HCV PRE AND POST-LIVER TRANSPLANTATION
Professor Didier SAMUEL
Centre Hépatobiliaire,
Inserm Unit 785, Paris XI University
Hopital Paul Brousse, Villejuif, France
C.H.B.
Evolution of Liver Transplantation for Viral Cirrhosis
in Europe.
Without HCC
With HCC
800
800
700
700
600
600
500
500
400
400
300
300
200
200
100
100
0
0
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
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
C.H.B.
Trends in Waiting List for HCV Cirrhosis in USA
Kim Gastroenterology 2009
PATTERN OF HCV RECURRENCE POST OLTx
NO HEPATITIS
20%
6 MTH
ACUTE HEPATITIS
70%
6 MTH
CHRONIC HEPATITIS
?
1 MTH
OLT
1 MTH
1 MTH
VIRAL
RECURRENCE
CHRONIC HEPATITIS

CHOLESTATIC
HEPATITIS
< 10 %
Adapted From McCaughan
DEATH
50%
CIRRHOSIS
CHOLESTATIC HEPATITIS C
McCaughan
J Hepatol 2011
FIBROSING CHOLESTATIC HEPATITIS C
Antonini AJT 2011
FCH in HCV-HIV Coinfected Patienst
Impact on Survival
Antonini AJT 2011
Pathobiology of Chronic HCV Post LT
Immunosuppression
-
The immune
response
+
HCV load
-
Inflammation +
IFN- related genes
IFN-
response
Proliferation
Apoptosis
Fibrosis
Stimulation of the IMMUNE
RESPONSE by more HCV WINS
Acute Rejection
Inflammation
Stress Response
McCaughan and Zekry J.Hepatol 2004, Samuel Easl Hepatol 2006
EVALUATION OF THE SEVERITY OF HCV RECURRENCE
• 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
C.H.B.
HPVG, Fibrosis at 1 Year Post-Transplant and Outcome
Blasco Hepatology 2006; 43: 492-499
Fibrosis Stage at 12 months at Liver Biopsy and Survival
Gallegos-Orozco Liver Transplant 2009
Non Invasive 3-MALG Test
and
Decompensation and Survival Post-Transplant
Carrion Gastro 2010
Liver Stiffness and Severity of HCV Recurrence
Carrion Hepatology 2010
Donor and Host Factors
of
HCV Recurrence
C.H.B.
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
Belli Liver Transplant 2007; 13: 733-740
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)
C.H.B.
No Impact of Steroid-Free IS on Graft HCV Fibrosis
Klintmalm Liver Transplant 2011
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
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.
ANTIVIRAL TREATMENT PRE-LT
Authors
Patients
Child
Treatment
Virologic
Response EOT
SVR
Post-LT
Tolerance
Forns
(2003)
30
(Time preLT 4
mths)
G1:83%
A 50%
B 43%
C 7%
INF 3M/d
+RBV
800mg
Mean
Duration :
12 wks
(2-33 wks)
9 (30%)
6/30
(20%)
Decrease INF
60%, RBV
23%
Stop 20%
Sepsis: 2
Liver Failure:
4
51
G1:80%
Meld
11
Peg 2a
180 g/wk
+RBV
0,8-1g/d
Mean
duration:
15 Wks
10/51
(20%)
infectious
risk
increased by
Trt (NS)
Carrion
(2008)
51
controls
Factors for
response : viral
laod pre-LT,
Decrease viral
load≥ 2 log Wk 4
15 (29%)
Factors response:
G non 1,
RVR Wk4
Forns J Hepatol 2003, Carrion J Hepatol 2008
C.H.B
Antiviral Treatment in Patients Waiting
for Liver Transplantation, Risk of Sepsis Related to CPT
Carrión JA et al. J Hepatol. 2009;50:719-28.
Antiviral Treatment in Patients Waiting
for Liver Transplantation, Norfloxacin Prophylaxis
Carrión JA et al. J Hepatol. 2009;50:719-28.
Antiviral Treatment Before Transplantation
Roche, Samuel Liver Int 2012
Direct Antiviral Agents Before LT
A 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.
Mechanism of HCV Entry
Zeisel J Hepatol 2011
Strategies Before and After Transplantation
Feray J Hepatol 2011
Antiviral Treatment Immediately after Transplantation
Roche, Samuel Liver Transplant 2010
Antiviral Therapy PegINF+ RBV Post-Transplantation
Authors
Studie
s
Patients
Years
ETVR
SVR
Tolerance
AR
Factors
linked with
SVR
Wang
21
(1RCT)
587
1980-05
42%
(30-37)
27% (2331)
Reduction 66%
(61-70%)
Stop: 26% (
20-32)
5%
(3-7)
No prior
antiviral tt
post-LT
Non-1 G
Berenguer
19
(2RCT)
611
2004-07
42%
(17-68)
30%
G1: 28%
G2: 71100%
G3:41%
(30-77%)
Reduction:68%
Stop 28%
6.4% EVR
G2
Adherence
Baseline
viremia
Xirouchakis
6 RCT
264
2005-07
-
30%
G1: 29%
G2: 71100%
G3: 41%
( 30-77)
-
5%
Roche, Samuel Liver Int 2012, Wang AJT 2006, Berenguer J Hepatol 2008
, Xirouchakis J Viral Hep 2008
C.H.B.
Auto(Allo)immune Hepatitis and IFN
Sharma Liver Transplant 2007
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 IL28 in all Genotype Transplant Patients
Lange J Hepatol 11
C.H.B.
SVR According to IL 28
Charlton
Hepatology 2011
C.H.B.
Survival (Death and Graft Loss) According to IL 28
IL 28 Recipient
Charlton Hepatology 2011
IL 28 Donor
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
C.H.B.
SVR According to IL 28 in Recipient, Donor, and FU Biopsy
Coto-Llorena J Hepatol 2012
C.H.B.
Histological Outcome in Relation with
Virological Response to PEGIFN+ Ribavirine
Variables associated with Histological improvement: EVR, BR, SVR
Carrion Gastroenterology 2007
C.H.B.
Impact of SVR on Suvival in Transplant HCV + Patients
Piciotto J Hepatol 2007
Berenguer M AJT 2008
Direct Antiviral Agents After LT
A 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
C.H.B.
Telaprevir and Cyclosprine and Tacrolimus Interactions
Cmax increased by 1.4X
Cmax increased by 9.3X
AUC Increased by 4.1-4.6X
AUC Increased by 70X
T1/2 increased by 4 X
T1/2 increased by 5 X
Garg Hepatology 2011
Evolution of Liver Transplantation for Viral Cirrhosis
in Europe.
Without HCC
With HCC
www.eltr.org
C.H.B.
Evolution of Patient Survival after LT for Virus C
Cirrhosis without HCC in Europe (ELTR: 1988-2010)
www.eltr.org
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
C.H.B.