Hepatitis C Imtiaz Alam M D Medical Director

Hepatitis C Imtiaz Alam, M. D. Medical Director, Austin Hepatitis Center

Hepatitis C & PCP’s LACK OF AWARENESS LACK OF APPROPRIATE ACTION 1. 35 -50% of PCP believe HCV can be cured 1. 50% PCP consider LFT’s as their “Initial” screen 2. <10% Aware of DAA’s and new treatment regimens 2. <25% pf PCPs order HCV RNA test 3. 20% Plan to screen all baby boomers 3. Only 20% of PCP “Would Definitely” refer an asymptomatic patient Expand Quantitative Landscape Study – Oct 2013 [Gilead Sciences] 2

The Critical Questions? WHY WHO Is There An Urgent Need For HCV Diagnosis? Is Most at Risk For HCV and What Is the Guidance on Testing? HOW WHAT How Can You Do You Test To Ensure Patients Your Patients For HCV At Are Not Only The Point Tested But of Care? Linked to Care? 3

Action Plan Aware Drive Awareness of HCV and Treatment Actions Engage Cultivate Interest and Intent to Learn Act Prompt consistent and Quality Screening, Diagnosis and Referral 4

HCV History �An RNA virus that used to be known as non-A, non-B hepatitis until it was discovered in 19881 �No vaccine available �First therapy approved in 19862 • Before 2011, HCV treatment could last as long as a year, with cure rates sometimes being at 40%-50% 3 • Since that time, scientific advances have made HCV treatment shorter and more effective than it was previously 1. CDC. MMWR Morb Mortal Wkly Rep. 1998; 47(RR-19): 1 -39. 2. FDA. http: //www. fda. gov/For. Consumers/By. Audience/For. Patient. Advocates/ucm 151494. htm. 3. Ghany MG et al. Hepatology. 2011; 54(4): 1433 -1444. 5

Epidemiology of HCV Infection: United States Distribution of HCV Genotypes (GTs) in the US 3 Approximately 3. 2 million persons in the United States have chronic hepatitis C virus (HCV) infection 1, a � Seroprevalence is higher among 2 › Individuals born between 1945 -1965 (3. 5%) › Black non-Hispanics (2. 2%) › Males (1. 9%) � a. This figure may be an underestimate because the sampling frame of National Health and Nutrition Examination Survey (NHANES) did not include certain high-risk populations. 4 1. Armstrong GL, et al. Ann Intern Med. 2006; 144: 705 -714; 2. Ditah I, et al. J Hepatol. 2013 Nov 27 [Epub ahead of print]; 3. Nainan OV, et al. Gastroenterology. 2006; 131: 478 -84; 4. Chak E, et al. Liver Int. 2011; 31: 1090 -1101. 6 6

HCV and HIV-1 Co-infection � Of people with HIV-1 in the US, about 25% are co-infected with HCV 1 About 85% of people with HIV who inject drugs also have HCV infection 2 � HIV infection in a person who is also infected with HCV results in 2 � › Higher levels of HCV in the blood › More rapid progression to HCV-related liver disease › Increased risk for cirrhosis and HCC All HIV-infected 1 HIV-infected Injection-drug users 2 HCC = hepatocellular carcinoma; HIV = human immunodeficiency virus. 1. Thomas DL. Ann Rev Med. 2008; 59: 473 -485; 2. Sulkowski MS, Thomas DL. Ann Intern Med. 2013; 138: 197 -207. 7 7

POPULATION STUDIES SHOW A SIGNIFICANT GAP IN HEPATITIS C CARE IN THE UNITED STATES US Cascade of Care, 2003 -20131 3. 5 Million 50% 43% 16% 73% GT 1 a 2 27% GT 1 b 2 Chronic HCV Diagnosed and infection aware 1. 2. Access to outpatient care Prescribed HCV treatment 9% Achieved sustained virologic response (SVR) 8 79% Genotype (GT) 12 Yehia BR, et al. PLo. S One. 2014; 9: e 101554. Zein NN, et al. Ann Intern Med. 1996; 125: 634 -639. 8

Natural History Acute Infection* Clearance of HCV RNA 15%-25% Chronic Infection 75%-85% Cirrhosis 10%-20% over 20 years HCC 1%-4% per year Decompensated Cirrhosis 5 -yr survival rate 50% Extrahepatic Manifestations *20%-30% of individuals are symptomatic. HCC=hepatocellular carcinoma. Adapted from Chen SL, Morgan TR. Int J Med Sci. 2006; 3: 47 -52. 9

Host Factors Associated with More Rapid Disease Progression Nonmodifiable Host Factors Older age at infection • Associated with accelerated cirrhosis development 1 Increasing age (longer duration of infection) • Associated with accelerated fibrosis progression 1 Male gender • Associated with accelerated fibrosis progression and more frequent HCC development 2, 3 IL 28 B CC allele • More likely to develop adverse clinical outcomesa but not associated with fibrosis progression 4 Transfusion-associated HCV • Associated with accelerated progression to cirrhosis (versus community- or childhood-acquired HCV)5 Hispanic ethnicity • Higher mortality rates from HCV-related cirrhosis 6 • Hispanic ethnicity is an independent risk factor for HCC-related mortality 7 Caucasian • Increased histologic activity and incidence of cirrhosis (as compared to blacks)2 a. Clinical outcomes were defined as one of the following: death, development of ascites, spontaneous bacterial peritonitis, variceal hemorrhage, hepatic encephalopathy, HCC, and increase in Child-Pugh-Turcotte score by ≥ 2 points on 2 consecutive clinic visits 12 weeks apart. 1. Malnick S, et al. Drugs Aging. 2014; 31: 339 -347; 2. Maasoumy B, Wedemeyer H. Best Pract Res Clin Gastroenterol. 2012; 26: 401 -412; 3. Nishida N, et al. Dig Dis. 2012; 30: 547 -553; 4. Noureddin M, et al. Hepatology. 2013; 58: 1548 -1557; 5. Missiha SB, et al. Gastroenterology. 2008; 134: 1699 -1714; 6. Yoon YH, et al. Alcohol Clin Exp Res. 2011; 35: 240 -249; 7. Younossi ZM, Stepanova M. Clin Gastroenterol Hepatol. 2010; 8: 718 -723. 10 10

Host Factors Associated with More Rapid Disease Progression (cont. ) Behavioral and Clinical/Laboratory Host Factors Moderate to high alcohol consumptiona • Associated with significant risk of advanced hepatic fibrosis and mortality (all-cause and liver-related)1, 2 Heavy smokingb • Factor for severe fibrosisc in CHC 3 HIV-1 co-infection • Associated with higher viral load, rapid progression to cirrhosis, liver failure, and HCC 4 HBV co-infection • Associated with increased risk of HCC 5 Iron overload • Correlated with decompensated cirrhosis, HCC, or death 6 Combined obesity and diabetes mellitus • Associated with 100 -fold increase in risk of HCC development 7 Insulin resistance • Independent predictor of HCC development 8 and associated with increasing fibrosis 9 Hepatic steatosis • Associated with ≥ 2 -point increase in Ishak fibrosis score 10 and HCC development 11 Platelet counts, AST/ALT ratio, bilirubin, and albumin • Independent predictors of fibrosis progression or clinical decompensation 10 HBV = hepatitis B virus. a. Moderate and high consumption were defined as 1 -19 g/day and ≥ 30 g/day, respectively. 2 b. Lifetime consumption of ≥ 20 pack-years. c. Liver biopsy staging/fibrosis score ≥ 4. 3 1. Lim JK, et al. Clin Infect Dis. 2014; 58: 1449 -1458; 2. Younossi ZM, et al. Aliment Pharmacol Ther. 2013; 37: 703 -709; 3. Tsochatzis E, et al. Scand J Gastroenterol. 2009; 44: 752 -759; 4. Kang W, et al. Expert Rev Gastroenterol Hepatol. 2014; 8: 247 -266; 5. Oh JK, et al. BMC Cancer. 2012; 12: 452; 6. Lambrecht RW, et al. Gastroenterology. 2011; 140: 1490 -1500; 7. Goossens N, Negro F. Clin Liver Dis. 2014; 18: 147 -156; 8. Hung CH, et al. World J Gastroenterol. 2010; 16: 2265 -2271; 9. El Ray A, et al. Eur J Gastroenterol Hepatol. 2013; 25: 421 -427; 10. Ghany MG, et al. Gastroenterology. 2010; 138: 136; 11. Kurosaki M, et al. Hepatol Res. 2010; 40: 870 -877. 11

