I SESSIONE Moderatori: G. Angarano, A. Di Leo Pre e post-trapianto di fegato nell’era dei nuovi antivirali • Quali vantaggi dalle nuove terapie? N. Caporaso • Stato dell’arte del paziente in lista d’attesa e del paziente trapiantato M. Rendina 26 giugno 2014 Bari Primary Indications of Liver Transplantation in 15936 Virus related Cirrhosis in Europe 01/1988 - 12/2008 Virus BC : 4% Virus BCD : 145 1% Other virus : 151 1% Virus BD : 1198 8% Virus B : 3893 24% Virus C : 9859 62% 26 giugno 2014 Bari Survival of Patients with Virus related Cirrhosis as the First Indication 01/1988 - 12/2008 (%) (%) 100 94 90 81 81 80 83 75 82 69 71 67 65 66 60 60 58 54 40 20 0 0 1 2 3 Virus C : 9826 4 5 6 Virus BC : 688 7 8 9 Yrs 10 Virus BCD : 144 26 giugno 2014 Bari Accelerated Progression of HCV Disease Following Liver Transplantation1,2 Nontransplant Patients Liver Transplant Recipients 20% after 20 years 10%–40% after 5 years • Cirrhosis to decompensation 2.9%–3.7% per year 42% after 1 year • Survival after decompensation 50% after 5 years 50% at 1 year 30 years 10 years • Chronic hepatitis to cirrhosis • Median duration to cirrhosis 1. Davis GL. Rev Gastroenterol Disord. 2004;4:7-17. 2. Rodriguez-Luna H, Douglas DD. Curr Opin Infect Dis. 2004;17:363-371. 26 giugno 2014 Bari The pre-transplant scenario: who they are? Pazienti CON C. HCV SENZA Cirrosi HCV 56% CON Cirrosi HCV 44% Femmine 17% Maschi 83% • Età media (±SD) al tx: 54 ± 8 anni Percetuali calcolate sul totale dei pazienti valutabili con dato disponibile (N=1001). 26 giugno 2014 Bari Punteggio MELD al tx in pazienti con e senza cirrosi HCV Pazienti SENZA C. HCV Pazienti CON C. HCV MELD <= 15 45% MELD <= 15 49% MELD > 15 51% MELD > 15 55% Analisi eseguite sul totale dei pazienti valutabili con cirrosi HCV (N=354) e senza cirrosi HCV (N=480). 26 giugno 2014 Bari eGFR al tx in pazienti con e senza cirrosi HCV Pazienti SENZA C. HCV Pazienti CON C. HCV eGFR < 60 14% eGFR >= 60 86% eGFR < 60 17% eGFR >= 60 83% Analisi eseguite sul totale dei pazienti valutabili con dato disponibile con cirrosi HCV (N=379) e senza cirrosi HCV (N=495). 26 giugno 2014 Bari 26 giugno 2014 Bari 26 giugno 2014 Bari 26 giugno 2014 Bari Goals of Antiviral Therapy in waitlisted cirrhotic patients • Halt or reverse disease progression • Prevents allograft hepatitis compensated decompensated 26 giugno 2014 Bari Outocome of antiviral therapy in HCV decompensated cirrhosis Author Patients Tx EOT SVR Jacobellis Forns Tekin Annichiarico 66 51 20 15 PEG/RBV PEG/RBV PEG/RBV PEG/RBV 49% 29% 45% 47% 20% 20% 30% 20% Everson Forns Thomas Amarapurkar Cripprin Totals 124 30 20 18 15 391 IFN/RBV IFN/RIBA IFN IFN/RBV IFN/RBV IFN/RBV 46% 30% 60% 61% 33% 44% 24% 20% 20% 38% 0% 23% 26 giugno 2014 Bari Treatment discontinuation in cirrhotic patients during combination therapy: safety warnings 278 Chronic hepatitis 87 Cirrhosis 85 Cirrhosis 66 Cirrhosis 90 Cirrhosis Ishak score: 0 to 4 Ishak score: 5 or 6 portal hypertension Decompensated Child A, B, C Decompensated Chid A, B, C 40% 21% 16% Infections Side effects 6% Floreani 2008 14% 11% 10% Floreani 2008 Giannini 2009 Iacobellis 2007 Massoumi 2009 8% Annichiarico 2008 26 giugno 2014 Bari Cumulative incidence of bacterial infections Carrion, J Hepatol 2009 26 giugno 2014 Bari Pre-transplant SOF + RBV to prevent post-transplant HCV recurrence Post-transplant virologic response rates • Listed for LT due to HCC meeting Milan criteria • MELD exception for HCC (mean MELD