9/21/2016. Hepatitis C Virus Treatment in Difficult-to-Treat Patient Populations: A Honey Badger s Guide. Michael R.

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1 Hepatitis C Virus Treatment in Difficult-to-Treat Patient Populations: A Honey Badger s Guide Michael R. Charlton, MBBS Director of Hepatology and Liver Transplantation Intermountain Medical Center Salt Lake City, Utah Chicago, Illinois: September 16, 2016 Slide 2 of 67 Slide 3 of 67 1

2 Slide 4 of 67 Treating HCV in Advanced Liver Disease F0 F1 F2 F3 F4 CTP A F4 CTP B F4 CTP C HCC Therapy has been targeted to those at greatest need: Advanced disease (F3/F4) Severe extrahepatic manifestations/fatigue Adapted from Asselah T, et al. J Hepatol 2014;61:193 5 CTP: Child Turcotte Pugh; F: fibrosis stage; GT: genotype; HCC: hepatocellular carcinoma Slide 5 of 67 Treating HCV in Advanced Liver Disease F0 F1 F2 F3 F4 CTP A F4 CTP B F4 CTP C HCC Previous therapy has been targeted to those at greatest need: Advanced disease (F3/F4) Severe extrahepatic manifestations/fatigue Most challenging Adapted from Asselah T, et al. J Hepatol 2014;61:193 5; Reddy KR, et al. Hepatology 2015 doi: /hep.27826; Bourlière M, et al. Lancet Infect Dis 2015;15: ; Flamm S, et al. AASLD 2014; Oral #239; Reddy KR, et al. AASLD 2014; Oral #8 Slide 6 of 67 Case 67 yr old man, HCV cirrhosis, GT 1a Listed for liver transplant MELD 19 h/o EV bleed, ascites CPT 11 Treatment inexperienced Wants to be treated 2

3 Slide 7 of 67 What is a recommended regimen: 0% 1. simeprevir + daclatasvir for 12 weeks 25% 2. sofosbuvir + daclatasvir for 24 weeks 38% 3. sofosbuvir + velpatasvir for 12 weeks 38% 4. sofosbuvir + velpatasvir + RBV for 12 weeks 0% 5. grazoprevir + elbasvir + RBV for 12 weeks What is a recommended regimen: Slide 8 of simeprevir + daclatasvir for 12 weeks 2. sofosbuvir + daclatasvir for 24 weeks 3. sofosbuvir + velpatasvir for 12 weeks 4. sofosbuvir + velpatasvir + RBV for 12 weeks 5. grazoprevir + elbasvir + RBV for 12 weeks Antiviral therapy in decompensated cirrhosis - Pharmacokinetics DAA Class Name AUC 24 (cf. healthy volunteers) CTP A CTP B CTP C NS3 PI NS5AI Simeprevir 2 4X 18X Paritaprevir Grazoprevir Daclatasvir Ledipasvir Velpatasvir Ombitasvir Elbasvir NA Non-NUC NS5B Dasabuvir NUC NS5B I Sofosbuvir Lawtitz E, et al. EASL Ouwerkerk-Mahadevan S, et al. 8 th Int Workshop Clinical Pharm Hep Therapy, Khatri A, et al. AASLD 2012; 4 Yeh W, et al. EASL Bifano M, et al. AASLD 2011; 6 German P, et al. AASLD 2013 Slide 9 of 67 7 Marshall W, et al. 15 th Int Workshop Clinical Pharm Hep Therapy,

