Η θζςη του grazoprevir /elbasvir ςτην ςφγχρονη αντιμετώπιςη αςθενών με Χρόνια Ηπατίτιδα C

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1 Η θζςη του grazoprevir /elbasvir ςτην ςφγχρονη αντιμετώπιςη αςθενών με Χρόνια Ηπατίτιδα C Ιωάννησ. Ελευςινιώτησ Αν. Καθηγητήσ Παθολογίασ Πανεπιςτημίου Αθηνών Πανεπιςτημιακή Παθολογική Κλινική Ηπατογαςτρεντερολογικό Εργαςτήριο Γενικό Ογκολογικό Νοςοκομείο Κηφιςιάσ «ΟΙ ΑΓΙΟΙ ΑΝΑΡΓΤΡΟΙ»

2 ΤΓΚΡΟΤΗ ΤΜΦΕΡΟΝΣΩΝ Advisory boards: Gilead, Abbvie Research grants: Abbvie

3 Diagnosis?? Treatment??

4 HCV Disease Progression in an Aging Population Anti-HCV+ HCV-RNA y HCV-cirrhosis Acute HCV Davis, Gastroenterology. 2010;138(2):

5 Natural History of Hepatitis C Westbrook R, Dusheiko G, J Hepatol 2014;61:S58-68 chronic Πιθανότητα εξζλιξησ? Ταχφτητα εξζλιξησ? age gender race symptoms/jaundice IL28B immune status Virus - Load - Genotype - Quasispecies Environment - Alcohol - HBV, HIV - IR/Diabetes - Drugs, cannabis - Steatosis, BMI - Iron - TREATMENT Host - Gender - Age - Race - Genetics -Immune response

6 Association Between SVR and All-Cause Mortality Among Patients With Chronic Hepatitis C and Advanced Hepatic Fibrosis 26% 27.4% 8.9% 1.9% 530 CHC patients 70% men median age=48y Ishak fibrosis score F4 (27%) F5 (19%) F6 (54%) median f/u:8.4y 21.8% 5.1% 29.9% 2.1% 192/530 (36%) SVR 10y all-cause mortality 8.9% (13 pts) SVR 26% (100 pts) no-svr Liver related mortality/lt 3 SVR 103 no-svr van der Meer AJ et al, JAMA 2012;308(24):

7 PEG/R SVR:50% DAAs SVR:90% DAAs SVR:90% all patients 100% 100% 100% treatment uptake 10-20% 10-20% 90% cure rates 5-10% 9-18% 81%

8 υνδυαςμοί 3 φαρμάκων Εφκολο δοςολογικό ςχήμα χήμα βραχείασ διάρκειασ ( 12w) Χωρίσ ribavirin Αςφάλεια Ειδικοί πληθυςμοί υγχορήγηςη με άλλα φάρμακα απουςία DDIs SVR: % Κλινικό όφελοσ

9 υνδυαςμοί 3 φαρμάκων Εφκολο δοςολογικό ςχήμα χήμα βραχείασ διάρκειασ (12w) Χωρίσ ribavirin HCV NS3/4A inhibitor 100 mg once daily, oral HCV NS5A inhibitor 50 mg once daily, oral Αςφάλεια Ειδικοί πληθυςμοί υγχορήγηςη με άλλα φάρμακα απουςία DDIs Grazoprevir (MK-5172) Elbasvir (MK-8742) SVR: % Κλινικό όφελοσ

10 NS5A INHIBITOR Elbasvir 50 mg NS3/4A INHIBITOR Grazoprevir 100 mg HCV NS5A inhibitor 50 mg once daily, oral Elbasvir (MK-8742) NS5A (-) Polyprotein cleavage (replication) protease HCV-RNA Replication and Assembly (-) Grazoprevir (MK-5172) HCV NS3/4A inhibitor 100 mg once daily, oral

11 Fixed-dose combination tablet administered once daily, without regard to food intake NS5A INHIBITOR Elbasvir 50 mg NS3/4A INHIBITOR Grazoprevir 100 mg (-) (-) HCV-RNA Replication and Assembly Renal impairement Liver impairement (Child A cirrhosis) Polyprotein cleavage (replication)

