samuel transplant foie
TRANSCRIPT
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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
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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
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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
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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?
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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
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C.H.B.
HBV Recurrence According to Initial Liver Disease
D. Samuel et al. NEJM 1993;329:1842-7
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C.H.B. D. Samuel et al. NEJM 1993;329:1842-7
HBV Recurrence According to HBV Prophylaxis
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C.H.B.
Survival In Relationship with Type of HBV Prophylax is
D. Samuel et al. NEJM 1993;329:1842-7
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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)
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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
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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)
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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]
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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
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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
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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)
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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
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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
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HBV Recurrence in Relation to
Pretransplant PCR HBV DNA Level
Lamivudine Monoprophylaxis Lamivudine + HBIG Prophylaxis
Marzano A et al. Liver Transpl. 2005;11:402
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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
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HBV Recurrence In Patients with and without HCC Paul Brousse 1995-2005
Faria Gastroenterology 2008 In press
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HBV Recurrence Is Associated with HCC Recurrence Paul Brousse 1995-2005
Faria Gastroenterology 2008 In press
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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
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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
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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
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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
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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
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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
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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)
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
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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?
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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C.H.B.
DYNAMIC OF HCV REPLICATION IN THE FIRST HOURS AFTER LT
Garcia-Retortillo Hepatology 2002: 35: 680
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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
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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
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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
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Blasco Hepatology 2006; 43: 492-499
HPVG, Fibrosis Stage 1 Year in HCV +ve Transplant P atients and 0utcome
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Samonakis Liver Transplant 2007; 13: 1305-1311
HPVG and Fibrosis Stage (Ishak) in HCV +ve Transpla nt Patients
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C.H.B.
Donor and Host Factors of
HCV Recurrence
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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
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C.H.B.
Relation Donor Age, HCV and Graft Fibrosis
Rifai J Hepatol 2004
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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
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Mutimer Transplantation 2006; 81: 7-14
Graft Survival According to Donor Age in HCV and AL D Patients
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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
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Humar AJT 2005; 5: 399-405
HCV Recurrence in Split, CDLT and LDLT
Histologic recurrence
Grade and stage of hepatitis C LDLT
LDLT
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Takada Transplantation 2006; 81: 350-354
Patient Survival after LDLT in HCV Patients
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C.H.B.
Impact of Immunosuppression on
HCV Recurrence
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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
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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
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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
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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).
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Berenguer Liver Transplant 2006
HCV and Calcineurine Inhibitors
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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
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Bahra AJT 2005; 5: 406-411
MMF And Hep C
Decrease of CNI And introduction of MMF: • Increase viral load • Decrease fibrosis • Decrease ALT
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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
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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
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C.H.B
ANTIVIRAL TREATMENT PRIOR LT
Treatment 48 Wks
Treatment 12-16 week
Follow-up Follow up
Follow-up
LT
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Kuo, Terrault AJT 2006; 6: 449-458
Antiviral Treatment In HCV +ve Cirrhotic Patients
Before Liver Transplantation
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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
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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
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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
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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?
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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
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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
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Kuo, Terrault AJT 2006; 6: 449-458
Preemptive Antiviral Treatment
In HCV+ve Liver Transplant Patients
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MEAN HCV VIRAL LOAD IN LIVER TRANSPLANT PATIENTS TREATED PREEMPTIVELY WITH PEGIFN ALPHA 2A
Chalasani Hepatology 2005; 41: 289-298
SVR: 8%
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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
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MEAN HCV VIRAL LOAD IN LIVER TRANSPLANT PATIENTS TREATED WITH PEGIFN ALPHA 2A
Chalasani Hepatology 2005; 41: 289-298
SVR : 8%
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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
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Castells J Hepatol 2005; 43: 53-59
KINETIC OF HCV RNA ACCORDING TO VIROLOGIC RESPONSE IN HCV POSITIVE TRANSPLANT PATIENTS
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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
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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
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C.H.B.
Histological Outcome in Relation with Virological Response to PEGIFN + Ribavirine
Carrion Gastroenterology 2007
Variables associated with Histological improvement: EVR, BR, SVR
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C.H.B.
Histological Outcome and HPVG Change
Carrion Gastroenterology 2007
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C.H.B.
Adverse Events During PegIFN + RBV
Carrion Gastroenterology 2007
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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
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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.
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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
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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
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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
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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
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Auto (Allo )immune Hepatitis and IFN
Kontorinis Liver Transplant 2006
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Auto (Allo )immune Hepatitis and IFN
Sharma Liver Transplant 2007
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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
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C.H.B.
FUTURE TREATMENT OF HCV RECURENCE AFTER TRANSPLANTATION ?
Antiprotease BILN 2061
Hinrichsen Gastroenterology 2004; 127:1347-1355
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C.H.B. Bizollon Gut 2003, 52, 283-287
Histological Outcome in SVR Transplant Patients Necroinflammatory score reduction, Fibrosis Score S tability
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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
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Bizollon AJT 2005; 6: 449-458
Survival Without Cirrhosis In HCV +ve Liver Transplant Patients With or Without SVR
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Abdelmalek Liver Transplant 2004; 10: 199-207
Long -Term Histology in SVR HCV Liver Transplant Patient s
Inflammatory Score Fibrosis Score
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Piciotto J Hepatol 2007; 46:459-465
Role of SVR After LT in HCV + Patients
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C.H.B
EFFET DU TRAITEMENT ANTIVIRAL C SUR LA SURVIE
Berenguer M AJT 2008
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C.H.B
EFFECT OF ANTIVIRAL TREATMENT ON SURVIVAL
Berenguer M AJT 2008
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Piciotto J Hepatol 2007; 46:459-465
Role of SVR After LT in HCV + Patients
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Belli Liver Transplant 2007; 13: 733-740
Improved Survival In HCV +ve Liver Transplant Patients
Italian Multicenter Study
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Tuluvath Liver Transplant 2007;
Patient (A) and Graft (B) Survival of HCV +ve vs HCV Neg
Liver Transplant Patients
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HCV Recurrence After LT Deceased vs living donors
Schmeding Liver Transplant 2007;
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Tuluvath Liver Transplant 2007;
Survival of Liver Transplant Patients Over Years in USA
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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
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Tuluvath Liver Transplant 2007;
Survival of HCV +ve Liver Transplant Patients in USA
Donor HCV- vs HCV +
Deceased vs LDLT
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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
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>=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