4 Slide 10 of 67 Antiviral therapy in decompensated cirrhosis - Pharmacokinetics DAA Class Name AUC 24 (cf. healthy volunteers) CTP A CTP B CTP C NS3 PI NS5AI Simeprevir 2 4X 18X Paritaprevir Grazoprevir Daclatasvir Ledipasvir Velpatasvir Ombitasvir Elbasvir NA Non-NUC NS5B Dasabuvir NUC NS5B I Sofosbuvir Lawtitz E, et al. EASL Ouwerkerk-Mahadevan S, et al. 8 th Int Workshop Clinical Pharm Hep Therapy, Khatri A, et al. AASLD 2012; 4 Yeh W, et al. EASL Bifano M, et al. AASLD 2011; 6 German P, et al. AASLD Marshall W, et al. 15 th Int Workshop Clinical Pharm Hep Therapy, Antiviral therapy in decompensated cirrhosis - Pharmacokinetics DAA Class Name AUC 24 (cf. healthy volunteers) CTP A CTP B CTP C NS3 PI NS5AI Simeprevir 2 4X 18X Paritaprevir Grazoprevir Daclatasvir Ledipasvir Velpatasvir Ombitasvir Elbasvir NA Non-NUC NS5B Dasabuvir NUC NS5B I Sofosbuvir Lawtitz E, et al. EASL Ouwerkerk-Mahadevan S, et al. 8 th Int Workshop Clinical Pharm Hep Therapy, Khatri A, et al. AASLD 2012; 4 Yeh W, et al. EASL Bifano M, et al. AASLD 2011; 6 German P, et al. AASLD Marshall W, et al. 15 th Int Workshop Clinical Pharm Hep Therapy, 2014 Slide 11 of Slide 12 of 67 Sofosbuvir/Velpatasvir Fixed-Dose Combination for the Treatment of HCV in Patients With Decompensated Liver Disease: the Phase 3 ASTRAL-4 Study M.P. Curry, 1 J.G. O'Leary, 2 N.H. Bzowej, 3 A.J. Muir, 4 K.M. Korenblat, 5 J.M. Fenkel, 6 K.R. Reddy, 7 E. Lawitz, 8 T.D. Schiano, 9 L.W. Teperman, 10 R.J. Fontana, 11 E.R. Schiff, 12 M.W. Fried, 13 B. Doehle, 14 D. An, 14 J. McNally, 14 A. Osinusi, 14 M. Natha, 14 D.M. Brainard, 14 J.G. McHutchison, 14 R.S. Brown, 15 M.R. Charlton 16 1 Intermountain Medical Center, Murray, UT; 2 Baylor Research Institute, Dallas, TX; 3 Ochsner Medical Center, New Orleans, LA; 4 Duke University, Durham, NC; 5 Washington University School of Medicine in Saint Louis, MO; 6 Thomas Jefferson University, Philadelphia, PA; 7 University of Pennsylvania School of Medicine, Philadelphia, PA; 8 Texas Liver Institute, San Antonio, TX; 9 Mount Sinai Hospital, New York, NY; 10 NYU School of Medicine, New York, NY; 11 University of Michigan, Ann Arbor, MI; 12 University of Miami, Coral Gables, FL; 13 University of North Carolina at Chapel Hill School of Medicine; 14 Gilead Sciences, Inc., Foster City, CA; 15 Columbia University Medical Center, New York-Presbyterian, New York, NY; 16 Beth Israel Deaconess Medical Center, Boston, MA N Engl J Med ; 373:

5 Slide 13 of 67 Study Design Wk 0 Wk 12 Wk 24 Wk 36 n=75 SOF/VEL SVR12 n=75 SOF/VEL + RBV SVR12 n=75 SOF/VEL SVR12 SVR12, sustained virologic response 12 weeks after treatment end. Open-label, randomized (1:1:1) US study (NCT ) HCV GT 1 6 treatment-naïve or -experienced patients with Child-Pugh-Turcotte (CPT) B cirrhosis Key eligibility criteria: creatinine clearance (CL cr ) >50 ml/min, platelets >30,000/mm 3 ; no hepatocellular carcinoma or liver transplant 13 Slide 14 of 67 ASTRAL-4: Baseline Liver Disease Characteristics Patients SOF/VEL 12 wk n=90 SOF/VEL+RBV 12 wk n=87 SOF/VEL 24 wk n=90 Ascites, n (%) 74 (82) 65 (75) 75 (83) Encephalopathy, n (%) 52 (58) 54 (62) 59 (66) Median total bilirubin, mg/dl (range) 1.3 ( ) 1.5 ( ) 1.6 ( ) Median albumin, g/dl (range) 3.2 ( ) 3.1 ( ) 3.1 ( ) Median INR (range) 1.2 ( ) 1.2 ( ) 1.2 ( ) INR, international normalized ratio. N Engl J Med 2015; 373: Slide 15 of 67 Overall SVR12 75/90 82/87 77/90 SOF/VEL 12 week SOF/VEL+ RBV 12 week SOF/VEL 24 week P-value < for comparison of SVR12 rate to 1% for each treatment group Error bars represent 95% confidence intervals. N Engl J Med 2015; 373:

6 Patients (%) 9/21/2016 Slide 16 of 67 SVR12 in GT 3 Patients Error bars represent 95% confidence intervals. 7/14 SOF/VEL 12 week 11/13 6/12 SOF/VEL+ RBV 12 week N Engl J Med 2015; 373: SOF/VEL 24 week 16 Slide 17 of 67 MELD Change: Baseline to Follow-up Week 12 Patients With SVR % Improved 8% Worsened 40 Baseline MELD > Change in MELD No follow-up Week 12 assessment for 5 patients. N Engl J Med 2015; 373: SOLAR 1 and 2 Studies LDV/SOF before and after liver transplantation Slide 18 of 67 Study Design Combined Analysis of 667 Patients From SOLAR-1 4 (North America) and SOLAR-2 (Europe and Oceania) Trials* (n=212) (n=455) *NCT and NCT , respectively. FCH, fibrosing cholestatic hepatitis. Gane E, et al. APASL Charlton M, et al. Gastroenterology 2015;149:

7 SVR12 (%) 9/21/2016 SOLAR 1 and 2 Studies SVR12 Pre Transplant Slide 19 of 67 LDV/SOF+RBV 12 Weeks 24 Weeks 7 relapses 2 relapses 1 death 2 deaths 3 relapses 3 relapses 3 deaths 5 deaths 1 LTFU 1 w/d CPT B CPT C 48/56 48/52 36/43 39/48 Overall: GT1: 45/52 46/50 35/40 38/46 GT4: 3/4 2/2 1/3 1/2 Analysis excluded 13 patients transplanted prior to posttreatment Week (FU) 12 with HCV RNA <LLOQ at last measurement prior to transplant, and 3 pretransplant patients who were CPT A at baseline. Error bars represent 95% confidence intervals (CIs). Gane E, et al. APASL 2016 SOLAR 1 and 2 Studies ΔCPT Score from Baseline to FU-24 in CPT B/C Slide 20 of 67 CPT B patients: CPT Class improved in 40% (72/180) CPT C patients: CPT Class improved in 76% (51/67) 64% CPT B; 12% CPT A Gane E, et al. APASL 2016 SOLAR 1 and 2 Studies Safety and Tolerability Slide 21 of 67 Patients, n (%) PRE-TRANSPLANT CPT B + CPT C n=215 POST-TRANSPLANT F0-F3 + CPT A n=330 CPT B + CPT C n=114 Any AE 208 (97) 316 (96) 109 (96) Grade 3 or 4 AE 51 (24) 76 (23) 33 (29) SAEs 61 (28) 49 (15) 34 (30) Serious treatment-related AE 5 (2) 10 (3) 4 (4) AE discontinuation of LDV/SOF 9 (4) 4 (1) 6 (5) Death 10 (5) 4 (1) 6 (5) Rejection episodes Graft loss Liver Transplantation No deaths were attributed to study treatment Treatment related serious adverse events were mostly related to RBV treatment 7 transplantations occurred during treatment period and 4 transplants occurred within 30 days post treatment Samuel D, et al. EASL