12 C-EDGE Πρωτοθεραπευόμενοι: τυχαιοποιημζνη, διπλή-τυφλή, (G1/4/6), χωρίσ RBV N= 421 N = 316 N = 105 Grazoprevir (GZR) 100 mg + Elbasvir (EBR) 50 mg Placebo N= G1a 131 G1b 18 G4 10 G6 cirrhosis 70/316 (22%) Follow-up GZR 100 mg + EBR 50 mg FUW12 D1 TW4 TW8 TW12 FUW4 FUW8 FUW12 FUW16 1 διςκίο / ημζρα, 12 εβδομάδεσ G1a: 50%, G1b: 41%, G4:6%, G6:3% Κιρρωτικοί: 22% Zeuzem et al. Ann Intern Med. 2015;163:1-13

13 Patients with SVR12 (%) Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4 or 6 C-EDGE TN: Results C-EDGE TN: SVR12 Results by Genotype C-EDGE Πρωτοθεραπευόμενοι: N= 421 G1a:50%, G1b:41%, G4:6%, G6:3% Κιρρωτικοί :22% (n=70) / / /131 18/18 8/10 All GT 1a GT 1b GT 4 GT 6 Primary efficacy analysis included all patients who received 1 dose of drug. Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

14 Patients (%) with SVR 12 Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4 or 6 C-EDGE TN: Results C-EDGE TN: SVR12 by Presence of Cirrhosis or High HCV RNA Level cirrhosis patients 0 231/246 68/70 94/94 205/222 No Cirrhosis Cirrhosis 800K IU/mL >800K IU/mL Presence of Cirrhosis SVR12-cirrhotics 68/70 (97%) Baseline HCV RNA Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

15 Patients, % SVR12(Naïve ± κίρρωςη): 95% με 12εβδ GRZ/EBR 100% 95% 92% 99% 100% 80% 75% 50% 25% 0% 299/ / /131 18/18 8/10 Oλοι οι αςθενείσ 299/316 GT1a GT1b GT4 GT6 144/ /131 18/18 Μη Ιολογική αποτυχία /10 Διαφυγή Τποτροπή C-EDGE Πρωτοθεραπευόμενοι: N= 421 τυχαιοποιημζνη, διπλή-τυφλή, G 1/4/6, χωρίσ RBV 1 διςκίο / ημζρα, 12 εβδομάδεσ G1a:50%, G1b:41%, G4:6%, G6:3% Κιρρωτικοί :22% (n=70) 4% SVR12-cirrhotics 68/70 (97%) Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

16 Patients (%) with SVR 12 Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4 or 6 C-EDGE TN: Results Baseline NS5A Resistance-Associated Variants and SVR12 in GT Baseline NS5A RAVs* No Baseline NS5A RAVs /19 133/135 17/18 112/112 Genotype 1a Genotype 1b *Patients with baseline GT1a RAVs with a 5-fold shift to elbasvir: SVR12=90% (9 of 10) *Patients with baseline GT1a RAVs with a >5-fold shift to elbasvir: SVR12=22% (2 of 9) Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

17 SVR12(%) 120 Rates of SVR according to the presence at baseline of NS5A RAS in patients infected with HCV genotype 1 included in Phase II or III trials who received sofosbuvir/ledipasvir regimens TREATMENT-NAÏVE PATIENTS (pooled data analysis) ION-studies, ELECTRON NS5A-RAS(>100 EC50) NS5A-RAS(<100 EC50) no-ns5a RAS /373 24/29 44/46 24/25 12/12 27/27 8/8 184/ /183 SOF/LDV±R(8w) SOF/LDV±R(12w) SOF/LDV±R(24w) Pawlotski JM. Gastroenterology 2016;151(1):70-86

18 Patients with SVR12 (%) Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1 PEARL-III and PEARL-IV: Results ,0 90,2 99,5 99, / / / /209 3D + RBV 3D 3D + RBV 3D Genotype 1a Genotype 1b 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir RBV = Ribavirin Ferenci P, et al. N Engl J Med. 2014;370:

19 Rates of SVR according to the presence at baseline of NS5A RAS in patients infected with HCV genotype 1a who received the combination of ombitasvir/paritaprevir/ritonavir and dasabuvir in Phase III trials SVR12(%) 97,5 97 3D+Ribavirin, 12w (G1a non-cirrhotics) 3D+Ribavirin, 24w (G1a cirrhotics) , , NS5A RAS no-ns5a RAS OBV-RAS no-obv RAS 94,5 94 3D+RBV (12w / 24w cirrhotics) Pawlotski JM. Gastroenterology 2016;151(1):70-86

