HCV PRE AND POST-LIVER TRANSPLANTATION
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HCV PRE AND POST-LIVER TRANSPLANTATION Professor Didier SAMUEL Centre Hépatobiliaire, Inserm Unit 785, Paris XI University Hopital Paul Brousse, Villejuif, France. Evolution of Liver Transplantation for Viral Cirrhosis in Europe. Without HCC. With HCC. www.eltr.org.

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Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

HCV PRE AND POST-LIVER TRANSPLANTATIONProfessor Didier SAMUELCentre Hépatobiliaire, Inserm Unit 785, Paris XI UniversityHopital Paul Brousse, Villejuif, France


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

Evolution of Liver Transplantation for Viral Cirrhosis

in Europe.

Without HCC

With HCC

www.eltr.org


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

Trends in Waiting List for HCV Cirrhosis in USA

Kim Gastroenterology 2009


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

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

< 10 %

VIRAL RECURRENCE

DEATH

50%

Adapted From McCaughan


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

CHOLESTATIC HEPATITIS C

McCaughan

J Hepatol 2011


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

FIBROSING CHOLESTATIC HEPATITIS C

Antonini AJT 2011


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

FCH in HCV-HIV CoinfectedPatienst

Impact on Survival

Antonini AJT 2011


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

Pathobiology of Chronic HCV Post LT

The immune response

-

+

HCV load

Inflammation + IFN- related genes

-

IFN- response

Proliferation

Apoptosis

Fibrosis

Acute Rejection

Inflammation

Stress Response

Immunosuppression

Stimulation of the IMMUNE RESPONSE by more HCV WINS

McCaughan and Zekry J.Hepatol 2004, Samuel Easl Hepatol 2006


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

EVALUATION OF THE SEVERITY OF HCV RECURRENCE

LiverBiopsyGold Standard, Bringadditional information thanfibrosis stage. HPVGInvasive, canbedonewithliverbiopsyNot routine for many Centres. Non invasive testsBiochemicalElastometry (fibroscan). Time post-LT as an adding variable


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

HPVG, Fibrosis at 1 Year Post-Transplant and Outcome

Blasco Hepatology 2006; 43: 492-499


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

Fibrosis Stage at 12 months at Liver Biopsy and Survival

Gallegos-Orozco Liver Transplant 2009


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

Non Invasive 3-MALG Test

and

Decompensation and Survival Post-Transplant

Carrion Gastro 2010


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

Liver Stiffness and Severity of HCV Recurrence

Carrion Hepatology 2010


Donor and host factors of hcv recurrence

Donor and Host Factorsof HCV Recurrence


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

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

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)


No impact of steroid free is on graft hcv fibrosis

No Impact of Steroid-Free IS on Graft HCV Fibrosis

KlintmalmLiver Transplant 2011


Hcv recurrence cyclosporine vs tacrolimus

HCV Recurrence , Cyclosporine vs Tacrolimus

  • There iscurrently no proof of superiority of one vs another

    • Antiviral effect of Cyclosporine only in vitro

    • Betterefficacy of IFN in Ciclosporine patients not confirmed

    • Randomizedstudiesshowedearlierreinfectionwith Tac but no difference in fibrosis stage, bettersurvivalwith Tac?

Samonakis, J Hepatol 2012 in Press, Berenguer Nat Rev Gastroenterol 2011


Antiviral treatment before liver transplantation

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


Antiviral treatment before liver transplantation1

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


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

ANTIVIRAL TREATMENT PRE-LT

Forns J Hepatol 2003, Carrion J Hepatol 2008


Antiviral treatment in patients waiting for liver transplantation risk of sepsis related to cpt

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

Antiviral Treatment in Patients Waiting for Liver Transplantation, Norfloxacin Prophylaxis

Carrión JA et al. J Hepatol. 2009;50:719-28.


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

Antiviral Treatment Before Transplantation

Roche, Samuel Liver Int 2012


Direct antiviral agents before lt a new challenge

Direct Antiviral Agents Before LTA New Challenge

  • Data In cirrhotic patients are lacking

  • Therapieswith IFN willremainpoorlytolerated

  • Increasepossibility to achieve SVR or on treatmentvirologicresponse

  • Increaserisk of virologicbreakthrough

  • Duration, safety issues to beanalysed

  • Therapieswithout IFN awaited


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

Mechanism of HCV Entry

Zeisel J Hepatol 2011


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

Strategies Before and After Transplantation

Feray J Hepatol 2011


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

Antiviral Treatment Immediately after Transplantation

Roche, Samuel Liver Transplant 2010


Antiviral therapy peginf rbv post transplantation

Antiviral TherapyPegINF+ RBV Post-Transplantation

Roche, Samuel Liver Int 2012, Wang AJT 2006, Berenguer J Hepatol 2008

, Xirouchakis J Viral Hep 2008


Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

Auto(Allo)immune Hepatitis and IFN

Sharma Liver Transplant 2007


Treatment with peg ifn rbv after lt svr dependent of fibrosis stage

Treatment with PEG IFN + RBV After LTSVR Dependent of Fibrosis stage

  • 27 Pts mildHepatitis C (F1-F2): SVR 48%

  • 27 Pts severehepatitis C (F3-F4), CholestaticHepatitis: SVR 18%

    • F3-4: 4/15

    • Cholestatichepatitis, 1/12 (Carrion Gastro 2007)

  • 20% F3-F4 vs 1% F1 Patients died or wereretransplanted( Roche Liver transplant 2008)


  • Svr and il28 in all genotype transplant patients

    SVR and IL28 in all Genotype Transplant Patients

    Lange J Hepatol 11


    Svr according to il 28

    SVR According to IL 28

    Charlton

    Hepatology 2011


    Survival death and graft loss according to il 28

    Survival (Death and GraftLoss) According to IL 28

    IL 28 Recipient

    IL 28 Donor

    Charlton Hepatology 2011


    Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

    IL 28 In the Donorshouldbedetermined on GraftReperfusionBiopsy or PBMC, not on follow-up Biopsies

    Coto-Llorena J Hepatol 2012


    Svr according to il 28 in recipient donor and fu biopsy

    SVR According to IL 28 in Recipient, Donor, and FU Biopsy

    Coto-Llorena J Hepatol 2012


    Histological outcome in relation with virological response to pegifn ribavirine

    Histological Outcome in Relation with Virological Response to PEGIFN+ Ribavirine

    Variables associated with Histological improvement: EVR, BR, SVR

    Carrion Gastroenterology 2007


    Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

    Impact of SVR on Suvival in Transplant HCV + Patients

    Berenguer M AJT 2008

    Piciotto J Hepatol 2007


    Direct antiviral agents after lt a new challenge

    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


    Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

    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

    GargHepatology 2011


    Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

    Evolution of Liver Transplantation for Viral Cirrhosis

    in Europe.

    Without HCC

    With HCC

    www.eltr.org


    Hcv pre and post liver transplantation professor didier samuel centre h patobiliaire inserm unit 785 paris xi univ

    Evolution of Patient Survivalafter LT for Virus C

    Cirrhosiswithout HCC in Europe (ELTR: 1988-2010)

    www.eltr.org


    Conclusion

    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


    Conclusion1

    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


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