STATE OF THE ART Update: Treatment Options 2016 Mark Sulkowski, MD

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STATE OF THE ART Update: Treatment Options 2016 Mark Sulkowski, MD Professor of Medicine Johns Hopkins University School of Medicine

Disclosures PI for research grants related to HCV with funds paid to Johns Hopkins University AbbVie, BMS, Gilead, Janssen, Merck DSMB related to HBV with funds paid to Johns Hopkins University Gilead Scientific advisor related to HCV Terms of these arrangement are being managed by the JHU in accordance with its conflict of interest policies AbbVie, Achillion, BMS, Cocrystal, Gilead, Janssen, Merck

Current HCV direct acting antiviral regimens cure the majority of persons treated in phase 3 trials Receptor binding and endocytosis Highly efficacious DAAs target different points in the HCV lifecycle 1 Transport and release Summary of New England Journal of Medicine studies on IFN-free therapy in GT 1 published in 2014 2 96% Fusion and uncoating Virion assembly Translation and polyprotein processing (+) RNA ER lumen NS3 protease inhibitors Membranous web LD LD ER lumen LD NS5A inhibitors RNA replication Nucleos(t)ide and Nonnucleoside NS5B inhibitors 3680/ 3826 Sustained Virologic Response [SVR] 1. Lindenbach BD, Rice CM. Nature 2005;436(Suppl):933 8; 2. Liang J, Ghany MG. N Engl J Med 2014;370:2043 7; 3. Burki T. Lancet Infect Dis 2014;14:452 3

Multiple, highly effective, antiviral regimens are available to treat persons with hepatitis C Antiviral NS3 NS5A Non-Nuc NS5B Nuc NS5B RBV Paritaprevir/ritonavir/Ombitasvir + Dasabuvir Grazoprevir/Elbasvir FDC Sofosbuvir/Ledipasvir FDC Sofosbuvir/Velpatasvir FDC Sofosbuvir + Daclatasvir 1a (all) 1a if RAVs at 28, 30, 31, or 93 Sofosbuvir + Simeprevir

Key information needed to decide how to treat a person with chronic HCV infection HCV genotype and, if genotype 1, subtype HCV RNA level (viral load) Testing for resistance associated variants (RAVs) in some patients with genotype 1a Presence of cirrhosis If cirrhosis, Child-Turcotte-Pugh classification A, B or C PT INR, total bilirubin, albumin Kidney function Estimated GFR Hemoglobin Ability to take ribavirin which causes hemolytic anemia (~ 2.5 g/dl decline in hemoglobin) Prior HCV treatment experience Payors may mandate one regimen over others

HCV genotype/subtype regimens are tailored to genotype Genotype 1 1b - easy to treat. No ribavirin 1a resistance may be an issue with simeprevir (PI) and regimens that do not include sofosbuvir). Add ribavirin for some. Genotype 2 Current SOF/RBV June 2016 SOF/Velpatasvir Genotype 3 Current SOF + Daclatasvir June 2016 SOF/Velpatasvir Genotype prevalence in the US GT 1, 75% (~60% 1a) GT 2, 15% GT 3, 10%

HCV genotype 1

HCV eradication with the fixed-dose combination of Ledipasvir/Sofosbuvir (NS5A/nuc NS5B) Persons with no prior HCV treatment 100 75 94 93 97 97 99 98 8 weeks 20 patients with relapse, 4.6%* HCV RNA < 6 million IU/mL, 2% 50 12 weeks 4 patients with relapse, 0.6%* 24 weeks 1 patient with relapse, 0.2%* 25 0 8 weeks 12 weeks 24 weeks Ribavirin No Ribavirin *Variants in patients with virologic failure: NS5A, L31V/M/I, Y93H, Q30R NS5B, None Kowdley KV et al. N Engl J Med. 2014 May 15;370(20):1879-88. Afdhal N et al. N Engl J Med. 2014 May 15;370(20):1889-98.