20 12 ΕΒΔ 16 ΕΒΔ C-EDGE αποτυχόντεσ ςε P/R n= 420, 12 vs 16w με ή χωρίσ RBV GZR + EBR (No RBV), n = 105 GZR + EBR + RBV, n = 104 GZR + EBR (No RBV) n = 105 GZR + EBR + RBV n = 106 -RBV +RBV SVR12* (Πρωτεφον καταληκτικό ςημείο) D1 TW8 TW12 TW16 SVR4 SVR8 SVR (35%) κιρρωτικοί TE: 182 nulls, 87 partials, 151 relapsers Kwo P et al, ILC 2015 #P0886

21 Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6 C-EDGE TE: Baseline Characteristics Baseline Characteristic EBR-GZR n= Week Treatment EBR-GZR + RBV n=104 EBR-GZR n= Week Treatment EBR-GZR + RBV n=106 Mean age, y (range) 56 (25 76) 56 (23 75) 55 (31 73) 55 (19 77) Male sex, % Race, % White Black Asian HCV Genotype, % 1a 1b Cirrhosis, % HIV coinfection, % Prior treatment response Relapse, % Partial response, % Null response, % Kwo P et al. EASL Abstract P0886.

22 SVR12 (%, 95% CI) υνολικά αποτελζςματα (G 1/4/6) SVR12 : 92-97% (tx exper. ± κίρρωςη) Weeks 16 Weeks No RBV 1 +RBV 2 No RBV 3 +RBV 4 Διαφυγή Rebound Τποτροπή LTFU/Early DC* * LTFU/Early DC = Lost to follow up / Early discontinuation due to reasons other than virologic failure Kwo P et al, ILC 2015 #P0886

23 Patients with SVR 12 (%) Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6 C-EDGE TE: Results C-EDGE TE: SVR 12* by Key Subgroups week 12-week + Ribavirin 16-week 16-week + Ribavirin /105 98/104 97/ /106 0 GT 1a Null responder Cirrhotic * Analysis per protocol: excluding patients who dropped out due to reasons other than virologic failure Kwo P et al. EASL Abstract P0886.

24 GZR/EBR: SVR12 ςυνολικά ανά προηγοφμενο τφπο ανταπόκριςησ, ± RBV SVR12: 100% relapsers, 91% null/partial responders: με 12εβδ, ΧΩΡΙ RBV C-EDGE αποτυχόντεσ ςε P/R: Ν= 420, 12εβδ ή 16εβδ με ή χωρίσ RBV G1,G4,G6 35% κιρρωτικοί n= 182 nulls, 87 partials, 151 relapsers Kwo P et al, ILC 2015 #P0886

25 Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1 C-SALVAGE Study: Design Week PI+PR experienced Genotype 1 Non-cirrhotic (N=45) Cirrhotic (N=34) N=79 EBR + GZR + RBV SVR12 Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin; PI = protease inhibitor; PR = peginterferon+ribavirin Drug Dosing: Elbasvir: 50 mg once daily Grazoprevir: 100 mg once daily Ribavirin (weight-based and divided bid): 800 to 1400 mg/day Buti M, et al. Clin Infect Dis. 2016;62:32-6.

26 Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1 C-SALVAGE Study: Participants Baseline Characteristic All Patients (N=79) Baseline NS3 RAVs* (N=34) No Baseline NS3 RAVs* (N=44) Mean age, years Male/Female, % 58.2/ / /45.5 HCV genotype, % 1a 1b Cirrhosis, % Previous PI, % Boceprevir Telaprevir Simeprevir Non-virologic failure +, % * Among evaluable patients + Reasons for the 13 non-virologic failure included adverse events/drug intolerance (n=12) and short course regimen in a clinical trial (n=1) Buti M, et al. Clin Infect Dis. 2016;62:32-6.

27 Patients (%) with SVR24 Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1 C-SALVAGE Study: Results C-SALVAGE: SVR 24* by Baseline Factors ,2 95,5 91,7 94, /79 63/66 33/36 32/34 All patients Prior virologic failure NS3 +/- NS5 RAVs Cirrhosis * Analysis per protocol: excluding patients who dropped out due to reasons other than virologic failure RAVs = resistance-associated variants (at baseline) Buti M, et al. Clin Infect Dis. 2016;62:32-6.

