This document discusses hepatitis C virus (HCV) recurrence before and after liver transplantation. It provides an overview of trends in liver transplantation for viral cirrhosis in Europe. It also summarizes patterns of HCV recurrence post-liver transplantation, risk factors for fibrosis, and evaluation of severity of HCV recurrence. The document discusses antiviral treatment before and after liver transplantation, including risks, response rates, and factors associated with response. It also addresses drug interactions between direct antiviral agents and immunosuppressants in transplant patients.

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 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 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 CHRONIC HEPATITIS
20% 6 MTH
?
1 MTH
ACUTE HEPATITIS
OLT 70% 6 MTH
CHRONIC HEPATITIS CIRRHOSIS
1 MTH
1 MTH 
CHOLESTATIC
VIRAL
HEPATITIS
RECURRENCE
< 10 %
DEATH
Adapted From McCaughan 50%

5. CHOLESTATIC HEPATITIS C
McCaughan
J Hepatol 2011

6. FIBROSING CHOLESTATIC HEPATITIS C
Antonini AJT 2011

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 Stimulation of the IMMUNE
RESPONSE by more HCV WINS
Proliferation
Acute Rejection
Apoptosis
Inflammation
Fibrosis
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

13. Liver Stiffness and Severity of HCV Recurrence
Carrion Hepatology 2010

14. Donor and Host Factors
of
HCV Recurrence
C.H.B.

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

16. 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.

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.

21. ANTIVIRAL TREATMENT PRE-LT
Authors Patients Child Treatment Virologic SVR Tolerance
Response EOT Post-LT
Forns 30 A 50% INF 3M/d 9 (30%) 6/30 Decrease INF
(2003) (Time pre- B 43% +RBV (20%) 60%, RBV
LT 4 800mg 23%
C 7% Factors for
mths) Mean response : viral Stop 20%
G1:83% Duration : laod pre-LT, Sepsis: 2
12 wks Decrease viral Liver Failure:
(2-33 wks) load≥ 2 log Wk 4 4
Carrion 51 Meld Peg 2a 15 (29%) 10/51 infectious
(2008) G1:80% 11 180 g/wk (20%) risk
+RBV increased by
Factors response: Trt (NS)
51 0,8-1g/d G non 1,
controls Mean RVR Wk4
duration:
15 Wks
Forns J Hepatol 2003, Carrion J Hepatol 2008
C.H.B.

22. Antiviral Treatment in Patients Waiting
for Liver Transplantation, Risk of Sepsis Related to CPT
Carrión JA et al. J Hepatol. 2009;50:719-28.

23. Antiviral Treatment in Patients Waiting
for Liver Transplantation, Norfloxacin Prophylaxis
Carrión JA et al. J Hepatol. 2009;50:719-28.

24. 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
C.H.B.

25. PegIFN + RBV Treatment Before LT
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)
Everson Hepatology 2012
C.H.B.

26. Antiviral Treatment Before Transplantation
Roche, Samuel Liver Int 2012

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. Strategies Before and After Transplantation
Feray J Hepatol 2011

31. Mechanism of HCV Entry
Zeisel J Hepatol 2011

32. Antiviral Treatment Immediately after Transplantation
Roche, Samuel Liver Transplant 2010

33. Antiviral Therapy PegINF+ RBV Post-Transplantation
Authors Studie Patients Years ETVR SVR Tolerance AR Factors
s linked with
SVR
Wang 21 587 1980-05 42% 27% (23- Reduction 66% 5% No prior
(1RCT) (30-37) 31) (61-70%) (3-7) antiviral tt
Stop: 26% ( post-LT
20-32) Non-1 G
Berenguer 19 611 2004-07 42% 30% Reduction:68% 6.4% EVR
(2RCT) (17-68) G1: 28% Stop 28% G2
G2: 71- Adherence
100% Baseline
G3:41% viremia
(30-77%)
Xirouchakis 6 RCT 264 2005-07 - 30% - 5%
G1: 29%
G2: 71-
100%
G3: 41%
( 30-77)
Roche, Samuel Liver Int 2012, Wang AJT 2006, Berenguer J Hepatol 2008
, Xirouchakis J Viral Hep 2008 C.H.B.

34. Auto(Allo)immune Hepatitis and IFN
Sharma Liver Transplant 2007

35. 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.

36. SVR and IL28 in all Genotype Transplant Patients
Lange J Hepatol 11
C.H.B.

37. SVR According to IL 28
Charlton
Hepatology 2011
C.H.B.

38. Survival (Death and Graft Loss) According to IL 28
IL 28 Recipient IL 28 Donor
Charlton Hepatology 2011
C.H.B.

39. 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.

