Management of chronic hepatitis C in difficult to treat patients and special groups

Transcription

1 Management of chronic hepatitis C in difficult to treat patients and special groups Decompensated cirrhosis Irene Rapti Consultant Physician in Internal Medicine and Hepatology Athens Medical Center

2 Decompensated cirrhosis By definition, decompensated are considered the cirrhotic patients that have or have had a history of ascites, hepatic encephalopathy, jaundice or variceal bleeding (Child-Pugh B or C). Most of these patients will need liver transplantation to survive and they should all be referred to a transplant center. Antiviral treatment for hepatitis C in such patients is a priority, yet it is quite complex/difficult since they have/develop a lot of AEs either due to the antivirals or/and their underlying condition and they need close monitoring by highly experienced medical practitioner. The goals of treatment of these patients are: 1. SVR and hopefully reversion of inflammation/fibrosis-if possible- and stabilization/improvement of their clinical condition. 2. If candidates for LT: a) delisting following their clinical improvement, b) protection of the graft from reinfection/better outcomes for the patient and the graft

3 How should they be treated? (which antivirals, duration of treatment) Should they be treated before or after liver transplantation? Will the history of hepatitis B (reversal of fibrosis/portal hypertension, delisting with NAs) be repeated in hepatitis C? Are there new/better antivirals coming?

4 EASL Guidelines AASLD Guidelines Greek Guidelines Gen 1,4,5,6 Gen 2 Gen 3 LDV/SOF +wriba x12 wks, DCV+SOF+ wriba x12wks DCV+SOF+ 600 mg ( ) RIBA x12wks, LDV/SOF +600 mg( ) RIBA x12 wks DCV+SOF+ RIBA x12wks, LDV/SOF +RIBA x12 wks SOF+RIBA x16-20 wks DCV+SOF+ 600mg( ) RIBA x12wks, SOF+wRIBA x(up to) 48 wks DCV+SOF+ wriba x12wks DCV+SOF +600mg( ) RIBA x12wks, SOF+wRIBA x(up to) 48 wks DCV+SOF+ wriba x12-24wks contraindicatio n/intolerance to RIBA LDV/SOF x24 wks, DCV+SOF x24 wks DCV+SOF x24 wks

5 Advanced cirrhosis N = 60 Post-liver transplant N = 53 DCV 60 mg QD + SOF 400 mg QD + RBV DCV 60 mg QD + SOF 400 mg QD + RBV Genotypes 1-6 Follow-up Week 0 Week Week SVR12 a Week 36 Primary endpoint: SVR12 in GT1 in each cohort 12 weeks of treatment: DCV 60 mg + SOF 400 mg + RBV RBV initially 600 mg/day, adjusted to 1000 mg/day based on Hgb levels and CrCl Advanced cirrhosis patients with trx interrupted by liver transplantation could receive an additional 12 wks of trx immediately post-transplant a HCV RNA < lower limit of assay quantitation (LLOQ) at posttreatment Week 12 by Roche HCV COBAS TaqMan Test v2.0 (LLOQ 25 IU/mL). Poordad F et al, EASL

6 SVR12, SVR12 by Cohort All Patients GT 1 (Primary Endpoint) % a Advanced cirrhosis Post-transplant 0 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 F et al, EASL 20156

7 SVR12, % SVR12 by HCV Genotype Advanced cirrhosis cohort N = 60 Post-transplant cohort N = a 1b a 1b Genotype Poordad F et al, EASL 20157

8 SVR12, % SVR12 by by Child-Pugh Baseline Class Disease Severity Cirrhosis Advanced cirrhosis Cohortcohort, all genotypes A B C Child-Pugh class No Yes No Yes > to 3.5 <2.8 Ascites HE Albumin, g /dl < to 2.3 INR >2.3< to 3.0 >3.0 T bili, mg/dl HE = hepatic encephalopathy Poordad F et al, EASL 20158