28 Tx-naive G1a 92% G1b 99% G4 100% Cirrhosis 97% SVR-12 GZP/EBV, 12w Tx-experienced G1a 90% G1b 100% G4 78% Cirrhosis 89% Tx-naive G1b G4 G1a, IU/ml G1a, > IU/ml 12w 16w+RBV Non-cirrhotics Tx-experienced G1b G1a, IU/ml G4, IU/ml 12w G1a, > IU/ml G4, > IU/ml 16w+RBV

29 Treatment recommendations for HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C without cirrhosis, including treatment-naïve patients and patients who failed on a treatment based on pegylated IFN-α and ribavirin (treatment-experienced, DAA-naïve patients).

30 Baseline Characteristic Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1 C-WORTHY: Baseline Characteristics Treatment-naïve + cirrhosis EBR + GZR + RBV N=63 EBR + GZR N=60 EBR + GZR + RBV N=65 Null responders EBR + GZR N=65 Mean age, y (range) 58 (41-79) 59 (42-82) 54 (24-76) 54 (18-77) Male, % Race White Non-white Hispanic/Latino, % HCV Genotype, % 1a 1b Unclassified IL28B CC, % Cirrhosis, % HCV RNA >2 million IU/mL, % Lawitz E, et al. Lancet 2015;385:

31 Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1 C-WORTHY: Study Design Cohort 1 (Cirrhosis) Week n = 31 EBR + GZR + RBV SVR12 Cohort 1 Treatment-Naive n = 29 EBR + GZR SVR12 Cirrhosis (n=123) n = 32 EBR + GZR + RBV SVR12 n = 31 EBR + GZR SVR12 Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin Drug Dosing Elbasvir: 50 mg once daily Grazoprevir: 100 mg once daily Ribavirin (weight-based and divided bid): 800 to 1400 mg/day median age: 56y 170 (67%) cirrhosis 192 (76%) VL>2M 163 (64%) G1a 206 (81%) non-cc Lawitz E, et al. Lancet 2015;385:

32 Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1 C-WORTHY: Study Design Cohort 2 (Null Responders) Week N=32 EBR + GZR + RBV SVR12 Cohort 2 Null Responders ( n=130) N=33 EBR + GZR N=33 EBR + GZR + RBV SVR12 SVR12 N=32 EBR + GZR Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin Drug Dosing Elbasvir: 50 mg once daily Grazoprevir: 100 mg once daily Ribavirin (weight-based and divided bid): 800 to 1400 mg/day SVR12 median age: 56y 170 (67%) cirrhosis 192 (76%) VL>2M 163 (64%) G1a 206 (81%) non-cc Lawitz E, et al. Lancet 2015;385:

33 Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis(c-worthy): a randomised, open-label phase 2 trial median age: 56y 170 (67%) cirrhosis SVR12 overall: 95% (240/253) 192 (76%) VL>2M (64%) G1a (81%) non-cc no-rbv RBV 88 80/84 81/86 61/65 63/65 76/82 76/81 40/41 46/46 cirrhosis null response G1a G1b Lawitz E et al. Lancet. 2015;385:

34 Patients with SVR 12 (%) Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1 C-WORTHY: Results for Naïve Cirrhotics (Cohort 1) C-WORTHY: SVR 12* by Treatment Duration and Regimen /31 28/29 31/32 29/31 EBR + GZR + RBV EBR + GZR EBR + GZR + RBV EBR + GZR 12-Week Regimen 18-Week Regimen Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin *Analysis per protocol: excluding patients who dropped out due to reasons other than virologic failure Lawitz E, et al. Lancet 2015;385:

35 Patients with SVR 12 (%) Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1 C-WORTHY: Results for Null Responders (Cohort 2) C-WORTHY: SVR 12* by Treatment Duration and Regimen /32 30/33 33/33 31/32 EBR + GZR + RBV EBR + GZR EBR + GZR + RBV EBR + GZR 12-Week Regimen 18-Week Regimen Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin *Analysis per protocol: excluding patients who dropped out due to reasons other than virologic failure Lawitz E, et al. Lancet 2015;385:

36 Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis(c-worthy): a randomised, open-label phase 2 trial SVR12(%) naïve-cirrhotics /31 28/29 31/32 29/31 30/32 30/33 33/33 31/32 (N=123) SVR12 overall: 95% (240/253) null-cirrhotics 92% null responders (N=130) 97 median age: 56y 170 (67%) cirrhosis 192 (76%) VL>2M 163 (64%) G1a 206 (81%) non-cc 12w+RBV 12w-RBV 18w+RBV 18w-RBV Lawitz E et al. Lancet. 2015;385:

