samuel hcv lt
TRANSCRIPT
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C.H.B.
HCV PRE AND POST-LIVER TRANSPLANTATION
Professor Didier SAMUEL
Centre Hépatobiliaire,
Inserm Unit 785, Paris XI University
Hopital Paul Brousse, Villejuif, France
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C.H.B.
Evolution of Liver Transplantation for Viral Cirrhosis
in Europe.
With HCCWithout HCC
0
100
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800
1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Virus Delta Virus B Virus C
0
100
200
300
400
500
600
700
800
1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Virus Delta Virus B Virus C
www.eltr.org
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Trends in Waiting List for HCV Cirrhosis in USA
Kim Gastroenterology 2009
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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 McCaughan
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McCaughanJ Hepatol 2011
CHOLESTATIC HEPATITIS C
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FIBROSING CHOLESTATIC HEPATITIS C
Antonini AJT 2011
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FCH in HCV-HIV Coinfected PatienstImpact on Survival
Antonini AJT 2011
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Immunosuppression
Proliferation
Apoptosis
Fibrosis
HCV load Inflammation +
IFN- related genes IFN- 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
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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
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Blasco Hepatology 2006; 43: 492-499
HPVG, Fibrosis at 1 Year Post-Transplant and Outcome
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Gallegos-Orozco Liver Transplant 2009
Fibrosis Stage at 12 months at Liver Biopsy and Survival
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Carrion Gastro 2010
Non Invasive 3-MALG Test and
Decompensation and Survival Post-Transplant
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Carrion Hepatology 2010
Liver Stiffness and Severity of HCV Recurrence
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C.H.B.
Donor and Host Factorsof
HCV Recurrence
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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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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)
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No Impact of Steroid-Free IS on Graft HCV Fibrosis
Klintmalm Liver Transplant 2011
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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 fibrosis stage, better survival with Tac?
Samonakis, J Hepatol 2012 in Press, Berenguer Nat Rev Gastroenterol 2011
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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
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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
» 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.
Authors Patients Child Treatment Virologic Response EOT
SVRPost-LT
Tolerance
Forns(2003)
30(Time pre-
LT 4 mths)
G1:83%
A 50%B 43%C 7%
INF 3M/d+RBV 800mgMean
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)
51G1:80%
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
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Antiviral Treatment in Patients Waiting
for Liver Transplantation, Risk of Sepsis Related to CPT
Carrión JA et al. J Hepatol. 2009;50:719-28.
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Antiviral Treatment in Patients Waiting
for Liver Transplantation, Norfloxacin Prophylaxis
Carrión JA et al. J Hepatol. 2009;50:719-28.
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C.H.B.
PegIFN + RBV Before LT
• Treatment PegIFN+RBV until LT
– 47 G1/4/6 patients
» 30 treated
» 17 not treated
• 32 G2/3 patients treated
» 29 treated
» 3 not treated
Everson Hepatology 2012
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C.H.B.
PegIFN + RBV Treatment Before LT
Everson Hepatology 2012
Meld score: 12, CTP score : 7
Serious Infection rate: 7/59 (12) pts vs 0% control
Death pre-LT: 5/59 vs 2/20 (NS)
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Roche, Samuel Liver Int 2012
Antiviral Treatment Before Transplantation
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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
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C.H.B.
Study ANRS HC29BOCEPRETRANSPLANT
Pilot study of Efficacy and Tolerablity of Boceprevir in combination with Peginterferon alpha-2b and Ribavirin in patients infected with HCV
genotype 1, naive or non responders with cirrhosis awaiting liver transplantation
Promoteur : ANRS
Coordinating investigator : Didier SamuelCo-investigators :
JC Duclos-Vallée, H Fontaine, B Roche
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C.H.B.
