Gestione del paziente nel pre e post trapianto di fegato

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1 Gestione del paziente nel pre e post trapianto di fegato Maria Rosaria Piras SSD SSD Coordinamento Trapianto di Fegato Azienda Ospedaliera Brotzu Cagliari

2 HCV Infection and Liver Transplantation HCV infection is the 1 cause of liver transplantation in industrialized countries BUT Universal reinfection after LT Negative impact on long-term survival Up to 1/3 of HCV transplanted patients will develop an accelerated course to cirrhosis within 5 yrs following LT Recurrence prevention Berenguer M et al Hepatology 2000;32: Neumann UP et al Transplantation 2004: 77: , Belli L et al Liver Transpl 2007;13: , Burra P et al J Hepatol 2013

3 Treatment Pre-LT with the Goal of Preventing HCV Recurrence Antiviral Antiviral Therapy Therapy for wks Strategy 1: Treat to Cure SVR LT 100% HCV-free post- LT No SVR 100% HCV- infected post-lt Strategy 2: Treat to Achieve HCV RNA Undectability Antiviral Therapy until HCV RNA negative for 4 wks LT Follow up On-Treatment Response 95% HCV-free post-lt if HCV RNA negative at LT Adapted from Terrault N EASL 2015

4 Treatment Pre-LT with the Goal of Preventing HCV Recurrence Antiviral Antiviral Therapy Therapy for wks Strategy 1: Treat to Cure SVR LT 100% HCV-free post- LT No SVR Shorter duration 100% HCV- infected post-lt of therapy Strategy 2: Treat to Achieve HCV RNA Undectability Antiviral Therapy until High HCV % of RNA patients negative achieve for TND 4 wks HCV RNA on DAAs On-Treatment Response LT Follow up 95% HCV-free post-lt if HCV RNA negative at LT Adapted from Terrault N EASL 2015

5 Solar-1: LDV/SOF + RBV in decompensated cirrhosis Results: SVR 12 N=108 HCV GT 1a 76% IL 28B non CC 72% TE 65% Flamm, AASLD, 2014, Oral #239

6 LABORATORY RESULTS: MELD SCORE CHANGE FROM BASELINE TO FOLLOW-UP WEEK 4 Laboratory results: MELD score change from baseline to follow up week 4 CPT B CPT C 12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)* (+10) 36% not improved 35% not improved n=5 n=5 n=2 n=3 *Missing FU-4: n=2 CPT B 12 wk; n=4 CPT B 24 wk; n=2 CPT C 12 wk; n=7 CPT C 24 wk. Flamm, AASLD, 2014, Oral #239

7 Advanced cirrhosis N=60 Post-LT N=53 DCV 60 mg QD SOF 400 mg QD+RBV Follow-up Week 0 Week 12 Week 24 Week 36 SVR 12 HCV GT 1-75% (GT1a 57%) IL28B non CC 78% Naive or experienced patients DAA failures allowed except NS5A HCC allowed CTP B-C 80% Advanced cirrhosis patients with treatment interrupted by LT could receive an additional 12 wks of treatment immediately post-lt

8 SVR 12 by HCV Genotype and CTP Class: Ally-1 Study Advanced cirrhosis cohort N=60 Patients with relapse: DCV + SOF + RBV 24 wks Ch Child-Pugh Class

9 Cirrhotic Patients Transplanted During Treatment: Ally-1 Study *Discontinued RBV after 11 days due to hyperbilirubinemia resulting from post-lt biliary obstruction

10 Post-Transplant HCV Recurrence in patients in whom HCV RNA was non detectable for 28 days prior to transplant No Recurrence (n=29) Recurrence (n=10) Cirrhosis + HCC CTP 7 MELD exception for HCC 48 wks or LT No AEs due to SOF/RBV No recurrence in 24/25 (96%) of patients who maintained HCV RNA TND >28 days 28. Curry MP et al, Gastroenterology 2015

11 EASL 2015 Guidelines Antiviral Therapy on the Waiting List in Decompensated Cirrhosis Pawlotsky JM EASL 2015

12 Antiviral therapy on the waiting list Objective: Improve liver function About 1/3 of CTP B or C patients not improved despite HCV suppression Predictors of potential de-listing still unknown About 2/3 of patients could be transplanted with lower MELD score Objective: prevent HCV recurrence Clear predictors of success Not always easy to apply Date of LT unpredictable Suitable for low MELD score Ideal for LDLT No impact on waiting list Openned questions Is 4 wks negativity the best prediction rule? Can adjuvant therapies e.g. HCIG improve SVR rates post-lt? Should DAA be continued post-lt for a limited time?

