5/10/2016. Management of Hepatitis C Virus Genotype 1 and 4 Treatment-Naive and Treatment-Experienced Patients. HCV life-cycle and antiviral targets

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1 5/1/216 Management of Hepatitis C Virus Genotype 1 and 4 Treatment-Naive and Treatment-Experienced Patients David L. Wyles, MD Associate Professor of Medicine University of California San Diego La Jolla, California FORMATTED: 4/18/16 Los Angeles, California: April 26, 216 HCV life-cycle and antiviral targets NS5A Inhib NS3 Inhib NS5B Inhib SOF/ LDV SOF DCV IFN-free Treatment Options in 216 SOF SMV EBR/ GZR OBV/ RBV PTV/r DSV SOF RBV Slide 2 of 61 Georgel et al. Trends in Molecular Medicine 16(21) Moradpour D. Nat Rev 27. Slide 3 of 61 Characteristics of Direct Acting Antiviral (DAAs) Simeprevir Drug Class Activity Potency Paritaprevir Resistance Barrier PI GT 1, 4 High Low (1b>1a) Grazoprevir GT 1, 4 & 6 Moderate Daclatasvir Ledipasvir Ombitasvir NS5A GT 1-6 GT 1, 4 & 6 Elbasvir GT 1,4 & 6 High Low (1b>1a) Velpatasvir* GT 1-6 Moderate Sofosbuvir Dasabuvir NS5B Nucleotide NS5B Non-Nuc GT 1-6 GT1 High Intermediate Very High Low *Pending FDA approval 1

2 5/1/216 Case 1 53 WF without significant PMH presents for further evaluation of recently diagnosed HCV. She was referred by her PCP. No significant complaints aside from moderate fatigue. No signs or symptoms of ESLD. SH: remote IDU; rare EtOH PMH: GERD Meds: omeprazole OTC Slide 4 of 61 Case 1 HCV RNA 2.7 million; genotype 1b ALT/AST 39/34 Tbili.7 ALB 3.9 Hgb 13.1 PLT 267 Cr.68 FIB U/S- normal appearing liver. She is interested in therapy. Told by her PCP, HCV treatment may not be warranted given her normal LFTs. Slide 5 of 61 Would you treat this patient for her HCV? 1. No- her PCP is right her LFTs are normal 2. No- I cannot get medication approved 3. Yes- everyone with HCV should be treated 4. Yes- her fatigue is an indication and her LFTs are NOT normal Slide 6 of 61 2

3 5/1/216 If you treat her, what additional testing/information is needed. % 1. NS5A RAV testing 13% 2. Fibrosis staging with transient elastography 5% 3. Specifics on her omeprazole use 38% 4. Nothing, I have all I need to treat her % 5. 1 and 3 % 6. 2 and 3 Slide 7 of 61 Slide 8 of 61 DDIs (DAA vs Other Selected Drugs) Concomitant Medication SOF SIM LDV PTV/RTV/OBV + DSV Acid-reducing agents LDV level PPI level Amiodarone X o X X X o Anticonvulsants (carbamazepine, phenytoin) X X X X X X Digoxin o o o o Ethinyl estradiol containing products Glucocorticoids o X (inhaled as well) PDE5 inhibitors Rifamycin antimicrobials X X Sedatives o X (midazolam)/o St John s wort X X X X X X Statins o X (rosuva) X (simva) o o X = don t do it. o = caution (be aware) X X o X DCV X EBR/GZR X o HCV Target: Impact of PPIs on LDV/SOF? SVR12 by PPI use No: 97.6% ( ) Yes: 93.3% ( ) Slide 9 of 61 Terrault N. #94 AASLD

