Michael W. Fried, M.D., FAASLD Professor of Medicine Director, UNC Liver Center University of North Carolina at Chapel Hill

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1 Michael W. Fried, M.D., FAASLD Professor of Medicine Director, UNC Liver Center University of North Carolina at Chapel Hill

2 Disclosures Michael W. Fried, M.D. Grants/Research Support AbbVie, BMS, Gilead, Janssen, Merck Consultant: AbbVie, BMS, Gilead, Janssen, Merck Stock/Shareholder: TARGET PharmaSolutions Speakers Bureau: None Other Financial Support: NIH Grants Some slides courtesy of Paul Kwo, MD

3 Hepatitis C is No Longer a Medical Science... It s Now a Social Science! Attributed to Ira Jacobson, 2017

4 High Rates of HCV Cure Across All Regimens: GT1, Non-Cirrhotic, Tx-Naïve Regimen Weeks Study SVR12 Sofosbuvir + ledipasvir (HCV RNA <6 M IU) (HCV RNA >6 M IU) Elbasvir/grazoprevir (1b) (-) -NS5A RAVs (1a) C-EDGE ION-3 119/123 (97%) 206/216 (95%) 133/135 (99%) 129/131 (99%) Sofosbuvir + velpatasvir 12 ASTRAL-1 323/328 (98%) Glecaprevir + Pibrentasvir 8 ENDURANCE-1 348/351 (99%) Not Head-to-Head Trials

5 High Rates of HCV Cure Across All Regimens: GT1, Non-Cirrhotic, Tx-Experienced* Regimen Weeks Study SVR12 Sofosbuvir/ Ledipasvir (Prior Peg/RBV or PI + Peg/RBV) Elbasvir /Grazoprevir 1B and 1A (RAV-) Sofosbuvir /Velpatasvir (Prior Peg/RBV or PI + Peg/RBV) Glecaprevir/ Pibrentasvir * Previous Treatment with PEG/RBV 12 ION-2 83/87 (95%) 12 C-EDGE 190/192 (99%) 12 ASTRAL-1 109/110 (99%) 8 ENDURANCE-1 131/132 (99%) Not Head-to-Head Trials

6 Treatment-Naïve, Compensated Cirrhotic (GT1a) Regimen Weeks Study SVR12 Sofosbuvir/ledipasvir 12 ION-1 32/33 (97%) Elbasvir/grazoprevir 1a (-) NS5A RAV 12 C-EDGE 135/138 (98%) Sofosbuvir/Velpatasvir 12 ASTRAL-1 48/48 (100%) Glecaprevir /Pibrentasvir 12 EXPEDITION-1 47/48 (99%) AASLD/IDSA Recommendations for testing, managing, and treating hepatitis C. Accessed 2/26/2016. Afdhal et al. NEJM 2014; 370: Poordad et al. NEJM 2014; 370: Zeuzem et al. Ann. Int. Med. 2015; 163:1-13. Feld et al. NEJM 2015; 373:

7 Recommended Treatment Regimens (alphabetically) for Treatment-Naïve Genotype 1a Patients without Cirrhosis Recommended Daily fixed-dose combination of elbasvir/grazoprevir); for patients in whom no baseline NS5A RASs for elbasvir are detected Daily fixed-dose combination of glecaprevir/pibrentasvir Daily fixed-dose combination of ledipasvir/sofosbuvir Daily fixed-dose combination of ledipasvir/sofosbuvir; for patients who are non-black, HIV-uninfected, and whose HCV RNA level is <6 million IU/mL Daily fixed-dose combination of sofosbuvir/velpatasvir Duration 12 weeks 8 weeks 12 weeks 8 weeks 12 weeks Antiviral Treatment for HCV Infection - 7

8 Recommended Treatment Regimens (alphabetically) for Treatment-Experienced Genotype 1a Patients without Cirrhosis Recommended Daily fixed-dose combination of elbasvir/grazoprevir; for patients in whom no baseline NS5A RASs for elbasvir are detected Daily fixed-dose combination of glecaprevir/pibrentasvir Daily fixed-dose combination of ledipasvir/sofosbuvir Daily fixed-dose combination of sofosbuvir/velpatasvir Duration 12 weeks 8 weeks 12 weeks 12 weeks Antiviral Treatment for HCV Infection - 8