8 Serum Creatinine (mmol/l) /21/2016 SOLAR 1 and 2 Studies Δ Renal Function during Treatment Slide 22 of 67 Pre-Transplant CPT B + C Post-Transplant F0-F3 + CPT A CPT B + C BL Samuel D, et al. EASL 2015 Slide 23 of 67 Hepa-C Registry: Treating HCV in Advanced Liver Disease Retrospective, observational analysis of pts with cirrhosis who were not LT candidates or who were listed for LT but did not receive LT during or for 12 wks after HCV treatment CP A (n = 564; 7% with HCC) CP B/C (n = 175; 10% with HCC) Pts treated for 12 or 24 wks with IFN-free regimens, with or without RBV: SMV + SOF (45%) DCV + SOF (22%) LDV/SOF (16%) OBV/PTV/RTV + DSV (10%) Fernández-Carrillo C, et al. EASL Abstract GS01. Slide 24 of 67 Hepa-C Registry: SVR, Safety, and Deaths With HCV Tx in Advanced Liver Disease SVR12 rate lower for CP B/C vs CP A (78% vs 94%; P <.001) SAE incidence higher for CP B/C vs CP A (50% vs 11.7%; P <.001) Death rate higher for CP B/C vs CP A (6.4 % vs 0.9%; P <.001) Predictor CP A vs B/C MELD MELD 18 Platelets Platelets < 100,000 OR (95% CI) SAE 2.16 ( ) 1.31 ( ) Multiv. P Value.004 <.001 Death (On Study) OR (95% CI) 1.73 ( ) 1.34 ( ) Multiv. P Value.034 <.001 NR.171 NR < ( ) 2.94 ( ) ( ).151 <.001 NR.711 Fernández-Carrillo C, et al. EASL Abstract GS01. Reproduced with permission. Kaplan-Meier Survival Estimates 99% 99% 97% 92% 78% 68% Time (days) MELD < 18 MELD 18 P <

9 Slide 25 of 67 Slide 26 of 67 Expert Guidance for HCV Treatment in Pts With Decompensated Cirrhosis AASLD/IDSA Refer to experienced HCV provider (ideally LT center) Avoid IFN, TVR, BOC, SMV, OBV/PTV/RTV + DSV, EBR/GZR HCV GT Recommended Regimens 1 and 4 SOF + VEL + RBV* for 12 wks DCV + SOF + RBV* for 12 wks SOF + LDV + RBV for 12 wks RBV weight-based for SOF /VEL 600mg/day, increasing as tolerated for SOF/DCV *Initial dose: 600 mg/day, increased as tolerated. Slide 27 of 67 Expert Guidance for HCV Treatment in Pts With Decompensated Cirrhosis AASLD/IDSA Refer to experienced HCV provider (ideally LT center) Avoid IFN, TVR, BOC, SMV, OBV/PTV/RTV + DSV, EBR/GZR HCV GT Recommended Regimens 2 and 3 SOF + VEL + RBV* for 12 wks DCV + SOF + RBV* for 12 wks RBV weight-based for SOF /VEL 600mg/day, increasing as tolerated for SOF/DCV *Initial dose: 600 mg/day, increased as tolerated. 9

10 UK Expanded Access: SOF + (DCV or LDV) ± RBV in Decompensated Cirrhosis Slide 28 of 67 HCV Research UK Database of pts with decompensated cirrhosis Enrolled at/after EAP start and treated: n = 409 SVR12: 80.4% (329/409) Enrolled 6 mos before EAP start: n = 261 Subsequently treated after EAP start: n = 177 Lower rate of liver events in treated vs untreated pts Adverse Events in First 6 Mos, % *P <.05 for treated vs untreated. Cheung MCM, et al. EASL Abstract PS097. Reproduced with permission. Foster GR, et al. J Hepatol. 2016;[Epub ahead of print]. Treated (n = 409) Untreated (n = 261) Total * Death Decompensation * New HCC Sepsis New OLT Hospital admission MELD worsening by > 2 points * Slide 29 of 67 HCC Risk Persists After DAA Therapy in Pts With HCV-Related Cirrhosis Retrospective analysis of 344 HCV-infected pts with CP A or B cirrhosis treated with DAAs (SVR: 89%) Pts followed for wks after treatment completion No HCC at baseline, but previous HCC permitted Overall HCC incidence after DAA therapy: 7.6% In pts without previous HCC: 3.2% In pts with previous HCC: 29.0% Buonfiglioli F, et al. EASL Abstract LBP506. More advanced liver disease and previous HCC significant risk factors for HCC after DAAs Factor No HCC (n = 318) HCC (n = 26) P Value CP class B, % Mean liver stiffness, kpa Liver stiffness, n.005 kpa < kpa > Mean platelets, x /mm 3 Previous HCC, n.0001 Yes No HCC Screening Guidelines Slide 30 of 67 EASL-EORTC Guidelines 2012 [1] : Pts at high risk for developing HCC should be entered into surveillance programs. Surveillance should be performed by experienced personnel in all at-risk populations using abdominal ultrasound every 6 mos High risk: cirrhosis CP A, B, or C (awaiting LT for CP C); noncirrhotic HBV carriers with active hepatitis or family HCC history; noncirrhotic pts with HCV and F3 fibrosis AASLD/IDSA HCV Guidance 2016 [2] : Surveillance for hepatocellular carcinoma with twice-yearly ultrasound examination is recommended for pts with advanced fibrosis (ie, Metavir stage F3 or F4) who achieve an SVR 1. EASL-EORTC. J Hepatol. 2012;56: AASLD/IDSA. HCV Guidance