4 5/1/216 LDV and acid-reducing agents Decreased solubility with increasing ph Separate administration with antacids by 4 hours H2-receptor antagonists to be administered simultaneously with or 12 hours apart Do not exceed comparable dose of famotidine 4mg twice daily Administer PPIs simultaneously Do not exceed comparable dose of omeprazole 2mg daily Slide 1 of 61 LDV and acid reducing agents PPI dosing equivalents Omeprazole 2mg Esomeprazole 2mg Pantoprazole 4mg Lansoprazole 3mg Rabeprazole 2mg H2 Receptor Antagonist Famotidine 4mg Ranitidine 3mg Cimetidine 8mg Slide 11 of 61 Global RPh Case continued She is taking omeprazole 2mg PO BID Transient elastography: 7.8kPa (IQR-.7/8.9%) You also remember to send serologies: HIV Ab HAV total Hep B core+, sab+ (567) Based on her elastography you feel you can get medications covered. Slide 12 of 61 4

5 5/1/216 What would you treat her with? 45% 1. LDV/SOF 8 weeks 41% 2. LDV/SOF 12 weeks 1% 3. EBR/GZR 12 weeks 3% 4. EBR/GZR 16 weeks + RBV % 5. PTV/r/OBV+DSV 12 weeks % 6. PTV/r/OBV+DSV 12 weeks + RBV Slide 13 of 61 If you picked 1 or 2 What would you do with her PPI 3% 63% 33% 1. Dose adjust? 2. Discontinue? 3. Nothing? Slide 14 of 61 Sofosbuvir/Ledipasvir: FDA-Approved Indication Population (Genotype 1) Recommended Treatment Duration Pivotal Trials Naïve with or without cirrhosis 12 wks* ION-1 12wk arm SVR in non-cirrhotic = 99% 12wk arm SVR in cirrhotic = 97% Experienced without cirrhosis 12 wks ION-2 12wk arm SVR = 94% Experienced with cirrhosis 12wks+RBV or 24 wks ION-2/SIRIUS 12wk arm SVR = 86% *8-wk duration can be considered in treatment-naive pts without cirrhosis who have pretreatment HCV RNA < 6 million IU/mL. Treatment-experienced pts who have failed treatment with pegifn/rbv ± HCV PI. Sofosbuvir/ledipasvir [package insert]. February 216. Slide 15 of 61 5

6 SVR12 (%) SVR12 (%) 5/1/216 8 vs. 12 weeks for naïve GT1: ION-3 and Target N=216 N=215 N=216 SOF/LDV SOF/LDV SOF/LDV/r ION Weeks Cirrhosis excluded Relapses 4-5% in 8 week arms 2/23 in 8 week arms 1% in 12 week arm wk 8wk 8wk+ R Slide 16 of 61 Kowdley K. NEJM 214. Terrault N. #94 AASLD 215. Post-hoc analysis of 8 vs. 12 weeks weeks 12 weeks Slide 17 of 61 Sulkowski M. IDSA 214. Paritaprevir/r/ombitasvir + dasabuvir FDA-Approved Indication Population Treatment Duration Pivotal Trials GT1a, without cirrhosis PrOD + RBV 12 wks SAPPHIRE I = SVR 95% Paritaprevir/r/ombitasvir + dasabuvir [package insert]. SAPPHIRE II = SVR 96% PEARL-IV = SVR 9% (wo RBV)/97% (RBV) GT1a, with cirrhosis 3DAA + RBV 24 wks TURQUOISE-II 12-wk arm = SVR 89% 24-wk arm = SVR 95% (Difference driven by null responders) GT1b w/wo cirrhosis PrOD 12 wks PEARL-II (TE) = SVR % PEARL-III (TN) = SVR 99% Slide 18 of 61 6