9 Recommended Treatment Regimens (alphabetically) for Treatment-Naïve Genotype 1a Patients with Compensated Cirrhosis Recommended Daily fixed-dose combination of elbasvir /grazoprevir; for patients in whom no baseline NS5A RASs for elbasvir are detected Daily fixed-dose combination of glecaprevir /pibrentasvir Daily fixed-dose combination of ledipasvir/sofosbuvir Daily fixed-dose combination of sofosbuvir/velpatasvir Duration 12 weeks 12 weeks 12 weeks 12 weeks Antiviral Treatment for HCV Infection - 9

10 The Therapeutic Landscape Will Not Change In The Foreseeable Future Current regimens leave no unmet needs Two promising regimens recently terminated NS5a + NUC NS5a + NUC Lawitz E, et al. AASLD 2017,#61 Zeuzem S, et al. AASLD #65

11 Pooled Analysis of Treatment Naïve GT3 Patients Treated for 8 or 12 weeks with Glecaprevir/Pibrebtasvir Similar results for 8 vs 12 weeks across all sub populations Flamm SL, et al. AASLD 2017, #62

12 Real-World Experience with Black Patients Treated for 8 Weeks VA retrospective analysis suggested that African American patients treated for 8 weeks had a ~3% lower SVR compared to Caucasian patients AASLD/IDSA Guideline suggests GT1, treatment-naïve, non-cirrhotic African American patients should be treated for 12 weeks, rather than 8-weeks for other racial groups Wilson E, et al. AASLD 2017,. #1131

13 Sofosbuvir/Velpatasvir for 12 Weeks in GT 1 4 HCV Liver Transplant Recipients No change to immunosuppression regimen Agarwal et al, AASLD 2017 #1069

14 Elbasvir/Grazoprevir in Patients With HCV and Chronic Kidney Disease: Results From the VA Kramer et al AASLD 2017; #1113

15 SOF/VEL/VOX 12 Weeks in NS5A Experienced Patients

16 Hepatitis C is No Longer a Medical Science... It s Now a Social Science! Attributed to Ira Jacobson, 2017

17 17 Substances Contributing to Medication or Drug Overdose Deaths North Carolina Residents, * Prescription Opioid Cocaine Heroin 350% increase in deaths since 1999 Fentanyl 738 Number of deaths ,000+ Deaths per year 20,000+ Emergency Dept. visits per year 884% increase in Heroin deaths since Source: N.C. State Center for Health Statistics, Vital Statistics-Deaths, *2015 Provisional Data (August 2016) Analysis by Injury Epidemiology and Surveillance Unit

18 Acute HBV and HCV Cases in North Carolina Number of Case Reports HCV cases HBV cases

19 HCV Vulnerability Assessment of North Carolina Counties Northampton Camden Alleghany Gates Rockingham Currituck Ashe Surry Warren Stokes Caswell Person Vance Hertford Pasquotank Halifax Watauga Wilkes Granville Perquimans Yadkin Mitchell Forsyth Orange Avery Guilford Franklin Bertie Chowa Yancey Caldwell Nash n Alexander Alamance Durham Madison Davie Edgecombe Washington Burke Iredell Martin Dare Davidson Wake Tyrrell Buncombe Haywood McDowell Catawba Randolph Chatham Wilson Rowan Pitt Swain Beaufort Graham Rutherford Lincoln Johnston Hyde Jackson Henderson Lee Greene Cabarrus Cherokee Polk Stanly Cleveland Gaston Montgomery Harnett Wayne Lenoir Macon Transylvania Craven Moore Clay Pamlico Mecklenburg Cumberland Union Anson Richmond Sampson Jones Hoke Duplin Scotland Carteret Onslow Robeson Bladen Pender RED = highest injection drug use and acute HCV incidence Columbus Brunswick New Hanover Courtesy of NC DHHS