37 Patients (%) with SVR 12 Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-experienced HCV GT 1 ION-2 Study: Results ION-2: SVR12 by Treatment Regimen and Liver Disease Without Cirrhosis With Cirrhosis Baseline resistance in 62 (14%) of 439 patients tested SVR12 in 55 (89%) of 62 patients with NS5A resistance /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-Week Treatment 24-Week Treatment Afdhal N, et al. N Engl J Med. 2014;370:

38 Patients (%) with SVR 12 3D + Ribavirin in GT1 and Compensated Cirrhosis TURQUOISE-II: Results for GT1a TURQUOISE II: Genotype 1a SVR12 Based on Prior Treatment ,2 92,9 93,3 3D + RBV x 12 Weeks 100,0 100,0 100,0 3D + RBV x 24 Weeks 80,0 92, /64 52/56 14/15 13/13 11/11 10/10 40/50 39/42 No Prior Treatment Prior Relapser Partial Responder Null Responder 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin Poordad F, et al. N Engl J Med. 2014;370:

39 υνδυαςτική ανάλυςη ςε κιρρωτικοφσ αςθενείσ από 6 μελζτεσ με EBR/GZR (n=402) Treatment naive patients 12 week treatment duration N=169 Treatment experienced patients 12/16/18 week treatment durations N=233 PN 035 C-WORTHY Treatment-naive (n=60) Treatment experienced (n =49) CKD 4/5 (n=4) PN 052 C-SURFER CKD 4/5 (n=3) PN 060 C-EDGE TN Treatment-naive (n=70) PN 061 C-EDGE HIV HCV/HIV coinfected (n=35) PN 048* C-SALVAGE Prior DAA failures (n=34) PN 068 C-EDGE TE Treatment-experienced (n=147) Jacobson I et al. AASLD 2015 #42.

40 Patients, % SVR12: 98% Naïve Kιρρωτικοί G1 12 εβδ EBR/GZR χωρίσ RBV All Patients GT1a GT1b / 1-other GT4 LTFU/Early Discon. 1 * 1 * 0 0 SVR12 (mfas ) 98.5% 97% 100% 100% (135/137) (73/75) (56/56) (6/6) Διαφυγή Τποτροπή *Death (coronary artery disease) mfas (modified full analysis set) excludes patients who discontinued treatment for reasons unrelated to study medication Jacobson I et al. AASLD 2015 #42.

41 Patients, % Κιρρωτικοί με προηγοφμενη αποτυχία SVR12 (Full analysis set) Treatment Naive Treatment Experienced No RBV +RBV No RBV +RBV No RBV +RBV 12 weeks 12 weeks 16 or 18 weeks LTFU/Early Discon. 1 * SVR12 (mfas ) 98.5% 90.3% 92.3% 92.5% 93.9% 100.0% (135/137) (28/31) (48/52) (74/80) (46/49) (49/49) Breakthrough Rebound Relapse *Death (coronary artery disease) Death (lymphoma) n=1;discontinued due to noncompliance, n=1 Death (motor vehicle accident) mfas :excludes patients who discontinued treatment for reasons unrelated to study medication Jacobson I et al. AASLD 2015 #42.

42 Tx-naive G1a 96% G1b 100% G4 100% Cirrhosis 97-98% SVR-12 GZP/EBV, 12w Tx-experienced Null 92% Cirrhosis 89% 16w 94% 16w+R 100% Tx-naive G1b G4 G1a, IU/ml G1a, > IU/ml 12w 16w+RBV Cirrhotics Tx-experienced G1b G1a, IU/ml G4, IU/ml 12w G1a, > IU/ml G4, > IU/ml 16w+RBV

43 Treatment recommendations for HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C with compensated (Child-Pugh A) cirrhosis, including treatment-naïve patients and patients who failed on a treatment based on pegylated IFN-α and ribavirin (treatment-experienced, DAA-naïve patients).

44 υνδυαςμοί 3 φαρμάκων Εφκολο δοςολογικό ςχήμα χήμα βραχείασ διάρκειασ ( 12w) Χωρίσ ribavirin Αςφάλεια Ειδικοί πληθυςμοί υγχορήγηςη με άλλα φάρμακα απουςία DDIs SVR: % Κλινικό όφελοσ

45 υνδυαςμοί 3 φαρμάκων Εφκολο δοςολογικό ςχήμα χήμα βραχείασ διάρκειασ ( 12w) Χωρίσ ribavirin Αςφάλεια Ειδικοί πληθυςμοί υγχορήγηςη με άλλα φάρμακα απουςία DDIs SVR: % Κλινικό όφελοσ