score = 8) • CTP score ≤7 • Excluded decompensated cirrhosis, renal impairment, living donor LT Response (%) Single-arm, open-label, Phase II study from 16 LT sites Pre-LT therapy: SOF 400 mg/day + RBV 1000–1200 mg/day for 48 weeks or until time of LT • Post-LT immunosuppression: ≥12 weeks of tacrolimus + prednisone + MMF CTP = Child-Turcotte-Pugh; LLOQ = lower limit of quantification; LT = liver transplant; MELD = model for end-stage liver disease; MMF = mycophenolate mofetil; pTVR = post-transplant virologic response. n N 41 44* 25 39*† * 3 subjects were >LLOQ at transplant. † 1 subject has not reached pTVR12, 1 subject lost to follow-up at week 8 post-transplant. Curry MP, et al. Hepatology 2013; 58 (Suppl 1):314–315A. Pre-Liver Transplant Study (SOF+RBV) Analysis of Post-Transplant Recurrence in GT 1–4 Days HCV RNA Continuously TND Prior to Transplant No Recurrence (n=29) Recurrence (n=10) No recurrence in 24/25 (96%) of patients who maintained HCV RNA TND >28 days Median days TND • No recurrence: 99 • Recurrence: 5.5 p <0.001* 28 28 *Wilcoxon rank sum test. Curry MP, et al. APASL 2014. Brisbane, Australia. Oral presentation 16 The transplant scenario Author’s Last Name, Conference Name, Year, Presentation # 17 The interplay in the chimera scenario Virus Level of replication Genotype IL28……… Host age, sex fibrosis comorbidities …………. Chimera factors donor (age, Il28b) CNI steroid boluses CMV immunologic imbalance 18 Baseline features of the Italian Recolt pts 464 HCV recurrent patients treated with antiviral therapy Median post-transplant follow up: 6.1 years (0.4-22.8) HCV features demography Pre-LT therapy Male 75% ALT 31% 171±165 Recipient age 53±8yrs Genotype 1-4 75% BMI 25±3 High viral load 84% Diabetes 50% Grading 6.1±3 Staging 2.1±1.2 Facts about intererferon based therapy in Liver transplant: applicability and safety Mostly due to anemia PEG-IFNα-2a PEG-IFNα-2b + ribavirin 1. Chalasani N et al. Hepatology. 2005;41:289-298. 2. Rodriguez-Luna H et al. Transplantation. 2004;77:190-194. 3. Castells L et al. J Hepatol. 2005;43:53-59. 4. Dumortier J et al. J Hepatol. 2004;40:669-674. Italian RECOLT-AISF cohort Survival 1-yr 5-yrs SVR 98.8±0.9% 87.2±3.0% Non-SVR 92.0±1.6% 67.8±3.0% Log-Rank p<0.001 Kaplan-Meier analysis of the cumulative survival from the start of therapy according to the type of response to antiviral Therapy (SVR vs non-SVR). Survival was significantly different in non-SVR compared with SVR patients (Log-rank test P< 0.001). Rendina et al, Hepatol 2011 PI Triple Therapy in Liver transplant patients Applicable to Genotype 1 only More drugs------more side effects +++++anaemia DRUG INTERACTIONS Low effect in prior partial and NR to Peg+RIBA 22 SVR rates with triple therapy in Liver Transplant patients 50% n = 273 n = 54 n = 95 n = 54 27/35 BOC …………………………………… TVR Wierner, Coilly, Puanpong, Stravitz, Nair 2013 23 Cmax increased by 9.3X AUC Increased by 70X Garg et al; Charlton M; Hepatol 201 24 Approach HCV eradication in transplant patients: a new era SOF + RBV for treatment of post-LT HCV recurrence Ongoing prospective, multicenter, single-arm, open-label pilot study SOF 400 mg/day + RBV 400–1200 mg/day for ≤24 weeks Response (%) • Median time since LT: 4.3 years (range: 1.02–10.6) • CTP ≤7 and MELD ≤17 • 83% GT1, 33% IL28B CC, 40% with compensated cirrhosis Virologic response rates n N 40 40 40 40 28 40 28 40 • RBV started at 400 mg/day and increased based on hemoglobin levels Samuel