HCV-TARGET: SVR12 and Relapse Rates LDV/SOF SVR Relapse LDV/SOF+RBV 100 97 97 95 100 97 92 80 80 60 60 40 40 20 0 150/154 4/154 8 weeks 3 3 5 607/627 20/627 153/161 8/161 12 weeks 24 weeks 20 0 1 86/89 1/89 12 weeks 8 12/13 1/1 24 weeks Wetzel T, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 1057.

Ledipasvir/Sofosbuvir + RBV for 12 weeks or Ledipasvir/Sofosbuvir alone for 24 weeks -- similar SVR in persons with prior treatment experience and cirrhosis Bourliere M, et al. Lancet 2015

Emergence of NS5B RAV S282T is rare after SOF-based treatment Pre-treatment, n=8598 No S282T was detected Treatment with SOF or LDV/SOF in clinical trials, n=12,012 Virologic failure, n=1025 Deep sequencing after virologic failure, n=901 S282T detected, n=10 1% SOF virologic failures <0.1% SOF-treated patients Patients with S282T N=10 Mean age, years (range) 56 (34 72) Male, n (%) 9 (90) Black, n (%) 2 (20) Mean BMI, kg/m 2 (range) 31 (22 37) Cirrhosis, n (%) 5 (50) IL28B non-cc, n (%) 8/9 (89) Mean HCV RNA, log 10 IU/mL (range) 6.6 (6.0 7.8) Prior Tx status, n (%) Tx-naive Tx-experienced, DAA-naive DAA-experienced 4 (40) 1 (10) 5 (50) Gane E, et al. AASLD 2015, San Francisco. #219

Simeprevir + Sofosbuvir for 12 weeks in persons with and without cirrhosis No Cirrhosis (OPTIMIST-1 [1] ) Cirrhosis (OPTIMIST-2 [2] ) 100 80 97 97 95 96 97 100 80 83 88 79 74 92 SVR12 (%) 60 40 SVR12 (%) 60 40 20 n/n = 0 150/ 155 All pts 112/ 115 Naive 38/ 40 Exp d 44/ 46 1a + Q80K 68/ 70 1a no Q80K 20 n/n = 0 86/ 103 All pts 44/ 50 42/ 53 25/ 34 Naive Exp d 1a + Q80K 35/ 38 1a no Q80K Treatment History HCV GT Treatment History HCV GT 1. Kwo P, et al. EASL 2015. Abstract LP14. 2. Lawitz E, et al. EASL 2015. Abstract LP04.

PrOD: Ribavirin prevents HCV virologic failure in patients with genotype 1a infection and is not required for 1b infection Ombitasvir/Paritaprevir/r + Dasabuvir with or with Ribavirin Genotype 1b 1 patient with breakthrough* Genotype 1a - No Ribavirin 16 patients with virologic failure (6 breakthrough and 10 relapse)* Genotype 1a plus Ribavirin 2 patients with virologic failure (1 breakthrough and 1 relapse)* *Variants in patients with virologic failure: NS3, D168V NS5A, M28T and Q30R NS5B,S556G Ferenci NEJM 2014

PrOD + RBV for 24 weeks was better than 12 weeks for treatment experienced patients with compensated cirrhosis and HCV genotype 1a Poordad F, et al. N Engl J Med. 2014;370:1973-82.

PrOD without RBV is effective for treatment experienced patients with compensated cirrhosis and HCV genotype 1b Feld JJ et al. Journal of Hepatology 2015

Grazoprevir Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial Ann Intern Med. 2015;163(1):1-13. doi:10.7326/m15-0785