13 Strategies to use antiviral therapy in the context of LT STRATEGIES TO USE ANTIVIRAL THERAPY IN THE CONTEXT in HCV positive recipients OF LIVER TRANSPLANTATION IN HCV POSITIVE RECIPIENTS Listing Transplant Follow-up Target population FCH RF BC F2 F0-F2 Antiviral therapy Cure the HCV recurrence FCH: fibrosing cholestatic hepatitis RF: rapid fibrosers BC: biliary complicathions

14 SVR rates with triple therapy in Liver Transplant patients P IFN+R BV 30% 52% n = 273 n = 54 n = 95 n = 54 Death Infections Anemia Renal failure Rejection DDI Rehospitalization 27/35 BOC TVR Wang CS et al Am J Transpl 2006;6: , Hirouchakis et al J Viral Hepat 2008;15: Wierner, Coilly, Puanpong, Stravitz, Nair 2013

15 Treatment after Liver Transplantation SOF + RBV 24 weeks Author N Genotype 1 Cirrhosis Time after LT Charlton M 40 83% 40% 4,3 yr Forns X % 50% (50% FCH) 17 mo Samuel D 40 83% 40% 4.3 yr Initial RBV dose 400 mg/d Charlton M et al, Gastroenterology 2015, Forns X et al Gastroenterology 2015, Samuel D et al EASL 2014

16 Results: Post-Transplant Virologic Response SOF + RBV 24 weeks 70% 70% NO DDI No rejection 59% Charlton Forns Samuel SVR 12 SVR 12 SVR 12 Charlton M et al, Gastroenterology 2015, Forns X et al Gastroenterology 2015, Samuel D et al EASL 2014C

17 Treatment after Liver Transplantation SOF Simeprevir RBV + ± weeks Author N GT 1 Cirrhosis RBV SVR Brown R % 60% 22% 91% Pupapon S % 29% 22% 91% Te H % 35% (F3- F4) 0% 71% Treatment safe and well tolerated 1-2 AASLD 2014, 3 EASL 2015

18 N=19 GT1a N=9 F4 53% 3 mos after LT TE 84% (21% + PI) 12 wks Safe & well tolerated 100% 90% 80% 70 60% 50% 40% 30% 20% 10% 0% F3 GT1a F4 F3 GT1b F4 SVR 12

19 Treatment after LT: ALLY-1 Study SOF Daclatasvir RBV + + Advanced cirrhosis N=60 Post-LT N=53 DCV 60 mg QD SOF 400 mg QD+RBV Follow-up Post-LT HCV GT1-77% (GTa 58%) IL 28B non CC 75% Naive or experienced patients F3/F4-55% 3 mo. after LT Any immunosuppressive regimen Week 0 Week 12 Week 24 Week 36 SVR 12 Poodard F et al EASL 2015

20 SVR12 by HCV Genotype and by cohort: ALLY-1 Study Patients with relapse: DCV + SOF + RBV 24 wks No DDI No graft rejection Well tolerated Poodard F et al EASL 2015

21 Treatment after LT: CUPILT Study SOF Daclatasvir RBV + ± N=130 Most F3-F4 FCH 10% Most patients 24 wks Most patients without RBV Safe and well tolerated Attention to renal failure Coilly et al, EASL 2015

22 Virological Resonse According to Treatment Duration CUPILT Study SOF + Daclatasvir ± RBV EOT SVR % 100% 100% 97% 98% 96% 67% 67% Virologic Breakthrough n=1 Lost of FU n=1 Relapse n=1 Death n=2 wk1 & FU wk6 SOF+DCV (n=11) Coilly et al, EASL 2015 SOF+DCV+RBV (n=3) SOF+DCV (n=64) Week 12 Week 24 SOF+DCV+RBV (n=52)

23 Treatment after LT: Solar-1 Study SOF Ledipasvir RBV + + Wk 0 Wk 12 Wk 24 Wk 36 N=112 LDV/SOF + RBV N= 223 GT1,4 TN & TE 3 mo. from LT F0-F3 N=111 CTP A (n=51),b (n=52),c (n=9) CTP B,C RBV dose escalation N=111 LDV/SOF + RBV SVR 12 were similar with 12 or 24 wks of treatment SVR12 SVR12 Reddy, AASLD 2014, #8 8 CTP B 24 wk & CTP C 24 wk patients have not reached the wk 12 post-treatment visit Error bars represent 2-sided 90% exact confidence intervals