D, et al. EASL 2014 [poster presentation 1232]. SOF + RBV ± PegIFN therapy: compassionate use program for patients with severe HCV recurrence Virologic response rates 100 Clinical outcomes 100 87.1 80 62.4 60 40 20 0 Patients (%) Patients (%) 80 57.7 60 40 21.2 21.2 60 104 22 104 22 104 Improved* Stable 20 n N 81 93 53 85 EOT SVR12 0 SOF 400mg/day for 24–48 weeks + RBV (± PegIFN) n=104 * Significant decrease in hepatic encephalopathy, improvement or disappearance of ascites, or improvement in liver-related laboratory values. n N Worsened/ deceased All patients who received >1 dose of SOF are included Forns X, et al. EASL 2014 [oral presentation 62]. Sofosbuvir compassionate protocol in Italy AISF sponsored SOFOLT Study M. Rendina & P. Andreone coordinators Start in April 2014 Preliminary data from 18 patients available from 7 centers on April 30: • Bologna (R. Vukotic) • Pisa (P. Carrai) • Bari (A. Di Leo) • Parma (A. Degli Antoni) • Roma (L. Loiacono) • Roma (M. Merli) • AISF-SOFOLT study preliminary data Genova (A. Picciotto) 27 Sofosbuvir compassionate protocol Inclusion criteria • • • • • Age >18 yrs Advanced liver disease (MELD ≥12; CTP ≥B7) Life expectancy ≤6 mo No access to experimental treatment Stable immunosuppressive regimen 28 Sofosbuvir compassionate protocol Exclusion criteria • • • • • Inability to sign informed consent No advanced liver disease (CTP <B7) Life expectancy >6 mo Unstable immunosuppressive regimen Pregnancy 29 Sofosbuvir compassionate protocol in Italy Today status 87 patients received at least 1 dose of SOF 38 investigators involved 26 centers involved 4 different treatment schedules • • • • SOF+RBV SOF+SMV SOF+DCV SOF+RBV+Peg-IFN 3 different duration of treatment • 12 wks 30 Results: Patient Disposition Death n=1 SOF + RBV for 24 wks n=18 Completed 4 weeks n=15 Completed 12 weeks n=11 Completed 24 weeks n=7 Completed 4 weeks FU n=5 Completed 12 weeks FU n=3 AISF-SOFOLT study preliminary data 31 Results: Baseline Characteristics n=18 Forns, EASL 2014 n=104 Male, n (%) 13 (76.5) 76 (73) Median age, y (range) 48 (25-56) 55 (16-76) 6.5 (1.3-7.3) 8.4 (1.3-8.9) 1a/1b 5/10 8/29/51 2/3/4 0/2/1 1/7/8 Median bilirubin, mg/dL (range) 3.3 (0.4-12) 3.1 (0.4-45) Median albumin, g/dL (range) 3.4 (2.6-4.7) 3.1 (1.3-12.2) Median INR (range) 1.3 (1-1.86) 1.3 (0.8-4.5) Median platelets, x103/µL (range) 131 (7-871) 78 (19-340) 15 (5-26) 15 (6-43) 48 (0.6-168) 17 (1-262) Median HCV RNA, log10 IU/mL (range) GT, n Median MELD (range) Median months from LT to treatment, (range) AISF-SOFOLT study preliminary data 32 Viral Kinetic HCV-RNA UI/ml baseline 4 wks 12 wks 24 wks AISF-SOFOLT study preliminary data 33 Lab results (1) BILIRUBIN mg/dl baseline 4 wks 12 wks 24 wks AISF-SOFOLT study preliminary data 34 Lab results (2) ALBUMIN mg/dl baseline 4 wks 12 wks 24 wks AISF-SOFOLT study preliminary data 35 Lab results (4) INR baseline 4 wks 12 wks 24 wks AISF-SOFOLT study preliminary data 36 Model for End Stage Liver Disease score MELD score baseline 4 wks 12 wks 24 wks AISF-SOFOLT study preliminary data 37 Child Turcotte Pugh score CTP score baseline 4 wks 12 wks 24 wks AISF-SOFOLT study preliminary data 38 Virological Response AISF-SOFOLT study preliminary data 39 Interaction SOF/TAC TACROLIMUS ng/ml baseline 4 wks 12 wks 24 wks AISF-SOFOLT study preliminary data 40 41 M12-999: ABT-450/RTV/Ombitasvir + Dasabuvir + RBV in Transplant Recipients • • • Open-label phase II trial in liver transplant recipients