C.H.B.

LIVER TRANSPLANTATION

IN VIRAL HEPATITIS

Natural Course, Overview

Didier SAMUEL, M.D.

Professor of Hepatology

CENTRE HEPATOBILIAIRE

INSERM PARIS XI UNIT 785

HOPITAL PAUL BROUSSE

VILLEJUIF, FRANCE

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Virus Delta Virus B Virus C

Evolution of Liver Transplantation

For Viral Cirrhosis without HCC in Europe

ELTR

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Virus Delta + HCC Virus B + HCC Virus C + HCC

Evolution of Liver Transplantation

For Viral Cirrhosis with HCC in Europe

ELTR

C.H.B.

LIVER TRANSPLANTATION

IN VIRAL HEPATITIS B

Natural Course, Overview

Liver Transplantation for Viral B Cirrhosis in USA

Kim WR Gastro 09

Prophylaxis of HBV Infection

Posttranplantation

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

Before transplantation

– Lamivudine or adefovir

– Nucleos(t)ide analogues

After transplantation

– Anti-hepatitis B immunoglobulins (HBIG)

– Lamivudine or Adefovir, or ETV monoprophylaxis

– Combination HBIG + lamivudine/adefovir

– Combination HBIG + nucleos(t)ide analogue

C.H.B.

Prophylaxis after

Liver Transplantation

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

HBV Recurrence and Survival

According to 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 in Relation

to Initial Liver Disease

Hôpital Paul Brousse: 19862000

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

56.554.4

49.449.4 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

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]

HBV Recurrence with Lam Monoprophylaxis

A Great Failure

Jiang WJG 2009

ETV Monoprophylaxis after LT

80 Patients

Mean follow up

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 in Press

Fung Gastro 2011 in Press

HBsAg Clearance after LT on ETV Monoprophylaxis

Fung Gastro 2011 in Press

HBsAg Relapse after LT on ETV Monoprophylaxis

Virology

HBV DNA and HBsAg Used 2 Distinct Pathways

Nguyen J Hepatol 2010Brunetto J Hepatol 2010

Antiviral alone not able to block HBsAg

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

Factors independently associated

with HBV recurrence:

• HBV DNA at LT> 105 copies/ml

• HCC at LT

• HBIG monoprophylaxis

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

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I

8P

rop

ort

ion

of

Pa

tie

nts

Wit

h

HB

V R

ec

urr

en

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Number

at risk147 124 89 56 14

Time Posttransplant (yr)

HBV Recurrence In Patients with and without HCC

Paul Brousse 1995-2005

Faria L. Gastroenterology 2008

HBV Recurrence Is Associated with HCC Recurrence

Paul Brousse 1995-2005

Faria L. Gastroenterology 2008

HBV Recurrence Is Associated with HBV DNA at LT

USA

Degertekin 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

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

Absence or Discontinuation of HBIG?

Cost?

Highly variable

– Depending countries, preparations ( ratio 1 to 4)

– High doses needed only at the start to control HBs Ag

– Medium term

Low doses in combination protocols

Decreased cost

Cost to be compared to combination new generation Nucs

Discontinuation of HBIG?

Few cases of HBV reinfection after 1-2 year

Yes but:

– Only if HBIG prophylaxis given

– On Lam, HBV reinfection cases increase with time

– Cases of long-term recurrence after discontinuation

– Residual HBV DNA in > 50% -70% of patients at 10 yr1,2

– Difficult to identify patients who have cleared virus

Roche Hepatology 2003, Hussain Liver Transplant 2007

Discontinuation of HBIG?

HBV Reinfection no more severe,

Nucs alone will give the same results?

HBV Reinfection no more severe?

– True if well monitored, but will be reinfected anyway

– Untrue if monitoring inaccurate, severe HBV reactivation

Nucs alone will give the same results?

– At best, it will be a non-inferiority comparison

– Will always be less good 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 + 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%)

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 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

Lenci I. J Hepatol 2011

Discontinuation of HBV Prophylaxis after LT :

Patients with HBV recurrence

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33

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6

0%

10%

20%

30%

40%

Ove

rall

HB

V

Recu

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ate

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

3633

18

6

Conclusion

HBIG + Nuc the Best combination at the start

At mid-term

– HBIG can be stopped in patients with low risk recurrence

Spontaneous HBV DNA negative patients at LT

FHF Patients

If Nuc are maintained

– In high risk Patients:

HBV DNA +ve at LT, HCC, HIV coinfection

Low dose HBIg + Nuc remain the best combination

C.H.B.

