Learning Objective. After completing this educational activity, participants should be able to:

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2 Learning Objective After completing this educational activity, participants should be able to: Use patient characteristics and preferences to select HCV treatment strategies that maximize the potential of achieving a cure

3 GZR/EBR in Treatment-Naïve and -Experienced Patients With HCV Genotype 1 and CKD n = 111 R n = 113 n = 11 GZR mg / EBR 5 mg Placebo GZR mg / EBR 5 mg (PK) Follow-up *GZR mg / EBR 5 mg Follow-up D1 TW4 TW8 TW12 FUW4 FUW8 FUW12 FUW16 Randomized, parallel-group, multisite, placebo-controlled trial Stratification by diabetes and hemodialysis status 224 patients randomized to immediate treatment with GZR/EBR or deferred treatment with placebo for 12 weeks then open-label GZR/EBR starting at FUW4 11 patients in open-label GZR/EBR arm underwent intensive PK sampling *Deferred open-label treatment arm (all randomized patients remained blinded to treatment until FUW4). GZR and EBR were administered as separate entities in the immediate and PK arms and as a fixed-dose combination in the deferred arm. Roth D, et al. Lancet. 15;386:

4 SVR12: Immediate Treatment Group 99% 94% Patients, % /116 Modified Full Analysis Set 115/122 Full Analysis Set GZR/EBR 12 weeks Relapse 1* 1 Discontinued unrelated to Tx 6 MFAS = primary efficacy analysis; FAS was a secondary analysis. *Noncirrhotic, IFN-intolerant patient with HCV GT 1b infection relapsed at FW12. LTFU, n = 2; n = 1 each for death, noncompliance, withdrawal by subject, and withdrawal by physician (due to violent behavior). Roth D, et al. Lancet. 15;386:

5 RUBY-I: OMV/PTV/RTV + DSV ± RBV in GT 1 Patients With Severe Renal Impairment or ESRD Multicenter, Open-Label, Phase 3b Study: Interim Results Week Week 12 Week 16 Week 24 n = OMV/PTV/RTV + DSV ± RBV SVR12 Once-daily dosing of OMV/PTV/RTV + DSV twice daily + RBV four times daily for GT 1a only Patients OMV/PTV/RTV + DSV ± RBV n = Male, n (%) 17 (85) HCV genotype, n (%) 1a/1b 13 (65)/7 (35) Degree of fibrosis, n (%) F-F1/F2/F3 1 (5)/6 (3)/4 () HCV viral load, log 1 (IU/mL), median (range) 6.6 ( ) Hemoglobin, g/dl, mean (SD) 12.6 (1.8) CKD stage, n (%) 4/5 7 (35)/13 (65) egfr, ml/min/1.73m 2, median (range) 1.9 ( ) Creatinine, mg/dl, median (range) 6.2 ( ) / / 18/ * 18/ * RVR EOTR SVR4 SVR12 Safety AEs more frequent in patients on RBV No treatment-related SAEs No study discontinuations *One death, one relapse. Pockros PJ, et al. EASL 15; Oral LO1; Pockros PJ, et al. AASLD 15; Abstract 139.

6 Long-Term Persistence of NS5A Variants After Treatment With LDV Patients With NS5A RAVs, % % 62/63 VF Parent Study % 58/58 Baseline 98% % 95% 42/43 45/45 52/55 FU-12 FU-24 FU-48 Registry Study 86% 5/58 FU-96 NS5A RAVs in patients who failed LDV treatment without SOF Positions 24, 28, 3, 31, 32, 58, and 93 that confer > 2.5-fold reduced susceptibility to LDV in vitro were included Dvory-Sobol H, et al. J Hepatol. 15;62:S221[Abstract O59].

7 Most NS5A and Non-Nucleoside NS5B Variants Persist Post-Treatment Patients, % GT 1a Patients With Persistent TEVs (%) /43 2/43 3 Targets NS3 + NS5A /43 NS5A + Non-NUC NS5B Post-Treatment Week /43 NS5A 7 3/43 Non-NUC NS5B Patients with TEVs by population sequencing (cut-off %) in nine OMV/PTV/RTV + DSV ± RBV trials In GT 1a patients, NS3 (9%), NS5A (96%), and non-nuc NS5B (57%) TEVs were still detectable to post-treatment week 48 Similar to first-generation PIs, NS3/4A variants resolve over 48 weeks Krishnan P, et al. J Hepatol. 15;62:S2[Abstract O57].