HCV GT 3 Was Associated with Accelerated Fibrosis Progression and Increased Risk of HCC � GT 3 was associated with accelerated fibrosis progression 1 Patients from the Swiss Hepatitis C Cohort Study enrolled before December 2008 (N=1189) › � GT 3 was associated with an increased risk of developing HCC 2 › Retrospective study of patients in the VA HCV Clinical Case Registry, 2000 -2009 Progression to fibrosis stage 3 -41 GT 1 or 4 (n=492, ref) GT 2 (n=65, P=. 003) GT 3 (n=244, P<. 001) 1. 00 Incident HCC 2 GT 1 or 4 (n=630, ref) GT 2 (n=92, P=. 04) GT 3 (n=342, P<. 001) 1. 00 0. 98 0. 90 Proportion Free of HCC Cumulative Incidence of Fibrosis Progression to fibrosis stage 1 -21 0. 80 0. 70 0. 60 0. 50 0. 40 0. 30 0. 20 0. 96 0. 94 0. 92 0. 88 0. 86 0. 84 0. 10 0. 82 0. 00 0. 80 0 5 10 15 20 Year 25 30 35 40 0 5 10 15 20 25 30 Year for prespecified demographic, clinical, and treatment factors. 2 HR = hazard ratio; VA = Veterans Administration. 35 40 GT 1 (n=88, 348) GT 2 (n=13, 077) GT 3 (n=8, 337) GT 4 (n=1, 082) 0. 90 N=110, 484 Adjusted HRa=1. 8 (1. 61, 2. 03) 0 1 2 3 4 5 6 Year a. Adjusted 1. Bochud PY, et al. J Hepatol. 2009; 51: 655 -666; 2. Kanwal F, et al. Hepatology. 2014; 60: 98 -105. 12 7 8 9 10 11

HCV Is Leading Cause of Liver Transplants in the US Primary cause of disease among adults on the liver transplant wait list, 2011 All others 26. 4% Primary cause of disease among adult liver transplant recipients, 2011 All others 22. 3% HCV 30. 1% Metabolic liver disease Acute hepatic necrosis HBV 6. 0% Malignancy 2. 5% Acute hepatic necrosis 2. 6% 2. 8% 9. 0% Alcoholic liver disease 23. 2% HCV 23. 5% 4. 0% Malignancy 20. 9% 9. 1% Cholestatic disease Alcoholic liver disease 17. 6% Cholestatic disease Available at: http: //srtr. transplant. hrsa. gov/annual_reports/2011/pdf/03_%20 liver_12. pdf. 13

PROGRESSIVE INCREASE IN INCIDENCE OF HCV-RELATED CIRRHOSIS AND HCC IN US Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected Veterans El-Serag HB. Gastroenterology 2012; 142: 1264– 1273. 14

Presentation of Patients Infected With HCV � Patients often asymptomatic in early stages of infection 1 Symptoms may include 1 § § § § § Fever Fatigue Loss of appetite Nausea Vomiting Abdominal pain Dark urine Grey-colored stools Jaundice Joint pain First symptoms may be those of extrahepatic manifestations 2 § § § Arthralgias Paresthesias Myalgias Pruritus Sicca syndrome 1. http: //www. cdc. gov/knowmorehepatitis/Media/PDFs/Fact. Sheet-Chronic. Hep. C-Gen. Info. pdf; 2. Ali A, Zein NN. Cleve Clin J Med. 2005; 72: 1005 -1008. 15

Extrahepatic Manifestations of HCV Strongly associated Possibly associated § Mixed cryoglobulinemia § Sjögren (sicca) syndrome § Lymphoproliferative disorders § Porphyria cutanea tarda § Neuropathy § Membranoproliferative glomerulonephritis § Cryoglobulinemic vasculitis § Corneal ulcers (Mooren ulcers) § Thyroid disease § Lichen planus § Pulmonary fibrosis § Type 2 diabetes § Systemic vasculitis (polyarteritis nodosa, microscopic polyangiitis) § Arthralgias, myalgias, inflammatory polyarthritis § Autoimmune thrombocytopenia Adapted from Ali A, Zein NN. Cleve Clin J Med. 2005; 72: 1005 -1008. 16

Mortality Rates in the US, 1999 -2007 Rate per 100, 000 PY* 7 6 HIV 5 4 Hepatitis C 3 2 1 Hepatitis B 7 20 0 6 20 0 5 20 0 4 20 03 2 20 01 20 00 19 99 0 Yr *Mortality rates = HBV, HCV, HIV listed as cause of death Because decedent can have multiple causes of death, a record listing more than 1 type of infection was counted for each type of infection Ly KN, et al. Ann Intern Med. 2012; 156: 271 -278. 17

HCV Viral Replication Associated With Higher All-Cause Mortality All Causes 35 Anti-HCV seropositives, HCV RNA detectable Anti-HCV seropositives, HCV RNA undetectable Anti-HCV seronegatives 25 30. 1% P <. 001 for comparison among 3 groups P <. 001 for HCV RNA detectable vs undetectable 20 15 Property Of Bio. Centra, LLC Cumulative Mortality (%) 30 12. 8% 12. 4% 10 5 0 0 2 4 6 Lee MH, et al. J Infect Dis. 2012; 206: 469 -477. 8 10 12 Follow-up (Yrs) 14 16 18 20 18 18

LIVER TRANSPLANT PROJECTION FROM 2013 TO 2043 Potential Transplant Need: Treatment of all candidates and SVR of 90% will still require ≈22, 000 transplants/year in 2033 180, 000 162, 559 150, 617 160, 000 Number of Persons 162, 747 140, 000 126, 296 No treatment 120, 000 25% treated 91, 310 100, 000 80, 000 50% treated 49, 013 60, 000 75% treated 40, 000 All treated 20, 000 18, 193 0 0 5 25, 573 27, 175 26, 207 24, 258 21, 994 10 15 20 25 30 Year in Model Desai et al. AASLD 2013. Abstract 1427 19

Health Care Cost (95% CI) Prevalence (Million) Prevalence (95% CI) Health Care Cost (Billion) Healthcare Costs § While the prevalence of HCV infection is declining from its peak, the incidence of advanced liver disease and associated health care costs continue to rise § Modeling does not take into account any impact of birth cohort screening A system dynamic modeling framework was used to quantify the HCV-infected population, the disease progression, and the associated cost from 1950 -2030. CI=confidence interval. Razavi H, et al. Hepatology. 2013. Epub ahead of print. 20

Average Annual All-Cause Healthcare Costs Patient Population Mean Annual All-Cause Healthcare Cost per Person, $ HCV uninfected[1] 9979 HCV positive, noncirrhotic[2] 17, 277 HCV positive, compensated cirrhosis[2] 22, 752 HCV positive, ESLD[2] 59, 995 1. Mc. Adam-Marx C, et al. J Manag Care Pharm. 2011; 17: 531 -546. 2. Gordon SC, et al. Hepatology. 2012; 56: 1651 -1660. 21

HCV-Related Health Care Costs by Liver Severity (USD 2010) 3505* 3328* (10, 996) HCV-Related Costs (per-patient-per-month) Non-cirrhotic liver disease (n=41, 858) Compensated cirrhosis (n=3718) End-stage liver disease (n=8220) (10, 996) 2608* (10, 359) 1060* (2941) 650 (2714) 467 663* (2815) (2648) Total Health Care Costs Total 579* 313 334 (2587) (2674) Inpatient Medical Costs 130 304* (1721) (587) 183 404* (847) (612) Ambulatory Pharmacy Costs Numbers in parentheses are +SD. *P<0. 001 versus non-cirrhotic liver disease. Gordon SC, et al. Hepatology. 2012; 56: 1651 -1660. 177* (444) 22 (591)