24 GT1a N=392 GT1b N=224 GT4 N= 42 N=658 Conclusions In these patient populations treatment with LDV/SOF + RBV was generally safe and well tolerated, irrespective of the degree of decompensation or whether patients were pre- or-post transplantation

25 12-24 wks N=12 Males 75% Caucasian 85% GT1a 75% TE 75% N=9 completed treatment N=3 on treatment No treatment discontinuation 5 SAEs (1TR dyspnea) On-treatment wk 4 Follow up wk 4 N=11/12 HCV RNA < LLOQ N=8/8 SVR

26 Treatment after LT: SATURN Study Daclatasvir Simeprevir RBV + + N=35 GT 1b Mild fibrosis N=21 F1-F4 N=14 TN & TE 24 week treatment CNI interaction (CsA/SMV) Treatment safe and well tolerated Forns et al, EASL 2015 F1-F2 F1-F4 Follow-up week 4

27 Treatment after LT Paritaprevir/R Ombitasvir Daclatasvir RBV N=34 All GT1 F2= 2 TN & TE CNIs adjustement for ABT450/RTV Mild AEs 5 patients recived EPO Kwo et al, NEJM 2014

28 EASL 2015 Guidelines Post-LT Recurrence DDI interactions

29 1-Conclusions Treatment of HCV infection in patients awaiting LT is a good strategy to prevent HCV graft infection: it will increase survival an simplify post-lt follow-up Viral clearance may be associated with improvement in liver function, leading to delisting in some cases Treatment is not recommended in patients with very advanced liver disease All patients with HCV infection after LT are candidates for IFN-free antiviral therapy Treatment is recommended at an early stage of hepatitis C recurrence, preferably when patients are in stable condition (immunosuppression, renal function.) In those cases of early recurrence (cholestatic forms) treatment shoud be administered as soon as the diagnosis is made

30 2-Conclusions Expected huge impact on patient and graft survival, selection of candidates for LT considered at great risk of severe HCV recurrence (females with high MELD score, HIV coinfected) Expected reduced impact of donor age and D/R match, suboptimal donors (steatosis,ischemia time, DCD) HCV positive donors

31 Complicanze pre e post Trapianto di fegato fpost-olt NAFLD Insufficienza renale acuta più frequente nel post operatorio Patogenesi multifatoriale e fattori in parte comuni a iperlipemia e diabete Stile di vita, modifiche immunosoppressione Osteopenia e fratture spontanee frequenti soprattutto I semestre Grazie post-olt per l attenzione Patogenesi m. colestatica, deficit e sintesi ed assorbimento vit.d, Malnutrizione, ipogonadismo, immobilità, diuretici, Cise rapida perdita massa, recente Osteopenia e fratture spontanee frequenti semestre post-olt Patogenesi multiffatoriale: m. colestatiche, deficit sintesi e metabolismo vit.d deficit assorbimanto calcio, malnutrizione, ipoginadismo, allettamento, diuretici rapida perdita massa ossea primo periodo post-olt, terapia immunosoppressiva, IRC jatrogena Calcio, vit. D e bifosfonati evidenza utilità Orlistat

32 EASL 2015 Guidelines Antiviral therapy is indicated in patients awaiting liver transplantation because it prevents graft infection Treatment should be initiated as soon as possible to complete a full treatment course before transplantation The optimal timing (i.e. before transplantation or post-transplantation) to maximize survival is still debatable and require individual assessment

33 Antiviral Therapy post-lt: Key Points Antiviral therapy after LT to cure HCV recurrence - The real extraordinary innovation - Effective and safe in all non cirrhotic recipients - Absent or easy manegeable DDI Expected huge impact on: - Patient and graft survival - Selection of candidates for LT considered at great risk of severe HCV recurrence ( females with high MELD score, HIV coinfected) Expected reduced impact of: - Donor age and D/R match - Suboptimal donors (steatosis,ischemia time, DCD) - HCV positive donors

34 Openned Questions Treat before or after LT? If before LT, when? (MELD?) Remove patients from the waiting list? Best combination for each patient? Duration of treatment? RBV yes or no? How to avoid relapse? Risk of liver failure? More data is needed concerning safety

35 Conclusions The number of liver tansplants due to HCV related cirrhosis will be influenced by the efficacy and the widespread applicability of antiviral therapies to prevent/reduce liver decompensation and HCC occurence The success of liver transplants in HCV related cirrhosis will be influenced by the efficacy an widespread applicability of antiviral therapies to prevent/cure HCV recurrence

