HCV Therapy in Liver Transplant Candidate

Transcription

1 PHC 216 HCV Therapy in Liver Professor Didier SAMUEL Transplant Candidate Dr Audrey COILLY Centre Hépato-Biliaire, Inserm 1193 Treat before orrearch afuniter? University Paris Sud A Villejuif u d r e yfrance COILLY Paul Brousse Hospital, HOPITALPAULBROUSSE DAAs In Transplanted Patients Centre Hépato-Biliaire

2 Control HCV Recurrence To achieve HCV clearance is crucial to improve both graft and patient survival IFN era Low efficacy Poor safety profile Risk of rejection Risk of infection BEFORE AFTER

3 Control HCV Recurrence To achieve HCV clearance is crucial to improve both graft and patient survival DAA era Subtle differences BEFORE AFTER

4 Agenda Difference in efficacy before and after LT? Difference in tolerance? Could we avoid liver transplantation?

5 Efficacy after LT Most regimens allow to achieve a SVR12 rate of >9% Approved regimens 95% 94% 95% 9% 7% SOF+ (1) ALLY SOF+LDV (2) SOF+DCV (3,4) 3D (5) Δ SOF+SIM (6,7) (1) Charlton M, Gastroenterology, 215; (2) Charlton M, Gastroenterology, 215; (3) Coilly A, EASL G15, 215; (4) Poordad F, Etats-Unis, EASL 215, Abs. L8; (5) Kwo py, NEJM, 214; (6) Pungpapong S, Hepatology 215. (7) Reddy R, Etats-Unis, EASL 215, Abs. O7

6 Impressive Efficacy in FCH Transplant Patients Sofosbuvir + Daclatasvir or Sofosbuvir + Ribavirine in 23 Patients with FCH-The Cupilt Cohort Leroy et al, Clin Gastroenterol Hepatol 215

7 Impressive Efficacy in FCH Transplant Patients Sofosbuvir + Daclatasvir or Sofosbuvir + Ribavirine in 23 Patients with FCH-The Cupilt Cohort Leroy et al, Clin Gastroenterol Hepatol 215

8 Efficacy Lower in Transplant Patients with Advanced Cirrhosis Compassionate use of Sofosbuvir + Ribavirine +- Peg IFN After LT- Clinical outcome Forns et al, Hepatology 215

9 Efcacy before LT Excellent results in compensated cirrhotic patients Lower efficacy in decompensated ones Approved regimens Compensated Child<11 88% SOF+LDV (1) 94% 82% SOF+DCV (2) 72% ALLY 3D (3) Δ SOF+SIM (4) (1) Charlton M. Gastroenterology 215; (2) Poordad F, Etats-Unis, EASL 215, Abs. L8; (3) Poordad F, Etats-Unis, EASL 214, Oral late breaker LB O163 (4) Reddy R, Etats-Unis, EASL 215, Abs. O7

10 Efficacy before LT SVR12 depends on severity of cirrhosis Using SOF+LDV or 3D, low platelets count and low albumin level are risk factors of relapse Compensated 88% SOF+LDV (1) 94% 82% SOF+DCV (2) 72% ALLY 3D (3) Δ SOF+SIM (4) (1) Charlton M. Gastroenterology 215; (2) Poordad F, Etats-Unis, EASL 215, Abs. L8; (3) Poordad F, Etats-Unis, EASL 214, Oral late breaker LB O163 (4) Reddy R, Etats-Unis, EASL 215, Abs. O7

11 Efficacy before LT SVR12 depends also on genotype Combinaison SOF and NS5A inhibitor + during 12 weeks 467 cirrhotic patients Child B7 SOF + LDV + SOF + LDV SOF + DCV 89 p <,5 82 SVR12 % (ITT) SOF + DCV ALLY Overall Foster G, UK, EASL 215, Abs. O Genotype Genotype 3 7 Δ Others 3

12 Next Generation: Is this going to change? Astral 4: Sofobuvir + Velpatasvir Ribavirin still required in most cirrhotic patients Curry NEJM 216

13 Conclusion 1: Differences in Efficacy Better results in term of efficacy after LT than before Mainly Child C patients Stage of cirrhosis is still a predictor of efficacy using DAA Unmet medical needs after LT Optimal duration Use of ribavirin Time of treatment initiation

14 Agenda Difference in efficacy? Difference in tolerance before and after LT? Could we avoid liver transplantation?

15 Safety after LT Good safety profile SAE rate of 2% (mainly due to ) Issue: drug-drug interactions Ciclosporine Tacrolimus Sofosbuvir Sofosbuvir/Ledipasvir Ciclosporine AUC - 2% Tacrolimus AUC + 13% Ciclosporine AUC Tacrolimus AUC +79% Ciclosporine AUC Dosage 5 Tacrolimus AUC mg/wk ou.2mg/2days Daclastavir Simeprevir Ombitasvir, paritaprevir, ritonavir, dasabuvir Coilly, A. Liver Int. 215

16 Good safety profile SAE rate of 2% (mainly due to ) Issue: drug-drug interactions Safety after LT ANRS C23 CUPILT cohort: SOF+DCV Tacrolimus Ciclosporine Everolimus MMF Number of patients Number who changed dosage n (%) 44 (56 %) 18 (49 %) 5 (38 %) 9 (13 %) Most changes occurred after 4 weeks of treatment, refecting improvement in liver function more than clinically relevant drug-drug interactions To monitor immunosuppressive drugs is still mandatory Coilly, A. France, G15, EASL 215.