PATIENTS SHOULD BE SCREENED FOR HCV ACCORDING TO BIRTH COHORT AND RISK FACTORS 1, 2 PATIENT SCREENING FOR HCV Birth Cohort Screening Risk Factor–Based Screening Persons Born Between 1945 and 19651, 2 Important Risk Factors 1, 2 • The 1945 -1965 birth cohort was selected on the basis of HCV prevalence and disease burden • One-time screening for HCV infection in the birth cohort may identify infected patients at earlier stages of disease • Past or current injection drug use • Incarceration • Receiving a blood transfusion before 1992 • Getting an unregulated tattoo • Long-term hemodialysis • Intranasal drug use • Other percutaneous exposures • Being born to an HCVinfected mother 1. Smith BD, et al. MMWR Recomm Rep. 2012; 61: 1 -32. Moyer VA; US Preventive Services Task Force. Ann Intern Med. 2013; 159: 349 -357. 23

Cost Per QALY Saved (Dollars) Cost-Effectiveness of HCV Testing vs Other Routine Preventive Services With Treatment 3 -Drug Treatment With Treatment 2 -Drug Treatment *Birth cohort testing, 1945 -1965. 2 -drug treatment=Peg. IFN+RBV; 3 -drug treatment=Peg. IFN+RBV+PI. QALY=quality-adjusted life-year. www. prevent. org/National-Commission-on-Prevention-Priorities/Rankings-of-Preventive-Services-for-the-US-Population. aspx. Rein DB, et al. Ann Intern Med. 2012; 156: 263 -270. 24

Laboratory Diagnosis of Chronic HCV Infection RNA testing identifies active disease in HCVseropositive patients � HCV antibodies appear by 6– 8 weeks following infection 1 � Anti-HCV Symptoms +/– Titer ALT › Can be detected by EIA 2 Serum ALT is not a reliable indicator of liver damage 1 � FDA-approved rapid point-of-care testing is available 3 ALT (U/L) HCV RNA ULN � 0 1 2 3 4 5 6 1 Months 2 3 Years Time After Exposure › Ora. Quick® HCV Test ALT=alanine aminotransferase; EIA=enzyme immunoassay; RNA=ribonucleic acid; ULN=upper limit of normal. Image adapted from Microbiology. Bytes: Virology: HCV 1 1. www. microbiologybytes. com/virology/HCV. html; 2. Alter MJ, et al. MMWR Recomm Rep. 2003; 52(RR-3): 1 -13, 15; 3. Shivkumar S, et al. Ann Intern Med. 2012; 157: 558 -566. 25 4

HCV Diagnostic Algorithm Based on Serologic Testing Anti-HCV Antibody Positive HCV RNA Negative No Further Testing No Active Disease HCV Genotype Positive Consider Liver Biopsy Vaccinate for HAV / HBV* *If patient lacks pre-existing antibodies to HAV or HBV. HAV=hepatitis A virus, HBV=hepatitis B virus. Ghany MG, et al. Hepatology. 2009; 49: 1335 -1374. 26

27

Scoring Systems for Histologic Stage Appearance Ishak Description Ishak METAVIR Score 1 Score 2 No fibrosis 0 Fibrous expansion of some portal areas ± short fibrous septa 1 Fibrous expansion of most portal areas ± short fibrous septa 2 Fibrous expansion of most portal areas with occasional portal to portal (P–P) bridging 3 Fibrous expansion of most portal areas with marked bridging (P–P and portal to central [P–C]) 4 Marked bridging (P–P and/or P–C) with occasional nodules (incomplete cirrhosis) 5 Cirrhosis 6 F 2 F 3 F 4 1. Bedossa P, Poynard T. Hepatology. 1996; 24: 289 -293; 2. Ishak K, et al. J Hepatol. 1995; 22: 696 -699. Figure adapted from Standish RA, et al. Gut. 2006; 55: 569 -578. 28

Invasive and Noninvasive Fibrosis Tests Transient Elastography MRE Measures direct and indirect serum markers* of fibrosis Liver stiffness by detection of ultrasound -propagated shear waves Liver stiffness by MRI of vibrationpropagated shear waves High Moderate (APRI) to high (Fibro. SURETM, ELF) High Accuracy for detecting intermediate fibrosis High Low (APRI) to moderate (Fibro. SURETM, ELF) Moderate to high High Risk of complications Risk of pain/bleeding Minimal Contraindications Coagulopathy Minimal Obesity; narrow rib spaces Claustrophobia; other MRI contraindications Limitations Sampling error Observer variation False-positives with hemolysis, inflammation, Gilbert’s syndrome False-positives with inflammation, congestion Longitudinal monitoring Unsuitable Indices may change with disease progression / therapy Liver stiffness changes with disease progression / therapy Cost Highest per-test cost Low per-test cost High initial equipment cost Very high initial equipment 29 cost Liver Biopsy Serum Markers Methodology Direct observation Accuracy for detecting cirrhosis Nguyen D, Talwalkar JA. Hepatology. 2011; 53: 2107 -2110.

Fibro. Scan 30

Indirect Serum Tests for Fibrosis Sensitivity (%)* Specificity (%)* PPV (%)* NPV (%)* Cirrhosis Discrimination Fibrosis Discrimination AST, ALT 53 100 81 + – APRI 2 AST/platelet count 77 72 70 79 + +/– (moderate) FIBROSpect II® 3, 4 HA, TIMP-1, a 2 macroglobulin 72 74 61 82 + + Fibro. SURETM a 2 -macroglobulin, haptoglobin, Apo A 1, GGT, total bilirubin, ALT 84 95 76 91 + + Hepa. Score® 7 Age, gender, bilirubin, GGT, HA, g 2 -macroglobulin 77 70 71 77 + + ELF 8 HA, N-terminal propeptide of type III collagen, TIMP-1 86 62 80 70 + + Test Components AST/ALT ratio 1 5, 6 • Fibro. Test ALT=alanine aminotransferase; Apo A 1=apolipoprotein A 1; GGT= gamma-glutamyl transpeptidase; HA=hyaluronic acid; NPV=negative predictive value; PPV=positive predictive value; TIMP-1=tissue inhibitor of metalloproteinase. *Sensitivity, specificity, PPV, and NPV values are for significant fibrosis, with the exception of AST/ALT ratio, where the values are for cirrhosis. 1. Sheth SG, et al. Am J Gastroenterol. 1998; 93: 44 -48; 2. Lin ZH et al. Hepatology. 2011; 53: 726 -736; 3. Zaman A, et al. Am J Med. 2007; 120: 280. e 9 -e 14; 4. www. prometheuslabs. com/Resources/Fibrospect_II_Product_Detail. pdf; 5. Poynard T, et al. Comp Hepatol. 2004; 3: 8; 6. www. labcorp. com/. Edos. Portlet/Test. Menu. Library? lib. Name=File+Library&comp. Name=L 1080; 7. Guéchot J, et al. Clin Chim Acta. 2010; 411: 86 -91; 8. Guéchot J, et al. Clin Chem Lab Med. 2012 ; 50: 693 -699. 31

Counseling Recommendations for HCV-Infected Individuals To Prevent HCV Transmission § Avoid sharing toothbrushes and dental or shaving equipment § Prevent blood contact with others § Stop using illicit drugs; those who continue to inject drugs should take precautions to avoid viral transmission § Risk of sexual transmission is low, but practice “safe sex” Additional Recommendations § Avoid alcohol consumption – Excess alcohol may lead to progressive liver disease, increased HCV RNA replication, and reduced response to treatment § Consider treatment for hepatitis C* § Vaccinate for hepatitis A and B § Get tested for HIV § Encourage family members to get screened *If patient meets generally accepted indications for HCV treatment. Adapted from Ghany MG, et al. Hepatology. 2009; 49: 1335 -1374. 32

Treatment Goal in HCV Is SVR HCV HBV Host Cell HIV Host Cell Viral RNA ccc. DNA Host DNA Nucleus Treatment Goal: SVR 1 Proviral DNA Host DNA Nucleus Treatment Goal: Life-long viral suppression 1 § Majority of patients who achieve an SVR do not experience viral recurrence 2 ccc. DNA=covalently closed circular DNA; HBV=hepatitis B virus. Images adapted from Soriano V, et al. 1 1. Soriano V, et al. J Antimicrob Chemother. 2008; 62: 1 -4; 2. Swain MG, et al. Gastroenterology. 2010; 139: 1593– 1601. 33