9 MELD score MELD Scores Baseline to Posttreatment Week 12 Advanced cirrhosis cohort Change in MELD score: Decrease Increase No change Child-Pugh A Child-Pugh B Child-Pugh C * * * * * ** * * * * Patient did not achieve SVR12. Poordad F et al, EASL 20159

10 On-Treatment Safety and Tolerability Advanced cirrhosis N = 60 Post-transplant N = 53 Event, n (%) Deaths 0 0 Serious AE a 10 (17) 5 (9) Grade 3 or 4 AE b 11 (18) 4 (8) Discontinuations due to AE All study medications 1 (2) c 1 (2) d Ribavirin only 10 (17) 4 (8) AE (any grade) on treatment in 10% of patients in either cohort, n (%) Headache 9 (15) 19 (36) Fatigue 11 (18) 15 (28) Anemia e 12 (20) 10 (19) Diarrhea 5 (8) 10 (19) Nausea 10 (17) 3 (6) Arthralgia 1 (2) 7 (13) a All considered unrelated to study medication. b Four events (anemia, non-cardiac chest pain, arthralgia, headache) considered related to study medication. c All treatment discontinuation at the time of transplantation; patient achieved SVR12. d Due to headache after 4 weeks of treatment; patient achieved SVR12. e Anemia events as reported by study investigators. Poordad F et al, EASL

11 Open-label, randomized phase IIIb study Primary endpoint: SVR12 Stratified by F3/F4 fibrosis stage Wk 12 Wk 16 Pts with GT3 HCV and F3/F4 liver disease (N = 50) DCV 60 mg/day + SOF 400 mg/day + RBV (n = 24) DCV 60 mg/day + SOF 400 mg/day + RBV (n = 26) All pts followed for SVR12 Leroy V, et al. AASLD Abstract LB-3. Slide credit: clinicaloptions.com

12 SVR12 (%) No virologic failures or AE-related discontinuations 12-wk DCV + SOF + RBV 16-wk DCV + SOF + RBV n/n = 0 21/ 24 All Pts 24/ 26 6/ 6 8/ 8 15/ 18 16/ 18 14/ 16 12/ 14 Advanced Cirrhosis Cirrhosis + Fibrosis Treatment (F3) Experienced Leroy V, et al. AASLD Abstract LB-3. Slide credit: clinicaloptions.com

13 No discontinuations or deaths deemed Txrelated Safety Outcome, % DCV + SOF + RBV Overall (N = 50) DCV + SOF + RBV 12 Wks (n = 24) Leroy V, et al. AASLD Abstract LB-3. DCV + SOF + RBV 16 Wks (n = 26) Any AE Serious AEs Death Discontinuation for AEs RBV dose reduction AEs in 20% pts in any arm Insomnia Fatigue Headache Irritability Grade 3 lab abnormalities Hemoglobin < 9.0 g/dl or decrease 4.5 g/dl TBI > 2.5 x ULN Slide credit: clinicaloptions.com

14 Charlton M et al, Gastroenterology 2015;149:649-59

15 Charlton M et al, Gastroenterology 2015;149:649-59

16 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 = 1000 mg; 75 kg = 1200 mg) CTP B and C cirrhosis: dose escalation, mg/d Manns, EASL, 2015, GO2

17 SVR12 (%) SOLAR-2: LDV/SOF + RBV in Decompensated and Post-LT Patients LDV/SOF + RBV 12 Weeks 24 Weeks /23 13/18 20/23 17/20 CTP B CTP C SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBV 27 subjects in the 24 week arm have not reached SVR12 7 subjects who were transplanted and 3 subjects did not meet inclusion criteria are excluded. Error bars represent 2-sided exact 90% confidence intervals. Manns, EASL, 2015, GO2 17

18 SVR12 (%) SOLAR-1 and SOLAR-2: LDV/SOF + RBV in Decompensated Cirrhosis SOLAR-1 96 SOLAR /30 22/26 LDV/SOF + RBV 12 wks CTP B 24/27 24/25 LDV/SOF + RBV 24 wks 19/22 17/21 LDV/SOF + RBV 12 wks CTP C 18/20 14/20 LDV/SOF + RBV 24 wks Comparable efficacy between SOLAR-1 and SOLAR-2 studies The SVR12 analysis included all subjects except those who had undergone LT prior to SVR12 at last visit prior to LT. Error bars represent 90% confidence intervals. Flamm, AASLD, 2014, Oral #239; Manns, EASL, 2015, GO2

