Breaking News Post-EASL

Presentazione sul tema: "Breaking News Post-EASL"— Transcript della presentazione:

1 Breaking News Post-EASL
Sardegna 2009 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

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

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

4 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

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

6 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

7 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

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

9 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

10 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

11 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 F F4 Nulls Naives Lawitz et al, EASL 2014, abs O165

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

13 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

14 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

15 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

16 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

17 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

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

19 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

20 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 ( ) Median serum albumin, g/dL (range) 3.1 ( ) Median INR (range) 1.2 ( ) 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

21 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

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

23 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

24 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

25 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

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

27 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

28 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

29 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

30 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 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 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

31 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 ( ) 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 ( ) INR 1.3 ( ) 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

32 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

33 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

34 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