Decompensated Cirrhosis

Transcription

1 Treatment Challenges in special patient populations Decompensated Cirrhosis Thomas Berg Sektion Hepatologie Klinik und Poliklinik für Gastroenterologie und Rheumatologie Universitätsklinikum Leipzig Leber- und Studienzentrum am Checkpoint, Berlin

2 DAA in the management of patients with HCV-induced decompensated cirrhosis Topics to discuss Virologic response Outcome predictors Clinical response Point of no return? Safety of DAA The patient on the waiting list Debate: should we start treatment before or after liver transplantation?

3 Current regimens used for patients with decompensated disease and virologic response rates

4 Selection of studies evaluating all oral interferon-free regimes in patients with HCV-induced decompensted disease Controlled trials REAL World -cohorts and Early Access Programme: DCV + SOF before and after LTx ALLY-1 1 HCV-TARGET 6 SOF + SMV +/- RBV SMV + SOF before LTx, Cirrhosis OPTIMIST-2 2 French ATU 7 SOF-containing regimen LDV + SOF before and after LTx SOLAR-2 3 UK EAP 8 SOF + DCV or LDV +/- RBV SMV + DCV after LTx SATURN 4 EU CUP 9 DCV + SOF +/- RBV PTV/r + OMV + DSV +/- RBV CORAL 5 Register studies in UK, France, and Germany 1. Poordad et al. EASL 15, abstract L Lawitz et al. EASL 15, abstract LP Manns et al. EASL 15, oral G Forns et al. EASL 15. Abstract Kwo PY, et al. N Engl J Med. 14;371: Reddy et al. EASL 15, abstract O De Ledinghen et al. EASL 15, abstract PO Foster et al. EASL 15, abstract O Welzel et al. EASL 15, Poster PO772.

5 Selection of studies evaluating all oral interferon-free regimes in patients with HCV-induced decompensted disease Controlled trials REAL World -cohorts and Early Access Programme: DCV + SOF before and after LTx ALLY-1 1 HCV-TARGET 6 SOF + SMV +/- RBV SMV + SOF Number of patients OPTIMIST-2 with before LTx, 2 Child Pugh French Stage ATU 7 C limited Cirrhosis Percentage LDV + SOF before of patients with MELD > 15 appr. 10% (0-22%) SOLAR-2 3 UK EAP 8 SOF + DCV or LDV and after LTx +/- RBV Treatment duration 12 or 24 weeks ± ribavirin SMV + DCV after LTx SATURN 4 EU CUP 9 SOF-containing regimen DCV + SOF +/- RBV PTV/r + OMV + DSV +/- RBV CORAL 5 Register studies in UK, France, and Germany 1. Poordad et al. EASL 15, abstract L Lawitz et al. EASL 15, abstract LP Manns et al. EASL 15, oral G Forns et al. EASL 15. Abstract Kwo PY, et al. N Engl J Med. 14;371: Reddy et al. EASL 15, abstract O De Ledinghen et al. EASL 15, abstract PO Foster et al. EASL 15, abstract O Welzel et al. EASL 15, Poster PO772.

6 Summary of SVR rates in studies evaluating all oral DAA in decompensated HCV cirrhosis Regimen SVR % Author SOF/SMV ± RBV 73-78% Saxena et al. 15 Aqel et al. 15 SOF/LDV ± RBV Solar 1 and 2 TARGET UK NHS E SOF/DCV ± RBV ALLY-1 UK NHS E CUP 86-89% Manns MP 15 Charlton M 15 Terrault 15 Foster GR % (98% CUP) Poordad F 15 Foster GR 15 Welzel T 15 3D (Turqouise) + RBV % (only Child B) Mantry 15 SOF/Valpatasvir ± RBV 83%-94% Curry MP 15

7 Response predictors Stage of decompensation Treatment duration Role of ribavirin

8 ALLY-1 (SOF/DCV + RBV, 12 weeks) SVR by Child Pugh Class SVR12, % A B C No Yes No Yes > to 3.5 <2.8 < to 2.3 >2.3 < to 3.0 >3.0 Child-Pugh class Ascites HE Albumin (g/dl) INR Bilirubin (mg/dl) * DCV + SOF are approved in Switzerland: for patients with HCV-GT1-infection without cirrhosis (12 or 24 weeks treatment duration). For patients with or without cirrhosis (12 weeks treatment duration). For patients with HCV-GT4 infection DCV is approved in combination with peg Interferon alfa and ribavirin (24 weeks treatment duration). HE = hepatic encephalopathy Poordad et al. EASL 15, abstract L08

9 Solar 1 and 2 clinical trials: SOF/LDV with RBV in decompensated patients SVR12 (% patients) n = N Overall efficacy pre-transplant Pre-transplant in GT-1 and GT LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks CTP B CTP C Comparable efficacy in SOLAR-1 1 and SOLAR-2 2 studies 1. Charlton et al. 15; Gastroenterology 149: Manns et al. EASL 15, abstract G02.