7 TN, non-cirrhotic 5/1/216 The role of RBV with the PrOD regimen. Slide 19 of 61 Ferenci P. NEJM 214. Grazoprevir/elbasvir FDA-Approved Indication - GT1 Population Treatment Duration Pivotal Trials GT1a GZR/EBR 12 wks C-EDGE TN (N = 421) TN or PR-TE Without NS5A RAVs GT1a = 92% SVR; GT1a GZR/EBR + RBV 16 wks GT1b = 99% SVR TN or PR-TE With NS5A RAVs (HCV VL > 8,; BL NS5A RAVs) C-SURFER GT1b GZR/EBR 12 wks [N = 122; stage 4/5 CKD (76% on HD)] SVR 94% TN or PR-TE GT1a or 1b GZR/EBR + RBV 12 wks C-SALVAGE (N = 79) PR/PI - TE 43% cirrhotic SVR 96% overall Grazoprevir/elbasvir [package insert]. Slide 2 of 61 GZR/EBR in Treatment Naive N=316 GZR/EBR SVR12 N=15 Placebo 4 wks GZR/EBR SVR12 Cirrhosis and noncirrhotic GT 1, 4, and 6 GZR/EBR Pbo Male 54% 53% 1a 5% 51% 1b 42% 38% 4 6% 8% 6 3% 3% Slide 21 of 61 Cirrhosis 22% 21% Zeuzem S. #G7 EASL

8 5/1/216 GZR/EBR in Treatment Naïve: Efficacy All 1a 1b 4 6 1/13 virologic failures in GT1a 246 No cirrhosis 7 Cirrhosis Slide 22 of 61 Zeuzem S. #G7 EASL 215. Sofosbuvir + simeprevir FDA-Approved Indications Population (GT-1) Treatment Duration Pivotal Trial TN and TE* without cirrhosis SOF + SMV 12 wks OPTIMIST-1 8wk arm SVR = 83% 12wk arm SVR = 97% TN and TE* with cirrhosis SOF + SMV 24 wks OPTIMIST-2** 12wk arm SVR = 83% (74% in 1a with Q8K) * Treatment-experienced: relapsers, partial responders and null responders to INF-based therapy ** Consider screening for Q8K polymorphism at baseline in GT-1a cirrhosis Simeprevir [package insert]. Revised Feb 216. Slide 23 of 61 Change case- what would you choose if she were treatment experienced with cirrhosis? 1% 1. LDV/SOF 12 weeks 4% 2. LDV/SOF 12 weeks + RBV 27% 3. EBR/GZR 12 weeks 13% 4. EBR/GZR 16 weeks + RBV 3% 5. PTV/r/OBV+DSV 12 weeks 7% 6. PTV/r/OBV+DSV 12 weeks + RBV Slide 24 of 61 8

9 SVR12 (%) 5/1/216 Sofosbuvir/Ledipasvir: FDA-Approved Indication Population (Genotype 1) Recommended Treatment Duration Pivotal Trials Naïve with or without cirrhosis 12 wks* ION-1 12wk arm SVR in non-cirrhotic = 99% 12wk arm SVR in cirrhotic = 97% Experienced without cirrhosis 12 wks ION-2 12wk arm SVR = 94% Experienced with cirrhosis 12wks+RBV or 24 wks ION-2/SIRIUS 12wk arm SVR = 86% *8-wk duration can be considered in treatment-naive pts without cirrhosis who have pretreatment HCV RNA < 6 million IU/mL. Treatment-experienced pts who have failed treatment with pegifn/rbv ± HCV PI. Sofosbuvir/ledipasvir [package insert]. February 216. Slide 25 of 61 N=19 N=111 N=19 N=111 Nucleotide plus NS5A for treatment experienced GT1: ION-2 Weeks SOF/LDV SOF/LDV+R SOF/LDV SOF/LDV+R ION-2 Treatment experienced 52% HCV PI failures 44% null responder 2% cirrhosis All relapses were in 12 week arms (11; 2%) 82-86% SVR in cirrhotics wk 12wk + R 24wk 24wk + R Slide 26 of 61 Afdahl N. NEJM 214. What is the role of duration and ribavirin in TE cirrhotic patients? N=77 N=78 placebo SOF/LDV + placebo RBV SOF/LDV + RBV Weeks SVR12 Double-blind study Treatment experienced cirrhotic patients All failed both Peg/RBV then P/R/PI Groups were well matched Plt <k: 18% vs 17% ALB <3.5: 8% vs. 17% Slide 27 of 61 Bourliere M. Lancet ID

