Liver transplantation and hepatitis C virus Where do we come from? Where are we? Where are we going? François Durand Hépatologie & Réanimation Hépato-Digestive INSERM U1149 Hôpital Beaujon, Clichy
HCV: indication for transplantation 2006-2015 : 1061 transplantations in Beaujon Hospital 205 (19%) transplantations for HCV cirrhosis ± HCC %81 %11 Decompensated HCV cirrhosis HCV cirrhosis and HCC Cirrhosis ± others %8
HCV and transplantation: natural history Candidate for transplant Treatment failure Circulating HCV(PCR +) Post transplant recurrence Viral replication Immunosuppressors Fibrogenesis Impact on survival Graft loss Gane E, et al. Liver Transpl. 2003;9:S28 S34.
Pegylated interferon + riba Post-transplant treatment Author Year Response Response end of tt (%) SVR (%) Tt discontinuation(%) Rodriguez H 2004 19 37 26 38 Neff GW 2004 57 25 14 31 Dumortier J 2004 20 55 45 20 Castells L 2005 24 58 35 12 Sharma P 2007 35 54 37 43 Angelico M 2007 21-33 33 Berenguer M. J Hepatol 2008, 49: 274
First generation protease inhibitors and cirrhosis Telaprevir Boceprevir Patients 299 212 Child A 95% 93% Genotype 1 89% 90% Sustained virological response 52% 43% Serious adverse event 53% 44% Discontinuation of therapy 48% 46% Deat: 2.2% Risk factors: Albumin < 35g/L Platelets < 100*10 9 /L Hézode C et al. Gastroenterology 2014; 147: 132
First generation protease inhibitors and transplantation Telaprevir Boceprevir Patients 19 18 Post-transplant interval (mo) 35 78 Fibrosis F3 (%) 42 50 Sustained virological response (%) 20 71 Cyclospirine dose reduction 3.4 1.8 Tacrolimus dose reduction 24 5.2 Coilly A et al. J Hepatol 2014; 60: 78.
Direct antiviral agents Naive and non naive HCV infected patients %100 %80 %60 %40 %20 %0 24SOF + DCV 12SOF + DCV 24SOF + DCV Genotype 1 Genotypes 2 et 3 Sulkowski MS et al. N Engl J Med 2014; 370: 211.
Antiviral agents, safety and cirrhosis Peg IFN + Boce + Riba Sofo + riba Author Hézode C Curry MP Year 2014 2015 Serious adverse event 32 18 Anemia (<9g/dL, %) 23 5 Transfusion (%) 6 0 Decompensation (%) 3 0 Discontinuation of therapy (%) 26 3 Hézode C et al. Gastroenterology 2014; 147: 132 Curry MP et al. Gastroenterology 2015; 148: 100
Direct antiviral agents and transplantation: main issues Before transplantation Reverse the complications of cirrhosis Removal from waiting list Prevent post transplant recurrence Undetectable HCV-RNA at the time of transplantation After transplantation Cure HCV infection Avoid retransplantation
Sofosbuvir + ribavirine Impact on HCV replication Curry MP et al. Gastroenterology 2015; 148: 100
Sofosbuvir + ribavirine and post transplant recurrence Curry MP et al. Gastroenterology 2015; 148: 100
Impact of SVR on MELD score Charlton M Gastroenterology 2015; 149: 649.
Sofosbuvir-based therapy: impact on outcome HCV cirrhosis awaiting for LT: n=151 Genotype 1: 56% SVR: 88% HCV cirrhosis + HCC: 56% Decompensated HCV cirrhosis: 44% Improvement and removal from the WL at 12 months Yes: 10% No: 90% Coilly A et al. Hepatology 2015; 62: 275A
Direct antiviral agents and transplantation: main issues Before transplantation Reverse the complications of cirrhosis Removal from waiting list Prevent post transplant recurrence Undetectable HCV-RNA at the time of transplantation After transplantation Cure HCV infection Avoid retransplantation
Sofosbuvir and ribavirin post transplant 40 patients with post LT recurrence of HCV Undetectable HCV-RNA Relapse %100 %80 %60 %40 %20 %0 70% 2S 4S 24S 12Post S Charlton M et al. Gastroenterology 2015; 148:108.
Sofosbuvir plus ribavirin for severe HCV recurrence after LR 104 patients: cirrhosis 50% Decompensation: 18% Undetectable HCV-RNA %80 59% %60 %40 %20 %0 4W 12W 24W 12Post W Forns X et al. Hepatology 2015; 61: 1485
Sofo + dacla ± riba post LT 158 patients Sofosbuvir + daclatasvir ± rabavirine 12 or 24 weeks Genotype 1: 79% yes %96 No %4 SVR Hervé C et al. Hepatology 2015; 62: 209A.
HCC and HCV CHC as an indication for LT: Child A cirrhosis in 66% RFA / TACE RFA / TACE Outside criteria Waiting list Transplantation T0 12-18 months Inside criteria Treatment of HCV Inside criteria
Antiviral therapy: impact on HCC transplantation 5-year recurrence rate Without therapy: 80% After SVR: 55% cirrhosis HCC Resection RFA Rcurrence Annual incidence of HCC Without treatment: 1-5% After SVR: 0.2-1% 50% of HCC > 7 y after SVR transplantation Van de Meer AJ et al. JAMA 2012; 308: 2584. Zhang W et al. Mol Clin Oncol 2014; 2: 1125.
Antiviral therapy and transplant activity HCC / HCV cirrhosis Decompensated HCV cirrhosis Deuffic-Burban S et al. Dig Dis Sci 2014; 46: 157.
Antiviral therapy and transplant activity Total candidates/ donor 2.5 2 1.5 1 0.5 0 2008 2009 2010 2011 2012 2013 Données Agence de la Biomédecine
Conclusions When to initiate antiviral therapy? Pre transplant HCV cirrhosis and HCC: 2-3 months before transplantation Pre transplant decompensated cirrhosis: at listing Post transplantation: no emergency (apart fibrosing cholestatic hepatitis) 6 mo-1y after transplantation Fibrosis F2 not justified Which therapy? Pre transplant HCV compensated cirrhosis and HCC, non 3 genotype Sofo + ledi + riba ou sofo + dacla + riba Ombitasvir + paritaprevir + ritonavir? Pre transplant HCV compensated cirrhosis and HCC, genotype 3 Sofo + dacla + riba Pre transplant decompensated HCV cirrhosis Sofo + ledi ou sofo + dacla (G3) Post transplant Sofo + ledi + riba ou sofo + dacla + riba (G3)
For how long? Conclusions Careful approach = 24 weeks 12 weeks: possibly enough with ribavirin Mistakers to be avoided: Protease inhibitors in patients with Child B or C cirrhosis Protease inhibitors post transplantation Except careful monitoring of calcineurin inhibitors Continue post transplant if therapy initiated 2 months pre transplant and HCV-RNA undetectable at the time of transplant Treating a patients with compensated cirrhosis and «uncontrolled» HCC
Conclusions What can be expected? Prevent post transplant recurrence Avoid progression of HCV recurrence Cirrhosis, graft loss, retransplantation Clinical improvement with the possibility for delisting Slow the progression of HCC? Decrease the rate of recurrence of HCC? Decrease the number of transplantations for HCV cirrhosis ± HCC No reduction in the total number of transplantations (in Western coutries)