10 Daclatasvir Plus Sofosbuvir With or Without Ribavirin in Patients With HCV Genotype 3 Infection: Interim Analysis of a French Multicenter Compassionate Use Program Christophe Hézode, 1 Victor De Ledinghen, 2 Helene Fontaine, 3 Fabien Zoulim, 4 Pascal Lebray, 5 Nathalie Boyer, 6 Dominique Larrey, 7 Christine Silvain, 8 Danielle Botta-Fridlund, 9 Vincent Leroy, 10 Marc Bourliere, 11 Louis d Alteroche, 12 Isabelle Hubert-Fouchard, 13 Dominique Guyader, 14 Isabelle Rosa, 15 Eric Nguyen-Khac, 16 Vincent Di Martino, 17 Larysa Fedchuk, 18 Raoudha Akremi, 18 Yacia Bennai, 18 Jean-Pierre Bronowicki, 19 on behalf of Bristol-Myers Squibb 1 Hépato-gastro-entérologie, CHU Henri-Mondor, Créteil; 2 Centre d Investigation de la Fibrose hépatique, Hôpital Haut-Lévêque, Centre Hospitalo-Universitaire de Bordeaux, Pessac; 3 Hôpital Cochin, AP-HP, Université Paris-René Descartes, Paris; 4 Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon; 5 Service d Hépatogastroentérologie, Hôpital Pitié Salpêtrière, Paris; 6 AP-HP, Hôpital Beaujon, Service d Hépatologie, Clichy; 7 Hépato-gastroentérologie, CHU de Montpellier, Hôpital Saint-Éloi, Montpellier; 8 Service d hépato-gastroentérologie et d assistance nutritive, laboratoire inflammation tissus epithéliaux et cytokines EA 4331, CHU Poitiers, Poitiers; 9 Hôpital de la Conception, Marseille; 10 CHU de Grenoble, Clinique universitaire d hépato-gastroentérologie, Grenoble; 11 Hôpital Saint-Joseph, Marseille; 12 CHU Trousseau, Tours; 13 Service d Hépato-Gastroentérologie, CHU Angers, Angers; 14 Service des Maladies du Foie, CHU Rennes, Rennes; 15 Centre Hospitalier Intercommunal, Créteil; 16 Service d Hépato-gastroentérologie, CHU Amiens Nord, Amiens; 17 Service d Hépatologie et de soins intensifs digestifs, CHRU Jean Minjoz, Besançon; 18 Bristol-Myers Squibb Research and Development, Rueil-Malmaison; 19 Centre Hospitalier Universitaire de Nancy and Université de Lorraine, Vandoeuvre-lès-Nancy, France The Liver Meeting 15: The 66th Annual Meeting of the American Association for the Study of Liver Diseases San Francisco, CA, November 13 17, 15 Oral 6 Corresponding author: Christophe Hézode (christophe.hezode@aphp.fr)

11 SVR12 by Baseline Child Pugh Score HCV RNA < LLOQ TD/TND (%) , Child Pugh A 33, Weeks DCV + SOF ± RBV a Overall SVR12: Child Pugh A: 87% (142/163) Child Pugh B: 67% (18/27) Child Pugh C: 50% (3/6) 90,0 90 Child Pugh B or C 84,8 70,6 70,0 a 4 patients received RBV for 12 weeks, all were Child Pugh A, and all achieved SVR12. Missing data for 26 patients of unknown Child Pugh score, and 2 patients of unknown treatment duration Weeks DCV + SOF Weeks DCV + SOF + RBV 11

