FCH in HCV-HIV Coinfected Patienst Impact on SurvivalAntonini AJT 2011
Pathobiology of Chronic HCV Post LTImmunosuppression - 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
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 OutcomeBlasco Hepatology 2006; 43: 492-499
Fibrosis Stage at 12 months at Liver Biopsy and SurvivalGallegos-Orozco Liver Transplant 2009
Non Invasive 3-MALG Test and Decompensation and Survival Post-TransplantCarrion Gastro 2010
Liver Stiffness and Severity of HCV RecurrenceCarrion 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 GenderRisk of Fibrosis: Stable over years, Higher in women receiving old donors Belli Liver Transplant 2007; 13: 733-740
No Impact of Steroid-Free IS on Graft HCV FibrosisKlintmalm 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 in Patients Waitingfor Liver Transplantation, Risk of Sepsis Related to CPTCarrión JA et al. J Hepatol. 2009;50:719-28.
Antiviral Treatment in Patients Waiting for Liver Transplantation, Norfloxacin ProphylaxisCarrión JA et al. J Hepatol. 2009;50:719-28.
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 treatedEverson Hepatology 2012 C.H.B.
PegIFN + RBV Treatment Before LTMeld score: 12, CTP score : 7Serious Infection rate: 7/59 (12) pts vs 0% controlDeath pre-LT: 5/59 vs 2/20 (NS) Everson Hepatology 2012 C.H.B.
Antiviral Treatment Before TransplantationRoche, 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.
Study ANRS HC29 BOCEPRETRANSPLANT Pilot study of Efficacy and Tolerablity of Boceprevir in combinationwith 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.
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.
Strategies Before and After TransplantationFeray J Hepatol 2011
Auto(Allo)immune Hepatitis and IFNSharma 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 ( RocheLiver transplant 2008) C.H.B.
SVR and IL28 in all Genotype Transplant PatientsLange J Hepatol 11 C.H.B.
SVR According to IL 28CharltonHepatology 2011 C.H.B.
Survival (Death and Graft Loss) According to IL 28 IL 28 Recipient IL 28 DonorCharlton Hepatology 2011 C.H.B.
IL 28 In the Donor should be determined on GraftReperfusion Biopsy or PBMC, not on follow-up BiopsiesCoto-Llorena J Hepatol 2012 C.H.B.
SVR According to IL 28 in Recipient, Donor, and FU BiopsyCoto-Llorena J Hepatol 2012 C.H.B.
Histological Outcome in Relation withVirological Response to PEGIFN+ Ribavirine Variables associated with Histological improvement: EVR, BR, SVRCarrion Gastroenterology 2007 C.H.B.
Impact of SVR on Suvival in Transplant HCV + PatientsPiciotto 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 XGarg Hepatology 2011
DAA Post-Transplantation The Hope of Non-IFN Based TherapiesMc Caughan J Hepatol 2012 C.H.B.
PegIFN +RBV+Daclatasvir for FCH after LTFontana Liver Transpant 2012 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• 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.