trt (NS)

10/51

(20%)

15 (29%)

Factors response: G non 1,

response virologic at wk4

Pegαααα2a 180µµµµg/sem

+RBV

0,8-1g/j

Durée moyenne:

15 sem

Meld 11

51

G1:80%

51 contrôles

Carrion

(2008)

Baisse INF 60%, riba

23%

Arrêt 20%

Sepsis: 2

Insuf hépatique: 4

6/30

(20%)

9 (30%)

Facteurs réponse: charge virale pré-

trt,

Diminution charge virale de 2 log sem 4

INF 3M/j

+RBV 800

Durée moyenne:

12 sem

(2-33 sem)

A 50%

B 43%

C 7%

30

(Délai pré-TH 4 mois)

G1:83%

Pts exclus 40%

Forns

(2003)

Tolérance SVR

Post-LT

Virologic Response during trt

treatment Child Patients auteurs

TREATMENT PRE -LT

C.H.B.

ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION

• Treatment in Child A patients waiting for LT

– Group of patients with HCC on Child A cirrhosis

– Child B patients

• There is place for treatment with the increased wai ting time

• However:

– Is it possible to delay LT to achieve SVR ?

– Balance between the aim to achieve SVR and the risk of hepatic deterioration or HCC growth

– Treatment until LT with virologic response without waiting for SVR?

C.H.B.

ANTIVIRAL TREATMENT DURING TRANSPLANTATION HYPERIMMUNE ANTI-HCV INMUNOGLOBULINS (HCIG )

• Polyclonal HCIG (Davis Liver Transplant 2005) – RCT:

» HCIG 75 mg/kg 17 infusions on 14 weeks » HCIG 200 mg/Kg 17 Infusions on 14 weeks » Placebo

• Decrease of ALT, No effect on HCV RNA – Monoclonal HCV Ab XTL 68 (Schiano Liver Transplant 2006)

» - 2.4 log HCV RNA decrease in 240 mg group vs - 1.5 log in placebo at d 2, no difference at d 7

» Significant increase of anti-E2 at d 7 in 240 mg gr oup

C.H.B.

PRE-EMPTIVE TREATMENT OF HCV RECURENCE AFTER TRANSP LANTATION

– In the first post-transplant weeks:

» Low viral load

» Risk of rejection high

• Frequent presence of acute rejection and hepatitis on the same liver biopsy during the first month

» High level of Immunosuppressive treatment

» Risk of poor hematological tolerance +++:

• Severe anemia, leucopenia and thrombocytopenia

• Patients are anemic before treatment

» Septic and surgical complications frequent

Kuo, Terrault AJT 2006; 6: 449-458

Preemptive Antiviral Treatment

In HCV+ve Liver Transplant Patients

MEAN HCV VIRAL LOAD IN LIVER TRANSPLANT PATIENTS TREATED PREEMPTIVELY WITH PEGIFN ALPHA 2A

Chalasani Hepatology 2005; 41: 289-298

SVR: 8%

Shergill AJT 2005; 5: 118-124

PREEMPTIVE TREATMENT IN IN HCV LIVER TRANSPLANT PATIENTS

Adherence to Treatment ETVR and SVR

51/124 Patients eligible, 44 Received one dose of t reatment 6/124 (5%) achieved SVR

MEAN HCV VIRAL LOAD IN LIVER TRANSPLANT PATIENTS TREATED WITH PEGIFN ALPHA 2A

Chalasani Hepatology 2005; 41: 289-298

SVR : 8%

TREATMENT INTERFERON-RIBAVIRINE AFTER TRANSPLANTATION

5% NA 18% 38 IFN 3MUX3/weeks+ RBV ( 1 year)

Shakil Hepatol 02

30% 35% 42% 26 IFN 3MUX3/weeks + rbv (1 year)

Menon Liver Transp 02

22% (6M) 17%(12M

33% 23%

ND 57 IFN 3MUX3/wks + Rbv (6 vs 12 Mths)

Lavezzo J Hepatol 02

8.3% 50% 75% 12 INF 3MU x 3 / wks + Ribavirine(1-17 M )

