Breaking News Post-EASL Sardegna 2009 06.11.2018 Hepatitis Journey: Breaking News Post-EASL Milano, 25 Giugno 2014 Pre e Post Trapianto di Fegato nell’era dei nuovi antivirali Alessio Aghemo, MD Unità Operativa di Gastroenterologia ed Epatologia Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Università degli Studi di Milano

Indication For Liver Transplantation Liver-Match M. Angelico et al , Digestive and Liver Diseases 2011

Decreased Survival Among HCV-infected Liver Transplanted Recipients 522 tranplanted pts (1991-2000); 283 pts HCV(+) and 239 HCV(-) Berenguer et al, Hepatology 2001

HCV survival after transplant (database USA/Europe) Autor N.pts Enrolment 5yr Surv Donor Age, yr Anti/HCV therapy Forman 2002, UNOS 4449 1992/98 69% 36 no Lake 2005, SRTR 3463 1995/01 71% 37 Mutimer 2006, ELTR 4736* 1987/01 68% 41 Thuluvath 2007, UNOS 7459** 1991/01 70% 34 Less than 5% * vs Etoh **vs non/HCV

lisbona 4 giugno 2014 06.11.2018 Reduced Liver-related Mortality in SVR Liver Graft Recipients with Recurrent HCV Picciotto et al, J. Hepatology 2007 Berenguer, Am. J. of Transplant. 2008

Safety and Efficacy of TVR/BOC For HCV after OLT BOC (n= 18) TVR (n=19) Death, No (%) 2 (11) 1 (5) Infections, No (%) 5 (27) 5 (26) Hb <8 g/dL, No (%) 7 (39) Renal Failure, No (%) 4 (21) Rehospitalization, No (%) 6 (33) 6 (32) Coilly A et al, J Hepatol 2014;60:78-86

Recurrent HCV Treatment by TVR-BOC + PegIFN/Rbv: Cohort and Clinical Studies DAA Pts Population HCV-1a SVR-12 Disco Faisal, et al TVR BOC 76 F0-F2 72% 58% 44% Stravitz et al TVR 125 F3-F4 =48% 58% 59% 20% Coilly et al TVR BOC 79 F3-F4,FCH =78% 33% 46% 55% Pungpapong et al TVR 60 F3-F4 50% FCH 8% 68% 50% 20% SVR predictors: Cya; (RVR, EVR), Treatment Duration, Predictors of infections: FCH, Bilirubin; Anemia, Trombocytopenia

Antiviral Treatment Strategies to Reduce Graft Loss in HCV Biggins SW, Terrault NA. Infect Dis Clin N Am 2006; 20:155

ION-1 SOF/LDV ± Rbv in HCV-1 Naïve Absence of Cirrhosis Cirrhosis SVR12 (%) 179/179 32/33 178/178 33/33 181/182 31/32 179/179 36/36 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12

ION-2 LDV/SOF±RBV in Treatment Failure Patients Absence of Cirrhosis Cirrhosis SVR12 (%) 83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12

COSMOS (Cohort 2): Sofosbuvir/Simeprevir +/- RBV in G1 Naives and Null Responders, F3-F4 Sub-type and Q80K Fibrosis score Cirrhosis SVR12 (%) 18/18 38/40 25/26 44/45 37/39 21/22 16/17 G1b G1a G1a wo with Q80K Q80K F3 F4 Nulls Naives Lawitz et al, EASL 2014, abs O165

Ideal IFN Free Regimens For HCV-1 NS5B NUC NS5A NS3 Rbv + or ± NS3 NS5A NS5B Non NUC Rbv + + ±

TURQUOISE-2: IFN-Free Regimens in Cirrhotic HCV-1 380 HCV-1 (1a 68%), TN/TE (Null Resp 36%) Cirrhosis Child A (allowed: US ascites, Plt > 60,000, bili < 3, alb > 2.8, varices) ABT-450/r/Ombitasvir + Dasabuvir + Rbv 12/24 Weeks 89 12-week arm 24-week arm 98 94 100 GT 1a GT 1b SVR12, % Patients 124/140 67/68 114/121 51/51 SAE: 6% Discontinuation due to AEs: 2% Decompensation: 1% Poordad F et al, ILC 2014 OC #163 & NEJM 2014 13

TURQUOISE-II :SVR12 Rates in HCV Subtype 1a 92.2 92.9 93.3 100 100 100 80.0 92.9 3D + RBV 12-week arm 24-week arm SVR12, % Patients 59/64 52/56 14/15 13/13 11/11 10/10 40/50 39/42 Naïve Prior Relapse Response Prior Partial Response Prior Null Response Poordad F et al, NEJM 2014 14