Inclusion criteria
• Age > 18 years• Chronic HCV infection proved with a positive HCV PCR
during 6 months or more• Genotype 1• Patient with cirrhosis and registered for LT• MELD score ≤ 18• With or without hepatocellular carcinoma• Naïve or non responders
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Feray J Hepatol 2011
Strategies Before and After Transplantation
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Zeisel J Hepatol 2011
Mechanism of HCV Entry
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Roche, Samuel Liver Transplant 2010
Antiviral Treatment Immediately after Transplantation
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C.H.B.
Antiviral Therapy PegINF+ RBV Post-TransplantationAuthors Studie
sPatients Years ETVR SVR Tolerance AR Factors
linked with SVR
Wang 21 (1RCT)
587 1980-05 42%(30-37)
27% (23-31)
Reduction 66% (61-70%)Stop: 26% ( 20-32)
5%(3-7)
No prior antiviral tt post-LTNon-1 G
Berenguer 19 (2RCT)
611 2004-07 42%(17-68)
30%G1: 28%G2: 71-100%G3:41% (30-77%)
Reduction:68%Stop 28%
6.4% EVRG2AdherenceBaseline viremia
Xirouchakis 6 RCT 264 2005-07 - 30%G1: 29%G2: 71-100%G3: 41% ( 30-77)
- 5%
Roche, Samuel Liver Int 2012, Wang AJT 2006, Berenguer J Hepatol 2008, Xirouchakis J Viral Hep 2008
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Auto(Allo)immune Hepatitis and IFN
Sharma Liver Transplant 2007
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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)
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C.H.B.
SVR and IL28 in all Genotype Transplant Patients
Lange J Hepatol 11
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C.H.B.
SVR According to IL 28
Charlton Hepatology 2011
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C.H.B.
Survival (Death and Graft Loss) According to IL 28
Charlton Hepatology 2011
IL 28 Recipient IL 28 Donor
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C.H.B.
IL 28 In the Donor should be determined on Graft Reperfusion Biopsy or PBMC, not on follow-up Biopsies
Coto-Llorena J Hepatol 2012
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C.H.B.
SVR According to IL 28 in Recipient, Donor, and FU Biopsy
Coto-Llorena J Hepatol 2012
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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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Piciotto J Hepatol 2007
Impact of SVR on Suvival in Transplant HCV + Patients
Berenguer M AJT 2008
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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
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Garg Hepatology 2011
Telaprevir and Cyclosprine and Tacrolimus Interactions
Cmax increased by 1.4X
AUC Increased by 4.1-4.6X
T1/2 increased by 4 X
Cmax increased by 9.3X
AUC Increased by 70X
T1/2 increased by 5 X
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Healthy volunteers Liver transplant patients
Alone Boce0
20
40
60
80
100
Alone Boce0
2
4
6
8
10
12
• Boceprevir in 5 transplant patients: the estimated oral clearance decreased
• Cyclosporine (n=3): 50% • Tacrolimus (n=2): up to 80%• Everolimus (n=1): 55%
Coilly, AAC, 2012
Cla
iranc
e or
ale
(L/h
)
Cyclosporine Tacrolimus
• CNI, cyclosporine or tacrolimus• PI: CYP 3A4 potent inhibitors• AUC increase
Garg, Hepatology, 2011Hulskotte, Hepatology, 2012
Boceprevir Telaprevir
Cyclosporine 2.7 4.6
Tacrolimus 9.9 70
Treatment After LT with Protease Inhibitors
One limitation: drug-drug interactions
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• Cohort study, N=37• 5 transplant centers in France
Villejuif, Lyon, Grenoble, Marseille, Montpellier
• Inclusion criteria:• Active genotype 1 HCV chronic hepatitis• HCV recurrence, ≥ F2 or cholestatic hepatitis• Steady-state of immunosuppressive regimen• No contraindication for protease inhibitors, PEG-IFN/RBV
French Collaborative study
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PEG-IFN/RBV PEG-IFN/RBV+Boceprevir (800mg tid)
PEG-IFN/RBV PEG-IFN/RBV+Telaprevir (750mg tid)
PEG-IFN/RBV+Telaprevir (750mg tid)
Week -4 Week 0 Week 4 Week 12
n=18
n=8
n=11
W48
Patients and Methods
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C.H.B.
