HCV In 2015: Maximizing SVR

HCV In 2015: Maximizing SVR Alnoor Ramji Gastroenterology & Hepatology Clinical Associate Professor Division of Gastroenterology University Of British Columbia ramji_a@hotmail.com

Disclosures (within Last 24 months) Company Name Abbvie BI BMS Gilead Sci. Inc Relationship Investigator, consultant Investigator, Consultant Investigator, Consultant, Speaker Investigator, Consultant, Speaker; Grants Janssen (J. & J.) Lupin Novartis Merck & Co. Vertex Pharmaceuticals Investigator, Consultant, Speaker Consultant Investigator Investigator, Consultant, Speaker; Grants Investigator, Consultant, Grants.

Objectives Review available regimens to maximize SVR: The Advanced Compensated Cirrhotic patient Decompensated Cirrhosis DAA Failures Genotype 2 Genotype 3

The Advanced Compensated Cirrhotic Patient: Not All Cirrhotic s are Equal 64 y.o. male Geno 1a: a) Fibroscan 14.5 kpa, Plt 156, Albumin 37 b) Fibroscan 20.5 kpa., Plt 88, Albumin 34

Treatment-Experienced GT1 Cirrhotic Pts.: Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV 12 vs. 24 wks. (TURQUOISE II) 100 92.2 92.9 GT1a 93.3 100 100 100 92.9 80.0 12 wks 24 wks 100 100 100 GT1b 100 100 85.7 100 100 100 80 80 SVR12 (%) 60 40 60 40 20 20 0 59/ 64 52/ 56 Naive 14/ 15 13/ 13 11/ 11 10/ 10 Relapse Partial Response 40/ 50 39/ 42 Null Response 0 22/ 22 18/ 18 Naive 25/ 25 20/ 20 Relapse Partial Response 6/7 3/3 14/ 10/ 14 10 Null Response Poordad F, et al. NEJM 370:21;1973. Note: Turquoise III: Feld JJ, et al. ISVHLD 2015; Late breaker oral presentation 333.

TURQUOISE-II: Regimens of Paritaprevir/r/Ombitasvir and Dasabuvir With Ribavirin: Geno. 1 Cirrhosis, effect of Baseline Characteristicson SVR 12 Overall SVR12: 91.8% 96.5% HCV GT1a IL28B non-cc IL28B TT Platelet <90 x 10 9 /L Albumin <35 g/l AFP 20 ng/ml SVR12 Rate, % ± 95% CI Fried, et al. EASL 2014. Abstract O81. Reproduced with permission. Poordad F, et al. NEJM 370:21;1973. Supplement

OPTIMIST-2: SMV + SOF for 12 Wks in Cirrhotic Tx-Naive and Tx-Expd GT1 Pts: SVR12 SVR12 Rate Treatment history 12 Wks of Simeprevir + Sofosbuvir (n = 103) % (n/n) 95% CI Naive 88 (44/50) 78.0-98.0 Experienced 79 (42/53) 67.4-91.1 HCV subgenotype 1a 83 (60/72) 74.0-92.6 1a with Q80K 74 (25/34) 57.2-89.8 1a without Q80K 92 (35/38) 82.2-100 1b 84 (26/31) 69.3-98.4 SVR12 Rate Platelet count 12 Wks of Simeprevir + Sofosbuvir (n = 103) % (n/n) 95% CI < 90,000/mm 3 68 (13/19) 44.9-92.0 90,000/mm 3 87 (73/84) 79.1-94.7 FibroScan score > 20 kpa 80 (12/15) 56.4-100 100 > 12.5 to 20 kpa 95.5-100 (11/11) Lawitz E, et al. EASL 2015. Abstract LP04.

Genotype 1 Naïve Cirrhosis (ION-1) (LDV/SOF±RBV x 12 or 24 wks.) SVR12 by Presence of Cirrhosis Absence of Cirrhosis Cirrhosis SVR12 (%) 179/17 32/33 9 LDV/SOF 178/17 33/33 8 LDV/SOF + RBV 181/18 31/32 2 LDV/SOF 179/17 36/36 9 LDV/SOF + RBV Mangia A, EASL, 2014, O164 12 Weeks 24 Weeks Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print] Cirrhosis = 12.5 Kpa, 2-5% plt <90 or Albumin <35

SOF/LDV Therapy In Compensated cirrhosis: Role of RBV & Effect of Negative Predictors. SVR12, % Integrated analysis of > 500 pts with cirrhosis treated with LDV/SOF ± RBV Treatment-experienced pts had previously received PR +/- PI Total (N = 513) Treatment Naive (n = 161) Treatment Experienced (n = 352) Overall 96 98 95 12 wks without RBV 92 96 90 12 wks with RBV 96 98 96 24 wks without RBV 98 97 98 24 wks with RBV 100 100 100 Baseline platelet count <75,000 32/38 (84) 9/10 (90) 23/28 (82) >75,000 461/475 (97) 148/151 (98) 313/324 (97) Albumin <3.5 61/63 (97) 20/21 (95) 1/42 (98) >3.5 432/450 (96) 137/140 (98) 295/310 (95) Reddy KR, et al. Hepatology. 2015;62:79-86.