TURQUOISE-2: More Advanced Cirrhotics 30/45 32/33 151/163 133/139 21/25 16/18 170/183 149/154 Platelets Albumin Poordad et al, EASL 2014 LB: NEJM 2014

Pretransplant Sofosbuvir + Ribavirin Patient population - DDLT candidates with HCV and HCC meeting MILAN criteria - MELD exception for HCC - CPT ≤7 Enrollment at 16 sites - 8 UNOS regions - 2 international sites 61 patients enrolled Original protocol: until LT or up to 24 weeks of treatment - Amendment: extend treatment duration to 48 weeks or LT Curry MP et al, AASLD 2013 & APASL 2014

Results: Post-Transplant Virologic Response *3 subjects were >LLOQ at transplant. †1 subject has not reached pTVR12, 1 subject LTFU at Week 8 post transplant. Curry MP et al, AASLD 2013 & APASL 2014

Days Continuously TND Prior to Transplant: No Recurrence vs Recurrence in GT 1–4 Curry MP et al, AASLD 2013 & APASL 2014

Patients with an Indication of Liver Transplantation Child-Pugh A with HCC: Sofosbuvir + ribavirin until liver transplantation Sofosbuvir + simeprevir or daclatasvir + ribavirin until liver transplantation probably better Finite (12 weeks) PegIFNa, ribavirin and sofosbuvir also acceptable EASL online HCV treatment recommendations J Hepatol in press

HCV-1 Patients with Decompensated Cirrhosis Arm-2: 20 HCV-1 Cirrhosis Child B SOF + LDV 12 Weeks GT 1 CPT Class B Median total bilirubin, mg/dL (range) 1.5 (0.7-3.7) Median serum albumin, g/dL (range) 3.1 (2.3-3.8) Median INR (range) 1.2 (1.0-3.0) Ascites, n (%) 4 (20) Hepatic encephalopathy, n (%) 6 (30) Median platelet count, 103/µL (range) 84 (44-162) 7 relapses SVR12 (%) 13/20 Gane EJ et al, ILC 2014 OC #6

SOF+RBV in Cirrhosis + Portal HTN ± Decompensation Randomized, open-label, safety and efficacy study of SOF+RBV for 48 weeks compared to observation for 6 months in patients with HCV cirrhosis and portal HTN (CTP 5–9) SOF + RBV n=25 Observation Male, n (%) 18 (72) 20 (80) Median age, y (range) 56 (43‒69) 55 (44‒69) BMI ≥30 kg/m2, n (%) 8 (32) 7 (28) Mean HCV RNA, log10 IU/mL (range) 6.1 (4.4‒7.0) 6.1 (3.8‒6.9) GT, n (%) 1a 10 (40) 9 (36) 1b 6 (24) 2 2 (8) 1 (4) 3 4 IL28B non-CC, n (%) 22 (88) Prior HCV treatment, n (%) 17 (68) 23 (92) Mean HVPG mmHg, n (range) 16.9 (9‒29) 16.2 (7‒27) HVPG >12 mmHg, n (%) 19 (76) SOF 400 mg + RBV 1000‒1200 mg SVR12 Observation Wk 0 Wk 24 Wk 48 Wk 96 Wk 72 Arm 1 n=25 Arm 2 Preliminary results Afdhal N, EASL, 2014, O68

Difficult-to-Treat Patients: Decompensated Cirrhosis and Portal Hypertension Afdhal N et al, ILC 2014 OC #68

MELD Changes During Treatment/Observation Difficult-to-Treat Patients: Decompensated Cirrhosis and Portal Hypertension (II) MELD Changes During Treatment/Observation Afdhal N et al, ILC 2014 OC #68

Decompensated Cirrhosis not in the Transplant List Patients with decompensated cirrhosis not on a transplant waiting list should be offered an IFN-free regimen This should be done only within a clinical trial, an expanded access program or within experienced centres, because the efficacy, safety and outcomes have not yet been established for this group EASL online HCV treatment recommendations J Hepatol in press

Patients with an Indication of Liver Transplantation Patients with decompensated cirrhosis awaiting liver transplantation (Child-Pugh B or C) Sofosbuvir + ribavirin in experienced centers under close monitoring Sofosbuvir + daclatasvir + ribavirin probably better EASL online HCV treatment recommendations J Hepatol in press

Antiviral Treatment Strategies to Reduce Graft Loss in HCV Biggins SW, Terrault NA. Infect Dis Clin N Am 2006; 20:155