GZV/EBR: Baseline RAVs impact response in patients with genotype 1a but not 1b GT1a-infected EBR/GZR 12 Weeks (No RBV): Lower SVR with key RAVS Population sequencing is adequate for clinical interpretation [no need for deep sequencing] RAV Position SVR12 Patients with RAVs (NGS 1% ST) SVR12 Patients with RAVs (PopSeq) 30 14/23 (60.9%) 4/10 (40.0%) 31 15/23 (65.2%) 5/13 (38.5%) 93 9/14 (64.3%) 5/8 (62.5%) GT1b-infected EBR/GZR 12 Weeks (No RBV): No impact of RAVS RAV Position SVR12 Patients with RAVs (PopSeq) 30 16/16 (100.0%) 31 17/19 (89.5%) 93 21/22 (95.5%) NGS 1% ST Supplemented by PopSeq when NGS was not available. NS5A Class RAV Listed = any variant from reference strain at NS5A position 24, 28, 30, 31, 32, 38, 58, 92, and 93. At position 31, SVR was achieved in 14/16 (87.5%) with L31M and 3/3 (100%) with L31I. At position 93, SVR was achieved in 20/21 (95.2%) with Y93H and 1/1 (100%) with Y93S. Jacobson I, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-22.

GZV/EBR: longer treatment (16 weeks) and addition of RBV overcome baseline RAVs Efficacy of EBR/GZR 16/18 Weeks (+ RBV) in GT1a PR Non-responders with Baseline NS5A RAVs Population Sequencing EBR RAVs NS5A Class RAVs Next-Generation Sequencing at 1% ST EBR RAVs NS5A Class RAVs Prevalence No RAVs: 51/52 (98%) 2% No RAVs: 44/52 (85%) 15 % No RAVs: 48/52 (92%) 8% No RAVs: 38/52 (73%) 27 % SVR12 (%) 100 80 60 40 20 0 100 100 100 100 100 100 100 100 51 51 1 1 EBR RAVs 44 44 8 8 NS5A class RAVs Patients without RAVs 48 48 4 4 EBR RAVs 38 38 Patients with RAVs 14 14 NS5A class RAVs Jacobson I, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-22.

Ribavirin considerations added to oral DAA regimens Teratogenic Renal clearance accumulates with decreased egfr Hemolytic anemia (doserelated) Compensatory reticulocytosis Not corrected by iron Mean Hb change ±RBV Ferenci P et al. N Engl J Med 2014;370:1983-92.

ASTRAL-1: SOF/VEL for 12 Weeks in HCV GT 1, 2, 4, 5, or 6 Phase 3 study in North America, Europe and Hong Kong Enrolled 740 patients; 624 treated with SOF/VEL Genotype 1, 2, 4 6 randomized 5:1 to SOF/VEL versus placebo Genotype 5 treated with SOF/VEL Feld J, et al. NEJM 2016 Placebo n=116 SOF/VEL n=624 Mean age, y (range) 53 (25-74) 54 (18-82) Male, n (%) 68 (59) 374 (60) White, n (%) 90 (78) 493 (79) Mean BMI, kg/m (range) 26 (18-40) 27 (17-57) US enrolled, n (%) 45 (39) 234 (38) Cirrhosis, n (%) 21 (18) 121 (19) Treatment experienced, n (%) 33 (28) 201 (32) IL28B CC, n (%) 36 (31) 186 (30) Median HCV RNA, log 10 lu/ml (range) 6.4 (4.7-7.5) 6.4 (1.1-7.8)

ASTRAL-1: SVR12 by HCV Genotype 100 99 98 99 100 100 97 100 80 SVR12 (%) 60 40 20 0 1 relapse 2 lost to follow-up 1 withdrew consent 618 624 206 210 1 relapse 1 death 117 118 104 104 116 116 Total 1a 1b 2 4 5 6 Genotype 34 35 41 41 Feld J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-2.

HCV genotype 1 approach Genotype 1b No ribavirin 12 weeks of treatment for most patients Genotype 1a LDV/SOF no RAV testing; 8 or 12 weeks for most patients with 24 weeks for TE patients with cirrhosis SOF/VEL no RAV testing; 12 weeks for most PrOD + Ribavirin no RAV testing; 12 weeks for most with 24 weeks for cirrhosis EBR/GZV RAV testing; if no RAV, 12 weeks for all; if RAV, 16 weeks + RBV for all

Resistance testing Genotype 1b not recommended Genotype 1a when considering GZV/EBR or whether or not to use RBV All patients who are not cured with first line DAA regimens