19 SVR12 (%) SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients LDV/SOF + RBV 12 Weeks 24 Weeks GT 1 GT /75 57/58 F0-F3 & CTP A 57/65 54/61 CTP B & C /1 1 7/7 F0-F3 & CTP A 4/7 6/7 CTP B & C Post-Transplant Pre- and Post-Transplant Post-Transplant High SVR rates among GT 1 and GT 4 patients Pre- and Post-Transplant 27 subjects in the 24 week arm have not reached SVR12; 7 subjects who were transplanted and 3 subjects did not meet inclusion criteria are excluded. Manns, EASL, 2015, GO2 Error bars represent 2-sided exact 90% confidence intervals. 19

20 Change in MELD Score SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients MELD Score Change Change in CTP Class Pre/Post-Transplant (CTP B and C, n=136*) Baseline CTP n=95 n=18 n=22 (+8) Follow -up Week 4 CTP A (5 6) n=73 B (7 9) n=100 C (10 12) n=54 A (5 6) 67 (96) 31 (35) 2 (5) B (7 9) 3 (4) 57 (65) 20 (48) C (10 12) (48) -8 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, EASL, 2015, GO2 20

21 Real-life data

22 SVR12 (%) 39 academic centers and 13 community centers in US, Germany, Israel, Canada SOF + RBV (n = 102) SOF + SMV (n = 117) SOF + SMV + RBV (n = 34) n/n = 0 3/ 7 31/ 40 6/ 10 21/ 26 10/ 26 GT1 Naive GT2 Exp d GT3 Exp d MELD MELD MELD > 21 37/ 67 67/ 92 19/ 28 5/ 8 7/ 10 2/ 3 0/1 6/ 6 1/ 1 Reddy RK, et al. EASL Abstract O007.

23 NHS England Early Access Program (EAP) GT 1 N=235 GT 3 N=189 Other GTs N=43 Total N=467 Mean age, years (range) 56.1 ( (29-54 (36-75) 59 (36-81) 76) 81) Male gender, n (%) 174 (74.0) 131 (69.3) 32 (74.4) 337 (72.2) Treatment experienced, n (%) 107 (45.5) 88 (46.6) 25 (58.1) 220 (47.1) Liver transplanted, n (%) 27 (11.5) 15 (7.9) 5 (11.6) 47 (10.1) Past or present decompensated cirrhosis, n 223 (94.9) 179 (94.7) 39 (90.7) 441 (94.4) (%) CTP B, n (%) 161 (68.5) 121 (64.0) 27 (62.8) 309 (66.2) CTP C, n (%) 19 (8.1) 24 (12.7) 3 (7.0) 46 (9.9) MELD mean (range) 11.9 (6-36) 11.3 (6-24) 12.6 (6-36) 11.9 (6-36) Active ascites, n (%) 97 (41.3) 67 (35.4) 14 (32.6) 178 (38.1) Previous variceal bleed, n (%) 61 (26.0) 55 (29.1) 11 (25.6) 127 (27.2) Active encephalopathy, n (%) 41 (17.4) 34 (18.0) 5 (11.6) 80 (17.1) Treatment, n (%)* LDV/SOF+RBV SOF+DCV+RBV SOF+NS5A without RBV *Choice of therapy was at clinician's discretion 164 (35.1) 45 (9.6) 26 (5.6) 61 (13.1) 114 (24.4) 14 (3.0) 27 (5.8) 13 (2.8) 3 (0.6) 252 (54) 172 (36.8) 43 (9.2) Foster GR, et al. EASL Abstract O

24 SVR12, % (ITT) Observational cohort study of National Health Service of England (N = 467) At physician s discretion, pts received 12 wks of SOF + LDV or DCV ± RBV 12-wk SOF + LDV + RBV 12-wk SOF + LDV 12-wk SOF + DCV + RBV 12-wk SOF + DCV P < n = All GT1 GT3 SVR12 among pts with other HCV GTs: 89% (n = 27) with SOF + LDV + RBV; 85% (n = 13) with SOF + DCV + RBV; 100% (n = 3) SOF + DCV Foster GR, et al. EASL Abstract O002.