SOF + RBV for Recurrent HCV Post-liver Transplant Primary endpoint: pTVR (SVR12 post-LT) Study inclusion criteria: Liver transplant ≥ 6 months and ≤ 150 months CPT ≤ 7 and MELD ≤ 17\ Treatment-naïve or experienced CPT ≤7 and MELD ≤17 Samuel D, EASL 2014, P1232

Virologic Response with SOF + RBV in Post-LT Patients Treated for 24 weeks 40/40 40/40 29/40 28/40 28/40 Relapse was not influenced by RBV dose or exposure No interactions reported between SOF and any immunosuppressive agents during the study Samuel D, EASL 2014, P1232 28

ABT450/r + Ombitasvir + Dasabuvir + RBV for 24 Weeks for Post-LT HCV 100% 96% Phase 2 Study N=34 G1, post-LT treatment naive F0-2 CNI doses adjusted for ABV450/r use Kwo P, EASL, London 2014

SOF 400 mg/d for 24-48 weeks plus RBV ± Peg-IFN FCH LIVER CLUB 24/06/2014 SOF Compassionate Use for Severe Recurrent Hepatitis C Including FCH following LT Severe recurrent hepatitis C post-LT likely to have <1 yr life expectancy SOF 400 mg/d for 24-48 weeks plus RBV ± Peg-IFN SOF Compassionate Use Program SOF + RBV ± PEG, n=104 Severe acute hepatitis/early recurrence (<12 mo from LT with typical biochemical-histological findings), n=48 Post-LT compensated (F4) or decompensated cirrhosis, n=56 Completed 24-48 weeks treatment n=72 Liver transplant n=12 Death n=13 Early term due to AE n=7 Infatti nel nostro centro abbiamo avuto la possibilità di trattare Pz con SOF + RBV in uso compassionevole. Vi presento qui i dati che Forns ha presentato al congresso Europeo di quest’anno. Pz con ricorrenza severa tra cui 48 Pz trapiantati da meno di un anno con dg di FCH e 56 Pz con cirrosi post-Tx anche scompensati sono stati trattati con SOF +RBV +/- Peg x 24/48 sett. Di questi 104 Pz, esclusi 7 pz che hanno dovuto sospendere x reaz avverse, 12 ritrapiantati e 13 deceduti, hanno completato le 24/48 sett di terapia in 72. Forns X. ILC 2014 30

Results: Baseline Characteristics FCH LIVER CLUB 24/06/2014 Results: Baseline Characteristics Overall (n=104) Age, years 55 (16-76) Male recipient 76 (73%) HCV RNA, log10 IU/mL 8.4 (1.3-8.9) GT HCV, 1 / 4 vs 2 / 3 88 / 8 vs 1 / 7 Bilirubin, mg/dL 3.1 (0.4-45) Albumin, g/dL 3.1 (1.3-4.2) INR 1.3 (0.8-4.5) ALT, IU/L 71 (8-1162) MELD 15 (6-43) Time from LT to treatment, months 17 (1-262) Interessante notare come in questa casistica vi siano Pz con vari tipi/gradi di malattia con un MELD variabile tra 6 e 43. Inoltre vi è molta diversità nella tempistica del trattamento con Pz al 1 mese post Tx e Pz che hanno iniziato il trattamento dopo molti anni dal Tx. 31

Results: Overall Virologic Response in 104 HCV Rec FCH LIVER CLUB 24/06/2014 Results: Overall Virologic Response in 104 HCV Rec 4/85 15% 13/85 18% Patients (%) I tassi di risposta virologica sono dell’87% come EOT e del 62% come SVR12. Il 18% Pz non ha risp al trattamento (Nr e relapser) mentre il 15% è deceduto. Da notare come la maggior parte degli eventi avversi severi è stata correlata ad una progressione di malattia e non al trattamento 87% 62% 32

Results: Clinical Outcomes All patients who received ≥1 dose of SOF are included Patients (%) La terapia è stata ben tollerata ed ha portato nel 62% dei casi ad un miglioramento delle condizioni cliniche e degli esami di laboratorio, nel 21% dei Pz la situazione è rimasta invariata mentre nei restante 21% vi è stato un peggioramento che come detto in prec non è dovuto al trattamento ma al fatto che alcuni Pz erano già in partenza troppo gravi * Significant decrease in hepatic encephalopathy, improvement or disappearance of ascites, or improvement in liver-related laboratory values. 33 33

Post-Transplant Recurrent Hepatitis C Patients with post-transplant recurrence of HCV infection should be considered for therapy IFN-free treatment is recommended No dose adjustment is required for tacrolimus or cyclosporine with any of the available combinations