17 Safety before LT Good safety profile SAE rate of 2% (mainly due to ) Hepatic function is one issue Pharmacokinetic changes according to liver function Hepatic function impairment Mild Avoid Moderate Severe Simeprevir Sofosbuvir Child C Ledipasvir3 No adjustement Paritaprevir/r Ombitasvir Dasabuvir Child C? Asunaprevir Child B/C Daclatasvir Child C 1. Ouwerkerk-Mahadeva S, et al. AASLD 213. Oral #65; 2. Gilead Sciences Europe. SOVALDI (sofosbuvir), Summary of Product Characteristics, January 214; 3. German P, et al. AASLD Oral #52; 4. Khatri A, et al. AASLD Oral #66; 5. Bifano M, et al. AASLD Oral #78.

18 Sofosbuvir and Cardiologic events 5 reported cases Role of amiodarone B-Blockers? Other? Unexpected adverse events in more severe patients

19 Conclusion 2: Differences in Tolerance Safety profiles are excellent before and after liver transplantation. Issues are Drug-drug interactions, mainly with immunosuppressive drugs Anemia Post Transplant () Hepatic impairment Both issues argue for the use of NS5A inhibitors more than protease inhibitors

20 Agenda Difference in efficacy? Difference in tolerance? Could we avoid liver transplantation?

21 HCC patients Improvement in hepatic function could make a treatment feasible to control HCC on waiting list No withdrawal of list N=84 RF Control group 1 Treatment with IFN+ % p =,2 72,4 8 59,5 6 47,6 4 26,2 2 Recurrence rate at 1 year Zhang N, China, EASL 214, Abs. P994 Recurrence rate at 3 years

22 Decompensated Cirrhosis Is Delisting Possible? Variations of MELD score Baseline/EOT in SOLAR I and II studies among Child>B cirrhotics 1 8 < <1 < < <1 Deterioration : 11 % Improvement : 76 % 2 Patients (%) Baseline MELD 15 (n = 72) Deterioration : 26 % 15 Patients (%) Baseline MELD < 15 (n = 199) Improvement: 56 % 2-4 Gane EJ, New Zealand, AASLD 215, Abs

23 Association Between Improvement and SVR Delta MELD Meta-analyses of 5 studies % -5 2 % 23 % -1 Only 28% had an improvement in the MELD score 3 points SVR12 (%) Some patients improve without achieving SVR Although achieving SVR, some patients worsen (comorbidities?) All MELD No change MELD improvement deterioration Munoz J, USA, AASLD 215, Abs. 22

24 Is there a Point of no Return? National cohort study in patients waiting for LT in France SVR12 = 88 % 183 patients ESLD without HCC N=77 LT 31% Delisting for improvement 16% Coilly A, France, AASLD 215, Abs. 95 HCC N=16 LT 54% Drop-out 6%

25 Is there a Point of no return? National cohort study in patients waiting for LT in France: SVR12 = 88 % Cirrhosis, n=53 72% Child A 36% 36% 21% Child B CHC, n=7 Compl et e improvem ent No re sponse 28% Partial improvement 25% Child C 7.5 MELD score could not be the good marker AUC:.814 Coilly A, France, AASLD 215, Abs. 95 ChildPugh score MELD score

26 Taking into account the System of Organs Allocation Deaceased donor Male 61 yo, G1b ESLD without HCC MELD 23 after SBP Listed for LT National allocation system

27 Taking into account the system of organs allocation Deaceased donor Male 61 yo, G1b ESLD without HCC MELD 23 after SBP Listed for LT Ascites Covert HE LT still indicates but no more access National allocation system HCV treatment

28 Conclusion 3: Management Proposal Treatment with DAA Before or Afer LT Patients on waiting list HCC ESLD No HCC Child A/B Child C Child B Child C Treat before LT Consider benefits Consider MELD score Treat after LT To control HCC: Treat Reduced access to LT: Delay Low: Treat High: Delay

29 Take Home Messages Treat hepatitis C using DAA before or after LT? Both strategies are feasible with excellent efficacy results and good safety profiles Regarding efficacy, better results are achieved after LT than before in decompensated cirrhotic patients Regarding safety, drug-drug interactions and degree of hepatic impairment are still issues, and favor the use of NS5A inhibitors Withdraw patients of waiting list is feasible and should concern about 3% of patients.

30 Centre Hépato-Biliaire A Coilly E De Martin F Chiappini B Roche R Sobesky F Saliba T Antonini JC Duclos-Vallée And all the Team at The CHB