1. 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.
2. 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.
3. Trends in Waiting List for HCV Cirrhosis in USA
Kim Gastroenterology 2009
4. 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
7. FCH in HCV-HIV Coinfected Patienst
Impact on Survival
Antonini AJT 2011
8. 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
9. 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.
10. HPVG, Fibrosis at 1 Year Post-Transplant and Outcome
Blasco Hepatology 2006; 43: 492-499
11. Fibrosis Stage at 12 months at Liver Biopsy and Survival
Gallegos-Orozco Liver Transplant 2009
12. Non Invasive 3-MALG Test
and
Decompensation and Survival Post-Transplant
Carrion Gastro 2010
15. 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
17. No Impact of Steroid-Free IS on Graft HCV Fibrosis
Klintmalm Liver Transplant 2011
18. 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.
19. 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.
20. 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.
27. 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.
28. Study ANRS HC29
BOCEPRETRANSPLANT
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 Samuel
Co-investigators :
JC Duclos-Vallée, H Fontaine, B Roche
C.H.B.
29. 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
C.H.B.
30. Pre-Transplant Sofosbuvir + RBV Until LT
Patient Demographics
SOF + RBV (n=61)
Male, n (%)
Median age, y (range)
49 (80)
59 (46–73)
White, n (%)
55 (90)
BMI < 30 kg/m2, n (%)
43 (70)
HCV RNA > 6 log10 IU/mL, n (%)
41 (67)
Genotype, n (%)
1a
1b
2
3a
4
24 (39)
21 (34)
8 (13)
7 (12)
1 (2)
Non-CC allele, n (%)
47/60 (78)
CTP score, n (%)
5
6
7
8
26 (43)
18 (30)
14 (23)
3 (5)
Median MELD score, (range)
8 (6–14)
Prior HCV treatment, n (%)
Curry AASLD 2013. Washington, DC. Oral #213
46 (75)
C.H.B.
31. Pre-Transplant Sofosbuvir + RBV Until LT Pre-Transplant
Virologic Response
Post-Transplant Virologic Response
Viral Response Rate (%)
100
93
80
64
60
40
20
41/44*
25/39*†
Transplant
0
PTVR 12
SOF + RBV was safe and effective in patients with well compensated cirrhosis,
and prevented post-transplant HCV recurrence in 64% of patients who had
HCV RNA < 25 IU/mL prior to transplant
Curry AASLD 2013. Washington, DC. Oral #213
C.H.B.
32. Pre-Transplant Sofosbuvir + RBV Until LT
Impact of Duration of Treatment on HCV Recurrence
No Recurrence (n=28)
Recurrence (n=10)
Median days TND
No recurrence 95
Recurrence 5.5
p <0.001
0
50
100
150
200
250
300
350
Days with HCV RNA Continuously TND Prior to Liver Transplant
*3 patients with recurrent HCV had 0 consecutive days TND before transplant.
Curry MP, et al. AASLD 2013.
C.H.B.
41. Survival (Death and Graft Loss) According to IL 28
IL 28 Recipient
Charlton Hepatology 2011
IL 28 Donor
C.H.B.
42. 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.
43. SVR According to IL 28 in Recipient, Donor, and FU Biopsy
Coto-Llorena J Hepatol 2012
C.H.B.
44. Histological Outcome in Relation with
Virological Response to PEGIFN+ Ribavirine
Variables associated with Histological improvement: EVR, BR, SVR
Carrion Gastroenterology 2007
C.H.B.
45. Impact of SVR on Suvival in Transplant HCV + Patients
Piciotto J Hepatol 2007
Berenguer M AJT 2008
46. 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.
47. 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
65. Evolution of Liver Transplantation for Viral Cirrhosis
in Europe.
Without HCC
With HCC
www.eltr.org
C.H.B.
66. Evolution of Patient Survival after LT for Virus C
Cirrhosis without HCC in Europe (ELTR: 1988-2010)
www.eltr.org
C.H.B.
67. 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.
68. 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
C.H.B.
