This is an AbbVie sponsored educational webinar which is being presented

Presented by Joseph Lim, MD April 5 th, 2017 AbbVie disclosures This is an AbbVie sponsored educational webinar which is being presented by Joseph Lim, MD, on behalf of AbbVie The purpose of the medical educational webinar is to foster increased awareness of the latest science in the management of HCV 1

Speaker disclosures Consulting honoraria: AbbVie, Bristol Myers Squibb, Gilead Research contracts (to Yale University): Bristol Myers Squibb, Conatus, Genfit, Gilead, Hologic, Intercept Objectives What EHMs are associated with HCV? What is the pathophysiology behind EHMs? What risks do HCV infected patients have of developing specific EHMs? What is the cost associated with EHMs? EHM, extra hepatic manifestations; HCV, hepatitis C virus; SVR, sustained virologic response. 2

Introduction Approximately 2% of the world s population has chronic HCV infection 1 3 Up to 3.4 million people in the USA have chronic HCV 2,4 55.5 million 14 million 3.4 million 1.7 million 485,000 HCV genotype proportion 1 2 3 4 5 6 It is estimated that up to 50% of HCV infected individuals in the USA are unaware of their infection status 3,5 1. WHO Guidelines for the screening, care and treatment of persons with chronic hepatitis C infection. April 2016. Available at: http://apps.who.int/iris/bitstream/10665/205035/1/9789241549615_eng.pdf Accessed February 2017; 2. Messina JP, et al. Hepatology. 2015;61:77 87; 3. El Serag HB. Gastroenterology. 2012;142:1264 73.e1; 4. Chak E, et al. Liver Int. 2011;31:1090 1101. 5. Younossi ZM, et al. J Viral Hepat. 2013;20:550 5. HCV can significantly impact the liver 1 Acute HCV infection Chronic infection 55 85% Mild fibrosis Moderate to severe fibrosis Cirrhosis 15 30% Decompensated cirrhosis HCC* (2 4% per year in cirrhosis) Liver transplant or early death *HCC can occur in the absence of cirrhosis 1. WHO Guidelines for the screening, care and treatment of persons with chronic hepatitis C infection. April 2016. Available at: http://apps.who.int/iris/bitstream/10665/205035/1/9789241549615_eng.pdf Accessed February 2017. 3

HCV is associated with disease beyond the liver: EHMs 1 3 EHMs can be systemic or organ specific Neurologic Endocrine Systemic Cardiovascular Metabolic Renal Skin Up to 74% of patients experience at least one extra hepatic manifestation 4 1. Cacoub P, et al. Dig Liver Dis. 2014;46:S165 73; 2. Ferri C, et al. Autoimmun Rev. 2016;15:1145 60; 3. Younossi Z, et al. Gastroenterology. 2016;150:1599 608. 4. Cacoub P, et al. Arthritis Rheum. 1999;42:2204 12. Immune related EHMs Organ related EHMs Mixed cryoglobulinemia Fatigue Depression Cryoglobulinemic vasculitis Hypothyroidism B cell NHL Sjögren's syndrome (Sicca) Autoantibodies Arthralgia/myalgia Cardiovascular disorders Type 2 diabetes Insulin resistance Glomerulonephritis Renal insufficiency PCT LP LP, lichen planus; NHL, non Hodgkin lymphoma; PCT, porphyria cutanea tarda. Cacoub P, et al. Dig Liver Dis. 2014;46:S165 73; Ferri C, et al. Autoimmun Rev. 2016;15:1145 60; Younossi Z, et al. Gastroenterology. 2016;150:1599 608; Cacoub P, et al. Ther Adv Infect Dis. 2016;3:3 14. 4

Prevalence of EHMs Mixed cryoglobulinemia Asymptomatic and symptomatic Prevalence in HCVinfected patients Prevalence in uninfected controls 30.1% 1.9% Symptomatic only 4.9% 0 Chronic renal disease 10.1% 7.6% Type 2 diabetes 15% 10% Cardiovascular disease 12.1% 10.3 Depression 24.5% 17.2% Malignancies 60% risk of lymphoma vs. uninfected controls Younossi Z, et al. Gastroenterology. 2016;150:1599 608. HCV increases the risk of mortality from both hepatic and extra hepatic diseases Cumulative mortality (%) 20 18 16 14 12 10 8 6 4 2 Mortality from hepatic diseases P<0.001 for comparison among 3 groups P<0.001 for active HCV vs. previous HCV 12.8% 1.6% 0.7% 0 0 2 4 6 8 10 12 14 16 18 20 20 18 16 14 12 10 8 6 4 2 Mortality from extra hepatic diseases P<0.001 for comparison among 3 groups P=0.002 for active HCV vs. previous HCV 19.8% 12.2% 11.0% 0 0 2 4 6 8 10 12 14 16 18 20 Active HCV infection Follow up (years) Previous HCV infection Never infected with HCV Large prospective cohort study of 18,541 anti HCV seronegative and 1095 anti HCV seropositive adults followed for a mean of 16.2 years Lee MH, et al. J Infect Dis. 2012;206:469 77. 5