12 Chance for recompensation in decompensated disease after achieving SVR point of no return?

13 ALLY-1: DCV + SOF + RBV in decompensated HCV cirrhosis Fontana RJ et al. AASLD 15

14 ASTRAL-4: Sofosbuvir plus Velpatasvir ± RBV for 12 or 24 weeks in decompensated HCV cirrhosis Curry MP et al. NEJM 15

15 ASTRAL-4: Sofosbuvir plus Velpatasvir ± RBV for 12 or 24 weeks in decompensated HCV cirrhosis Curry MP et al. NEJM 15

16 SOF+RBV for 48 weeks in Compensated and Decompensated Cirrhosis with Portal Hypertension HVPG Change Over Time Afdhal, EASL, 15, LB13

17 SOF+RBV for 48 weeks in Compensated and Decompensated Cirrhosis with Portal Hypertension HVPG Change after treatment in the subset of patients with baseline HVPG 12 mmhg (n=33) Afdhal, EASL, 15, LP13

18 Chance for delisting when treating patients on a liver transplantation waiting list?

19 Clinical and biological responses to antiviral therapy HCC N=70 Decompensated Cirrhosis N=53 MELD score 30% 13% 57% Complete response* Partial response** No response * Total bilirubin < 35μmol/L + PT>50% + albumin>35g L + no ascites + no hepatic encephalopathy ** Child Class Change % 8 patients with a MELD score of 28% LT LT 36% MELD J0 Patients Baseline FUW12 MELD FUS12 72% Child A 21% Child B 25% Child C Coilly A et al. Hepatology 15; 62(Suppl. S1): 257A.

20 Delisting 183 patients Cirrhosis HCC N=77 N=106 LT N=24 (31%) Delisting N=14 (18%) Improvement N=12 (16%) LT N=57 (54%) Drop out N=6 (6%) Other* N=2 (3%) Mean time of follow-up: 68 weeks [12-95] *Two alcohol relapses. Coilly A et al. Hepatology 15; 62(Suppl. S1): 257A.

21 Australian experience in patients with MELD 15 (SOF/DCV 24 W; TOSCAR study) 30 62% MELD < improved by 2 MELD points 10 50% (17/34) (all initial MELD < ) finished Rx with MELD < 15 0 pretx EOT +4wk +12wk McCaughan G et al. AASLD 15 Hepatology 15; 62(Suppl. S1): 257A.

22 Safety

23 Pharmacokinetics of DAAs*: Effects of hepatic impairment on drug exposure *Asunaprevir is not authorized in Switzerland. Lens S et al. Semin Liver Dis 14; 34: 58

24 3D + RBV in patients with decompensated cirrhosis Turquoise CPB n=11 (HCV subtype 1a N=10), TN und TE,Child Score 7-9 (MELD 18, PLT 25, Alb 2,8) SVR12 (%) /68 RVR EOT SVR4 SVR12 SAEs Hyponatremia SBP GI bleeding HE Anemia (related) Pancytopenia Bilirubin increase grade 3 (7/11) HCC Renal insufficiency Pharmacokinetic OBV AUC % PTV/DSV AUC + -0% FDA Due to post-approval SAE reports trial was stopped Mantry et al., AASLD 15, #722

25 Summary of safety outcomes when using DAA regimens in patients with HCV-induced decompensated cirrhosis Serious adverse events: 15% Adverse events requiring hospitalisation % Hepatic decompensation events: % Treatment discontinuation rate: 10% Death rate: 0-4% (2%)

26 DAA-induced hepatoxicity in decompensated HCV cirrhosis first reports Case 1 Case 2 SOF/LDV + RBV SOF/DCV + RBV MELD Bilirubin Bilirubin MELD Dyson JK et al. J Hepatol 15 epub

27 Simeprevir plus Sofosbuvir in Child Pugh B/C Cirrhosis: Adverse Events (N=55) (MELD > 15 N=0) Sayena V et al. Hepatology 15; 62: 715

28 The patient on the waiting list : should we start treatment before or after liver transplantation?

29 When should we treat? Compensated cirrhosis Patients are treatable with high SVR rates Damage to the liver is possibly reversible Pre-emptive post-transplant treatment Treat early to prevent HCV recurrence Early treatment may reduce the risk of disease progression Response to treatment can vary Decompensated cirrhosis Overall health of the patient has deteriorated Transplant is usually required Damage to the liver is potentially irreversible Reactive treatment Treat HCV recurrence when it occurs Wait until graft has stabilised Which therapy? Issues with DDIs with calcineurin inhibitors Pre-transplant Post-transplant DDI: drug drug interaction

30 Pre-transplant Sofosbuvir plus Ribavirin prevent HCV recurrence after liver transplantation Curry MP et al. Gastroenterology 15; 148:

31 Efficacy of SOF/LDV + RBV for 12 or 24 weeks in patients with cholestatic hepatitis C recurrence (FCH) after liver transplantation Forns X et al. EASL 15

32 Issues when treating patients with decompensated disease on the waiting list Time to transplant can be significant (unpredictable) Potential need for long-term treatment, high costs Patients are at risk for acute intercurrent illnesess, diseases, hospitalisation, and decompensation (i.e. kidney failure, ) Risk for drug toxicity, premature tx discontinuation Risk for resistance development before transplant Limited experience in patients with high MELD score Safety?