SOF/LDV Therapy In Compensated Cirrhosis: Role of baseline NS5A RAV s Treatment experienced patients had previously received HCV PI or Peg/ Rbv SVR12, % (n/n)18 With NS5A RAVs Without NS5A RAVs Overall 91 (86/94) 98 (407/417) 12 wks without RBV 88 (23/26) 95 (86/91) 12 wks with RBV 94 (32/34) 97 (164/169) 24 wks without RBV 85 (17/20) 100 (113/113) 24 wks with RBV 100 (14/14) 100 (44/44) Reddy KR, et al. Hepatology. 2015;62:79-86.

DAA Failures And NS5A RAV s DAA Failures with Persistence of Variants: Persistence of NS5A RAV / TEV in 95-96% at week 48, and 86% at week 96. NS5B: 42% at week 48. NS3: 7% at week 48. Krishnan P, et al. EASL 2015; #0057. Wyles D, et al. EASL 2015; #O059.

Re-Treatment For DAA Failures: 24 Wks. LDV/SOF After Failure of 8-12 Wks. LDV/SOF-Based Therapy: SVR12 100 100 SVR12 (%) 80 60 40 71 68 74 80 46 60 20 n/n = 0 29/ 41 15/ 22 All No Yes Cirrhosis Lawitz E, et al. EASL 2015. Abstract O005. 14/ 19 24/ 30 5/ 11 8 Wks 12 Wks Previous Tx Duration 11/ 18/ 11 30 No Yes BL NS5A RAVs

Re-Treatment For DAA Failures: 24 Wks. LDV/SOF: SVR12 by Base-line RAV s Number of NS5A RAV(s) Type of Single NS5A RAV 11/11 11/16 7/14 5/5 4/5 2/6 NS5B variants emerged during retreatment in 33% of pts (4/12) with virologic failure: S282T: n = 2; L159F: n = 1; S282T + L159F: n = 1 Adapted from Lawitz E, et al. Presented at EASL 2015; Oral presentation #O005.

Re-Treatment For DAA Failures. Should only consider if resistance testing available. At present consider: addition of RBV; duration; use multiple DAA s. LB-20 Retreatment of HCV Genotype 1 DAAfailures with Ombitasvir/Paritaprevir/r, Dasabuvir, and Sofosbuvir : Fred Poordad. LB-12: C-SWIFT Retreatment (Part B): 12 weeks of Elbasvir/Grazoprevir with Sofosbuvir and Ribavirin Successfully Treated GT1-infected Subjects who Failed Short-Duration All-Oral Therapy. Eric Lawitz

The Decompensated Patient

SOLAR-2: SVR12 and Safety in GT1 or 4 HCV by Liver Disease Subgroup Outcome Posttransplantation F0-F3 or CTP A LDV/SOF + RBV for 12 Wks (n = 86) LDV/SOF + RBV for 24 Wks (n = 82) Pre- and Posttransplantation CTP B or C LDV/SOF + RBV for 12 Wks (n = 78) LDV/SOF + RBV for 24 Wks (n = 82) SVR12, % (n/n) Genotype 1 96 (72/75) 98 (57/58) 88 (57/65) 89 (54/61) Genotype 4 91 (10/11) 100 (7/7) 57 (4/7) 86 (6/7) Safety, n (%) SAE 12 (14) 12 (15) 22 (28) 23 (28) Trt-related SAE 0 3 (4) 2 (3) 4 (5) Trt discont. for AE 0 1 (1) 1 (1) 4 (5) Deaths 2 (2) 1 (1) 3 (4) 4 (5) Manns M, et al. EASL 2015. Abstract G02.

ALLY-1: DCV/ SOF/ RBV x 12 Wks. SVR 12 by Child-Pugh Class and by Albumin Level By Child-Pugh Class By Albumin Level 11/12 30/32 9/16 10/11 30/31 10/18 Adapted from Poordad F, et al. Presented at EASL 2015; Oral presentation #L08.