Gopal Liver Transp 01

21.4% 32% ND 28 INF 3MU x 3 / wks + Ribavirine(12 M )

Samuel Gastro 2003

ND 48 %

24%

100% 21 IFN 3MU x 3 / week +

Ribavirine(6 M ) then Rbv(6 M )

Bizollon Hepatology 1997

SVR HCV RNA Neg

Bioch response

(%)

Pts (N)

Treatment Authors

Castells J Hepatol 2005; 43: 53-59

KINETIC OF HCV RNA ACCORDING TO VIROLOGIC RESPONSE IN HCV POSITIVE TRANSPLANT PATIENTS

C.H.B.

Treatment with PEG Interferon + Ribavirine

• 20 patients treated With Peg IFN (0.5µg/Kg to 1 µg/ Kg) +

Ribavirin 400 to 800 mg/d)

• 80% infected with genotype 1

• 4 withdrawn

• 13 required doses reduction of ribavirin due to ane mia

• End of treatment virologic response 65%

• SVR: 9/20: 45%

Dumortier J Hepatol 2004

C.H.B.

Treatment with PEG Interferon + Ribavirine

Carrion Gastroenterology 2007

27 patients mild Hepatitis C (F1-F2): SVR: 48% 27 Patients with severe hepatitis C (F3-F4) , cholestatic hepatitis C: SVR: 18% (1/12 Cholestatic hepatitis, 4/15 F3-4

C.H.B.

Histological Outcome in Relation with Virological Response to PEGIFN + Ribavirine

Carrion Gastroenterology 2007

Variables associated with Histological improvement: EVR, BR, SVR

C.H.B.

Histological Outcome and HPVG Change

Carrion Gastroenterology 2007

C.H.B.

Adverse Events During PegIFN + RBV

Carrion Gastroenterology 2007

C.H.B.

Treatment with PEG Interferon + Ribavirine

• Transpeg Study:

– 100 patients

– Peg IFN alpha 90 µg/wk + Ribavirin 600 mg/d then i ncreased to

PegIFN 180 µg/wk + Ribavirin 100 mg/d for one year

– Randomisation at M 12 placebo vs RBV maintainance

• At Week 52, 60/97 (62%) patients had a virologic re sponse by

ITT;75 % by per-protocol (PP ).

• At week 78, SVR : 34% Genotype 1- 4, 75% Genotype 2-3

• 37% Use of EPO

Calmus, Samuel AASLD 2006

C.H.B

FACTEURS PREDICTIFS DE REPONSE AU TRAITEMENT

Sharma P, et al. liver Transpl 2007;13:1100-1108 Facteurs significatifs en analyse univariée, non significatifs En analyse multivariée.

C.H.B

1 Year and Long Term Histological Outcome after Treatment In Relation With Initial Stage of Fibrosi s

Roche Liver Transplantation 2008 In Press

20% of F3-F4 patients died or were retransplanted a fter treatment vs 1% of F1-F2

C.H.B.

Predictive Factors for Response To IFN in Genotype 1 Transplant Patients

• 67 Patients

• EOT virological response: 45 %

• SVR: 33%

• Predictive factors of response:

– At baseline and on treatment:

» Peg IFN vs standard IFN

» Early virological response

» EPO use

Berenguer Liver Transplant 2006

C.H.B.

Tolerance to Treatment

• The tolerance is poor

• 40-80% rate of doses reduction

• 40-50% discontinuation rate

• Anaemia++ is the first cause of discontinuation

• EPO is required in many cases

C.H.B.