Virologic Response to Therapy ETR† HCV RNA (log 10 IU/m. L) Null Response Partial Response Relapse Undetectable RVR EVR SVR Weeks After Start of Therapy †Shown for 48 -week fixed-treatment course; follow stopping rules for treatment. Adapted from Ghany MG, et al. Hepatology. 2009; 49: 1335 -1374. 34

Sustained Virologic Response (SVR) Achieved After Treatment Is Durable SVR = HCV RNA negative (by a sensitive assay, <25 IU/m. L) at 12 weeks after cessation of treatment 1 � 99% of patients who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the followup period 2, * � › “These data suggest that the recurrence of HCV RNA is extremely rare in patients who achieve an SVR, and it now appears likely that such patients may be considered “cured” from a virologic standpoint” 2 � For patients with cirrhosis, current guidelines recommend monitoring those who have achieved an SVR at 6 - or 12 month intervals for the development of HCC 1 *After treatment with peginterferon alfa-2 a ± ribavirin; mean follow-up, 3. 9 years (range, 0. 8– 7. 1 years). 1. Ghany MG, et al. Hepatology. 2009; 49: 1335 -1374; 2. Swain MG, et al. Gastroenterology. 2010; 139: 1593– 1601. 35

SVR and All-cause Mortality in CHC Patients with Advanced Fibrosis 530 patients followed for a median of 8. 4 years SVR patients Non-SVR patients 29. 9 30 27. 4 26. 0 10 -year cumulative occurrence rate (%) Baseline factors significantly associated with all-cause mortality: � Older age � GT 3 (2 -fold increase in mortality and HCC) � Higher Ishak fibrosis score � Diabetes � Severe alcohol use Van der Meer A, et al. JAMA 2012; 308: 2584‒ 2593. 25 21. 8 20 15 10 8. 9 5. 1 5 2. 1 1. 9 0 All-cause mortality Liver-related mortality or liver transplant HCC Liver failure 36

SVR Reduced Risk of All-Cause Mortality in a Retrospective VA Study Genotype 1 (n=12, 166) (n=1794) (n=2904) SVR rate: 35% Cumulative Mortality (%) Genotype 3 Genotype 2 SVR rate: 62% SVR rate: 72% Non. SVR Non-SVR P<. 0001 SVR 0 1 2 3 Years 4 5 P<. 0001 SVR 6 0 1 2 3 4 SVR 5 6 0 Years Retrospective analysis of veterans who received pegylated interferon plus ribavirin at any VA medical facility (2001 -2008). SVR=sustained virological response. Backus LI, et al. Clin Gastroenterol Hepatol. 2011; 9: 509 -516. 1 2 3 Years 37 4 5 6

Achieving SVR Was Associated With a 62 -84% Reduction in the Risk of All-Cause Mortality Saleem J et al, AASLD 2014; Abstract #44 38

Achieving SVR Was Associated With a 68 -79% Reduction in the Risk of HCC Saleem J et al, AASLD 2014; Abstract #44 39

Achieving SVR Was Associated With a 90% Reduction in the Risk of Liver Transplantation Saleem J et al, AASLD 2014; Abstract #44 40

SVR Was Associated with Improved Quality of Life in a Real-World Clinic Population A study of community patients from hospitals in Vancouver has shown that sustained responders reported higher scores than treatment failures on each domain of the SF-36 and on utility measures Mean Difference Mean difference in scores (SVR versus treatment failure) * * † † † * Bodily Pain General Physical Role Social Health Functioning Emotional Functioning Vitality Mental Health PCS ≠ MCS SF-36 Scales This analysis was part of a larger study examining the quality of life and economic burden of HCV in community patients recruited from 5 clinical settings in Vancouver, British Columbia, and included a cross-sectional administration of questionnaires with retrospective review of medical records. Of these, 235 patients (133 responders and 102 treatment failures) completed questionnaires at an average of 3. 7 years after end of treatment. Patients with advanced liver disease were excluded. Sustained responders = undetectable HCV viral levels 6 months after therapy; treatment failures = detectable HCV viremia after therapy, or patients with an end-of-treatment response who relapsed. MCS = mental summary score (0 -100); PCS = physical summary score (0 -100). *P<. 0001; †P<. 001; ≠P<. 01. John-Baptiste AJ, et al. Am J Gastroenterol. 2009; 104: 2439 -2448. 41

Mean Change From Baseline SVR Was Associated With Improved HRQOL in a Survey of Patients With Advanced Fibrosis or Cirrhosis HRQOL Scale Study assessed change from baseline to week 72 in HRQOL and sexual health in patients with advanced fibrosis or cirrhosis in the HALT-C Trial. HRQOL=Health-related quality of life. HRQOL was assessed with the 36 -item Short Form Health Survey (SF-36), plus 3 additional questions that addressed self-reported sexual functioning, desire, and satisfaction and were hypothesized to measure sexual effects of chronic HCV and its treatment. Bonkovsky HL, et al. J Hepatol. 2007; 46: 420 -431. 42

Treating HCV Has Been Shown to Reduce Healthcare Costs in the US Mean per-patient-per-month (PPPM) follow-up costs by treatment history and liver disease severity (2010) HCV-related costs Medical costs Total costs CC = compensated cirrhosis; ESLD = end-stage liver disease; NCD = noncirrhotic disease. Covariates adjusted for in the analysis included age, sex, geographical region, index year, baseline comorbidities, and baseline treatment for HCV. Gordon SC, et al. Aliment Pharmacol Ther. 2013; 38: 784 -793. 43

The Good News DAAs 2011 100 Peg. IFN SVR (%) 80 60 2001 RBV Standard IFN 1998 1991 90+ 70+ 55 42 40 2017 34 39 16 20 6 0 IFN 6 mos IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos Peg. IFN/ RBV/ DAA +/- RBV Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27 -28, 2011, Silver Spring, MD. 44

Multi-targeted Approach for Treatment: Approved Protease, Polymerase and NS 5 A Inhibitors Ledipasvir Ombitasvir Daclatasvir Elbasvir Simeprevir Paritaprevir Grazoprevir Asunaprevir *agents in red will be briefly discussed but are investigational in the US Sofosbuvir Adapted from Mc. Govern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48: 1700 -12 Dasabuvir Beclabuvir 45

DAAs in Late-Stage Clinical Development for Chronic HCV Infection NS 3/4 A Protease Inhibitors Approved Simeprevir Boceprevir Telaprevir Paritaprevir/r Grazoprevir Phase 3 Asunaprevir ABT-493 GS-9857 Phase 2 Vedroprevir Sovaprevir Not all inclusive. Nucleotide NS 5 B Polymerase Inhibitors Non-Nucleoside NS 5 B Polymerase Inhibitors NS 5 A Replication Complex Inhibitors Sofosbuvir Dasabuvir Ledipasvir Ombitasvir Daclatasvir Elbasvir Beclabuvir Velpatasvir ABT-530 TMC 647055 Odalasvir MK-8408 PPI-668 ACH-3422 MK-3682 ALS-335 Cyclophilin Inhibitors SCY-635 46

AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 1 Duration of Therapy (weeks) Genotype 1 a Genotype 1 b No Cirrhosis With Cirrhosis* Ledipasvir/sofosbuvir (90/400 mg qd) 12 12 Elbasvir/grazoprevir (50/100 mg) 12† 12 12 Ombitasvir/paritaprevir/r (25/150/100 mg qd) + dasabuvir (250 mg bid) + RBV 12 NR 12 12 (no RBV) (with RBV) Sofosbuvir (400 mg qd) + simeprevir (150 mg qd) 12 NR Daclatasvir (60 mg qd)‡ + sofosbuvir (400 mg qd) 12 NR *Compensated cirrhosis. †No baseline high fold-change NS 5 A RAVs for elbasvir (includes M 28 A/G/T, Q 30 D/E/H/G/K/L/R, L 31 F/M/V, Y 93 C/H/N/S). ‡Dose may need to increase or decrease when used concomitantly with cytochrome P 450 3 A/4 inducers and inhibitors, respectively. NR: not an AASLD-IDSA recommended regimen for this patient type. Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 47