with recurrent HCV GT1 Primary endpoint: SVR12 Inclusion criteria: GT1,naïve after transplant, METAVIR score ≤ F2, no previous steroid-resistant rejection, stable CNI-based immunosuppressant regimen Wk 24 Liver transplant recipients with recurrent HCV GT1 (N = 34) ABT-450/RTV/Ombitasvir + Dasabuvir + RBV ABT-450/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV dosed at discretion of treating physician. Dosing of calcineurin inhibitors based on phase I PK study. Recommended tacrolimus dose modified to 0.5 mg once wkly or 0.2 mg every 3 days. Recommended cyclosporine dose modified to 20% of daily dose administered before study drugs. Prednisone ≤ 5 mg/day permitted. No use of mTOR inhibitors. Kwo P, et al. EASL 2014. Abstract O114 Study M12-999: liver transplant recipients with recurrent HCV GT1 infection – ongoing efficacy results 100 97.0 96.2 34 34 34 34 32 33 25 26 RVR EOTR SVR4 SVR12 (Week 4) (Week 24) Patients (%) 100 n N No patient experienced a viral breakthrough and one patient had a relapse (post-treatment day 3) • At the time of relapse, this patient had R155K in NS3 protease, M28T+Q30R in NS5A, and G554S+G557R in NS5B, none of which were present at baseline EOTR = end of treatment response. Kwo P, et al. EASL 2014 [oral presentation 114]. Study M12-999: liver transplant recipients with recurrent HCV GT1 infection – safety data Adverse events in >15% of patients, n (%) Any AE Headache Fatigue Cough Insomnia Asthenia Diarrhea Nausea Rash Anemia Dizziness Muscle spasms Pyrexia 3D + RBV (N=34) 33 (97.1) 15 (44.1) 14 (41.2) 10 (29.4) 9 (26.5) 8 (23.5) 8 (23.5) 8 (23.5) 7 (20.6) 6 (17.6) 6 (17.6) 6 (17.6) 6 (17.6) No episodes of acute or chronic rejection 1 patient discontinued study drug due to AEs (moderate rash, memory impairment, and anxiety) after week 18 • Patient achieved SVR12 2 patients had serious AEs: • Hypotension and tachycardia associated with initiation of tamsulosin (Flomax) after elective surgery • Moderate peripheral edema and pain in extremity in a diabetic patient with history of peripheral edema Kwo P, et al. EASL 2014 [oral presentation 114]. Open issues…….. - The potential of drug-drug interaction (CNI, HBV coinfection) - Renal dysfunction - Duration and doses - Clinical impact of relapse - Renal pts - Resistance profile 26 giugno 2014 Bari Decreto 8 maggio 2003 - Uso speciale dei farmaci…cosi’ detto anche uso compassionevole • normativa di riferimento che disciplina in Italia l’accesso a terapie farmacologiche sperimentali, per un uso al di fuori della sperimentazione clinica, a pazienti affetti da malattie gravi o rare o che si trovino in pericolo di vita, quando, a giudizio del medico, non vi siano ulteriori valide alternative terapeutiche • . Decreto 8 maggio 2003 - Uso speciale dei farmaci…cosi’ detto anche uso compassionevole • • • • • • • Richiesta del medicinale formulata dal medico con assunzione di responsabilità al trattamento secondo protocollo ai sensi dell’art. 4 comma 2 lettera a) del DM 8/5/2003; Notifica del/dei pazienti candidati al trattamento accompagnata da breve motivazione clinica; Protocollo d’uso del medicinale; Documentazione di informazione al paziente accompagnata dal modulo per l’acquisizione del consenso informato; Dichiarazione di disponibilità della ditta alla fornitura del medicinale; Parere espresso dal Comitato Etico; Documentazione attestante la produzione del medicinale secondo GMP in accordo alla normativa nazionale e comunitaria;