10 SVR12 (%) 5/1/216 SOF/LDV ± RBV: 12 vs 24 wks in treatment experienced cirrhosis /77 75/77 SOF/LDV + RBV SOF/LDV 1 pt discontinued due to AE (placebo phase) All VF were relapses 4% 12wks; 3% 24wks Adverse events similar between arms 1 (1%) with Hgb <8.5g/dL in RBV arm Slide 28 of 61 Bourliere M. Lancet ID 215. Paritaprevir/r/ombitasvir + dasabuvir FDA-Approved Indication Population Treatment Duration Pivotal Trials GT1a, without cirrhosis 3DAA + RBV 12 wks SAPPHIRE I = SVR 95% SAPPHIRE II = SVR 96% PEARL-IV = SVR 9% (wo RBV)/97% (RBV) GT1a, with cirrhosis 3DAA + RBV 24 wks TURQUOISE-II 12-wk arm = SVR 89% 24-wk arm = SVR 95% (Difference driven by null responders) GT1b w/wo cirrhosis PrOD 12 wks PEARL-II (TE) = SVR % PEARL-III (TN) = SVR 99% TURQUOISE III: % SVR12 (6/6) in GT1b, CPTA cirrhosis with 12 weeks no RBV Slide 29 of 61 Paritaprevir/r/ombitasvir + dasabuvir [package insert]. Feld JJ. J Hepatol 215. Grazoprevir/elbasvir FDA-Approved Indication - GT1 Population Treatment Duration Pivotal Trials GT1a GZR/EBR 12 wks C-EDGE TN (N = 421) TN or PR-TE Without NS5A RAVs GT1a = 92% SVR; GT1a GZR/EBR + RBV 16 wks GT1b = 99% SVR TN or PR-TE With NS5A RAVs (HCV VL > 8,; BL NS5A RAVs) C-SURFER GT1b GZR/EBR 12 wks [N = 122; stage 4/5 CKD (76% on HD)] SVR 94% TN or PR-TE GT1a or 1b GZR/EBR + RBV 12 wks C-SALVAGE (N = 79) PR/PI - TE 43% cirrhotic SVR 96% overall Grazoprevir/elbasvir [package insert]. Slide 3 of 61 1

11 5/1/216 GZR/EBR in Treatment Experienced N=15 N=14 N=15 N=16 GZR/EBR GZR/EBR + RBV GZR/EBR GZR/EBR + RBV SVR12 SVR12 GT 1, 4, or 6 Prior interferon plus RBV failures HIV co-infection allowed (4-6%) Slide 31 of 61 12wk 12 + RBV 16wk 16 + RBV Male 63% 69% 66% 6% 1a 58% 58% 46% 55% Non-1a 33% 28% 46% 36% Cirrhosis 35% 34% 36% 35% Null/Partial 67% 63% 64% 63% Kwo P. #P886 EASL 215. GZR/EBR in Treatment Experienced: Efficacy Overall Partial/Null Responders Virologic failures R R R R Null 92% (12) 67% (6) 88% (8) % (1) Cirrhosis Slide 32 of 61 Kwo P. #P886 EASL 215. Only 12 weeks of EBR/GZR for GT1b SVR12 % (34/34) TE GT1b patients with 12 weeks of therapy. Treatment experienced Slide 33 of 61 Kwo P. #P886 EASL 215.Zeuzem S. #7. AASLD