HCV genotype 2

FISSION: PegIFN/RBV versus Sofosbuvir + RBV for 12 weeks in persons with HCV genotype 2 or 3 infection Patients (%) with SVR 12 100 80 60 40 20 0 67 67 GT 2 and 3 (n=496) 97 Sofosbuvir + RBV 78 GT 2 (n=137) 56 PEG + RBV 63 GT 3 (n=359) Lawitz E, et al. N Engl J Med. 2013;368:1878-87

ASTRAL-2: Randomized controlled trial of SOF/VEL vs. SOF + RBV in HCV Genotype 2 SOF/VEL n=134 SOF + RBV n=132 Mean age, y (range) 57 (26 81) 57 (23 76) Male, n (%) 86 (64) 72 (55) Race White, n (%) 124 (93) 111 (84) Black, n (%) 6 (4) 12 (9) Mean BMI, kg/m 2 (range) 28.0 (17.4 44.6) 29.3 (19.0 61.0) Cirrhosis, n (%) 19 (14) 19 (14) TE, n (%) 19 (14) 10 (15) IL28B CC, n (%) 55 (41) 46 (35) Mean HCV RNA, log 10 IU/mL (SD) 6.5 (0.8) 6.4 (0.7) Sulkowski M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 205.

ASTRAL-2: SVR12 by Treatment Arm p=0.018 100 99 94 80 SVR12 (%) 60 40 20 1 LTFU 6 Relapse 2 LTFU 133/134 124/132 0 SOF/VEL SOF + RBV Error bars represent 95% confidence intervals. Sulkowski M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 205.

HCV genotype 3

Interferon + SOF + RBV for 12 weeks was more effective than SOF + RBV for 24 weeks in persons with HCV genotype 3 SVR12 (%) SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PEG-IFN/RBV12 weeks 100 83 96 90 91 94 82 82 76 77 86 80 57 47 60 40 20 n/n = 0 58/ 70 65/ 72 68/ 71 12/ 21 18/ 22 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis Treatment Naïve Treatment Experienced Foster G. Gastroenterology 2015. 21/ 23 41/ 54 44/ 54 49/ 52 17/ 36 26/ 34 30/ 35

Daclatasvir + Sofosbuvir for Treatment of Persons with HCV Genotype 3 Infection ALLY-3+: 12 vs 16 weeks + Ribavirin 100 88 96 100 ALLY-3: 12 weeks 97 94 69 80 80 58 SVR4 (%) 60 40 SVR12 (%) 60 40 20 n/n = 0 21/ 24 12 Weeks 25/ 26 16 Weeks Nelson DR, et al. Hepatology. 2015;61(4):1127-1135. Leroy V, et al. AASLD 2015. LB-3. 20 n/n = 0 73/ 75 Cirrhosis absent Cirrhosis present 11/ 19 32/ 34 9/ 13 Treatmentnaïve Treatmentexperienced

ASTRAL-3: SOF/VEL 12 Weeks vs. SOF + RBV for 24 Weeks in HCV GT 3 SOF/VEL for 12 Wk (N=277) SOF + RBV for 24 Wk (N = 275) Mean age (range) yr 49 (21-76) 50 (19-74) Male sex no. (%) 170 (61) 174 (63) Mean body-mass index (range) 26 (17-48) 27 (17-56) Race no. (%) White 250 (90) 239 (87) Black 3 (1) 1 (<1) Asian 23 (8) 29 (11) Other 1 (<1) 6 (2) HCV RNA Mean log 10 IU/ml 6.2±0.72 6.3±0.71 800,000 IU/ml no. (%) 191 (69) 194 (71) IL28B genotype no. (%) CC 105 (38) 111 (40) CT 148 (53) 133 (48) TT 24 (9) 31 (11) Compensated Cirrhosis no. (%) 80 (29) 83 (30) Mangia A, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 249.