8 SVR12 by Baseline NS5A RAV: 24 Weeks of LDV/SOF After Failing 8 or 12 Weeks of LDV/SOF-Based Therapy SVR12, % /11 11/16 7/14 None 1 2 Number of NS5A RAV(s) 5/5 4/5 2/6 Q3R or M28T* L31M Y93H/N Type of Single NS5A RAV *M28T (n = 1). Lawitz E, et al. J Hepatol. 15;62:S192[Abstract O5].

9 Annual Age-Adjusted Mortality Rates From HBV, HCV, and HIV 7 Rate per, Persons HIV HCV HBV Year Ly KN, et al. Ann Intern Med. 12;156:271-8.

10 TURQUOISE-I: PTV/r + OMV + DSV + RBV (3D + RBV) 3D + RBV 3D + RBV SVR12 SVR12 HCV GT 1 HIV-1 Included HCV treatment-naïve, treatment-experienced, cirrhotic, and noncirrhotic patients 3D: Co-formulated Paritaprevir/ritonavir/ombitasvir (15 mg/ mg/25 mg) + dasabuvir (25 mg) RBV: 1,-1, mg daily, weightbased Patients on atazanavir for HIV were instructed to discontinue their standalone ritonavir during 3D therapy SVR12, % Patients Weeks Phase 2/ Weeks 2 patients in the 24-week group had reinfection, not relapse. Sulkowski MS, et al. JAMA. 15;313:

11 ION-4: SVR12 Rates by Subgroup and Baseline Characteristics for 12 Weeks of LDV/SOF in HIV/HCV Coinfection 96% 96% 95% % 96% 96% 96% % 99% 9% 8 SVR12, % / / / 59 36/ / / 25 74/ 77 8/ 8 215/ / 115 Overall Male Female BL HCV RNA < 8K BL HCV RNA 8K GT 1a All relapsers in the Black cohort had cirrhosis AEs included headache, fatigue, and diarrhea GT 1b GT 4 Non- Black Black Statistically significant in multivariate analysis Naggie S, et al. N Engl J Med. 15;373:75-13.

12 ALLY-2 Study: SVR12 Rates for DCV + SOF in HIV/HCV Coinfection 8-Week Regimen HCV treatment-naïve 12-Week Regimen HCV treatment-naïve HCV treatment-experienced 97% 98% 96% 98% % % % % SVR12, % % 76% 83% 67% Relapse (n = 1) Relapse Relapse (n = 1) (n = 1) Overall (n = 11/52/5) GT 1 (n = 41/83/44) GT 2 (n = 6/11/2) GT 3 (n = 3/6/4) 12-week regimen: no impact of race, baseline HCV RNA, cirrhosis, baseline NS5A RAVs, or ART regimens on SVR12 GT 4 results not shown (n = 3) AEs included nausea, fatigue, and headache Wyles D, et al. N Engl J Med. 15;373:

13 C-EDGE: SVR12 Rates for GZR/EBR in HCV/HIV Coinfection % 93.1% 93.2% % 92.9% 94% SVR12, % 6 4 Overall (n = 218) 1a (n = 144) 1b (n = 44) Genotype 4 (n = 28) SVR12 by ART containing: abacavir (95.7%), tenofovir DF (97.5%), raltegravir (96.4%), dolutegravir (%), rilpivirine (94.6%) AEs included fatigue, headache, and nausea Yes No (n = 35) (n = 183) Baseline Cirrhosis Rockstroh JK, et al. The Lancet HIV. 15;2:e

14 ASTRAL-5: SVR12 Rates for 12 Weeks of SOF/VEL * in HIV/HCV Coinfection SVR12, % relapse 1 LTFU LTFU withdrew consent Total 1a 1b Genotype Error bars represent 95% confidence intervals AEs included fatigue, headache, arthralgia, diarrhea, upper respiratory tract infection, nausea, and insomnia *Investigational. Accessed May 24, 16.