25 SVR12, % NHS England EAP: SOF+NS5A±RBV for 12 Weeks /21 LDV/SOF LDV/SOF +RBV Majority of patients received RBV 141/164 3/5 37/45 SOF+DCV SOF+DCV +RBV LDV/SOF±RBV for 12 weeks resulted in high SVR rates in GT 1 decompensated cirrhotics Foster GR, et al. EASL Abstract O

26 SVR12, % NHS England EAP: SOF+NS5A±RBV for 12 Weeks /7 LDV/SOF 36/61 LDV/SOF +RBV Majority of patients received RBV 5/7 80/114 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 GR, et al. EASL Abstract O

27 *p<0,005 Foster GR, et al. EASL Abstract O002.

28 Welzel TM, 1 Petersen J, 2 Ferenci P, 3 Gschwantler M, 4 Herzer K, 5 Cornberg M, 6 Schott E, 7 Berg T, 8 Spengler U, 9 Weiland O, 10 van der Valk M, 11 Geier A, 12 Rockstroh JK, 9 Peck-Radosavljevic M, 3 Zhao Y, 13 Jimenez-Exposito MJ, 14 Zeuzem S 1 1 Universitätsklinikum der Johann Wolfgang Goethe Universität, Frankfurt, Germany; 2 IFI Institut für Interdisziplinäre Medizin, Hamburg, Germany; 3 Medizinische Universität Wien, Vienna, Austria; 4 Wilhelminenspital, Vienna, Austria; 5 Universitätsklinikum Essen (AöR), Essen, Germany; 6 Medizinische Hochschule Hannover, Hannover, Germany; 7 Charité Universitätmedizin Berlin, Berlin, Germany; 8 Universitätsklinikum Leipzig, Leipzig, Germany; 9 Universitätsklinikum Bonn, Bonn, Germany; 10 Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; 11 Academic Medical Center, Amsterdam, Netherlands; 12 Universitätsklinikum Würzburg, Würzburg, Germany; 13 Bristol-Myers Squibb, Hopewell, NJ, USA; 14 Bristol-Myers Squibb, Princeton, NJ, USA AASLD 2015

29 European program of compassionate use of DCV Day 1 Week 24 # Week 36 Week 48 Week 72 DCV (60 mg)* + SOF (400 mg) ± RBV # F-UP Further F-UP (optional) # The addition of RBV and shorter duration of trx according to doctor s judgment Inclusion criteria Age 18 years SVR12 Primary end-point SVR24 HCV RNA < LLOQ, TD ή TND week 12 after trx Exclusion criteria CrCl 30 ml/min In danger of decompensation or death within 12 months without trx Urgent need of viral clearance (extra hepatic manifestations/comorbidities) Pregnancy or no use of contraception Welzel TM, et al. AASLD Abstract 37. 3

30 SVR12 (%) 100 Pts treated with DCV 60 mg + SOF 400 mg QD for 24 wks; RBV added or duration shortened to 12 wks per physician discretion Most common AEs: fatigue, nausea, anemia Tx-related serious AEs (n = 1 each): pancytopenia, HE, HCC, circulatory collapse DCV + SOF DCV + SOF + RBV n/n = 0 42/ 49 29/ 33 All Pts 37/ 42 25/ 29 Cirrhosis 19/ 19 11/ 13 12/ 15 12/ 14 6/ 8 A B C Naive Exp d 12 wks 24 wks Child-Pugh Class 2/ 2 19/ 21 12/ 12 23/ 28 Tx History 17/ 21 6/ 7 5/ 7 36/ 42 Tx Duration 24/ 26 Welzel TM, et al. AASLD Abstract 37. Slide credit: clinicaloptions.com

