IL TRAPIANTO DI FEGATO: QUALE FUTURO CON LE NUOVE TERAPIE PER LE MALATTIE EPATICHE?

Transcription

1 IL TRAPIANTO DI FEGATO: QUALE FUTURO CON LE NUOVE TERAPIE PER LE MALATTIE EPATICHE? Francesco Paolo Russo Department of Surgery, Oncology and Gastroenterology Multivisceral/ Gastroenterology Section University Hospital Padova

2 Liver transplantation in Italy

3 Patient and graft survival (1 year) ,6 87,387,4 86,8 86,486,8 88,1 86,7 83, ,7 83,2 83,3 83,2 83,9 83, ,1 82,2 82, ,4 78,2 80,8 Patient Graft Italy 81.5 Italy 86,2 UK UK 92 UNOS 86,4 UNOS 89,7

4 ANDAMENTO TRAPIANTI PD * Trapianti * Al

5 TRAPIANTO DI FEGATO-PADOVA DATI

6 Patient and graft survival after liver transplantation for virus-related chronic liver disease according to the indication for liver transplantation Burra et al 2013 J Hepatology

7 What determines the natural history of recurrent hepatitis C after liver transplantation? Berenguer 2005 J Hepatology

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11 Adverse events and management of anemia during triple therapy after liver transplantation Colly et al 2014 J Hepatology

12 Guidelines in post-transplant patients EASL G1 e 4 SOF+DAC + RIBA 12-24w or SOF+SIM + RIBA 12-24w G3, 4, 5, 6 As G1 AASLD SOF+SIM + RIBA 12-24w or SOF+ RIBA + Peg-IFN 24w G2 SOF+RIBA 12-24w SOF+RIBA 24 w Decompensated SOF+RIBA up 48 w

13 First-Generation PI Triple Therapy in Transplantation Recipients Positives Higher response rates more cures SVR rates similar to non transplantation patients Negatives Greater adverse effects, requiring high intensity of monitoring Significant DDIs with CNIs/mTORi kidney toxicity, rejection risk Limited eligibility for treatment

14 Opportunities and Challenges Prior to Transplant We now have pre-olt therapy that can prevent reinfection of graft No dose adjustment of SOF required Anemia with RBV more problematic in more advanced liver disease Data thus far only in Childs A/B with CTP 7, MELD < 22, HCC within Milan criteria Unknown: MELD > 22, CTP > 7 Duration of therapy wks can make timing of transplant difficult for some centers SVR (SOF/SIM) may be a more cost-effective goal than suppression (SOF/RBV) Elimination of RBV also more effective Additional data required in those with more advanced disease Ascites and encephalopathy may improve Kwo Clinical Care Options

15 Pre-Transplant

16 Sofosbuvir + Ribavirin to Prevent Post-transplantation HCV Single-arm, open-label phase II study from 16 liver transplantation sites across 8 UNOS regions and 2 international sites GT1-4 HCV LT candidates based on MILAN criteria MELD exception for HCC CTP score 7 (N = 61) SOF 400 mg + RBV mg Wk 48 or LT Excluded decompensated cirrhosis, renal impairment, living donor LT Original protocol: 24 wks of treatment or until LT; amended to extend treatment duration to 48 wks or LT Curry MP, et al. Gastroenterology in press

17 The disposition of patients throughout the study Curry MP, et al. Gastroenterology in press

18 Duration of Undetectable HCV RNA Before Transplant Predicted Lack of Recurrence > 30 days TND No recurrence (n = 28) Recurrence (n = 10) 64% of pts HCV RNA negative 12 wks post-lt Continuous days TND pre-lt only factor predicting HCV recurrence in multivariate analysis Only 1/24 pts with > 30 days TND experienced recurrence Median days TND (P <.001) No recurrence: 95 Recurrence: Days With HCV RNA Continuously TND Prior to Liver Transplant Curry MP, et al. Gastroenterology in press

19 Post-Transplant Virologic Response by Visit for Patients With HCV-RNA Level Less Than the LLO Qat the Last Measurement Before Liver Transplantation Curry MP, et al. Gastroenterology in press

20 SOFOSBUVIR PLUS SIMEPREVIR + RIBA SVR 12 Flamm et al (G1, 12w) 75% (ex 76%, na 75%; 1a=72%,1b=81%) LEDIPASVIR PLUS SOFOSBUVIR + RIBA Bourliere et al (G1, 12w+R) Bourlier et al (G1, 24w+R) Bourlier et al ( G1, 12wplacebo+12w+RIBA, PI Fail) 109/ /204 (92/96 %) exp=nai, PLT<75 131/133-58/58(98/100 %) exp=nai, PLT<75 74/77(96%) Bourlier et al ( G1, 24w, PI Fail) 75/77 (97%) Wyles et al (G1, 12w, SOF Fail 29% cirr) 50/51 (98%) Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV Fried et al (G1, 12-24w) 191/208 (92%)- 167/172 (97%) Daclatasvir/Asunaprevir/ Beclabuvir ± RBV in Cirrhotics Muir et al (G1, 12w, + RIBA, naive vs ex) 54/55-53/57 (98-93%), 42/45-39/45 (93-87%)

21 SVR12 (%) SVR by previous treatment, genotype and IL28 12 wks 24 wks n/n = 0 Factor 81/ 86 71/ 74 Naive 28/ 29 23/ 23 17/ 18 13/ 13 Relapser Partial Responder 65/ 75 59/ 62 Null Responder 124/ 115/ GT1a 67 51/ / GT1b HCV Subtype Fried MW, et al. AASLD Abstract 81. Reproduced with permission. 33/ 35 CC 33/ / 102/ CT IL28B Genotype P Value IL28B TT genotype.021 Previous null response to pegifn/rbv.038 GT1a HCV / 41 TT 31/ 33