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 1 Patients Treatment-Naïve, No Cirrhosis Percent (n/N) SVR 12 Rate Relapse Rate Discontinuations Due to Adverse Events Ledipasvir/sofosbuvir 8 weeks 12 weeks 97 (119/123) 97 (385/395) 2 (2/123) <1 (3/395) 0 (0/123) <1 (2/395) Elbasvir/grazoprevir 12 weeks (non-cirrhotics and cirrhotics combined)* 97 (271/279)* 4 (10/279)* 1 (4/279)* Ombitasvir/paritaprevir/r + dasabuvir Genotype 1 a (with RBV), 12 weeks Genotype 1 b (no RBV), 12 weeks 97 (97/100) 99 (207/209) 1 (1/98) 0 (0/207) 0 (0/98) 0 (0/207) Simeprevir + sofosbuvir 12 weeks 97 (112/115) 3† (4/154) 0 (0/115) Daclatasvir + sofosbuvir 12 weeks 98 (111/113) <1 (1/113) 0 (0/113) Ledipasvir/sofosbuvir: 8 weeks (ION-3, pre-treatment HCV RNA <6 M IU/m. L), 12 weeks (ION-3 and ION-1). Elbasvir/grazoprevir: 12 weeks (C-EDGE, C-WORTHY). Ombitasvir/paritaprevir/r + dasabuvir: genotype 1 a (PEARL-IV), genotype 1 b (PEARL-III). Simeprevir + sofosbuvir: 12 weeks (OPTIMIST-1 [SVR 12 rate for genotype 1 a+Q 80 K: 96%, 44/46]). Daclatasvir + sofosbuvir (not FDA approved for genotype 1): 12 weeks (study 040 and ALLY-2). *Genotype 1 a: no baseline high fold-change NS 5 A RAVs for elbasvir (SVR 12 rate for genotype 1 a + these RAVs: 22%, 2/9). †Includes treatment-naïve and treatment-experienced patients. Kowdley KV, et al. N Engl J Med. 2014; 370: 1879 -1888; Afdhal N, et al. N Engl J Med. 2014; 370: 1889 -1898; Zeuzem S, et al. Ann Intern Med. 2015; 163: 1 -13; Sulkowski MS, et al. Lancet. 2015; 385: 1087 -1097; Ferenci P, et al. N Engl J Med. 2014; 370: 1983 -1992; Kwo P, et al. Hepatology. 2016; Jan 22. [Epub ahead of print]; Sulkowski MS, et al. N Engl J Med. 2014; 370: 211 -221; Wyles DL, et al. N Engl J Med. 2015; 373: 714 -725. 48

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 1 Patients Treatment-Naïve, Compensated Cirrhosis Percent (n/N) SVR 12 Rate Relapse Rate Discontinuations Due to Adverse Events Ledipasvir/sofosbuvir 12 weeks 94 (32/34) 3 (1/34) 0 (0/34) Elbasvir/grazoprevir 12 weeks* 97 (96/99) 1 (1/99) 2 (2/99) Ombitasvir/paritaprevir/r + dasabuvir Genotype 1 b (no RBV), 12 weeks 100 (22/22) 0 (0/22) Ledipasvir/sofosbuvir: 12 weeks (ION-3 and ION-1). Elbasvir/grazoprevir: 12 weeks (C-EDGE, C-WORTHY). Ombitasvir/paritaprevir/r + dasabuvir: genotype 1 b (TURQUOISE-II). *Genotype 1 a: no baseline high fold-change NS 5 A RAVs for elbasvir. Afdhal N, et al. N Engl J Med. 2014; 370: 1889 -1898; Lawitz E, et al. Lancet. 2015; 385: 1075 -1086; Poordad F, et al. N Engl J Med. 2014; 370: 1973 -1982; AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 49

AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 2 Duration of Therapy (weeks) No Cirrhosis Compensated Cirrhosis Sofosbuvir (400 mg qd) + RBV 12 16 -24 Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd) Not eligible to receive RBV 12 16 -24 *Dose may need to increase or decrease when used concomitantly with cytochrome P 450 3 A/4 inducers and inhibitors, respectively. Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 50

AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 3 Duration of Therapy (weeks) Sofosbuvir (400 mg qd) + PR Eligible to receive peg. IFN Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd) + RBV No Cirrhosis Compensated Cirrhosis 12 12 12 24 (no RBV) (+ RBV) *Dose may need to increase or decrease when used concomitantly with cytochrome P 450 3 A/4 inducers and inhibitors, respectively. PR: peg. IFN/RBV. Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 51

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 3 Patients Treatment-Naïve, No Cirrhosis Percent (n/N) SVR 12 Rate Relapse Rate Discontinuations Due to Adverse Events Sofosbuvir + PR 12 weeks 96 (68/71) 5* (9/181) 1† (1/94) Daclatasvir + sofosbuvir 12 weeks 97 (73/75) 3 (2/75) 0 (0/75) Treatment-Naïve, Compensated Cirrhosis Daclatasvir + sofosbuvir 24 weeks (+RBV) 85 (155/183) 7* (16/219) <1*‡ (3/468) Sofosbuvir + PR: 12 weeks (FISSION and VALENCE). Daclatasvir + sofosbuvir: 12 weeks (ALLY-3); 24 weeks (French Compassionate Use Program). *Includes genotype 3 treatment-naïve/experienced patients regardless of cirrhosis status. †Also includes genotype 3, treatment-naive cirrhotics and genotype 2, treatment-naive cohort. ‡Combined data from the 12 - and 24 -week treatment groups. Foster GR, et al. Gastroenterology. 2015; 149: 1462 -1470. Nelson DR, et al. Hepatology. 2015; 61: 1127 -1135. Hezode C, et al. Hepatology. 2015; 62(suppl S 1): 314 A. Abstract 206. 52

AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 4 Duration of Therapy (weeks) No Cirrhosis Compensated Cirrhosis Ledipasvir/sofosbuvir (90/400 mg qd) 12 12 Elbasvir/grazoprevir (50/100 mg) 12 12 Ombitasvir/paritaprevir/r (25/150/100 mg qd) + RBV 12 12 Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 53

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 4 Patients Treatment-Naïve, Treatment-Experienced SVR 12 Rate Percent (n/N) Relapse Discontinuations Rate Due to Adverse Events Ledipasvir/sofosbuvir 12 weeks No cirrhosis Compensated cirrhosis 93 (39/42) 100 (10/10) 7 (3/42) 0 (0/10) 0 (0/42) 0 (0/10) Elbasvir/grazoprevir 12 weeks No cirrhosis Compensated cirrhosis 96 (54/56) 100 (6/6) 2 (1/56) 0 (0/10) 0 (0/56) 0 (0/6) Ombitasvir/paritaprevir/r + RBV 12 weeks No cirrhosis Compensated cirrhosis 100 (91/91) 96 (52/54) 0 (91/91) 0 (0/52) 0 (0/91) 0 (0/52) Ledipasvir/sofosbuvir: 12 weeks (study 1119 and ION-4 [no cirrhosis]). Elbasvir/grazoprevir: 12 weeks (pooled analysis of phase 2/3 studies). Ombitasvir/paritaprevir/r + RBV: 12 weeks (PEARL-I [non-cirrhotics] and AGATE-1[cirrhotics]). *Includes cirrhotics/non-cirrhotics. Abergel A, et al. J Hepatol. 2015; 62(suppl 2): S 219. Abstract O 056; Naggie S, et al. N Engl J Med. 2015; 373: 705 -713; Asselah T, et al. Hepatology. 2015; 62(suppl S 1): 340 A. Abstract 251; Hezode C, et al. Lancet. 2015; 385: 2502 -2509; Asselah T, et al. J Hepatol. 2016; 64(suppl 2): S 827. Abstract SAT-278. 54

AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 5 and 6 Duration of Therapy (weeks) Ledipasvir/sofosbuvir (90/400 mg qd) AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. No Cirrhosis Compensated Cirrhosis 12 12 55