31 HCV RNA < LLOQ, TD ή TND, % SVR12 (mitt) cirrhotic patients DCV + SOF DCV + SOF + RBV Cirrhosisᵃ A B C < to 15 > 15 Child-Pugh MELD score β a Excluded were 4 patients with unknown CP or MELD score (1 DCV+SOF, 3 DCV+SOF+RBV), they all achieved SVR12. Five patients were not cirrhotic (4 DCV+SOF, 1 DCV+SOF+RBV), all but one (DCV+SOF) achieved SVR12. B Excluded was 1 cirrhotic patient with unknown MELD score at baseline. The patient interrupted trx on week 4 due to AE and did not achieve SVR12. Welzel TM, et al. AASLD Abstract 37. 7

32 IU/L g/l Changes in liver function tests from baseline to wk12 post-trx platelets 10 9 /L 10 9 /L mol/l ALT Baseline Follow-up n = 100 n = Total Bilirubin Baseline Follow-up n = 75 n = Albumin Baseline Follow-up n = 87 n = 60 Platelets Baseline Follow-up n = 101 n = 70 Welzel TM, et al. AASLD Abstract

33 80 consecutive pts with advanced HCV cirrhosis (34 pts with Child B/C) (G1 50 pts, G2 4 pts, G3 24 pts, G4 2 pts) SOF/RBV 56 pts SOF/SMV±RBV 15 PTS SOF/DCV±RBV 9 pts Deterding K et al, APT 2015;42:

34 Single-center experience, Hannover (80 consecutive pts) Deterding K et al, APT 2015;42:

35 Deterding K et al, APT 2015;42:

36 To treat before or after liver transplantation? that is the question! HCV patient with decompensated cirrhosis are in serious risk of death awaiting for transplantation (organ shortage), but also trx poses great risks with SAEs/death being more common in such patients ( trx can kill the virus AND the patient )

37 Pros for pre-lt treatment: SVR usually means reduction of all-cause mortality (esp in not so sick patients) and prolong survival (??? prevent HCC) successful pre-lt trx might decrease inflammation, improve liver function and portal hypertension and a) can delay or prevent LT (but is this good???), b) can make surgery during LT easier, c) can make HCC trx (pre-lt) easier HCV RNA undetectability for at least days pre-lt, protect graft from reinfection/ prevention of fibrosing cholestatic hepatitis HCV pts transplanted virus-free do better post-transplant vs viremic ones with SVR pre-lt, no confusion post-lt between rejection and acute reinfection post-lt complications due to HCV omitted (renal impairment in cryoglobulinemia) no need to adjust immunosuppressant drugs dose post-lt Barsa JE et al, Clin Transpl 2015;29: Saxena V, Terrault N, Clin Liver Dis 2015;19: Carrion A et al, Liver Transpl 2016, doi: /lt Deterding K et al, APT 2015;42: van der Meer A et al, JAMA 2012;308:

38 Hepatitis C Virus (HCV) eradication in pts with varying severity of cirrhosis: impact on portal hypertensive complications, liver transplant (LT) and death 93 pts under SMV+SOF±RBV vs untrx controls Saxena V et al, AASLD 2015, abstract 1825

39 Curing decompensated wait listed HCV patients with the new DAAs: the potential significant impact on liver transplant wait list and organ allocation Evaluation of the MELD lowering capacity of the DAA therapies Analysis of patient data from 5 clinical trials of DAAs in decompensated cirrhosis Construction of a model: proportion of listed pts achieving MELD of 15, 1-year after trx and no of donor livers becoming available for allocation 322/381 (84,6%) decomp DAA-trx pts had SVR, 212/381 (56%) MELD reduction Prediction that 993 ( pts) MELD<15 during the first 12 mos post-trx (delisting), leading to 515 ( ) donor livers becoming available for redistribution Munoz S et al, AASLD 2015, abstract 202

