C.H.B.

Didier SAMUELDidier SAMUEL

C.H.B.

TREATMENT OF HEPATITIS C

BEFORE AND AFTER LIVER TRANSPLANTATION

Professor Didier SAMUEL

Centre Hépatobiliaire,

Inserm Unit 785, Paris XI University

Hopital Paul Brousse, Villejuif, France

PATTERN OF HCV RECURRENCE POST OLTx

OLT

DEATH50%

NO HEPATITIS20%

CHRONIC HEPATITIS

ACUTE HEPATITIS70%

CHOLESTATIC HEPATITIS

< 10 %

VIRAL RECURRENCE

1 MTH

6 MTH

CHRONIC HEPATITIS CIRRHOSIS

?

6 MTH1 MTH

1 MTH

Adapted From McCaughanAdapted From McCaughan

0%

10%

20%

30%

40%

50%

0 1 2 3 4 5Years Posttransplant

Pre

vale

nce o

f C

irrh

osis

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

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

C.H.B.Gane Gastroenterology 1996

SERUM HCV RNA LEVEL BEFORE AND AFTER LT

C.H.B.

DYNAMIC OF HCV REPLICATION IN THE FIRST HOURS AFTER LT

Garcia-Retortillo Hepatology 2002: 35: 680

Cholestatic HCV :Intrahepatic Viral Load

( X

106

m-R

NA

cop

ies

/ ug

RN

A)

Chol = Cholestatic HCV post transplantAR = Acute rejection + HCVCHI = HCV post transplantCHC = HCV pre transplant

Intr

ah

epa

tic v

iral

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 Between Histology and Liver HCV RNARelation Between Histology and Liver HCV RNA

HCV RNA (CU)HCV RNA (CU)

NormalNormalcholestasischolestasisCAHCAHlobular lobular hepatitishepatitis

220220200200180180160160140140120120100100808060604040202000

** p=0.01** p=0.01

3434

28

7 15

****

Di Martino et al. Hepatology 1997

CAHCAHAcute hepatitisAcute hepatitis

••

••

••••

•• ••••••••

••

••••

••••

••

••

10001000

100100

1010

11

.1.1

••

••

••••

••

••

••••

••

••

••

••••

••

••

••

••

HCV RNA Log (CU)HCV RNA Log (CU)

••

p < 0.03p < 0.03

High HCV RNA at time of acute hepatitisDecrease of HCV RNA with progression to CAHHigh 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 Patients and 0utcome

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

» Never been treated or are ”false” non responders

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 (600 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 LIVER 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.

ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION

• Treatment should be envisaged in Child A patients waiting for LT

– Group of patients with HCC on Child A cirrhosis

– Child B patients

• There is a place for the treatment with the increased waiting 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

C.H.B.

ANTIVIRAL TREATMENT DURING LIVER TRANSPLANTATION

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 AbXTL 68 (Schiano Liver Transplant 2006)

» - 2.4 log HCV RNA decrease in 240 mg (high doses) group vs

- 1.5 log in placebo at day 2, no difference at day 7

» Significant increase of anti-E2 at day 7 in 240 mg group

C.H.B.

PRE-EMPTIVE TREATMENT OF HCV RECURENCE AFTER TRANSPLANTATION

– 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 treatment6/124 (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

Authors TreatmentPts

(N)

Bioch

response (%)

HCV RNA

NegSVR

Bizollon Hepatology 1997

IFN 3MU x 3 / week + Ribavirine(6 M)

then Ribavirine (6 M)21 100%

48 %

24%

ND

Samuel

Gastro 2003INF 3MU x 3 / weeks +

Ribavirine(12 M) 28 ND 32% 21.4%

Gopal

Liver Transp 01INF 3MU x 3 / weeks +

Ribavirine(1-17 M) 12 75% 50% 8.3%

Lavezzo

J Hepatol 2002

IFN 3MUX3/weeks + Ribavirin (6 vs 12

Mths)57 ND

33%

23%

22% (6M)

17%(12M)

Menon

Liver Transp 2002IFN 3MUX3/weeks +

ribavirin (1 year) 26 42% 35% 30%

Shakil

Hepatol 02IFN 3MUX3/weeks+

RBV ( 1 year) 38 18% NA 5%

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 anemia

• End of treatment virologic response 65%

• SVR: 9/20: 45%

Dumortier J Hepatol 2004

C.H.B.