Genotype 2

Genotype 2: BOSON: SOF/Rbv x 16 wks. vs. SOF/Rbv x 24 wks. vs. Peg/ Rbv / SOF x12 wks. Geno 2 all with cirrhosis and treatment experienced 100 87% 100% 94% 80 SVR (%) 60 40 20 13/15 17/17 15/16 0 SOF+RBV X 16 wks SOF+RBV X 24 wks PegIFN/RBV X 12 wks Foster G. et al. Gastroenterology Nov. 2015; 149:6

Genotype 3

Geno 3: BOSON: SVR12 by Treatment History and Cirrhosis Status SOF + RBV 16 wks SOF + RBV 24 wks SOF + PegIFN/RBV 12 wks 100 80 83 90 96 57 82 91 76 82 94 47 77 86 SVR12 (%) 60 40 20 n/n = 0 58/ 70 65/ 72 68/ 71 12/ 21 Treatment Naive 18/ 22 21/ 23 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis Foster G. et al. Gastroenterology Nov. 2015; 149:6 41/ 54 44/ 54 49/ 52 17/ 36 26/ 34 Treatment Experienced 30/ 35

ALLY-3: DCV + SOF x 12 weeks: SVR-12 Treatment-naive (n=101) or experienced (n=51), including patients with cirrhosis 100 80 96 63 No cirrhosis 97 58 Cirrhosis 94 69 SVR12 (%) 60 40 20 n/n = 0 105/ 109 20/ 32 Overall Treatment-Naive Pts Of 16 pts with relapse, 11 had cirrhosis 1 of 16 relapses occurred between posttreatment Wks 4 and 12 73/ 75 11/ 19 Nelson DR, et al. Hepatology. 2015;61:1127-1135. 32/ 34 9/ 13 Treatment- Experienced Pts

Sofosbuvir + Daclatasvir for GT-3 Patients: Preliminary Real-life Data from a French Multicenter Compassionate Use Program N=601 GT-3 patients 77% cirrhotic 73% treatment-experienced Treated with sofosbuvir + daclatasvir for 12 or 24 weeks Duration at physicians' discretion 22/29 52/59 11/12 5/6 CCO Slideset. Adapted from Hezode C, et al. Presented at EASL 2015; Poster #LP05.

All-Oral Treatment With Daclatasvir (DCV) Plus Sofosbuvir (SOF) Plus Ribavirin (RBV) for 12 or 16 Weeks in HCV Genotype (GT) 3-lnfected Patients With Advanced Fibrosis or Cirrhosis: The ALLY-3+ 50 patients : (12 weeks, 24; 16 weeks, 26). Treatment experienced- 74% (10% prior relapse on SOF+RBV) 72% had cirrhosis V.. Leroy et al. AASLD 2015 LB-3

All-Oral Treatment With Daclatasvir (DCV) Plus Sofosbuvir (SOF) Plus Ribavirin (RBV) for 12 or 16 Weeks in HCV Genotype (GT) 3-lnfecleted Patients With Advanced Fibrosis or Cirrhosis: The ALL Y-3+ N (%) 12 wks (n=24) 16 wks (n=26) SVR-4 21 (88) 25 (96) Advanced fibrosis 6/6 (100) 8/8 (100) Cirrhosis 15/18 (83) 17/18 (94) Virologic breakthrough 0 0 Relapse 2 (8) 1 (4) V.. Leroy et al. AASLD 2015 LB-3

Summary Using available regimens we can optimize SVR: The advanced cirrhotic patient: Plt. <90.;? Albumin <3.5 When regimen s fail.. Use resistance testing prior to re-treatment? Role of Rbv?, duration of therapy, additional DAA s. Genotype 2: Tx. Exp. Cirrhotic: SOF/ Rbv x 24 wks. Genotype 3: PRS x12 Wks. or DCV/SOF+/- RBV: 12-16 wks.

HCV In 2015: Maximizing SVR Alnoor Ramji Gastroenterology & Hepatology Clinical Associate Professor Division of Gastroenterology University Of British Columbia ramji_a@hotmail.com

DAA Failures And NS5A RAV s Baseline NS5A: ION-3: 116 of 647 had a NS5A variant at baseline (deep sequencing), with 90% SVR. Combined compensated cirrhosis patients with baseline NS5A treated with SOF/LDV +/- Rbv 12/24 wks. SVR 91% DAA Failures with Persistence of Variants: NS5A RAV / TEV in 95-96% at week 48, and 86% at week 96. NS5B: 42% at 48 weeks NS3/4A: 7% at 48 weeks Reddy KR, et al. Hepatology. 2015;62:79-86. Wyles D, et al. EASL 2015; #O059. Krishnan P, et al. EASL 2015; #0057.