40 Cons for pre-lt treatment: patients with advanced liver disease are more likely to suffer from SAEs and death due to trx (more common with MELD>20) MELD might improve and prevent LT while patients are still too sick (MELD purgatory) in countries where HCV(+) organs can be transplanted to anti-hcv (+) recipients, SVR before LT prevent such donation post-lt (esp early, before severe disease of the graft) SVR rates are higher and SAEs less Barsa JE et al, Clin Transpl 2015;29: Saxena V, Terrault N, Clin Liver Dis 2015;19: Carrion A et al, Liver Transpl 2016, doi: /lt.24383

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42 development of lactic acidosis during trx with DAAs (7 episodes in 5 patients (out of 35 in total), 2 died (the story of HBV????) Welker M-W et al, J Hepatol accept. manuscript doi.org /j.jhep deaths during trx attributed to DILI from DAAs (out of approx. 500 patients with decompensated cirrhosis) Dyson J et al, J Hepatol 2016;64:

43

44 Improving liver function and delisting of patients awaiting liver transplantation for HCV cirrhosis: do we ask too much to DAA? 151 pts listed for LT, 23 French centers, mean MELD score:10±5(6-32) SOF±RIBA(n=84)±DCV (n=90) or SMV(n=9) or LDV(n=17) All pts were cirrhotic (73: 48% decompensated) 103/117 pts (88%) SVR12 14/73 (19%) decompensated cirrhotics after 12 wks and 31/73 (42% ) after 12 wks post-trx had complete response (normal bilirubin level, no ascites, no HE) Among MELD 20 83% still an indication for LT at the end of trx Only 10 (6%) of pts) were delisted SAEs: 24(19%) (liver events, anemia, sepsis) Coilly A et al, AASLD 2015, Abstract 95

45 The future

46 SVR12 (%) Open-label trial; HCC and liver transplantation excluded In pts with BL MELD > 15, SVR12, score improved in 84%, worsened in 8%; in pts with BL MELD < 15, SVR12, score improved in 52%, worsened in 27% AEs consistent with advanced liver disease and RBV toxicity SOF/VEL 12 wks SOF/VEL + RBV 12 wks SOF/VEL 24 wks n/n = 0 75/ 90 82/ 87 77/ 90 60/ 68 65/ 68 65/ 71 7/ 14 11/ 13 All Pts 1 3 6/ 12 2, 4, and 6 HCV Genotype Charlton MR, et al. AASLD Abstract LB-13. Curry MP, et al. N Engl J Med. 2015;[Epub ahead of print]. Slide credit: clinicaloptions.com 8/ 8 6/ 6 6/ 7

47 Patients G1,4 with advanced liver disease-portal hypertension CP-A =19, CP-B =21, MELD <10: 55%, 10-15: 40%, >15: 5% Fibroscan 27 (15-75) Median age: 58,5, ΒΜΙ: 28,5 Bil<3xULN, PLT>30000, Alb>2,5, INR<2.5 18% bil increase 1 upper GI bleeding E. Lawitz Abs 39

48 SVR12 (%) GT1 HCV-infected pts with CP B cirrhosis (n = 30) Grazoprevir 50 mg QD + Elbasvir 50 mg QD Wk 12 SVR12, % 90 GT1 HCV-infected pts without cirrhosis (n = 10; for PK analysis) n/n = / 30 All / 21 6/ 7 Grazoprevir 100 mg QD / 2 CP 7 CP 8 CP 9 Pts With CP B Cirrhosis Elbasvir 50 mg QD Safety Outcome, n (%) SAE (all unrelated to study tx) 100 CP B (n = 30) Noncirrhotic (n = 10) 4 (13.3) 0 D/C for AE 0 0 Gr 3/4 ALT/AST incr. 0 0 Gr 3/4 bilirubin incr. 4 (13.3) 0 Death* 1 (3.3) 0 *Nontreatment-related spontaneous bacterial peritonitis with subsequent cerebral infarction, bacterial peritonitis, and hepatic failure. Jacobson IM, et al. EASL Abstract O008.

