HCV PRE AND POST-LIVER TRANSPLANTATION Professor Didier SAMUEL Centre H

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HCV PRE AND POST-LIVER TRANSPLANTATION
Professor Didier SAMUELCentre Hépatobiliaire,
Inserm Unit 785, Paris XI UniversityHopital
Paul Brousse, Villejuif, France
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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
NO HEPATITIS 20
CHRONIC HEPATITIS
6 MTH
?
1 MTH
ACUTE HEPATITIS 70
OLT
CIRRHOSIS
CHRONIC HEPATITIS
6 MTH
1 MTH
?
1 MTH
CHOLESTATIC HEPATITIS lt 10
VIRAL RECURRENCE
DEATH 50
Adapted From McCaughan
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CHOLESTATIC HEPATITIS C
McCaughan J Hepatol 2011
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FIBROSING CHOLESTATIC HEPATITIS C
Antonini AJT 2011
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FCH in HCV-HIV Coinfected Patienst Impact on
Survival
Antonini AJT 2011
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Pathobiology of Chronic HCV Post LT
Immunosuppression
Stimulation of the IMMUNE RESPONSE by more HCV
WINS
McCaughan and Zekry J.Hepatol 2004, Samuel Easl
Hepatol 2006
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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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HPVG, Fibrosis at 1 Year Post-Transplant and
Outcome
Blasco Hepatology 2006 43 492-499
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Fibrosis Stage at 12 months at Liver Biopsy and
Survival
Gallegos-Orozco Liver Transplant 2009
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Non Invasive 3-MALG Test and Decompensation and
Survival Post-Transplant
Carrion Gastro 2010
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Liver Stiffness and Severity of HCV Recurrence
Carrion Hepatology 2010
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Donor and Host Factorsof HCV Recurrence
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Fibrosis on the Graft In HCVve 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
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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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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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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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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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ANTIVIRAL TREATMENT PRE-LT
Authors Patients Child Treatment Virologic Response EOT SVR Post-LT Tolerance
Forns (2003) 30 (Time pre-LT 4 mths) G183 A 50 B 43 C 7 INF 3M/d RBV 800mg Mean 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) 51 G180 51 controls Meld 11 Peg?2a 180?g/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)
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. 200950719-28.
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Antiviral Treatment in Patients Waiting for
Liver Transplantation, Norfloxacin Prophylaxis
Carrión JA et al. J Hepatol. 200950719-28.
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Antiviral Treatment Before Transplantation
Roche, Samuel Liver Int 2012
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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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Mechanism of HCV Entry
Zeisel J Hepatol 2011
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Additive Effect of Anticlaudin, AntiE2 and HCVIg
on HCV Entry and Infection
Fofana Gastro 2010
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Strategies Before and After Transplantation
Feray J Hepatol 2011
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Antiviral Treatment Immediately after
Transplantation
Roche, Samuel Liver Transplant 2010
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Antiviral Therapy PegINF RBV Post-Transplantation
Authors Studies Patients 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-LT Non-1 G
Berenguer 19 (2RCT) 611 2004-07 42 (17-68) 30 G1 28 G2 71-100 G341 (30-77) Reduction68 Stop 28 6.4 EVR G2 Adherence Baseline 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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Treatment with PEG IFN RBV After LTSVR
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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SVR and IL28 in all Genotype Transplant Patients
Lange J Hepatol 11
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SVR According to IL 28
Charlton Hepatology 2011
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Survival (Death and Graft Loss) According to IL 28
IL 28 Recipient
IL 28 Donor
Charlton Hepatology 2011
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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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SVR According to IL 28 in Recipient, Donor, and
FU Biopsy
Coto-Llorena J Hepatol 2012
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Histological Outcome in Relation with Virological
Response to PEGIFN Ribavirine
Variables associated with Histological
improvement EVR, BR, SVR
Carrion Gastroenterology 2007
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Impact of SVR on Suvival in Transplant HCV
Patients
Berenguer M AJT 2008
Piciotto J Hepatol 2007
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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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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
Garg Hepatology 2011
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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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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