Treatment with PEG Interferon + Ribavirine• Transpeg Study:

– 100 patients

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

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

– Randomisation at one year placebo vs ribavirin maintainance

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

Castells J Hepatol 2005; 43: 53-59

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

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 alone (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 treated 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 persistence

• Differences may be due to:

– Underdiagnosed in NR patients with persistent 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

C.H.B.

Tolerance to Treatment

• Rejection does exist

– Rate: variable

– Type: variable: acute, chronic

• “Allo or autoimmune“ hepatitis

– During or after end of treatment

• Viral load rebound and deterioration of LFTs

– At the end of treatment

– More severe in F3-F4 patients

• Fatal liver failure observed in F3-F4 patients (personal communication)

C.H.B.

How to Improve the Efficacy of Treatment

• Avoid reduction or discontinuation of IFN or RBV

– Adapt dosage of Ribavirin to renal clearance

– Use of EPO ++( 40% of patients)

– Maintain treatment >6 months after serum HCV RNA clearance

• Duration to be adapted to the kinetic of HCV RNA level decline

• New drugs: Viramidine, Albuferon, Protease, polymerase

inhibitors…?

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

Histological Outcome in SVR Transplant PatientsNecroinflammatory score reduction, Fibrosis Score Stability

Abdelmalek Liver Transplant 2004; 10: 199-207

Long-Term Histology in SVR HCV Liver Transplant Patients

Inflammatory Score Fibrosis Score

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

C.H.B.

FUTURE TREATMENT OF HCV RECURENCE

AFTER TRANSPLANTATION ?

Antiprotease BILN 2061

Hinrichsen Gastroenterology 2004; 127:1347-1355

Patient Survival after Liver Transplantation in Europe

ELTR- 01/1988 - 12/2004

72

87 87 85 8593

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

(%)

8165

6660 55

8581 78

7470

PBC : 3578

6873

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

urv

ival

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

91% 86% 84%

Patient survival according to the year of LTHBV and HCV Cirrhosis

ELTR update of December 2004

0

.2

.4

.6

.8

1

% S

urv

ival

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

83% 72% 67%

HBV HCV

>=2000 : 3194

<1985 : 6

1995 to 2000 : 2705

1990 to 1995 : 1357

1985 to 1990 : 127

C.H.B.

CONCLUSION AND PERSPECTIVES

• Rate of HCV reinfection high

• No improvement in survival in the past years

• HCV fibrosis more rapid and severe than in non-transplant patients

• Improvement in antiviral treatment.

– SVR in treated patients: 30-40% genotype 1, 60-70% Genotype 3

– But not all patients can be treated

– EPO necessary in 40% of patients

C.H.B.

CONCLUSION AND PERSPECTIVES

• Better understanding of mechanisms of fibrosis progression

• Better evaluation of fibrosis progression

– Routine liver biopsy ++

– Non invasive fibrosis monitoring

» Fibroscan (elastometry)

» Fibrotest

C.H.B.

CONCLUSION AND PERSPECTIVES

• Timing for antiviral treatment to be determined:

– Preemptive treatment difficult or imposible in most cases

– At time of acute hepatitis?

– At time of chronic hepatitis? Yes, but when?

» Not too late (before 2 years in most cases)

• Results better in F1-F2 patients (to be confirmed)

• Complications more severe in F3-F4 patients

• Prevention of severe fibrosis

• Fibrosis slowly or not reversible

• Improvement of efficacy and tolerance of antiviral treatments

• Non-antiviral treatments: antifibrotics