DAA Post-TransplantationPractical Issues
Coilly Liver Int 2013
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ITT ITTPP PP
Bocéprévir (n=18) Télaprévir (n=19)
89%
63%
89%
75%
ITT ITTPP PP
Bocéprévir (n=13) tELA
64%
50%
67%
50%
ITT PP
p=ns p=ns
Virological response
EVR at Week 12 ETVR at Week 48
Boceprevirn=18
Telaprevirn=19
Boceprevirn=13
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S-4 S2 S4 S8 S12 S16 S20 S24 S28 S32 S36 S40 S44 S480
1
2
3
4
5
6
7
8
9
Mean treatment duration: 42 ± 8.7 weeks
Treatment discontinuation Null response, n=1 Virological breakthrough , n=1 Adverse events, n=2
End of treatment with undetectable viral load, n=7
On going, n=7
HCV
vira
l loa
d (lo
g 10
IU/m
L)
Treatment duration
Boceprevir group, n=18
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Mean treatment duration: 33 ± 10.2 weeks
S-4 S0 S4 S8 S12 S16 S20 S24 S28 S32 S36 S40 S44 S480
1
2
3
4
5
6
7
8
9
On going, n=10
HCV
vira
l loa
d (lo
g 10
IU/m
L)
Treatment duration
Telaprevir group, n=19
Treatment discontinuation Null response, n=4 Virological breakthrough , n=2 Adverse events, n=2
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Boceprevir (n = 18)
Telaprevir (n = 19) p
Death – n°(%) 1 (5 %) 1 (5 %) ns
Infections – n° (%) 3 (17 %) 4 (21 %) ns
Hematotoxicity – n° (%)Anemia< 10 g/dL< 8 g/dLNeutropenia (<1 G/L)Thrombopenia (< 50 G/L)
18 (100 %)7 (39 %) 11 (61 %)5 (28 %)
16 (84 %)3 (15 %) 4 (21 %)3 (15 %)
ns
Dermatological toxicity –n° (%) 1 (5 %) 1 (5 %) ns
Renal failure – n° (%) 0 2 (9 %) ns
Diabetes mellitus – n° (%) 2 (10 %) 0 (26%) ns
Adverse events
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Boceprevir Telaprevir
CNI dose reduction
Cyclosporine 1.8 3.4
Tacrolimus 5.2 23.8
CNI-PI interactions
• Dose reduction of CNI constantly required• No overdose• No biopsy-proven acute rejection
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C.H.B.
Evolution of Liver Transplantation for Viral Cirrhosis
in Europe.
With HCCWithout HCC
www.eltr.org
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C.H.B.
Evolution of Patient Survival after LT for Virus C
Cirrhosis without HCC in Europe (ELTR: 1988-2010)www.eltr.org
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C.H.B.
DAA Post-TransplantationThe future Possibilities
Mc Caughan J Hepatol 2012
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C.H.B.
DAA Post-TransplantationThe Hope of Non-IFN Based Therapies
Mc Caughan J Hepatol 2012
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C.H.B.
PegIFN +RBV+Daclatasvir for FCH after LT
Fontana Liver Transpant 2012
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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
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C.H.B.
CONCLUSION
• Triple antiviral therapies with IFN in cirrhotics remains difficult
– Increase in SVR expected
– High rate of anemia , risk of sepsis and death
– Strategies to improve tolerance are necessary
– Treatment without IFN are strongly awaited
• First results of triple therapies after LT are encouraging
– Increased virologic response
– Acceptable tolerance and drug-drug interactions manageable
– Treatment without IFN awaited but IFN might remain
necessary in some patients