11 Predicted fibrosis score (KPa) 9/21/2016 Slide 31 of 67 How many people are co-infected with HIV/HCV? Slide 32 of 67 Worldwide 40 million HIV HCV 10 million 175 million 1. NACO Annual Report Available at: [accessed April 2015]; Slide 33 of 67 Faster progression with age even when controlling for alcohol and other co-morbidities Liver fibrosis and age among HIV/HCV co-infected patients and HCV mono-infected patients HIV/HCV HCV years Age (years) Kirk D, et al. Ann Intern Med 2013;158:

12 Median age at death Deaths (%) 9/21/2016 Liver-related Death is a Frequent cause of Non- AIDS Death in the HAART Era D:A:D Study: Causes of death in n=49,734 HIV-infected patients followed Slide 34 of 67 AIDS Liver-related disease Cardio -vascular or other heart disease Non-AIDS malignancies Other Weber R, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. THAB HIV/HCV co-infected patients are at increased risk of fibrosis, cirrhosis, decompensation, HCC and premature death Pinchoff J, et al. Clin Infect Dis 2014;58: ; 2 World Health Organization. Protocol 6; 3 Sherman KE, et al. Gastroenterology 2005;128:313 27; 4 Vallet-Pichard A, Pol S. J Hepatol 2006;44(S1):S No HCV or HIV HCV mono-infected HIV/HCV coinfected Slide 35 of 67 HIV coinfection reduces life expectancy in patients with HCV infection in the HAART Era Median Age at Death and % Premature Deaths (<65 years) in New York City ( ) 1 25% died prematurely 64% died prematurely 94% died prematurely Slide 36 of 67 ION-4 Study Ledipasvir/Sofosbuvir in GT1/4 + HIV Coinfection Design: Open-label, phase 3 trial, using LDV/SOF for 12 weeks in treatment-naïve or treatment-experienced patients with GT 1 or 4 and HIV coinfection GT 1 or 4 N = 335 Ledipasvir- Sofosbuvir SVR12 Week Drug Dosing: Ledipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once daily Antiretrovirals allowed: tenofovir-emtricitabine plus either efavirenz, rilpivirine, or raltegravir Naggie S, et al. N Engl J Med 2015;373:

13 ION-4 Study Antiretroviral regimens Slide 37 of 67 ION-4: HIV Antiretroviral Regimen Antiretroviral Agent Antiretroviral Received (n = 335) Tenofovir-emtricitabine 335 (100) Efavirenz 160 (48) Rilpivirine 29 (9) Raltegravir 146 (44) Naggie S, et al. N Engl J Med 2015;373: ION-4 Study Efficacy Results: SVR 12 Slide 38 of / / / /268 63/67 Prior Treatment Status Liver Status Naggie S, et al. N Engl J Med 2015;373: Recommendations for treatment of HCV in HIV/HCV co-infected patients Slide 39 of 67 Indications for HCV treatment in HIV/HCV coinfected persons are identical to those in patients with HCV mono-infection (A1) The same IFN-free treatment regimens can be used in HIV-co-infected patients as in patients without HIV infection, as the virological results of therapy are identical (A1) EASL. J Hepatol 2015; doi.og/ /j.jhep EASL: European Association for the Study of the Liver; IFN: interferon 13