33 Antiviral treatment modalities in HCV-infected patients before and after liver transplantation Achieving SVR avoid transplantation Treatment-associated morbidity (mortality?) Intensified regimens higher costs Transplantation Open questions: Reversal of cirrhosis Reversal of portal hypertension Long-term HCC risk Achieving response avoid reinfection Transplantation Better outcome after transplantation Transplantation Treat significant reinfection Prevent reinfection by immediate treatment (potential of very short intervention)

34 Management of the transplant patient Favours treatment before transplantation High chance for cure with a 12 week regimen Compensated disease with HCC (Milan) Decompensated disease with MELD < 10, no HCC HCC and MELD > 10 and < 18 (?) DAA therapy part of the HCC treatment concept? Favours treatment after transplantation High risk for relapse (need for extended tx duration) NS5A RAVs + other negative predictors Chance for avoiding OLT low + risk for tx-associated morbidity/ mortality high Decompensated disease with MELD > 18 (cut-off?) HCC and MELD > (?)

35 SVR12 by Cohort All Patients GT 1 (Primary Endpoint) SVR12, % a Advanced cirrhosis Post-transplant Advanced cirrhosis Post-transplant In a regression analysis, no difference by gender, age, IL28B, or HCV RNA in the advanced cirrhosis cohort with GT 1 a HCV RNA < LLOQ (25 IU/mL); error bars reflect 95% confidence intervals. Poordad et al. EASL 15, abstract L08. 35

36 SVR12 by HCV Genotype Advanced cirrhosis cohort N = 60 Post-transplant cohort N = SVR12, % a 1b a 1b Genotype Poordad et al. EASL 15, abstract L08. 36

37 SVR12 by Child-Pugh Class Advanced cirrhosis cohort, all genotypes SVR12, % A B C No Yes No Yes > to 3.5 <2.8 < to 2.3 >2.3 < to 3.0 >3.0 Child-Pugh class Ascites HE Albumin, g/dl INR T bili, mg/dl HE = hepatic encephalopathy Poordad et al. EASL 15, abstract L08. 37

38 SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients LDV/SOF+RBV for 12 or 24 Weeks in 329 Decompensated and Post-Liver Transplant HCV GT 1 and GT 4 Patients Week Pre-Transplant CTP B (7 9) CTP C (10 12) Fibrosis (F0 F3) LDV/SOF + RBV SVR12 CTP A (5 6) Post-Transplant CTP B (7 9) LDV/SOF + RBV SVR12 CTP C (10 12) FCH Broad inclusion criteria: No hepatocellular carcinoma (HCC) Total bilirubin 10 mg/dl, Haemoglobin 10 g/dl CrCl 40 ml/min, Platelets > 30,000/mL RBV dosing F0 F3 and CTP A cirrhosis: weight-based (< 75 kg = 0 mg; 75 kg = 10 mg) CTP B and C cirrhosis: dose escalation, mg/d Manns et al. EASL 15, abstract G02. 38

39 Clinical trials: SOF/LDV with RBV is effective in decompensated and postliver transplantation patients SVR12 (% patients) n = N Overall efficacy pre-transplant Pre-transplant in GT-1 and GT LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks SVR12 (% patients) n = N 0 Overall efficacy post-transplant in GT-1 and GT Post-transplant 12 weeks 24 weeks 12 weeks 24 weeks CTP B CTP C CTP B CTP C SOLAR-1 SOLAR-2 Comparable efficacy in SOLAR-1 1 and SOLAR-2 2 studies 1. Charlton et al. 15; Gastroenterology 149: Manns et al. EASL 15, abstract G02.