12 5/1/216 Sofosbuvir + simeprevir FDA-Approved Indications Population (GT-1) Treatment Duration Pivotal Trial TN and TE* without cirrhosis SOF + SMV 12 wks OPTIMIST-1 8wk arm SVR = 83% 12wk arm SVR = 97% TN and TE* with cirrhosis SOF + SMV 24 wks OPTIMIST-2** 12wk arm SVR = 83% (74% in 1a with Q8K) * Treatment-experienced: relapsers, partial responders and null responders to INF-based therapy ** Consider screening for Q8K polymorphism at baseline in GT-1a cirrhosis Simeprevir [package insert]. Revised Feb 216. Slide 34 of 61 Case 2 59 Hispanic male, type II DM, HTN and chronic HCV GT1a infection. He was treated in 29 (PEG/RBV) for his HCV with a null response. A biopsy prior to therapy in 211 showed stage 5/6 cirrhosis. No history of hepatic decompensation. History of heavy EtOH- significantly decreased since 29. Current labs: HCV RNA 6.2 million ALT/AST 62/79 ALB 3.7 TBili.9 INR 1.1 PLT 127 Hgb 13.9 Cr 1.12 Slide 35 of 61 What additional testing is needed in a cirrhotic patient? % 1. HCC screening with AFP 1% 2. HCC screening with imaging (e.g. US) 6% 3. Transient elastography to confirm cirrhosis % 4. EGD to evaluate for varices 13% 5. 1,2, and 4 71% 6. 2 and 4 Slide 36 of 61 12

13 5/1/216 Which regimen would you use? 4% 1. PrOD for 24 weeks 4% 2. PrOD + RBV for 24 weeks 31% 3. LDV/SOF + RBV for 12 weeks 23% 4. LDV/SOF + RBV for 24 weeks 4% 5. SMV/SOF + RBV for 12 weeks 4% 6. EBR/GZR + RBV for 16 weeks 31% 7. I would do NS5A resistance testing before deciding Slide 37 of 61 Available Resistance Testing (US) Ultra-deep (or NGS) vs population (Sanger) What is available: 1. LabCorp/Monogram Biosciences NGS with 1% detection level reported 2. Quest Diagnostics RT-PCR with DNA sequencing Both assays now available for GT1 (1a and 1b) and GT3 Slide 38 of Examples: NS5A resistance genotyping Slide 39 of 61 13

14 5/1/216 Examples: NS5A resistance genotyping Slide 4 of 61 Comments: NS5A RAVs at positions(s) 28, 3, 31 or 93 DETECTED. If considering an NS5A inhibitor-containing regimen, please refer to the prescribing information or current guidelines, to determine the appropriate treatment regimen and duration. Broad cross-resistance with early generation NS5As Fold-change 1a 1b M28T Q3R L31M/V Y93H/N L31V Y93H/N >x/ >1,x/ LDV 2x >x >x >1, <3x >1,x/ Ombitasvir >x >x >x >1,x >x/ >1,x/ DCV >x >x >x >1,x >1x >1,x/ Elbasvir 2x >x >x >1,x >x/ Velpatasvir <1x <3x 2x/5x >x >x/-- <1x 2x/5x <1x 2x/5x <1x >x/-- <3x/-- ACH-312 3x 2x <1x >x/>x <3x/<3x ABT-53 <3x <3x <3x <1x/<1x <3x <3x/<3x MK-848 <1x <1x <1x <1x <1x <1x Slide 41 of 61 Wang C. AAC 212. Cheng G. #1172. EASL 212. Zhao Y. #A845 EASL 212. Yang G. EASL 213. Ng T. #639 CROI 214. Asante-Appiah E. AASLD 214. You decide to do resistance testing- NS3: no RAVs NS5A: L31M (possible resistance to EBR, LDV, DCV) Slide 42 of 61 14

15 5/1/216 Which regimen would you use? 17% 1. PrOD + RBV for 24 weeks 11% 2. LDV/SOF + RBV for 12 weeks 6% 3. LDV/SOF for 24 weeks 17% 4. LDV/SOF + RBV for 24 weeks 6% 5. SMV/SOF for 24 weeks 39% 6. EBR/GZR + RBV for 16 weeks 6% 7. EBR/GZR + RBV for 12 weeks Slide 43 of 61 Grazoprevir/elbasvir FDA-Approved Indication - GT1 Population Treatment Duration Pivotal Trials GT1a GZR/EBR 12 wks C-EDGE TN (N = 421) TN or PR-TE Without NS5A RAVs GT1a = 92% SVR; GT1a GZR/EBR + RBV 16 wks GT1b = 99% SVR TN or PR-TE With NS5A RAVs (HCV VL > 8,; BL NS5A RAVs) C-SURFER GT1b GZR/EBR 12 wks [N = 122; stage 4/5 CKD (76% on HD)] SVR 94% TN or PR-TE GT1a or 1b GZR/EBR + RBV 12 wks C-SALVAGE (N = 79) PR/PI - TE 43% cirrhotic SVR 96% overall Grazoprevir/elbasvir [package insert]. Slide 44 of 61 Impact of NS5A RAVs in GT1a with EBR/GZR Key EBR RAVs (GT1a): M28A/G/T, Q3D/E/H/G/K/L/R, L31F/M/V, Y93C/H/N/S Slide 45 of 61 Jacobson I. #LB-22 AASLD