14 Slide 40 of 67 Slide 41 of 67 Case. 48 yr old woman with stage 4 chronic kidney disease Dialysis dependent. Has HCV genotype 1 infection, treatment experienced (relapse following PEF-IFN + RBV) Liver biopsy in 2014 showing stage 2 (periportal) fibrosis, platelets and ultrasound normal GFR 18 mls/minute Has potential living kidney donor What is the best choice for antiviral therapy: Slide 42 of 67 22% 1. sofosbuvir + velpatasvir for 12 weeks 67% 2. grazoprevir + elbasvir for 12 weeks 0% 3. grazoprevir + daclatasvir for 12 weeks 4. paritaprevir/ritonavir + ombitasvir + ribavirin for 0% 12 weeks 11% 5. none of the above, because all are contraindicated in end-stage renal disease 14

15 What is the best choice for antiviral therapy: Slide 43 of sofosbuvir + velpatasvir for 12 weeks 2. grazoprevir + elbasvir for 12 weeks 3. grazoprevir + daclatasvir for 12 weeks 4. paritaprevir/ritonavir + ombitasvir + ribavirin for 12 weeks 5. none of the above, because all are contraindicated in end-stage renal disease Slide 44 of 67 Metabolism of Sofosbuvir SOF (GS-7977) is the oral prodrug Only SOF enters hepatocytes and then converted to the active triphosphate No hepatic metabolism so no dose adjustment in hepatic impairment SOF undergoes extrahepatic metabolism to form major metabolite (GS ) which is eliminated in urine GS-7977 and GS exposure in HCV(-) subjects with renal impairment Current recommendations for SOF only if GFR >30ml/min Sofosbuvir, Product information, March Kirby AASLD 2013 GS-7977 (prodrug) GS (M1 metabolite) GS (uridine-mp) GS (uridine) Renal Excretion TP: triphosphate Plasma Hepatocyte GS-7977 (prodrug) GS (uridine) (-TP) GS (M1 metabolite) GS (uridine-mp) PSI-7410 (uridine-dp) GS (uridine-tp) SOF+RBV in severe renal impairment GS-US Study Design Slide 45 of 67 Week Part 1 n=20 Part 2 n=15 SOF200 mgqd+ RBV SVR12 SOF400 mgqd+ RBV SVR12 LDV 90mg/ SOF200 mgqd+ RBV SOF 400mgQD SVR12 Open-label study of SOF-based therapy in patients with ESRD HCV GT 1 or 3 in Part 1 and GT 1 in Part 2 Any cause of renal disease allowed Martin P, et al. AASLD 2015, San Francisco. #1128 Gane E, et al. AASLD 2014, Boston. #966 QD: once-daily; RBV: ribavirin; SOF: sofosbuvir 15

16 GS AUC (ng h/ml) Mean HCV RNA (log 10 IU/mL) 9/21/2016 SOF+RBV in severe renal impairment GS-US Efficacy Slide 46 of 67 SVR12 in Severe RI (<30ml/min) On-treatment viral suppression in Severe RI and normal Renal Fn SOF 400 mg + RBV 200 mg and GFR <30ml/min (n=10) SOF 400 mg + RBV 200 mg and GFR >60ml/min (n=114)* LLOQ 0 BL *PHOTON-1 study Week Martin P et al. AASLD 2015, San Francisco. #1128 Gane E, et al. AASLD 2014, Boston. #966 SOF+RBV in severe renal impairment GS-US Safety Slide 47 of 67 SOF and GS pharmacokinetics at Wk 12 GS SOF 100,000 10,000 10,000 6X 1.4X 1000 SOF AUC (ng h/ml) SVR12 Viral relapse 1000 Severe RI (400 mg) Historical (400 mg) Severe RI (400 mg) Historical (400 mg) 100 AEs due to RBV toxicity. NO evidence of SOF toxicity Improvement in mean egfr during treatment (26 36 ml/min) Next group will be LDV/SOF for 12 weeks without RBV Martin P et al. AASLD 2015, San Francisco. #1128 Gane E, et al. AASLD 2014, Boston. #966 Slide 48 of 67 RUBY-1: OBV/PTV/RTV + DSV ± RBV in Txnaive, Noncirrhotic GT1 Pts With CKD Multicenter, open-label phase IIIb study 12 Wks Tx-naive, noncirrhotic GT1 pts with GT1a: OBV/PTV/RTV + DSV + RBV* egfr < 30 ml/min/1.73m 2 GT1b: OBV/PTV/RTV + DSV (N = 20) SVR12, % (n/n) 90 (18/20) *RBV dosed at 200 mg QD and managed as follows: RBV dosed 4 hrs before hemodialysis in hemodialysis pts; 69% of pts with GT1a required RBV dose reduction for anemia No discontinuations for anemia No cases of grade 3 or higher ALT elevations Pockros P, et al. AASLD Abstract