22 SVR12 (%) SOLAR-1: SVR12 and Safety According to CTP Score in Decompensated Cirrhosis 100 LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks /52 42/47 3 relapses 1 death 1 relapse 2 deaths 1 relapse 1 death 1 LTFU 1 relapse 1 death 26/30 24/27 19/22 18/20 Overall CPT B CPT C Pts, n (%) CPT B CPT C Flamm SL, et al. AASLD Wks (n = 30) 24 Wks (n = 29) 12 Wks (n = 23) 24 Wks (n = 26) AE 29 (97) 27 (93) 23 (100) 26 (100) SAE 3 (10) 10 (34) 6 (26) 11 (42) Treatment-emergent, -related SAEs 2 (7) (8) Treatment discontinuation due to AE 0 1 (3) 0 2 (8)

23 Post-Transplant

24 Sofosbuvir + Ribavirin to treat Post-transplantation HCV recurrence Charlton M, et al. Gastroenterology in press

25 HCV-RNA <25 IU/mL during and after treatment Charlton M, et al. Gastroenterology in press

26 SOFOSBUVIR PLUS SIMEPREVIR EOT SVR 12 SVR 24 Lutcham et al (G1, 12w) 43/44(98%) 25/31 (81%) Ripper et al (G1, 12w) 25/25 (100%) 23/25 (80%) Ford (G1, 12w + RIBA) 36/37 (97%) 34/37 (92%) O Dell et al (G1, 12w) 18/18 (100%) 7/7 (100%) Londono et al (G1/4, 24w+R) 7/7 (100%) 2/2 (100%) DACLATASVIR PLUS SOFOSBUVIR Papadouplulos (G1, 24w+R) 5/6 (83%) 4/6 (67%) Vokotic et al (G1-4, 24w) 3/3 (100%) 3/3 (100%) DACLATASVIR PLUS SIMEPREVIR Fontana RY et al ( G1, 24w+R) 19/24-30 (63-79%) 9/30-12 (30-75%) Londono et al (G1/4, 24w+R) 8/9 (89%) 5/8 (62%) SOFOSBUVIR PLUS RIBAVIRIN Vokotic et al (G1-4, 24w) 36/36 (100%) 19/26 (73%) Vokotic et al (G1-4, 24w) SOFOSBUVIR PLUS RIBAVIRIN

27 Safety No rejection episodes Severe adverse events (SAEs) occurred in 12 (16.9%): 4 deaths (5.6%) 1 re-olt (1.4%) 7 hospitalizations (9.9%) Vukotic et al AASLD 2014

28 CORAL I: High SVR Rates Preserved With New DAA Combinations Post-OLT Open-label phase II trial in LT recipients with recurrent GT1 HCV Inclusion criteria: GT1, LT resulting from HCV infection within 12 mos of screening, no HCV therapy after transplantation, METAVIR score F2, no previous steroid-resistant rejection, receiving stable tacrolimus- or cyclosporine-based immunosuppressant regimen LT recipients with recurrent GT1 HCV (N = 34) ABT-450/RTV/Ombitasvir + Dasabuvir + RBV Wk 24 SVR12 96% ABT-450/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV closely monitored, dosed at discretion of treating physician. Kwo et al 2014 NEJM

29 Calcineurin Inhibitor Dosing With ABT-450/RTV/Dasabuvir + Ombitasivr Phase I study: dosing tacrolimus or cyclosporine with the 3 DAA regimen compared with either alone resulted in: 7-fold increase in tacrolimus half-life 3-fold increase in cyclosporine half-life Based on these findings, recommended dosing during 3 DAA treatment was: Tacrolimus 0.5 mg once weekly or 0.2 mg every 3 days Cyclosporine 1/5 of the daily pre-3 DAA treatment dose given once daily Kwo et al 2014 NEJM

30 An Interferon-free Antiviral Regimen for HCV after Liver Transplantation Kwo et al 2014 NEJM

31 Sofosbuvir/Ledipasvir + RIBA in patients with Post-OLT recurrence of GT1 or 4 HCV N=223 pts % experienced Median time from OLT 4.4 ys (range: ) Median HCV-RNA 6.4 log 10 IU(mL (range ) Most cirrhotic patients with MELD>10 (60%) Median PLT= K, median albumin= g/dl Improvements in MELD, bilirubin, and albumin noted 5 pts discontinued study treatment due to AES 7 pts died Reddy KR et al AASLD 2014 Abstract 8

32 Sofosbuvir/Ledipasvir + RIBA in patients with Post-OLT recurrence of GT1 or 4 HCV 100% % 60% 40% SOF/LED/RIBA 12w SOF/LED/RIBA 24w 20% 0% 53/ 55/ / 24/ / 15/ / 5 2/ 3 F0-F3 CPTA CPTB CPTC Reddy KR et al AASLD 2014 Abstract 8

33 Drug-drug interactions between DAAs and calcineurin inhibitors Gambato et al 2014 J Hepatology

34 Therapeutic approaches of HCV infection in 3 different patient populations: Gambato et al 2014 J Hepatology Aghemo et al Gatroenterology un press

35 CONCLUSION Current oral therapy limited to compassionate use of: Sofosbuvir + ribavirin + Peg-IFN Sofosbuvir + simeprevir or daclatasvir + Ribavirin Additional all-oral therapies for GT1 will be approved in ABT-450/RTV/ombitasvir + dasabuvir + Ribavirin Sofosbuvir/ledipasvir + Ribavirin Daclatasvir + asunaprevir or simeprevir+ Ribavirin Expect > 90% SVR, 12- to 24-wk duration Interferon will not be required RBV-free therapies also desirable