C.H.B. Didier SAMUEL. C.H.B. TREATMENT OF HEPATITIS C BEFORE AND AFTER LIVER TRANSPLANTATION...
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Transcript of C.H.B. Didier SAMUEL. C.H.B. TREATMENT OF HEPATITIS C BEFORE AND AFTER LIVER TRANSPLANTATION...
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