20 Meeting HCV Elimination Goals Requires Attention to Different Populations To reduce transmission: actively injecting drug users Younger, often imprisoned or homeless Low extent of liver disease SVR benefit: prevent progression to advanced fibrosis and related complications To prevent progression of disease: all patients with HCV Fibrosis progression is unpredictable Response rates remain best for those without cirrhosis who can be treated with shorter duration of therapy To reduce mortality/morbidity: cirrhotic patients Older, less likely to transmit virus Advanced fibrosis or at risk of cirrhosis/hcc SVR benefit: longer life expectancy, improved QOL, restored liver function, avoid liver transplant QOL = quality of life. NASEM. Eliminating the Public Health Problem of Hepatitis B and C in the US: Phase One Report. Washington, DC: The National Academies Press; 2016.

21 Treatment of Persons Who Inject Drugs with Elbasvir/Grazoprevir: COSTAR Tx-naive pts with GT1, 4, or 6 HCV cirrhosis on opiate agonist therapy 3 mos (N = 301) SVR EBR/GZR 100/50 mg QD (n = 201) Placebo (n = 100) Wk 12 Wk 16 Wk 28 EBR/GZR 100/50 mg QD (n = 100) Overall reinfection rate 8 patients = 4.0 reinfections/100 yrs (95% CI: ) Persistent reinfection rate 5 patients = 2.5 reinfections/100 yrs (95% CI: All pts followed 24 wks post treatment Randomized, doubleblind, placebocontrolled phase III trial of PWID on Opiate Substitution Therapy Most patients tested positive for drugs during 12 weeks of therapy High rate of adherence Treating PWID is increasingly important in light of heroin epidemic and IOM report on controlling viral hepatitis by 2030 Dore et al, 2016

22 Low Risk of HCV Reinfection After Treatment with Elbasvir/Grazoprevir in Patients on OAT Open to all participants who received 1 dose of EBR/GZR in COSTAR Assessments every 6 months HCV RNA Comparison of viral sequences at baseline and virologic recurrence to determine reinfection Urine drug screen Participant-reported behaviors Behavioral questionnaire: selfreported drug use Reinfection rate was 2.3/100 person-years, with a persistent reinfection rate of 1.6/100 personyears Dore et al HEPATOLOGY (1). 195

23 HCV reinfection and injecting risk behavior following EBR/GZR treatment in participants on opiate agonist therapy (OAT): CO-STAR Part B Incidence of reinfection Part B: Part A: Part A: Through Through FW12Through FW2424 months of f/u 5 reinfections 1 reinfection 74 participants (37%) reported injection drug use Rate of reinfection: 4.2 reinfections/100 PY 95% CI: reinfections 10 reinfections 2.3 reinfections per 100 PY Increased risk of reinfection based on reported injection drug use during f/u 199 participants enrolled in Part B from the EOT through all available follow up 125 participants (63%) reported NO injection drug use Rate of reinfection: 0.4 reinfections/100 PY 95% CI: All reinfections: From EOT through 24 months of f/u 10 reinfections 426 person-years 2.3 reinfections per 100 PY (95% CI: 1.1, 4.3) Persistent reinfections: From EOT through 24 months of f/u (includes only those participants with persistent HCV RNA) 7 reinfections 429 PY 1.6 reinfections per 100 PY (95% CI: 0.7, 3.4) Clearance of reinfection was observed in 3/10 (30%) reinfection cases After SVR, IDU was stable in PWID receiving OAT (25%) Reinfection rates were low and consistent with prior estimates Dore GJ, et al. AASLD 2017, #195

24 Hepatitis C: Going the Last Mile Drug development for HCV is no longer a priority Current generation of medications fulfill all previously unmet needs Major issue now is delivering treatment to those in need Underserved populations remain a reservoir for new HCV infections Opiate epidemic fueling increasing HCV incidence among young people Injecting drug users can be successfully treated with a relatively low risk of reinfection Innovative care models are needed now to minimize future disease burden