46 υνδυαςμοί 3 φαρμάκων Εφκολο δοςολογικό ςχήμα χήμα βραχείασ διάρκειασ ( 12w) Χωρίσ ribavirin Αςφάλεια Ειδικοί πληθυςμοί υγχορήγηςη με άλλα φάρμακα απουςία DDIs SVR: % Κλινικό όφελοσ

47 υνδυαςμοί 3 φαρμάκων Εφκολο δοςολογικό ςχήμα χήμα βραχείασ διάρκειασ ( 12w) Χωρίσ ribavirin Αςφάλεια Ειδικοί πληθυςμοί υγχορήγηςη με άλλα φάρμακα απουςία DDIs SVR: % Κλινικό όφελοσ

48 υνδυαςμοί 3 φαρμάκων Εφκολο δοςολογικό ςχήμα χήμα βραχείασ διάρκειασ ( 12w) Χωρίσ ribavirin Αςφάλεια Ειδικοί πληθυςμοί υγχορήγηςη με άλλα φάρμακα απουςία DDIs SVR: % Κλινικό όφελοσ

49 υνδυαςμοί 3 φαρμάκων Εφκολο δοςολογικό ςχήμα χήμα βραχείασ διάρκειασ ( 12w) Χωρίσ ribavirin Αςφάλεια Ειδικοί πληθυςμοί υγχορήγηςη με άλλα φάρμακα απουςία DDIs Νεφροπαθείσ-αιμοκαθαιρόμενοι Χρήςτεσ τοξικών/άλλων ουςιών HIV, αιμοςφαιρινοπάθειεσ κ.α SVR: % Κλινικό όφελοσ

50 Αςθενείσ με Χρόνια Νεφρική Νόςο

51 1. Roth D et al. Lancet. 2015;386: ; 2. Roth D et al. Poster presented at: Kidney Week 2015; November 2015; San Diego, CA. ΔΗΜΟΓΡΑΦΙΚΑ ΧΑΡΑΚΣΗΡΙΣΙΚΑ ΜΕ EBR/GZR Gender, n (%) Male Female Race, n (%) White African-American Asian Other HCV genotype, n (%) G1a G1b G1 other Prior treatment history, n (%) Naive Experienced GZR + EBR (ITG + PK group) 12 weeks (n = 122) 92 (75) 30 (25) 61 (50) 55(45) 5 (4) 1 (<1) 63 (52) (48) 1 (<1) 101 (83) 21 (17) Placebo (DTG) 12 weeks (n = 113) 80 (71) 33(29) 48(43) 53(47) 9 (8) 3 (3) 59 (52) 53 (47) 1 (<1) 88 (78) 25 (22) Cirrhosis, n (%) 7 (6) 7 (6) Diabetes, n (%) 44 (36) 36 (32) Dialysis, n (%) 92 (75) 87 (77) CKD stage, n(%) stage 4 stage 5 χωρίσ RBV 22 (18) 100 (82) 22 (19) 91(81) DTG = deferred treatment group; ITG = immediate treatment group; PK = Intensive PK group

52 Elbasvir + Grazoprevir in HCV GT1 and Renal Disease C-SURFER Study: Study Design Week χωρίσ RBV N=111 Immediate Treatment EBZ + GRZ SVR12 TN TE GT 1 Stage 4 or 5 CKD N=113 Deferred Therapy Placebo Deferred Therapy EBZ + GRZ SVR12 Intensive PK N=11 SVR12 EBZ + GRZ Drug Dosing Grazoprevir 100 mg once daily and Elbasvir 50 mg once daily; given as separate medications in Immediate treatment and Intensive PK arms; given as fixed dose combination in Deferred arm Roth D, et al. Lancet 2015;386:

53 Patients, % 1. Roth D et al. Lancet. 2015;386: ; 2. Roth D et al. Poster presented at: Kidney Week 2015; November 2015; San Diego, CA. Elbasvir + Grazoprevir in HCV GT1 and Renal Disease C-SURFER Study SVR12: 94.3% Full analysis set Modified full analysis set 100% 94,3% 99,1% 95,1% 98,0% 75% 50% 25% 0% 115 / /116 Immediate treatment 97 /102 Deferred treatment Relapse 1 a 1 2 c 2 D/c unrelated to treatment 6 b 0 3 d 0 97 /99