17 C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease Slide 49 of 67 W12 W16 W28 18 years HCV infection, Genotype 1 CKD stage 4/5** ± hemodialysis Treatment naïve or pre-treated with IFN-based regimen Compensated cirrhosis allowed No HBV or HIV co-infection N = 111 N = 113 Open label N = 11 GZR + EBR Placebo GZR + EBR (Intensive PK) GZR/EBR Objective SVR 12 (HCV RNA < 15 IU/ml) > 45% in immediate and PK groups : reference rate, with 2-sided significance level of 0.05 Roth D. Lancet 2015; Oct 6; 386: Slide 50 of 67 C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease SVR 12 (HCV RNA < 15 IU/ml), % (95% CI), mitt % 100 Primary analysis 99.1 ( ) 94.3 ( ) ( ) ( ) ( ) ( ) Modified Full analysis Set Full analysis Set Relapse 1* 1 Discontinuation unrelated to treatment a 1b Yes No Genotype Diabetes Modified full analysis set excluded patients who died or discontinued for reasons unrelated to treatment * Genotype 1b, non cirrhotic, CKD stage 5, NS5A RAV at baseline : L31M, at failure : L31M + Y93H C-SURFER Roth D. Lancet 2015; Oct 6; 386: Slide 51 of 67 17

18 HCV-related costs per year /21/2016 Health Care Costs in Chronic HCV Increase After Development of Cirrhosis Slide 52 of 67 $145,056 $112,547 $59,995 $17,277 $22,752 Gordon. Hepatology Non-cirrhotic Compensated Decompensated Hepatocellular Liver liver disease cirrhosis Carcinoma Transplant The development of cirrhosis is a major milestone in HCV because of its association with expensive medical costs. 5 2 Slide 53 of 67 So, why all the denials? The Financial Disincentive for Payers to Treat Early Stages of Chronic HCV 20 Private payer savings A l l c o s t s a r e f u l l y r e c o v e r e d a f t e r 1 5 y e a r s. Slide 54 of Cumulative net benefit * -40 (2015 $billions) E a r l y t r e a t m e n t c o s t s p r i v a t e p a y e r s $ 8 3 b n b y years years -100 *Net benefit is private payer medical costs saved minus private payer s HCV treatment costs. Private payers do not earn return on investment in early treatment unless patients stay for 16 years Moreno. Am J Manag Care Lakdawallla. Leonard D. Schaeffer Center For Health Policy and Economics Year 18

19 Absolute Denials (%) 9/21/2016 The Consolidation of the Private Health Insurance Industry Estimated National Market Share of the Largest Insurers For years (last year data is available) Slide 55 of 67 Aetna Cigna United Anthem BCBS** 83% 17% Others (e.g., Regional plans, system-led plans, Kaiser Permanente) **With a few exceptions, Blue Cross Blue Shield (BCBS) affiliates have exclusive, non-overlapping market territories and do not compete with one another. All 36 BCBS affiliates are therefore treated as a single firm. The US Justice Department has filed lawsuits to block two health insurance acquisitions: Aetna s $37 billion deal with Humana Anthem s $48 billion pursuit of Cigna. Dafny. The Commonwealth Fund. November Picker & Abelson. NY Times. July 22, Slide 56 of 67 Restrictions to Treatment Nearly One-Half of All Prescriptions for HCV Treatment Were Denied by Medicaid Incidence of absolute denial of HCV treatment by insurance P<0.001 Slide 57 of 67 46% P< % 10% 5% 377/ /503 40/ /1023 Extent to Which Payers Restricted Access to HCV Treatment Evaluated in 4 States Utilizing Data From a Specialty Pharmacy from 11/1/14-4/30/15. Lo Re. AASLD, #LB-5 Excludes 21 patients with incomplete prior authorization after 60 days 57 19