HCV AND LIVER TRANSPLANTATION

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 MTH1 MTH

1 MTH

Adapted From McCaughan

McCaughan

J Hepatol 2011

CHOLESTATIC HEPATITIS C

Immunosuppression

Proliferation

Apoptosis

Fibrosis

HCV loadInflammation +

IFN- related genesIFN-response

-

Acute Rejection

Inflammation

Stress Response

The immune response

-

+

Pathobiology of Chronic HCV Post LT

McCaughan and Zekry J.Hepatol 2004, Samuel Easl Hepatol 2006

Stimulation of the IMMUNE

RESPONSE by more HCV WINS

T Pietschmann Nature 2009

HCV Entry in Hepatocyte

Ciesek Gastro 2010, Fafi Kremer J Hepatol 2010

Streoids Increase HCV Entry in Liver Transplantation

Gc: Glucocorticoids

Gr: Glucocorticoid

Receptor

Fofana Gastro 2010

Additive Effect of Anticlaudin, AntiE2 and HCVIg

on HCV Entry and Infection

C.H.B.

• Liver Biopsy

Gold Standard,

Bring additional information than fibrosis stage

. HPVG

Invasive, can be done with liver biopsy

Not routine for many Centres

. Non invasive tests

Biochemical

Elastometry (fibroscan)

. Time post-LT as an adding variable

EVALUATION OF THE SEVERITY OF HCV RECURRENCE

Blasco Hepatology 2006; 43: 492-499

HPVG, Fibrosis at 1 Year Post-Transplant and Outcome

Gallegos-Orozco Liver Transplant 2009

Fibrosis Stage at 12 months at Liver Biopsy and Survival

Carrion Gastro 2010

Non Invasive Test (3-M-ALG) and HPVG at 6 and 12 Months

in Control and HCV Reinfected Patients

Carrion Gastro 2010

Non Invasive 3-MALG Test

and

Decompensation and Survival Post-Transplant

Carrion Hepatology 2010

Liver Stiffness and Severity of HCV Recurrence

C.H.B.

Donor and Host Factorsof

HCV Recurrence

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

EFFECT OF DONOR AGE

ON THE DEVELOPMENT OF HCV GRAFT FIBROSIS AND CIRRHOSIS

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

Cirrhosis and donor age Fibrosis and donor age

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

C.H.B.

STEROIDS AND HCV

• Controversial role

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

– Increase viral hepatocyte entry (Gastro 2010)

– Boluses of steroids deleterious (Berenguer J Hepatol 2000)

– Rapid withdrawal deleterious (Berenguer Hepatology 2003,

McCaughan J Hepatol 2004, Vivarelli J Hepatol 2007)

» Immune rebound?

– Immunosuppression without steroids: not yet proven beneficial

(Klintmaln Liver Transplant 2007)

Vivarelli J Hepatol 2007

Rapid Steroid Withdrawal Deleterious for Hep C Recurrence

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 vs Tacrolimus

• There is currently no proof of superiority of one vs another

– Antiviral effect of Cyclosporine only in vitro

– Better efficacy of IFN in Ciclosporine patients not confirmed

– Randomized studies showed earlier reinfection with Tac but no

difference in survival and fibrosis stage

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29

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60

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80

1999-2000 (n=52) 2001-2003 (n=90)

F3,4,FCH FCH AH

Overall Role of IS

1999-2000 2001-2003 P

Duration Pred (d)

Bolus MP

249

21

350

4.5

<.0001

.002

> Is double (%) 25 10 .001

IFN preTH (%)

Donor age (yr)

9

51

30

57

.006

.07

Berenguer

J Hepatol 2006

C.H.B.

ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION

– Difficult to manage in decompensated cirrhotic patients

– 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 responders

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

» 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

Authors Patients Child Treatment Virologic Response EOT

SVR

Post-LT

Tolerance

Forns

(2003)

30

(Time pre-LT 4

mths)

G1:83%

A 50%

B 43%

C 7%

INF 3M/d

+RBV 800mg

Mean Duration :

12 wks

(2-33 wks)

9 (30%)

Factors for response : viral

laod pre-LT,

Decrease viral load≥ 2 log Wk 4

6/30

(20%)

Decrease INF 60%, RBV

23%

Stop 20%

Sepsis: 2

Liver Failure: 4

Carrion

(2008)

51

G1:80%

51 controls

Meld 11

Peg2a 180g/wk

+RBV

0,8-1g/d

Mean duration: 15 Wks

15 (29%)

Factors response: G non 1,

RVR Wk4

10/51

(20%)

infectious risk

increased by Trt (NS)

ANTIVIRAL TREATMENT PRE-LT

Forns J Hepatol 2003, Carrion J Hepatol 2008

Roche, Samuel Liver Transplant 2010

Antiviral Treatment Before Transplantation

Roche, Samuel Liver Transplant 2010

Antiviral Treatment Immediately after Transplantation

C.H.B.