16 SVR12 (%) 5/1/216 GZP/EBR in GT1a: Resistance is key predictor eor (95% CI) p value GT 1a TN-PEP Slide 46 of 61 Zeuzem S. #7 AASLD 215. EBR/GZR in Treatment Experienced N=15 N=14 N=15 N=16 EBR/GZR EBR/GZR + RBV EBR/GZR EBR/GZR + RBV SVR12 SVR12 GT 1, 4, or 6 Prior interferon plus RBV failures HIV co-infection allowed (4-6%) 12wk 12 + RBV 16wk 16 + RBV Male 63% 69% 66% 6% 1a 58% 58% 46% 55% Non-1a 33% 28% 46% 36% Cirrhosis 35% 34% 36% 35% Slide 47 of 61 Null/Partial 67% 63% 64% 63% Kwo P. #P886 EASL 215. EBR/GZR in Treatment Experienced: Efficacy Overall Partial/Null Responders R R Virologic failures R R Null Cirrhosis 92% (12) 67% (6) 88% (8) % (1) Slide 48 of 61 Kwo P. #P886 EASL

17 SVR12 (%) 5/1/216 Sofosbuvir/Ledipasvir: FDA-Approved Indication Population (Genotype 1) Recommended Treatment Duration Pivotal Trials Naïve with or without cirrhosis 12 wks* ION-1 12wk arm SVR in non-cirrhotic = 99% 12wk arm SVR in cirrhotic = 97% Experienced without cirrhosis 12 wks ION-2 12wk arm SVR = 94% Experienced with cirrhosis 12wks+RBV or 24 wks ION-2/SIRIUS 12wk arm SVR = 86% *8-wk duration can be considered in treatment-naive pts without cirrhosis who have pretreatment HCV RNA < 6 million IU/mL. Treatment-experienced pts who have failed treatment with pegifn/rbv ± HCV PI. Sofosbuvir/ledipasvir [package insert]. February 216. Slide 49 of 61 Integrated analysis of responses in cirrhotic patients Slide 5 of 61 Reddy R. Hepatology 215. Impact of baseline NS5A RAVs with SOF/LDV SVR12 to guideline recommended regimens of LDV/SOF by LDV RAV* status TN NC: 12wks TN Cirr: 12wks TE NC: 12wks TE Cirr: 12wks + R TE Cirr: 24wks Slide 51 of 61 RAVs No RAVs RAVs No RAVs % SVR12 (14/14) in cirrhotic patients treated with 24wks LDV/SOF + RBV (TN&TE; 1a&1b) *LDV RAVs at 24, 28, 3, 31, 32, 58, and cutoff Zeuzem S. #91 AASLD 215. Sarrazin C. #P773. EASL