49 Conclusions patients with decompensated cirrhosis can be successfully treated for HCV ideally they should be taken care of in transplant centers by experts since they experience more AEs than the non-cirrhotic HCV patients, the decision for treatment before or after LT should be individualized patients with MELD score<10 and without serious complications of portal hypertension could be treated before-lt, thus expecting clinical improvement and-why not-delisting on the other hand, decompensated HCV patients with higher MELD scores and/or seriously impaired renal function may preferably be offered HCV treatment early after LT

50 in countries where LT waiting time is very long (>12 months), treatment should be initiated before-lt with the hope that clinical improvement will counteract for the AEs and moreover, accomplish their delisting in cases of living donor LT, the time of the operation can be predicted and treatment can be given accordingly, in order to achieve undetectable HCV RNA for at least 30 days before LT new, promising drugs are in the pipeline of the companies, making the future of HCV treatment even for the difficult-to-treat decompensated cirrhotics, hopefully easier

51 ???

52 Back-up slides

53

54 Greek HCV treatment guidelines ΚΕΕΛΠΝΟ, Dec 2015

55 Class A N = 12 Class B N = 32 Class C N = 16 Parameter Ascites present, n (%) 0 21 (66) 16 (100) Encephalopathy present, n (%) 2 (17) 19 (59) 16 (100) Native MELD score, n (%) a < 10 7 (58) 7 (22) (42) 20 (63) 3 (19) (16) 9 (56) (19) > (6) Albumin, median (range) g/dl 3.7 ( ) 3.2 ( ) 2.5 ( ) INR, median (range) 1.2 ( ) 1.4 ( ) 1.7 ( ) T bilirubin, median (range) mg/dl 0.9 ( ) 1.6 ( ) 3.0 ( ) Platelets, median (range) 10 9 cells/l 94 (41 179) 86 (35 182) 72 (35 147) α-fetoprotein, median (range) 13.0 ( (1.8 ng/ml b 49.6) 86.2) 7.7 ( ) a Entry criteria: MELD scores b Included 6 HCC patients: 1 CP A, 2 CP B, 3 CP C Poordad F et al, EASL

56 High rates of sustained virologic response at post-treatment Week 12 (SVR12) have been achieved with DCV + SOF ±ribavirin (RBV) in multiple challenging patient populations 1-5 Baseline NS5A resistance associated variants (RAVs) can impact virologic response to some combinations of direct-acting antivirals This analysis investigated the impact of baseline NS5A RAVs on SVR12 rates by pooling data from individual patients treated for 12 weeks in one phase 2 (AI ) and two phase 3 (ALLY-1, -2) clinical studies of DCV + SOF ±RBV Daclatasvir(DCV) PangenotypicaNS5A inhibitor, low potential for drug drug interactions Studied in > 13,000 patients Safe and well tolerated Approved in the US, Europe, Japan and multiple nations across Latin America, the Middle East, and Asia Pacific Sofosbuvir (SOF) PangenotypicNS5B inhibitor, low potential for drug drug interactions Safe and well tolerated Approved in the US, Europe, and other countries ALLY-1 N = 113 ALLY-2 N = 203 ALLY-3 N = 152 ALLY-3+ ALLY Phase 3 Program Cirrhosis or post-liver transplant GT 1 to 6 DCV + SOF + RBV, 12 weeks HIV/HCV coinfection GT 1 to 6 DCV + SOF, 8 or 12 weeks a Pangenotypic: GT 1-6 in vitro and GT 1-4 in clinical trials. N = 50 b b ALLY-3+ is a phase 3b study, follow-up to ALLY-3 in patients with advanced fibrosis or cirrhosis; results to be presented at this congress (Leroy V, et al. Oral presentation LB-3). GT 3 Treatment-naive or -experienced DCV + SOF, 12 weeks GT 3, advanced fibrosis/cirrhosis DCV + SOF + RBV, 12 or 16 weeks

57 SVR12 (%; ITT) 12-wk SOF + LDV + RBV 12-wk SOF + LDV 12-wk SOF + DCV + RBV 12-wk SOF + DCV n = All GT1 Foster GR, et al. EASL Abstract O002.