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 5 and 6 Patients Genotype 5: Treatment-Naïve, Treatment-Experienced SVR 12 Rate Ledipasvir/sofosbuvir 12 weeks No cirrhosis Compensated cirrhosis 97 (31/32) 89 (8/9) Percent (n/N) Relapse Discontinuations Rate Due to Adverse Events 3 (1/32) 11 (1/9) 0 (0/32) 0 (0/9) Genotype 6: Treatment-Naïve, Treatment-Experienced Ledipasvir/sofosbuvir 12 weeks No cirrhosis/compensated cirrhosis 96 (24/25) 4 (1/25) 0 (0/25) Ledipasvir/sofosbuvir (12 weeks): genotype 5 (study 1119) and genotype 6 (ELECTRON). Abergel A, et al. Lancet Infect Dis. 2016; 16: 459 -464. Gane EJ, et al. Gastroenterology. 2015; 149: 1454 -1461. 56

AASLD-IDSA: Alternative HCV Regimens for Treatment-Naïve Patients Genotype No Cirrhosis Compensated Cirrhosis 1 a None Ombitasvir/paritaprevir/r (25/150/100 mg qd) + dasabuvir (250 mg bid) + RBV for 24 weeks Elbasvir/grazoprevir* (50/100 mg) + RBV for 16 weeks Sofosbuvir (400 mg qd) + simeprevir† (150 mg qd) + RBV for 24 weeks Daclatasvir (60 mg qd)‡ + sofosbuvir (400 mg qd) + RBV for 24 weeks 1 b None Sofosbuvir (400 mg qd) + simeprevir (150 mg qd) + RBV for 24 weeks Daclatasvir (60 mg qd)‡ + sofosbuvir (400 mg qd) + RBV for 24 weeks 2 None 3 Sofosbuvir (400 mg qd) + RBV for 24 weeks (daclatasvir and INF ineligible, with/without compensated cirrhosis) 4 Sofosbuvir (400 mg qd) + PR for 12 weeks (INF eligible, with/without compensated cirrhosis) 5 and 6 Sofosbuvir (400 mg qd) + PR for 12 weeks (INF eligible, with/without compensated cirrhosis) *With baseline high fold-change NS 5 A RAVs for elbasvir (includes M 28 A/G/T, Q 30 D/E/H/G/K/L/R, L 31 F/M/V, Y 93 C/H/N/S). †No baseline Q 80 K detected. ‡Dose may need to increase or decrease when used concomitantly with cytochrome P 450 3 A/4 inducers and inhibitors, respectively. PR: peg. IFN/RBV. Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 57

AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 1 Duration of Therapy (weeks) Genotype 1 a No Cirrhosis Ledipasvir/sofosbuvir (90/400 mg qd) + RBV With Cirrhosis* Genotype 1 b No Cirrhosis With Cirrhosis* 12 12 (no RBV) (with RBV) 24 24 (no RBV) Elbasvir/grazoprevir (50/100 mg) 12† 12 12 Ombitasvir/paritaprevir/r (25/150/100 mg qd) + dasabuvir (250 mg bid) + RBV 12 NR 12 12 (no RBV) (with RBV) Sofosbuvir (400 mg qd) + simeprevir (150 mg qd) 12 NR Daclatasvir (60 mg qd)‡ + sofosbuvir (400 mg qd) 12 NR *Compensated cirrhosis. †No baseline high fold-change NS 5 A RAVs for elbasvir (includes M 28 A/G/T, Q 30 D/E/H/G/K/L/R, L 31 F/M/V, Y 93 C/H/N/S). ‡Dose may need to increase or decrease when used concomitantly with cytochrome P 450 3 A/4 inducers and inhibitors, respectively. PR: peg. IFN/RBV. NR: not an AASLD-IDSA recommended regimen for this patient type. Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 58

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 1 Patients Prior PR Failure, No Cirrhosis Percent (n/N) SVR 12 Rate Relapse Rate Discontinuations Due to Adverse Events Ledipasvir/sofosbuvir 12 weeks 95 (83/87) 5 (4/86) 0 (0/86) Elbasvir/grazoprevir 12 weeks (no cirrhosis and cirrhosis combined)* 94 (90/96)* 5 (15/96)* 1 (1/96)* Ombitasvir/paritaprevir/r + dasabuvir Genotype 1 a (with RBV), 12 weeks Genotype 1 b (no RBV), 12 weeks 96 (286/297) 100 (91/91) 2 (7/293) 0 (0/91) 1 (3/297) 0 (0/91) Simeprevir + sofosbuvir 12 weeks 95 (38/40) 3 (4/154) 0 (0/155) Daclatasvir + sofosbuvir 12 weeks 100† (20/20) -- -- Ledipasvir/sofosbuvir: 12 weeks (ION-2). Elbasvir/grazoprevir: 12 weeks (C-EDGE-TE from full prescribing information). Ombitasvir/paritaprevir/r + dasabuvir: 12 weeks genotype 1 a (SAPPHIRE-II) and genotype 1 b (PEARL-II). Simeprevir + sofosbuvir: 12 weeks (OPTIMIST-1 [SVR 12 rate for genotype 1 a+Q 80 K: 96%, 44/46]). Daclatasvir + sofosbuvir (not FDA approved for genotype 1): 12 weeks (HEPATHER). *Genotype 1 a: no baseline high fold-change NS 5 A RAVs for elbasvir (SVR 12 rate for genotype 1 a + these RAVs: 64%, 9/14). †Includes treatment-naïve and treatment-experienced patients. Afdhal N, et al. N Engl J Med. 2014; 370: 1483 -1493; Elbasvir/grazoprevir full prescribing information; Zeuzem S, et al. N Engl J Med. 2014; 370: 1604 -1616; Andreone P, et al. Gastroenterology. 2014; 147: 359 -365; Kwo P, et al. Hepatology. 2016; Jan 22. [Epub ahead of print]; Pol S, et al. J Hepatol. 2015; 62(suppl 2): 258. Abstract LO 3. 59

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 1 Patients Prior PR Failure, Compensated Cirrhosis Percent (n/N) SVR 12 Rate Relapse Rate Discontinuations Due to Adverse Events Ledipasvir/sofosbuvir 12 weeks (with RBV) 24 weeks (no RBV) 94 (93/99) 98 (97/99) 6 (6/99) 3 (3/99) 0 (0/99) Elbasvir/grazoprevir 12 weeks (no cirrhosis and cirrhosis combined)* 94 (90/96)* 5 (15/96)* 1 (1/96)* Ombitasvir/paritaprevir/r + dasabuvir Genotype 1 b (no RBV), 12 weeks 98 (45/46) 1. 5† (1/68) 2† (2/172) Ledipasvir/sofosbuvir: 12 weeks (ION-2 and SIRIUS). Elbasvir/grazoprevir: 12 weeks (C-EDGE-TE from full prescribing information). Ombitasvir/paritaprevir/r + dasabuvir: genotype 1 b (TURQUOISE-II). *Genotype 1 a: no baseline high fold-change NS 5 A RAVs for elbasvir. Afdhal N, et al. N Engl J Med. 2014; 370: 1483 -1493; Bourlière P, et al. Lancet Infect Dis. 2015; 15: 397 -404; Elbasvir/grazoprevir full prescribing information; Poordad F, et al. N Engl J Med. 2014; 370: 1973 -1982; Pol S, et al. J Hepatol. 2015; 62(suppl 2): 258. Abstract LO 3. 60

AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 2 Duration of Therapy (weeks) No Cirrhosis Compensated Cirrhosis Sofosbuvir (400 mg qd) + RBV 12 16 -24 Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd) Not eligible to receive RBV 12 16 -24 *Dose may need to increase or decrease when used concomitantly with cytochrome P 450 3 A/4 inducers and inhibitors, respectively. PR: peg. IFN/RBV. Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 61

AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 3 Duration of Therapy (weeks) Sofosbuvir (400 mg qd) + PR Eligible to receive peg. IFN Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd) + RBV No Cirrhosis Compensated Cirrhosis 12 12 12 (no RBV) 24 (+ RBV) (IFN ineligible) *Dose may need to increase or decrease when used concomitantly with cytochrome P 450 3 A/4 inducers and inhibitors, respectively. PR: peg. IFN/RBV. Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 62