36 Treatment Pre-LT with the Goal of Preventing HCV Recurrence Antiviral Antiviral Therapy Therapy for for wks Strategy 1: Treat to Cure SVR LT 100% HCV-free post- LT No SVR 100% HCV- infected post-lt Strategy 2: Treat to Achieve HCV RNA Undectability Antiviral Therapy until HCV RNA negative for 4 wks LT Follow up On-Treatment On-Treatment Response Response Terrault N EASL 2015 with permission 95% HCV-free post-lt if HCV RNA negative at LT

37 Treatment after Liver Transplantation SOF Simeprevir RBV + ± weeks Author N GT 1 Cirrhosis RBV SVR Brown R % 60% 22% 91% Pupapon S % GT1a 62% Te H % GT1a 62% 29% 22% 91% 35% (F3- F4) 0% 71% 1-2 AASLD 2014, 3 EASL 2015

38 Antiviral Therapy in Transplant Setting EASL 2015 Guidelines SOF + RBV GT 2 SOF/SIM* + RBV GT 1-4 SOF/LDV + RBV GT SOF/DCV/ + RBV All 3D# ± RBV GT 1 *Not recommended for decompensated cirrhosis #Paritaprevir-r/Ombitasvir/Daclatasvir not recommended for decompensated cirrhosis

39 Real world experience in the HCV-Target cohort: An International Consortium

40 Safety and Efficacy of Post-Transplant Patients Treated with SOF-Containing Regimens for HCV HCV-Target -Post Transplant Brown AASLD 2014#LB-4

41 Safety and Efficacy of Post-Transplant Patients Treated with SOF-Containing Regimens for HCV HCV-Target -Post Transplant Brown AASLD 2014#LB-4

42 SVR 4+ (%) Safety and Efficacy of new DAA-based therapy for HCV posttransplant -SVR 4 + in GT1 with SMV +SOF ±RBV HCV-Target -Post Transplant 61 /68 9 /11 52 /57 32 /37 29 /31 33 /37 26 /31 11 /12 10 /13 30 /36 18 /19 Yes No Yes No < a 1b Brown AASLD 2014#LB-4

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46 EASL Recommendations on Treatment of Hepatitis C 2015 Journal of Hepatology DOI: /j.jhep Copyright 2015 European Association for the Study of the Liver Terms and Conditions

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51 Mean egfr change (ml/min) Patients (%) Mean creatinine change (mg/dl) DDI interactions (SOF) and renal parameters (SOF/LDV) in transplanted patients ERADICATE select KT Study mean (NIAID, CR CHANGES SOFL/DV) Sofosbuvir Creatinine ARV Untreated ARV Treated TAC MMF P CyA Aza TAC tacrolimus, MMF mycophenolate mofetil, P prednisone CyA cyclosporin AZA azathioprin No interactions reported between SOF and any immunosuppressive agents Charlton MR EASL Day 0 Wk 2 Wk 4 Wk 8 Wk 12 SVR 2 SELECT GFR NARV vs ARV SVR 12 Estimated Glomerular Filtration Rate ARV Untreated ARV Treated -30 Day 0 Wk 2 Wk 4 Wk 8 Osinusi A, EASL 2014 Wk 12 SVR 2 SVR 12

52 LDV/SOF + RBV for Treatment of HCV in Patients with Post-Transplant Recurrence SOLAR-1 Wk 0 Wk 12 Wk 24 Wk 36 N=112 LDV/SOF + RBV SVR12 N=111 LDV/SOF + RBV SVR12 N= 223 GT1,4 TN & TE 3 mo. from LT F0-F3 N=111 CTP A (n=52),b (n=52),c (n=9) CTP B,C RBV dose escalation Reddy, AASLD 2014, #8 8 CTP B24 wk & CTP C 24 wk patients have not reached the wk 12 post-treatment visit Error bars represent 2-sided 90% exact confidence intervals

53 Treatment Pre-LT with the Goal of Preventing HCV Recurrence Strategy 1: Treat to Cure Antiviral Therapy for wks SVR LT 100% HCV-free post- LT No SVR 100% HCV- infected post-lt Strategy 2: Treat to Achieve HCV RNA Undectability Antiviral Therapy until HCV RNA negative for 4 wks LT Follow-up On-Treatment Response 95% HCV-free post-lt if HCV RNA negative ay LT Adapted from Terrault N EASL 2015

54 Advanced cirrhosis cohort: SVR 12 by HCV GT and CTP Ally Ally-1 Study N=60 Patients with relapse: DCV+ + SOF + RBV 24 wks

55 MELD Scores Baseline to Posttreatment week 12