58 SVR12 (%) wk DCV + SOF wk DCV + SOF + RBV All pts n/n = 0 39/ 40 19/ 20 58/ 60 24/ 24 21/ 22 45/ 46 1/1 1/1 2/2 A B C CP Score Treatment naive or treatment experienced ~ 40% with CP B or C, ~ 60% GT1 DCV dose determined by country; inclusion of RBV based on physician discretion Welzel TM, et al. EASL Abstract P0772.

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60 EASL CPG 2015

61 EASL CPG 2015

62 EASL CPG 2015

63 AASLD/IDSA HCV Guidance Panel Hepatology 2015;62:

64 AASLD/IDSA HCV Guidance Panel Hepatology 2015;62:

65 Hepatology 2015;62:

66 Hepatology 2015;62:

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68 Changes in MELD Score NHS England EAP: SOF+NS5A±RBV for 12 Weeks Non-transplanted Transplanted on treatment 5 0 n = 131 n = 33-5 n = Number of Patients -20 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 GR, et al. EASL Abstract O

69 Hezode C, 1 de Ledinghen V 2, Fontaine H 3, Zoulim F 4, Lebray P 5, Boyer N 6, Larrey DG 7, Silvain C 8, Botta-Fridlund D 9, Leroy V 10,11, Bourlière M 12, d Alteroche L 13, Fouchard-Hubert I 14, Guyader D 15, Isabelle Rosa16, Nguyen-Khac E 17, Di Martino V 18, Carrat F 19, Fedchuk L 20, Akremi R 20, Bennai Y 20, Bronowicki J-P 21 1Department of Hépato-Gastroenterology, CHU Henri Mondor, Créteil, France; 2Liver fibrosis investigational center, Haut-Lévêque Hospital, Bordeaux University Hospital, Pessac, France; 3Department of Hepatology, Cochin Hospital, APHP, Paris, France; 4Department of Hepatology, La Croix-Rousse Hospital, Lyon Civil Hospices, Lyon, France; 5Department of Hepato-Gastroenterology, Pitié Salpêtrière Hospital, Paris, France; 6Department of Hepatology, Beaujon Hospital, APHP, Paris, France; 7Department of Hepato-Gastroenterology, Saint- Eloi Hospital, CHU Montpellier, Montpellier, France; 8Department of Hepato-Gastroenterology and of nutritional support, epithelial tissues and cytokines laboratory EA 4331, CHU Poitiers, Poitiers, France; 9Department of Hepato- Gastroenterology, Conception Hospital, Marseille, France; 10Grenoble University hospital, Hepato-Gastroenterology University Clinic, Grenoble, France; 11Inserm, 823 Unity, Grenoble, France; 12Department of Hepatology and Gastroenterology, Saint-Joseph Hospital, Marseille, France; 13Unit of Hepatology, Department of Hepato- Gastroenterology, CHU Trousseau, Tours, France; 14Department of Hepato-Gastroenterology, CHU Angers, Angers, France; 15Department of liver diseases, CHU Rennes, Rennes 1 University, Rennes, France; 16Department of Hepatology and Gastroenterology, CHI Créteil, Créteil, France; 17Department of Hepato- Gastroenterology, CHU Amiens Nord, Amiens, France; 18Department of Hepatology and of digestive intensive care unit, CHRU Jean Minjoz, Besançon, France; 19Inserm UMR-S 707, Pierre-et-Marie-Curie University Paris 6, Paris, France; 20Bristol-Myers Squibb Research and Development, Rueil-Malmaison, France; 21INSERM Unité 954, CHU Nancy and Lorraine University, Vandoeuvre- lès-nancy, France AASLD 2015

70 SVR12 (%) Child-Pugh A Child-Pugh B or C / 30 2/ 6 DCV + SOF ± RBV 12 Wks 90/ / 17 DCV + SOF 24 Wks 28/ 33 7/ 10 DCV + SOF + RBV 24 Wks Hezode C, et al. AASLD Abstract 206. Slide credit: clinicaloptions.com