15 What About New Therapies? ASTRAL-4: SOF/VEL Fixed-Dose Combination for HCV in Patients With Decompensated Liver Disease Wk Wk12 Wk24 Wk 36 n = 75 SOF/VEL SVR12 n = 75 SOF/VEL + RBV SVR12 n = 75 SOF/VEL SVR12 Open-label, randomized (1:1:1) US study GT 1-6 treatment-naïve or -experienced patients with CPT B cirrhosis Eligibility criteria: CrCL > 5 ml/min, platelets > 3, x 1 3 /μl; no HCC or liver transplant Weight-based RBV dosing (1, or 1, mg/day) AEs included fatigue, nausea, headache, and anemia Curry MP, et al. N Engl J Med. 15;373:

16 Results: SVR12 in ASTRAL-4 Study SVR12 GT 1 GT 3 GT 2, 4, or 6 Overall SOF/VEL 12 weeks (95% CI, 74-9) SOF/VEL + RBV (95% CI, 87-98) weeks SOF/VEL 24 weeks (95% CI, 77-92) Curry MP, et al. N Engl J Med. 15;373:

17 SOLAR-1: SVR12 Rates in Liver Transplant Patients Receiving LDV/SOF + RBV SVR12, % n/n = 53/ 55 F-F3 55/ 56 25/ 26 24/ 25 F4 CPT A 12 wks LDV/SOF + RBV 24 wks LDV/SOF + RBV In the 24-week arm, 8 patients with CPT B and 1 patient with CPT C have not reached the follow-up week 12 visit MELD scores improved from baseline through follow-up week 4 in 15/48 patients with CPT A and 8/41 patients with CPT B disease Forty instances have been reported of investigators adjusting immunosuppression due to improved hepatic function after viral clearance No relapses have occurred in the 24-week arm with preexisting NS5A variants Most common AEs were infection, vomiting, and diarrhea Charlton M, et al. Gastroenterology. 15. [epub ahead of print].

18 ALLY-1: SOF + DCV + RBV 6 mg Post Liver Transplant SVR12 by HCV GT N = SVR12, % 6 4 5/53 3/31 9/1 Overall 1a 1b Genotype 1/11 1/1 3 6 All 3 relapses with NS5A RAVs by population sequencing AEs included headache, fatigue, anemia, diarrhea, nausea, and arthralgia Poordad F, et al. Hepatology. 16;63:

19 CORAL-1: SVR Rates in GT 1 Liver Transplant Patients Receiving PrOD + RBV for 24 Weeks % 9% 8% 7% 6% 5% 4% 3% % 1% % % 97% 97% 97% EOTR SVR4 SVR12 SVR24 No breakthroughs reported One patient had a relapse (post-treatment day 3) At the time of relapse, this patient had R155K in NS3 protease, M28T + Q3R in NS5A, and G554S in NS5B, none of which were present at baseline Study now includes F3-F4, 12-week duration, no RBV for naïve GT 1b AEs included fatigue, headache, and cough Kwo PY, et al. N Engl J Med. 14;371:

20 HCV-TARGET: Post-Transplant HCV RNA Outcomes for SOF + SMV ± RBV GT 1 Interim Analysis 88% 86% 91% 85% 93% 86% 93% 91% 67% 8 SVR, % /14 Overall 52/6 Tx Experienced Yes No 42/44 51/58 27/28 59/67 35/37 8/1 8/1 GT 1a 1b Cirrhotic Yes No MELD < 1 1 AEs included fatigue, headache, infection, rash, influenza-like illness, nausea/vomiting, and anemia Brown RS, et al. Liver Transpl. 16;22:24-33.

21 Acknowledgment of Commercial Support This activity is supported by educational grants from AbbVie and Gilead Sciences, Inc. Contact Information Call (toll-free) Please visit us online at for additional activities provided by Med-IQ.

22 To receive credit, click the Get Credit tab at the bottom of the Webcast for access to the evaluation, attestation, and post-test. 16 the AGA Institute and Med-IQ. All rights reserved. Unless otherwise indicated, photographed subjects who appear within the content of this activity or on artwork associated with this activity are models; they are not actual patients or doctors.