ASTRAL-3: SVR12 By Cirrhosis Status and Treatment History 100 97 91 97 90 87 86 SOF/VEL SOF+RBV 80 66 63 SVR12 (%) 60 40 20 0 4 relapses 2 other 191 197 16 relapses 8 other 163 187 22 relapses 6 other 7 relapses 7 relapses 1 non-response 23 relapses 2 other 73 80 No Yes Naïve Experienced Cirrhosis Status 55 83 4 relapses 2 other 200 206 15 relapses 13 other 176 204 64 71 Treatment History 45 71 Feld J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-2; Sulkowski M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 205. Mangia A, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 249.

Advanced kidney disease

Considerations in patients with renal dysfunction CrCl 30 ml/min: No dosage adjustments required with sofosbuvir or ledipasvir/sofosbuvir FDC or simeprevir or paritaprevir/ritonavir/ombitasvir FDC + dasabuvir BID CrCl < 30 ml/min: Consult an expert How to dose ribavirin Creatinine clearance RBV dose daily > 50 ml/min <75 kg = 1000 mg 75 kg = 1200 mg 30 50 ml/min Alternate 200 mg & 400 mg QD < 30 ml/min 200 mg QD Hemodialysis Copegus package insert. 200 mg QD

RUBY-I: OMB/PTV/RTV + DSV for Treating HCV G1 Infection in Patients With Severe Renal Impairment or End-stage Renal Disease ITT Virologic Response, N=20 Hb change with OMB/PTV/RTV + DSV ± RBV 200 mg/day 3 Change from baseline (g/dl) 2 1 0-1 -2-3 BL W1 W2 W3 W4 W6 W8 W12/EOT PTW4 Pockros PJ, et al. AASLD 2015. Abstract 1039. Pockros PJ. Presented at: EASL 2015; April 22-26; Vienna, Austria. Abstract LO1. G1b (DAA only) G1a (DAA + RBV) *8 of 14 patients held RBV

C-SURFER: GZR + EBR in Treatment-naïve and Treatmentexperienced Patients with HCV G1 Infection and CKD n=111 n=113 Randomized GZR 100 mg / EBR 50 mg Placebo Follow-up GZR 100 mg / EBR 50 mg n=11 GZR 100 mg / EBR 50 mg (PK) Follow-up D1 TW4 TW8 TW12 FUW4 FUW8 FUW12 FUW16 Virologic response (ITG) Roth D, et al. Lancet. 2015 [epub ahead of print]. Patients (HCV RNA <LLQ, %) 100 90 80 70 60 50 40 30 20 10 0 66 81/ 122 90 109/ 121 TWk2 TWk4 TWk12 (EOT) 100 100 99 119/ 119 118/ 118 FWk4 115/ 116 FWk12 (SVR12) 1 G1b, non-cirrhotic, patient relapsed at FWk12

Advanced liver disease (decompensated cirrhosis)

Consideration in patients with cirrhosis (CTP A, B or C) Use NS5A inhibitors + SOF (and Ribavirin) Ledipasvir/sofosbuvir ± RBV Daclatasvir + sofosbuvir ± RBV Do not use protease inhibitors Paritaprevir, Grazoprevir, Simeprevir FDA warning for PrOD Serious liver injury risk Since approval, 26 cases reported worldwide to the FDA with most cases 1-4 weeks after starting When treating patients with cirrhosis, monitor for increasing direct bilirubin and clinical signs of hepatic decompensation AASLD/IDSA/IAS USA: Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed October 16, 2015. Viekira Pak (ombitasvir, paritaprevir and ritonavir + dasabuvir) tablets [package insert

Key information needed to decide how to treat a person with chronic HCV infection HCV genotype and, if genotype 1, subtype HCV RNA level (viral load) Testing for resistance associated variants (RAVs) in some patients with genotype 1a Presence of cirrhosis If cirrhosis, Child-Turcotte-Pugh classification A, B or C PT INR, total bilirubin, albumin Kidney function Estimated GFR Hemoglobin Ability to take ribavirin which causes hemolytic anemia (~ 2.5 g/dl decline in hemoglobin) Prior HCV treatment experience Payors may mandate one regimen over others