40. SVR According to IL 28 in Recipient, Donor, and FU Biopsy
Coto-Llorena J Hepatol 2012
C.H.B.

41. Histological Outcome in Relation with
Virological Response to PEGIFN+ Ribavirine
Variables associated with Histological improvement: EVR, BR, SVR
Carrion Gastroenterology 2007
C.H.B.

42. Impact of SVR on Suvival in Transplant HCV + Patients
Piciotto J Hepatol 2007 Berenguer M AJT 2008

43. 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.

44. 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

45. Treatment After LT with Protease Inhibitors
One limitation: drug-drug interactions
Healthy volunteers Liver transplant patients
• CNI, cyclosporine or tacrolimus 100 12
10
Clairance orale (L/h)
80
• PI: CYP 3A4 potent inhibitors 60
8
6
• AUC increase 40
4
20 2
0 0
Alone Boce Alone Boce
Boceprevir Telaprevir Cyclosporine Tacrolimus
Cyclosporine 2.7 4.6 • Boceprevir in 5 transplant patients:
the estimated oral clearance
Tacrolimus 9.9 70 decreased
Garg, Hepatology, 2011 • Cyclosporine (n=3): 50%
Hulskotte, Hepatology, 2012 • Tacrolimus (n=2): up to 80%
• Everolimus (n=1): 55%
Coilly, AAC, 2012

46. French Collaborative study
• 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

47. Patients and Methods
PEG-IFN/RBV PEG-IFN/RBV+Boceprevir (800mg tid) n=18
n=8
PEG-IFN/RBV PEG-IFN/RBV+Telaprevir (750mg tid)
PEG-IFN/RBV+Telaprevir (750mg tid) n=11
W48
Week -4 Week 0 Week 4 Week 12

48. DAA Post-Transplantation
Practical Issues
Coilly Liver Int 2013
C.H.B.

49. Virological response
EVR at Week 12 ETVR at Week 48
p=ns p=ns
89% 89%
75%
67%
64%
63%
50%
ITT PP ITT PP ITT PP ITT PP ITT PP
Boceprevir
Bocéprévir (n=18)
Telaprevir
Télaprévir (n=19)
Boceprevir
Bocéprévir (n=13) t
n=18 n=19 n=13

50. Boceprevir group, n=18
9
Mean treatment duration: 42 ± 8.7 weeks
8
7  End of treatment with undetectable
viral load, n=7
6
 On going, n=7
5
HCV viral load (log10
Treatment discontinuation
4  Null response, n=1
 Virological breakthrough , n=1
IU/mL)
3  Adverse events, n=2
2
1
0
S-4 S2 S4 S8 S12 S16 S20 S24 S28 S32 S36 S40 S44 S48 Treatment duration

51. Telaprevir group, n=19
9
Mean treatment duration: 33 ± 10.2 weeks
8
7
 On going, n=10
6
5
HCV viral load (log10
Treatment discontinuation
4
 Null response, n=4
 Virological breakthrough , n=2
3
IU/mL)
 Adverse events, n=2
2
1
0
S-4 S0 S4 S8 S12 S16 S20 S24 S28 S32 S36 S40 S44 S48 Treatment duration

52. Adverse events
Boceprevir Telaprevir
p
(n = 18) (n = 19)
Death – n°(%) 1 (5 %) 1 (5 %) ns
Infections – n° (%) 3 (17 %) 4 (21 %) ns
Hematotoxicity – n° (%)
Anemia
< 10 g/dL 18 (100 %) 16 (84 %)
ns
< 8 g/dL 7 (39 %) 3 (15 %)
Neutropenia (<1 G/L) 11 (61 %) 4 (21 %)
Thrombopenia (< 50 G/L) 5 (28 %) 3 (15 %)
Dermatological toxicity –n° (%) 1 (5 %) 1 (5 %) ns
Renal failure – n° (%) 0 2 (9 %) ns
Diabetes mellitus – n° (%) 2 (10 %) 0 (26%) ns

53. CNI-PI interactions
Boceprevir Telaprevir
CNI dose reduction
Cyclosporine  1.8  3.4
Tacrolimus  5.2  23.8
• Dose reduction of CNI constantly required
• No overdose
• No biopsy-proven acute rejection

54. Evolution of Liver Transplantation for Viral Cirrhosis
in Europe.
Without HCC With HCC
www.eltr.org
C.H.B.

55. Evolution of Patient Survival after LT for Virus C
Cirrhosis without HCC in Europe (ELTR: 1988-2010)
www.eltr.org
C.H.B.

56. DAA Post-Transplantation
The future Possibilities
Mc Caughan J Hepatol 2012
C.H.B.

57. DAA Post-Transplantation
The Hope of Non-IFN Based Therapies
Mc Caughan J Hepatol 2012
C.H.B.

58. PegIFN +RBV+Daclatasvir for FCH after LT
Fontana Liver Transpant 2012 C.H.B.

59. 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.

60. 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.