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 3 Patients Prior PR Failure, Non-Cirrhotic Percent (n/N) SVR 12 Rate Relapse Rate Discontinuations Due to Adverse Events Sofosbuvir + PR 12 weeks 94 (49/52) 5* (9/181) 1† (1/103) Daclatasvir + sofosbuvir 12 weeks 94 (32/33) 3 (2/75) 0 (0/75) Prior PR Failure, Compensated Cirrhosis Sofosbuvir + PR 12 weeks Daclatasvir + sofosbuvir 24 weeks (+RBV) 86 (30/35) 5* (9/181) 1† (1/103) 85‡ (155/183) 7* (16/219) <1*§ (3/468) Sofosbuvir + PR: 12 weeks (BOSON). Daclatasvir + sofosbuvir: 12 weeks (ALLY-3); 24 weeks (French Compassionate Use Program). *Includes genotype 3 cohort (regardless of prior treatment experience and cirrhosis status). †Includes genotype 2 and 3 cohorts (regardless of prior treatment experience and cirrhosis status). ‡Includes treatment-naïve and treatment-experienced patients. §Combined data from the 12 - and 24 -week treatment groups. Foster GR, et al. Gastroenterology. 2015; 149: 1462 -1470. Nelson DR, et al. Hepatology. 2015; 61: 1127 -1135. Hezode C, et al. Hepatology. 2015; 62(suppl S 1): 314 A. Abstract 206. 63

AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 4 Duration of Therapy (weeks) Ledipasvir/sofosbuvir (90/400 mg qd) + RBV Elbasvir/grazoprevir (50/100 mg) + RBV Prior PR relapse Prior PR failure Ombitasvir/paritaprevir/r (25/150/100 mg qd) + RBV No Cirrhosis Compensated Cirrhosis 12 12 (with RBV) 24 (no RBV) 12 (no RBV) 16 (with RBV) 12 12 PR: peg. IFN/RBV. Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 64

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 4 Patients Treatment-Naïve, Treatment-Experienced Percent (n/N) Ledipasvir/sofosbuvir 12 weeks No cirrhosis Compensated cirrhosis Elbasvir/grazoprevir* Prior PR relapse, 12 weeks (no RBV) Prior PR failure, 16 weeks (with RBV) Ombitasvir/paritaprevir/r + RBV 12 weeks No cirrhosis Compensated cirrhosis SVR 12 Rate Relapse Rate Discontinuations Due to Adverse Events 93 (39/42) 100 (10/10) 7 (3/42) 0 (0/10) 0 (0/42) 0 (0/10) 100 (2/2) 100 (5/5) 0 (0/2) 0 (0/5) 100 (91/91) 96 (52/54) 0 (91/91) 0 (0/52) 0 (0/91) 0 (0/52) Ledipasvir/sofosbuvir: 12 weeks (study 1119 and ION-4 [no cirrhosis]). Elbasvir/grazoprevir: 12 weeks (pooled analysis of phase 2/3 studies). Ombitasvir/paritaprevir/r + RBV: 12 weeks (PEARL-I [non-cirrhotics] and AGATE-1[cirrhotics]). *Includes cirrhotics/non-cirrhotics. Abergel A, et al. J Hepatol. 2015; 62(suppl 2): S 219. Abstract O 056; Naggie S, et al. N Engl J Med. 2015; 373: 705 -713; Asselah T, et al. Hepatology. 2015; 62(suppl S 1): 340 A. Abstract 251; Hezode C, et al. Lancet. 2015; 385: 2502 -2509; Asselah T, et al. J Hepatol. 2016; 64(suppl 2): S 827. Abstract SAT-278. 65

AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 5 and 6 Duration of Therapy (weeks) Ledipasvir/sofosbuvir (90/400 mg qd) No Cirrhosis Compensated Cirrhosis 12 12 PR: peg. IFN/RBV. Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 66

General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 5 and 6 Patients Genotype 5: Treatment-Naïve, Treatment-Experienced Percent (n/N) Ledipasvir/sofosbuvir 12 weeks No cirrhosis Compensated cirrhosis SVR 12 Rate Relapse Rate Discontinuations Due to Adverse Events 97 (31/32) 89 (8/9) 3 (1/32) 11 (1/9) 0 (0/32) 0 (0/9) Genotype 6: Treatment-Naïve, Treatment-Experienced Ledipasvir/sofosbuvir 12 weeks No cirrhosis/compensated cirrhosis 96 (24/25) 4 (1/25) 0 (0/25) Ledipasvir/sofosbuvir (12 weeks): genotype 5 (study 1119) and genotype 6 (ELECTRON). Abergel A, et al. Lancet Infect Dis. 2016; 16: 459 -464. Gane EJ, et al. Gastroenterology. 2015; 149: 1454 -1461. 67

AASLD-IDSA: Alternative HCV Regimens for Prior PR Failure Genotype No Cirrhosis 1 a None Ombitasvir/paritaprevir/r (25/150/100 mg qd) + dasabuvir (250 mg bid) + RBV for 24 weeks Elbasvir/grazoprevir* (50/100 mg) + RBV for 16 weeks Sofosbuvir (400 mg qd) + simeprevir† (150 mg qd) + RBV for 24 weeks Daclatasvir (60 mg qd)‡ + sofosbuvir (400 mg qd) + RBV for 24 weeks 1 b None Sofosbuvir (400 mg qd) + simeprevir (150 mg qd) + RBV for 24 weeks Daclatasvir (60 mg qd)‡ + sofosbuvir (400 mg qd) + RBV for 24 weeks 2 None Sofosbuvir (400 mg qd) + PR for 12 weeks (IFN eligible) 3 None 4 5 and 6 Compensated Cirrhosis Sofosbuvir (400 mg qd) + PR for 12 weeks (IFN eligible, no cirrhosis and compensated cirrhosis) Sofosbuvir (400 mg qd) + RBV for 24 weeks (IFN ineligible, no cirrhosis and compensated cirrhosis) Sofosbuvir (400 mg qd) + PR for 12 weeks (INF eligible, with/without compensated cirrhosis) *With baseline high fold-change NS 5 A RAVs for elbasvir (includes M 28 A/G/T, Q 30 D/E/H/G/K/L/R, L 31 F/M/V, Y 93 C/H/N/S). †No baseline Q 80 K detected. ‡Dose may need to increase or decrease when used concomitantly with cytochrome P 450 3 A/4 inducers and inhibitors, respectively. PR: peg. IFN/RBV. Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 68

AASLD-IDSA: Recommended HCV Regimens for Prior NS 3 PI + Peg. IFN/RBV Failure, Genotype 1 Duration of Therapy (weeks) Ledipasvir/sofosbuvir (90/400 mg qd) + RBV Elbasvir/grazoprevir (50/100 mg) + RBV Genotype 1 b Genotype 1 a based on presence of baseline high fold-change NS 5 A RAVs for elbasvir No Yes Daclatasvir (60 mg qd)‡ + sofosbuvir (400 mg qd) No Cirrhosis Compensated Cirrhosis 12 12 (with RBV) 24 (no RBV) 12 12 12 16 12 24 (+ RBV) *Dose may need to increase or decrease when used concomitantly with cytochrome P 450 3 A/4 inducers and inhibitors, respectively. NS 3 PIs: telaprevir, boceprevir, or simeprevir. Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). Baseline high fold-change NS 5 A RAVs for elbasvir (includes M 28 A/G/T, Q 30 D/E/H/G/K/L/R, L 31 F/M/V, Y 93 C/H/N/S). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 69

AASLD-IDSA: Recommended HCV Regimens for Prior Sofosbuvir + RBV + Peg. IFN Failure, Genotype 1 Duration of Therapy (weeks) Ledipasvir/sofosbuvir (90/400 mg qd) + RBV No Cirrhosis Compensated Cirrhosis 12 24 Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 70

AASLD-IDSA: Recommended HCV Regimens for Prior Sofosbuvir + RBV Failure, Genotype 2 and 3 Duration of Therapy (weeks) No Cirrhosis Compensated Cirrhosis Sofosbuvir (400 mg qd) + PR IFN eligible 12 12 Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd) + RBV Not eligible to receive peg. IFN and/or RBV 24 24 *Dose may need to increase or decrease when used concomitantly with cytochrome P 450 3 A/4 inducers and inhibitors, respectively. PR: peg. IFN/RBV. Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]). AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 71