54 Virologic Response Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir in GT1 & Renal Disease RUBY-I: Baseline Results RUBY-I: SVR 12 Rates* GT1a: OBV/PTV/r + DSV + RBV GT1b: OBV/PTV/r + DSV /13 7/7 85/88 11/13 7/7 91/9111/13 7/7 EOT SVR4 SVR12 OBV/PTV/r + DSV = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin Pockros PJ, Gastroenterology. 2016;150:

55

56 Use the lowest statin dose Atorvastatin 20 mg Rosuvastatin 10 mg

57 HIV/HCV υλλοίμωξη

58 1. C-EDGE CO-INFECTION χωρίσ RBV EBR 50 mg / GZR 100 mg Follow-up D1 TW4 TW8 TW12 FUW4 FUW8 FUW12 FUW24 Ν=218 Πολυκεντρική μελζτη, ανοιχτοφ- τφπου Naïve: GT 1,4,6 16% κιρρωτικοί Backbone HAART: 21% υπό abacavir, 75% tenofovir Βaseline CD4+ κφτταρα (μζςη τιμή): 568 cells/μl Rockstroh JK et al. Lancet HIV. 2015;2:e319 e327

59 Patients with SVR12 (%) Elbasvir-Grazoprevir in HCV-HIV Coinfection GT 1, 4 or 6 C-EDGE CO-INFECTION: Results C-EDGE CO-INFECTION: SVR12 Results by Genotype SVR-12 > 95% HIV/HCV / /144 42/44 27/28 0 All GT1a GT1b GT4 Genotype Overall SVR12 results includes the 2 patients with GT 6, who both achieved SVR12. Rockstroh JK et al. Lancet HIV. 2015;2:e319 e327

60 Elbasvir-Grazoprevir in HCV-HIV Coinfection GT 1, 4 or 6 C-EDGE CO-INFECTION: Adverse Events Adverse Event (AE), n (%) Elbasvir-Grazoprevir (N=218) Discontinuation due to AE 0 Serious AEs 2 (1%) Deaths 0 Any AE in >5% of patients Fatigue Headache Nausea Upper respiratory tract infection Diarrhea Insomnia 29 (13%) 27 (12%) 20 (9%) 18 (8%) 16 (7%) 15 (7%) Grade 3 or 4 laboratory abnormality Total bilirubin ALT elevation AST elevation Hemoglobin Grade 3 1 (<1%) 3 (1%) 0 0 Grade (1%) 1 (<1%) 0 Rockstroh JK et al. Lancet HIV. 2015;2:e319 e327

61 Φάρμακα που δεν απαιτοφν προςαρμογή δοςολογίασ ςτη ςυγχορήγηςη με το EBR/GZR Acid reducing agents Pantoprazole Simetidine Antacids Antiarrhythmics Digoxin HCV antivirals Ribavirin Sofosbuvir Oral contraceptive pills Immunosuppressant Prednisone Mycophenolate mofetil Phosphate binders HMG-CoA Reductase Inhibitors Pitavastatin Pravastatin Opiate agonist therapy Buprenorphine/naloxone Methadone HIV medications Abacavir, Dolutegravir Emtricitabine Entecavir Lamivudine Raltegravir Rilpivirine Tenofovir disoproxil fumarate EBR/GZR Summary of Product Characteristics,2016.

62 Αςθενείσ υπό αγωγή με αγωνιςτζσ οπιοειδών

63 Elbasvir-Grazoprevir in HCV GT 1, 4, or 6 in PWID on Opiate Agonist Therapy C-EDGE CO-STAR: Study Features Week χωρίσ RBV Treatment-naïve GT 1, 4 or 6 (N=301) N=201 N=100 Elbasvir-Grazoprevir- Placebo SVR12 Elbasvir-Grazoprevir- SVR12 Drug Dosing Grazoprevir-elbasvir (100/50 mg): fixed dose combination; one pill once daily Dore G, et al. AALSD. 2015; Abstract 40.

64 Patients (%) with SVR 12 Elbasvir-Grazoprevir in HCV GT 1, 4, or 6 in PWID on Opiate Agonist Therapy C-EDGE CO-STAR: Results C-EDGE CO-STAR: SVR12 Results with Modified Full Analysis Set^ SVR-12 ~ 95% /158 38/40 83/85 106/113 83/85 106/113 No Yes 2 million > 2 million Negative Positive Cirrhosis HCV RNA IU/ml Drug Screen ^Excludes patients who discontinued trial for non-treatment related reasons Dore G, et al. AALSD. 2015; Abstract 40.