20 New cases of acute HCV 9/21/2016 Slide 58 of 67 Medicaid Access In November 2015, CMS issued new guidance to state Medicaid agencies: Expressing concern that states were denying beneficiaries access to the new HCV treatments, CMS reminded states of their obligations to make medically necessary prescription drugs available to Medicaid beneficiaries. CMS specifically noted that states may not unreasonably restrict access to HCV treatments by imposing unreasonable coverage standards including fibrosis scores, abstinence from drug or alcohol use or consultation with specific specialists. Drugs/Downloads/Rx-Releases/State-Releases/state-rel-172.pdf New Cases of HCV: Emerging Epidemic Slide 59 of 67 3,000 2,500 2,000 1,500 1, New cases of HCV infection are primarily in Caucasians years of age and living in non-urban areas. 1 Abuse of prescription opioid drugs, and then transition to heroin responsible for most of new cases Based upon analysis of cases reported, the CDC believes almost 30,000 new HCV infections are now occurring yearly Centers for Disease Control and Prevention. Division of Viral Hepatitis. Viral hepatitis surveillance Zibbell. MMWR Morb Mortal Wkly Rep Klevens. Am J Public Health Slide 60 of 67 Increased Injection Drug Use in Adolescents and Young Adults Is Shifting the Demographics of HCV Infection in the US Newly Reported Confirmed HCV Cases, Massachusetts, B a b y B o o m e r s. B a b y B o o m e r s. P r i m a r i l y P r i m a r i l y C a u c a s i a n C< a u c a s i a n < 3 0 y e a r s 3o 0 f y e a r s o f a g e. a g e. B a b y B o o m e r s. Increased injection drug use is not unique to Massachusetts; these data may be indicative of emerging trends in HCV transmission in other regions of the US. CDC. MMWR. 2011;60: a Excludes 35 cases with missing age or sex information. b Excludes 346 cases with missing age or sex information. 20

21 Deaths/year from HCV vs. other notifiable infectious conditions* 9/21/2016 Slide 61 of 67 Emerging Epidemic of New HCV in Young Non-Urban Persons Who Inject Drugs 30 of the 34 states and territories that report to the CDC had an increased incidence of new HCV infections from 2006 to The incidence of HCV infection is likely to be underestimated due to the disparate access to diagnosis and care in these at-risk populations and their reluctance to seek care due to the associated stigma associated with IDU. Suryaprasad. Clin Inf Dis Hepatitis C is a Disease of the Marginalized HCV disproportionately affects groups who are underserved in the healthcare system. Slide 62 of 67 US Population 2% African American Men yrs 14% Hospitalized 17% Severely Mentally Ill 29% Incarcerated 35% Injection Drug Users < 10 years 50% Injection Drug Users > 10 years 90% Prevalence of Chronic Hepatitis C in Different Populations Edlin. Nature Comparison of HCV to HIV Slide 63 of 67 Mortality from HCV exceeds all other nationally notifiable infectious conditions. 30,000 25,000 20,000 15, infectious disease conditions (Including HIV)* Hepatitis C * 60 infectious conditions other than HCV, as reported to CDC 10,000 5, Comparison of treating HCV to HIV: 2 Lifetime cost of treating 1 patient with HCV: $58,000. Lifetime cost of treating 1 patient with HIV: $315,000. Total federal budget for treating HIV with ARV: $17.5 billion/year. Total predicted budget for treating all with HCV: $7.4 billion/year for 5 years. 1. Holmberg. ID Week Chhatwal. Clin Gastrol Hepatol. October

22 Slide 64 of 67 Slide 65 of 67 Thank you! 22