AASLD-IDSA Recommendations for Genotype 1 Patients Who Failed Other DAA-Based Regimens � Prior simeprevir + sofosbuvir or HCV NS 5 A inhibitor -based regimen failures › For patients without an urgent need for treatment, deferral of retreatment is recommended pending the availability of additional data › Compensated cirrhosis or those with an urgent need for retreatment �Test for RAVs to determine susceptibility status to NS 3 PIs and NS 5 A inhibitors �Adjust retreatment regimen based on RAV testing results �When using nucleotide-based (eg, sofosbuvir) dual therapy, a treatment duration of 24 weeks with weight-based RBV is recommended �If available, nucleotide-based (eg, sofosbuvir) triple or quadruple DAA regimens may be considered (with RBV* for 12 to 24 weeks is recommended) *Unless contraindicated. AASLD-IDSA. http: //www. hcvguidelines. org/full-report-view. February 24, 2016. 72

Long-Term Follow-Up of HCV Patients Treated With DAA Regimens � Prospective, observational cohorts Registry Characteristics › SVR Registry: SVR 12 achievers (n=5433) SVR (n=5433) 54 Sequence (n=563) 54 Male (%) 63 78 White (%) 85 84 Cirrhotics (%) 20 22 HCV genotype (%) 1 2 3 4 5 6 67 10 20 3 <1 <1 62 5 32 <1 <1 0 � Median follow-up: 71 weeks › Sequence Registry: virologic failure patients (n=536) � Median follow-up: 44 weeks � Maintained SVR: 99. 7% (5414/5433) › Late virologic relapse: 0. 1% › HCV reinfection: 0. 2% Low rates of clinical disease progression � Incidence of HCC � › SVR registry: 0. 3% (16/5433) › Sequence registry: 0. 9% (5/536) Lawitz EJ, et al. J Hepatol. 2016; 64(suppl 2): S 612 -S 613. Abstract FRI-166. Median age (years) 73

Considerations for Follow-Up of SVR Patients SVR 12 (baseline F 0/F 1) (baseline F 2/F 3) (baseline F 4 [cirrhosis]) Post-SVR Week 48 HCV RNA Non-Invasive Tests (F 0/F 1) HCV RNA Non-Invasive Tests (F 2/F 3) HCV RNA PWID, MSM Alcohol, Obesity, Diabetes No HCV RNA Every 12 Months Non-Invasive Tests Every 12 Months Serfaty L, et al. Liver Int. 2016; 36(suppl S 1): 67 -71. Yes Lifestyle Changes Diabetes Control Liver Biopsy if Elevated ALT/AST Liver Ultrasound Every 6 Months 74

Strategies To Advance HCV Patient Care PATIENT IDENTIFICATION Outreach & Awareness Need For: • Patient Awareness regarding risk factors & testing • Provider education & awareness regarding HCV testing Diagnosis. Need For: • HCV Testing Protocols • Clearly defined roles & responsibilities for HCV testing among providers • Patient education & engagement upon diagnosis HCV DISEASE MANAGEMENT SPECIALIST REFERRAL Care Coordination - Need For: • Appropriate link to quality care – “Linkage To C Care” • Improved data sharing & communication between PCP & specialist Patient Stratification- Need For: • Provider understanding of benchmarks to ensure appropriate management • CLINICAL – HCV genotype, fibrosis scores, comorbidities • SOCIOECONOMIC – Health literacy Managing Patients. Need For: 75 • HCV care management protocols/AASLD Guidelines • Clearly defined roles & responsibilities for HCV management • Patient involvement to improve adherence & treatment success 75

Hep. Cure Alliance Vision Educate HCPs on the importance of HCV and their role in the care continuum � Implement rapid testing/screening protocols to increase the number of identified HCV patient � Increase the number of HCV Ab [+] patients that go on for PCR testing & decrease the fall off rates � Increase the number of diagnosed patients linked to care & decrease the fall off rates � 76

PCP HCV Screening, Referral & Treatment Primary Care Visit Birth Age Cohort – 1945 -65 Risk Factors Abnormal LFT HCV antibody Ora. Quick or Phlebotomy NEGATIVE No Referral REFER TO GI/HEPATOLOGY PRIMARY CARE PROVIDER TREATMENT PER HCV PROTOCOL Risk Factors Past or current injection drug use Recipients of clotting factors (prior 1987) Chronic hemodialysis Persistently abnormal ALT Recipients of transfusions or organ transplants [prior 1992] Persons with recognized exposures (needlesticks, mucosal exposures) HIV-infected persons Birth to an infected mother POSITIVE HCV RNA PCR Quantitative HCV Genotype Hepatitis B Surface antigen Hepatitis B Surface Antibody Hepatitis B Core Total Antibody Hepatitis A Total Antibody HIV Antibody Abdominal Ultrasound & Fibroscan Hepatitis A & B Vaccination Alcohol Abstinence Counselling

EHCO Model: HCV Treatment by Primary Care Providers � Retrospective analysis (2012 -2015) › Academic/speciality sites (n=6) › Multiple ECHO sites (PCP and subspecialist) › Arizona, New Mexico, Oklahoma, Texas, Utah, Washington ECHO 100 Demographics of patients are similar, except for race and treatment history › � SVR 12 Rates (m. ITT) More treatment-experienced, genotype 1 and 3 patients were treated by specialist Regimens › Genotype 1 � Ledipasvir/sofosbuvir + RBV (8 and 12 weeks) 97% Specialty 98% 93% 89% 81% 80 SVR 12 (%) � 82% 60 40 � Simeprevir + sofosbuvir + RBV (12 weeks) � › Genotype 2: sofosbuvir + RBV (12 weeks) › Genotype 3: sofosbuvir + RBV (24 weeks) PCPs were as effective as specialists at treating HCV when using the ECHO model 20 0 1 (n=150|373) 3 (n=43|67) 2 (n=48|82) Genotype Georgie F, et al. J Hepatol. 2016; 64(suppl 2): S 818 -S 819. Abstract SAT-260. 78

ASCEND Study: HCV Treatment by Primary Care Providers (2015) Multicenter, open-label, phase 4 study (n=600 HCV patients) › Washington, DC (3 community health) › Providers underwent 3 -hour training on AASLD-IDSA guidelines › � � 100 97% 95% Overall PCP NP Specialist (n=304) (n=60) (n=79) (n=165) 94% 92% 80 Patients › Male (66%), HCV genotype 1 a (72%), F 3/4 (36%), HIV coinfection (24%) › HCV treatment experienced (18%), HCV RNA >6 million (19%) 60 40 Treatment duration › � Ledipasvir/sofosbuvir per full prescribing information SVR 12 Rates SVR 12 (%) � 8 (5%), 12 (90%), 24 (5%) weeks 20 HCV treatment administered independently by PCPs and NPs was safe and equally effective as with experienced specialists 0 Specialist: infectious disease or hepatology. Kattakuzhy S, et al. J Hepatol. 2016; 64(suppl 2): S 224. Abstract LBP 524. 79

WHAT’S NEXT? Pangenotypic “breakthrough” sofosbuvir/velpatasvir (Gilead) – expected June 2016 ABT-493(NS 3/4 A) + ABT-530 (NS 5 A) (Abb. Vie) – expected late 2017 Hep B NASH tenofovir alafenamide (Gilead) obeticholic acid (Phase III, Intercept) Therapeutic Vaccines – in Phase I and II clinical trials (Gilead, ABIVAX, Inovio, Ichor/Jansen) elafibranor (Phase III, Genfit) Many others Liver Cancer nivolumab (Opdivo®, BMS) sorafenib (Nexavar®, Bayer FDA approved Oct 2015) Lawitz E, et al. EASL 2016: Abstract PS 008. Poordad F, et al. EASL 2016: Abstract GS 11. Hepatitis B Foundation http: //www. hepb. org/professionals/hbf_drug_watch. htm www. cancerresearch. org 80