65 Adherence, % EBR/GZR: CO-STAR 1 ΣΥΜΜΟΡΦΩΣΗ τωρίς RBV 80% adherence (>67 doses) 90% adherence (>76 doses) 95% adherence (>79 doses) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% n N 100% 99% 97% 100% 100% Immediate Treatment Arm (N=199) % Deferred Treatment Arm (N=97) 97% ηων αζθενών ηης μελέηης έλαβαν ηοσλάτιζηον 81 από ηις 84 δόζεις, παρόηι περιζζόηεροι από ηοσς μιζούς ζσνέτιζαν να λαμβάνοσν ναρκωηικές οσζίες καηά ηη διάρκεια ηης θεραπείας. Dore GJ, Altice F, Litwin AH et al. Ann Intern Med Aug 9.

66 EBR/GZR (DDIs)

67 EBR/GZR (DDIs)

68 Αςθενείσ με κληρονομικζσ αιματολογικζσ διαταραχζσ C-EDGE:IBLD

69 Gender, n (%) Male Female Race, n (%) White African-American Asian Other HCV genotype, n (%) G1a G1b G1 other G4 G6 ΔΗΜΟΓΡΑΦΙΚΑ ΣΟΙΧΕΙΑ ΜΕ EBR/GZRcs χωρίσ RBV Prior treatment history, n (%) Naive Experienced GZR + EBR (Immediate) 12 weeks (n = 107) 80 (74.8) 27 (25.2) 81 (75.7) 19 (17.8) 6 (5.6) 1 (0.9) 47 (43.9) 46 (43.0) 2 (1.9) 12 (11.2) 0 (0) 53 (49.5) 54 (50.5) Placebo (Deferred) 12 weeks (n = 52) 39 (75.0) 13 (25.0) 40 (76.9) 9 (17.3) 3 (5.8) 0 (0) 18 (34.6) 27 (51.9) 0 (0) 6 (11.5) 1 (1.9) 27 (51.9) 25 (48.1) Cirrhosis, n (%) 26 (24.3) 12 (23.1) HIV coinfected, n (%) 6 (5.6) 4 (7.7) IL28B CC, n (%) 27 (25.2) 9 (17.3) Blood disorder, n(%) Sickle Cell Anemia ß Thalassemia von Willebrand / Hemophilia A/B 19 (17.8) 41 (38.3) 47 (43.9) 10 (19.2) 20 (38.5) 22 (42.3) Hezode et al EASL 2016 sat-128

70 SVR12 SVR12: (immediate treatment group) 100% 93.5% 75% 50% 25% 0% 100/107 Full analysis set Breakthrough 0 Relapse 6 LTFU/Early DC 1 Discontinued due to non-compliance and did not continue within the study Full analysis set includes all patients who received 1 dose of study medication Hezode et al EASL 2016 sat-128

71 ΑΙΜΑΣΟΛΟΓΙΚΕ ΠΑΡΑΜΕΣΡΟΙ χωρίσ RBV Immediate treatment EBR/GZR for 12 weeks N = 107 Deferred treatment Placebo for 12 weeks N = 52 Hemoglobin (g/dl) (11.2) 5 (9.6) (17.8) 12 (23.1) (15.9) 7 (13.5) <7.0 5 (4.7) 3 (5.8) Prothrombin INR ULN 25 (23.4) 15 (28.8) ULN 4 (3.7) 2 (3.8) ULN 1 (0.9) 2 (3.8) >3.0 ULN 0 (0) 1 (1.9) Platelets ( 10 3 /µl) (5.7) 2 (3.9) (2.8) 4 (7.8) (0.9) 0 (0) <25 0 (0) 0 (0) Hezode et al EASL 2016 sat-128

72 ΤΜΠΕΡΑΜΑΣΑ χωρίσ RBV 12 w Πρωτοθεραπευόμενοι (κιρρωτικοί και μη-κιρρωτικοί αςθενείσ) γονοτφπων 1b, 4, 1a-LVL Επαναθεραπευόμενοι (κιρρωτικοί και μη-κιρρωτικοί αςθενείσ) γονοτφπων 1b, 4-LVL, 1a-LVL οβαρζσ ςυν-νοςηρότητεσ (ΧΝΝ, HIV, PWID, IBLD) Περιοριςμζνοσ αριθμόσ αλληλεπιδράςεων με άλλεσ φαρμακευτικζσ ουςίεσ Καλό προφίλ αςφάλειασ