18 SVR12 (%) 5/1/216 Paritaprevir/r/ombitasvir + dasabuvir FDA-Approved Indication Population Treatment Duration Pivotal Trials GT1a, without cirrhosis PrOD + RBV 12 wks SAPPHIRE I = SVR 95% SAPPHIRE II = SVR 96% PEARL-IV = SVR 9% (wo RBV)/97% (RBV) GT1a, with cirrhosis PrOD + RBV 24 wks TURQUOISE-II 12-wk arm = SVR 89% 24-wk arm = SVR 95% (Difference driven by null responders) GT1b w/wo cirrhosis PrOD 12 wks PEARL-II (TE) = SVR % PEARL-III (TN) = SVR 99% No impact of baseline RAVs in GT1a when RBV used. Slide 52 of 61 Paritaprevir/r/ombitasvir + dasabuvir [package insert]. Sulkowski M. #539LB CROI 216 N=28 N=172 Boosted PI regimen in cirrhotic subjects: TURQUOISE-II PTV/r/OBV + DSV + R PTV/r/OBV + DSV + R SVR12 SVR12 Slide 53 of 61 Weeks Compensated cirrhosis Child-Pugh A < Plt 6, 6 Albumin Relapse was significantly more likely in 12 week group All 1a 1b 1a Null 5.9% vs..6% Genotype 1a (OR:.1) and prior null response (OR:.33) associated with lack of SVR12 Poordad F. NEJM Sofosbuvir + simeprevir FDA-Approved Indications Population (GT-1) Treatment Duration Pivotal Trial TN and TE* without cirrhosis SOF + SMV 12 wks OPTIMIST-1 8wk arm SVR = 83% 12wk arm SVR = 97% TN and TE* with cirrhosis SOF + SMV 24 wks OPTIMIST-2** 12wk arm SVR = 83% (74% in 1a with Q8K) * Treatment-experienced: relapsers, partial responders and null responders to INF-based therapy ** Consider screening for Q8K polymorphism at baseline in GT-1a cirrhosis Simeprevir [package insert]. Revised Feb 216. Slide 54 of 61 18

19 5/1/216 Would you use something different if no NS5A RAVs? 14% 1. PrOD for 24 weeks % 2. PrOD + RBV for 24 weeks 48% 3. LDV/SOF + RBV for 12 weeks 5% 4. LDV/SOF for 24 weeks % 5. SMV/SOF for 24 weeks 14% 6. EBR/GZR + RBV for 16 weeks 19% 7. EBR/GZR for 12 weeks Slide 55 of 61 HCV GT4 Slide 56 of 61 Case 7 4 y.o. Egyptian M with HCV G4 and no other significant medical problems. HCV hx: uncertain risk factors. No h/o IVD or IN cocaine. No MSM. Multiple childhood surgeries for leg fracture but uncertain if blood transfusions. Clinical status: No evidence of cirrhosis by Fibrosure, imaging, PE or labs. HCV RNA 4.1 million IU/ml Prior HCV Rx with PegIFN+RBV x 48 wks relapse. Slide 57 of 61 19

20 5/1/216 Which regimen has poor efficacy for G4 treatment and would NOT be recommended? 16% 1. Ledipasvir/sofosbuvir x 12w 26% 2. Sofosbuvir + ribavirin x 12w 5% 3. Sofosbuvir + ribavirin x 24w 42% 4. Peginterferon + ribavirin + sofosbuvir x 12 w 11% 5. Paritaprevir/ritonavir/ombitasvir + ribavirin x 12w Slide 58 of 61 Optimism for Patients with GT4 HCV Journal of Hepatology, Volume 62, Issue 5, 215, Slide 59 of 61 Integrated analysis of EBR/GZR for GT4 Slide 6 of 61 Asselah T. #251 AASLD 215 2

21 5/1/216 GT-4 AASLD/IDSA Endorsed Regimens Population SOF/RBV PR/SOF SOF/LDV PrOD GZR/EBR TN wo cirrhosis 12 wks 12 wks 12 wks + RBV 12 wks TN w cirrhosis 12 wks 12 wks 12 wks + RBV 12 wks TE wo cirrhosis 12 wks 12 wks 12 wks + RBV PR-relapsers 12 wks PR-null 16w + RBV TE w cirrhosis 24 wks 12 wks 12w + RBV Or 24w 12 wks + RBV PR-relapsers 12 wks PR-null 16w + RBV AASLD/IDSA Guidance Feb 216 Slide 61 of 61 21