Tolerance to Treatment: Risk of Rejection

• Risk of Rejection controversial: 0-35% after IFN al one (Gane

Hepatology 98, Wright Hepatology 94, Feray Hepatology 95)

• 5% in 2 randomized studies(4%) (Samuel Gastro 03, Chalasani Hepatol 05 )

• 25-35% in non randomized studie, in patients treat ed with IFN , PEG

IFN alone or with Ribavirine (Saab Liver Transpl04, Stravitz Liver

Transplant 04, Dumortier J Hepatol 04)

• Risk of rejection not dependent of HCV RNA persiste nce

• Differences may be due to:

– Underdiagnosed in NR patients with high LFTs

– Different type and level of immunosuppression

– Different risk by using IFN , Peg IFN ± Ribavirin

Auto (Allo )immune Hepatitis and IFN

Kontorinis Liver Transplant 2006

Auto (Allo )immune Hepatitis and IFN

Sharma Liver Transplant 2007

Telaprevir (VX -950) + pegIFN: antiviral effect in treatment-naïve patients with HCV G 1

-6

-5

-4

-3

-2

-1

0

1

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

Treatment day

HCV RNA median change from baseline (log10 IU/mL)

Telaprevir + pegIFN

Telaprevir

PegIFN + placebo

Baseline

0

Reesink HW et al. EASL 2006

C.H.B.

FUTURE TREATMENT OF HCV RECURENCE AFTER TRANSPLANTATION ?

Antiprotease BILN 2061

Hinrichsen Gastroenterology 2004; 127:1347-1355

C.H.B. Bizollon Gut 2003, 52, 283-287

Histological Outcome in SVR Transplant Patients Necroinflammatory score reduction, Fibrosis Score S tability

Bizollon AJT 2005; 6: 449-458

Graft Histology In HCV +ve Liver Transplant Patients With or Without SVR

Median Follow-up : 57 Months in NR and 52 months in SVR

Bizollon AJT 2005; 6: 449-458

Survival Without Cirrhosis In HCV +ve Liver Transplant Patients With or Without SVR

Abdelmalek Liver Transplant 2004; 10: 199-207

Long -Term Histology in SVR HCV Liver Transplant Patient s

Inflammatory Score Fibrosis Score

Piciotto J Hepatol 2007; 46:459-465

Role of SVR After LT in HCV + Patients

C.H.B

EFFET DU TRAITEMENT ANTIVIRAL C SUR LA SURVIE

Berenguer M AJT 2008

C.H.B

EFFECT OF ANTIVIRAL TREATMENT ON SURVIVAL

Berenguer M AJT 2008

Piciotto J Hepatol 2007; 46:459-465

Role of SVR After LT in HCV + Patients

Belli Liver Transplant 2007; 13: 733-740

Improved Survival In HCV +ve Liver Transplant Patients

Italian Multicenter Study

Tuluvath Liver Transplant 2007;

Patient (A) and Graft (B) Survival of HCV +ve vs HCV Neg

Liver Transplant Patients

HCV Recurrence After LT Deceased vs living donors

Schmeding Liver Transplant 2007;

Tuluvath Liver Transplant 2007;

Survival of Liver Transplant Patients Over Years in USA

Tuluvath Liver Transplant 2007;

Survival of Liver Transplant Patients Over Years in USA

Lower graft Survival and no Improvement in HCV +ve Patients

HCV Positive

HCV Negative

Tuluvath Liver Transplant 2007;

Survival of HCV +ve Liver Transplant Patients in USA

Donor HCV- vs HCV +

Deceased vs LDLT

Patient Survival after Liver Transplantation in Europe

ELTR- 01/1988 - 12/2004

72

87 87 85 85 93

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

Virus B : 3162

Virus BD : 883

Virus C : 8061

Alcoholic : 10093

Yrs

(%)

81 65

66 60 55

85 81 78

74 70

PBC : 3578

68 73

HDV

HBV

HCV

>=2000 : 1410

<1985 : 10

95 to 2000 : 1196

90 to 95 : 915

85 to 90 : 287

0

.2

.4

.6

.8

1

% S

urvi

val

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

91% 86% 84%

Patient survival according to the year of LT HBV and HCV Cirrhosis

ELTR update of December 2004

0

.2

.4

.6

.8

1

% S

urvi

val

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

83% 72% 67%

HBV HCV

>=2000 : 3194

<1985 : 6

1995 to 2000 : 2705

1990 to 1995 : 1357

1985 to 1990 : 127