PegIFN+RBV for Established Infection after Transplantation

• SVR: 25-45%

– Genotype 1: 30-35%

– Genotype 2-3: 60-70%

• Variables associated with SVR:

– Non-1 Genotype

– EVR, RVR

– Adherence to therapy

– Low pretreatment viral load

Berenguer J Hepatol 2008, Roche Liver Transplant 2010

C.H.B.

Treatment with PEG IFN + RBV After LT

SVR Dependent of Fibrosis stage

• 27 Pts mild Hepatitis C (F1-F2): SVR 48%

• 27 Pts severe hepatitis C (F3-F4), Cholestatic Hepatitis: SVR 18%

• F3-4: 4/15

• Cholestatic hepatitis, 1/12 ( Carrion Gastro 2007)

• 20% F3-F4 vs 1% F1 Patients died or were retransplanted ( Roche

Liver transplant 2008)

C.H.B.

SVR and Snp near IL28 gene in Donor, Recipient, Combined in Genotype 1 Transplant Patients

Fukuhara Gastro 2010 In Press

C.H.B.

SVR and IL28 mRNA expression in Transplant Liver in Genotype 1 Transplant Patients

Fukuhara Gastro 2010 In Press

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 ( > 30%)

• Risk of rejection and alloimmune hepatitis ( 2-15%)

Auto(Allo)immune Hepatitis and IFN

Sharma Liver Transplant 2007

C.H.B.

Histological Outcome in Relation with Virological Response to PEGIFN+ Ribavirine

Carrion Gastroenterology 2007

Variables associated with Histological improvement: EVR, BR, SVR

Piciotto J Hepatol 2007; 46:459-465

Role of SVR After LT in HCV + Patients

McHutchison NEJM 09

Telaprevir In Naive HCV Non-Transplant Patients

C.H.B.

Direct Antiviral Agents Before LTA New Challenge

• Data In cirrhotic patients are lacking

• Therapies with IFN will remain poorly tolerated

• Increase possibility to achieve SVR or on treatment

virologic response

• Increase risk of virologic breakthrough

• Duration, safety issues to be analysed

• Therapies without IFN awaited

C.H.B.

Direct Antiviral Agents After LTA New Challenge

• Increase possibility to achieve SVR or on treatment virologic

response

• Interaction between anti NS3 protease and calcineurin

inhibitors

• Duration, safety issues to be analysed

• Therapies without IFN awaited

Interaction Telaprevir-Cyscloporine, Telaprevir-Tacrolimus

Garg Hepatology 2011

Dose normalised AUC X 4.5 Dose-normalised AUC X 70

Virus D (n=1148)

Virus C (n=8545)

Virus B (n=3398)

0

,2

,4

,6

,8

1

Surv

ie C

um

.

0 1 2 3 4 5 6 7 8 9 10

Years

82%73%

67%81%

67%

55%

92%88%

85%

0

,2

,4

,6

,8

1

Surv

ie C

um

.

0 1 2 3 4 5 6 7 8 9 10

Years

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 Transplantation

For Viral Cirrhosis in Europe

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

With HCCWithout HCC

Before 1990

After 2005

1995 to 2000

1990 to 1995

2000 to 2005

0

,2

,4

,6

,8

1Surv

ie C

um

.

0 1 2 3 4 5 6 7 8 9 10

Years

Evolution of Patient Survival after LT

For Viral Cirrhosis without HCC in Europe

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

0

,2

,4

,6

,8

1Surv

ie C

um

.

0 1 2 3 4 5 6 7 8 9 10

Years

Before 1990

After 2005

1995 to 2000

1990 to 1995

2000 to 2005

Evolution of Patient Survival after LT

For Virus C Cirrhosis without HCC in Europe

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

Patient survival according to the year of LT

HBV CirrhosisELTR 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%

C.H.B.

CONCLUSION

• Survival still affected by HCV recurrence

• Monitoring combining liver biopsy and non invasive methods

• Treatment before Transplantation poorly effective

– SVR before LT , no recurrence post-LT

– HCVRNA negativity at LT, Risk of post transplant recurrence

reduced by 70%

• Treatment after transplantation :

– Effective at time of Chronic hepatitis before the F3 stage

» 30-40% SVR in G1 Patients

» 70% SVR in G2-G3 Patients

C.H.B.

CONCLUSION

• Advent of Direct antiviral agents will open a new era

• Before LT: Presence of IFN in the treatment arm will remain a

limitating factor

• After LT: new strategies will arise

• Viral breakthrough, tolerance, interaction with calcineurin

inhibitors, treatment duration:

– Open questions for the close future