40 SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients Liver Function Change from Baseline to Follow-Up Week 4 MELD Score Change Change in CTP Class Pre/Post-Transplant (CTP B and C, n=136*) Baseline CTP 4 (+8) A (5 6) n=73 B (7 9) n= C (10 12) n=54 Change in MELD Score n=95 n=18 n=22 Followup Week 4 CTP A (5 6) 67 (96) 31 (35) 2 (5) B (7 9) 3 (4) 57 (65) (48) C (10 12) 0 0 (48) no assessment: CTP A, n=3; CTP B, n=12; CTP C, n=12-10 (-11) (-17) *Missing FU-4: n=24 Majority of patients showed improvements in MELD and CTP scores Manns et al. EASL 15, abstract G02. 40

41 OPTIMIST-2: SVR12 by platelets, albumin and Fibroscan score (ITT) Lawitz E. et al. EASL 15, LB-Poster 04

42 NHS England EAP: SOF + NS5A ± RBV for 12 Weeks SVR12 in GT 1 Patients with History of Decompensated Cirrhosis SVR12, % /21 141/164 3/5 37/45 LDV/SOF LDV/SOF +RBV Majority of patients received RBV SOF+DCV SOF+DCV +RBV LDV/SOF±RBV for 12 weeks resulted in high SVR rates in GT 1 decompensated cirrhotics Foster et al. EASL 15, abstract O002 42

43 NHS England EAP: SOF + NS5A ± RBV for 12 Weeks SVR12 in GT 3 Patients with History of Decompensated Cirrhosis SVR12, % /7 36/61 5/7 80/114 LDV/SOF LDV/SOF +RBV Majority of patients received RBV SOF+DCV SOF+DCV +RBV SVR rates were comparable to those seen in other studies of SOF+NS5A±RBV for 12 weeks in decompensated cirrhotics Foster et al. EASL 15, abstract O002 43

44 NHS England EAP: SOF + NS5A ± RBV for 12 Weeks MELD Improvement in GT 1 and 3 Patients with History of Decompensated Cirrhosis Changes in MELD Score n = 131 Non-transplanted Transplanted on treatment Number of Patients n = 33 n = 53 Improvement of > 2 MELD scores was observed in 41% by FU Week 4 and 48% had no significant changes Comparative MELD scores available for 217 patients Foster et al. EASL 15, abstract O002 44

45 HCV TARGET: SMV + SOF +/- RBV SVR4+ (%) / /180 61/81 95/99 154/180 88/93 Non-cirrhotic Cirrhotic Prior decomp. Cirrhotic w/o prior decomp. G1a G1b PI experienced excluded Crude SVR4+ rates. Groups include patients with decompensated liver disease unless otherwise indicated G: genotype; w/o: without Adapted from Jensen D, et al. AASLD 14. Oral presentation 45

46 CUP: DCV+SOF +/-RBV Post-Liver Transplant c No Liver Transplant d SVR12 (%) a,b DCV + SOF DCV + SOF + RBV Overall Cirrhosis e f No cirrhosis Cirrhosis No cirrhosis a HCV RNA < LLOQ (TD or TND). b Observed values. c 9 patients on DCV + SOF and 2 patients on DCV + SOF + RBV had indeterminate cirrhosis status; all 11 achieved SVR12. d 10 patients on DCV + SOF had indeterminate cirrhosis status; all 10 achieved SVR12; 1 patient on DCV + SOF + RBV with indeterminate cirrhosis status did not achieve SVR12. e 1 relapse. f 1 relapse, 1 HCV RNA > LLOQ but discontinuation before week 12. Welzel TM, et al. EASL 15, Poster PO772.

47 CUP: DCV+SOF +/-RBV SVR12 (%) a,b DCV + SOF DCV + SOF + RBV Overall d d h e e A B C Child-Pugh Class a HCV RNA < LLOQ (TD or TND). b Observed cases. d 1 relapse. e 1 HCV RNA > LLOQ but discontinuation before week 12. h 2 relapse. Descriptive analysis only, results cannot be directly compared across subgroups or by treatment group. Welzel TM, et al. EASL 15, Poster PO

48 Management of patients with RAVs after DAA failure?

49 Persistence of NS5A RAVs Proportion of Patients With Any NS5A RAVs at More Than 1% Patients With NS5A RAVs (%) /63 58/58 42/43 45/45 52/55 50/58 VF Baseline FU-12 FU-24 FU-48 FU-96 Parent Study Registry Study NS5A RAVs persisted in majority of patients for 96 weeks 49 Wyles D et al. EASL 15