Mixed Cryoglobulinemia Mixed cryoglobulinemic syndrome has a significant prevalence in patients with HCV 1 Mixed cryoglobulinemia has a significant association to HCV, which is directly involved in disease pathogenesis 1,2 Cryoglobulinemia describes the presence of large amounts of proteins (antibody) in a patient s blood 3 The proteins clump together to form complexes which are deposited in blood vessels 3 This causes vessels to become blocked and damaged = vasculitis 3 Serum cryoglobulins are detected in 50 70% of patients with HCV 2 15 30% of patients may develop mixed cryoglobulinemia 2 HCV infection is the cause of cryoglobulinemia vasculitis in ~80% of cases 1 1. Cacoub P, et al. Dig Liver Dis. 2014;46:S165 73; 2. Ferri C, et al. Autoimmun Rev. 2016;15:1145 60; 3. Ragab G, et al. J Adv Res. 2017;8:99 111. 6

Mixed cryoglobulinemia is associated with several EHMs of HCV 1,2 Mixed cryoglobulinemia contributes to the pathology of many EHMs: 1,2 Skin is the most frequently involved organ (eg, palpable purpura) Kidneys (eg, glomerulonephritis) Nervous system (eg, sensory axonopathy) Joints Disease expression ranges from mild (arthralgia) to serious (widespread vasculitis) 1,2 1. Cacoub P, et al. Ther Adv Infect Dis. 2016;3:3 14; 2. Cacoub P, et al. Dig Liver Dis. 2014;46:S165 73. Renal 7

HCV can induce acute and chronic renal disease Acute kidney injury Vasculitis HCV Formation of protein complexes Glomerulonephritis CKD Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Direct cytotoxicity can accelerate progression of CKD CKD, chronic kidney disease. Barsoum RS, et al. J Adv Res. 2017;8:113 30. HCV is associated with a higher incidence of CKD HCV infected patients have a 23% higher risk of presenting with CKD vs. non HCV infected patients 1 Cohort study of US veterans data 2004 2006: n=100,518 HCV+ vs. n=920,531 HCV 2 15% higher incidence of decreased kidney function 2 fold higher incidence of ESRD 2.2 fold higher mortality ESRD, end stage renal disease. 1. Park H, et al. J Viral Hepat. 2015;22:897 905; 2. Molnar M, et Hepatology. 2015;61:1495 502.al. 8

Renal disease is associated with a faster progression of cirrhosis in patients with HCV Database study evaluating the progression of liver disease and kidney disease in patients with HCV and CKD Time to fibrosis stage progression: 784 patients with HCV and CKD vs. 1573 patients with HCV Time to egfr progression: 458 patients with HCV and CKD vs. 916 patients with CKD % of patients with outcome 25 20 15 10 5 HCV + CKD HCV P<0.001 0 0 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Years to outcome Liver disease progression is defined as an increase FIB4 stage: F0 F1 to F2 or F3 F4, and F2 to F3 F4. Kidney disease progression is defined as a 4 ml/min/1.73 m2 per year decline in egfr. egrf, estimated glomerular filtration rate. AbbVie Inc. Data on file H17.DoF.08 80 70 60 50 40 30 20 10 HCV + CKD CKD P<0.001 9 HCV infected patients have higher rates of mortality from renal diseases than uninfected patients Community based cohort study of 23,820 individuals aged 30 65 years enrolled from 1991 to 1992 and followed until December 2008 Cumulative risk (%) Cumulative mortality from nephritis, nephrotic syndrome, and nephrosis* 6 5 4 3 Active HCV infection Previous HCV infection Never infected with HCV P=0.008 for comparison among 3groups P=0.71 for active HCV vs. previous HCV 2 1.48% 1 0.92% 0.47% 0 0 2 4 6 8 10 12 14 16 18 20 Follow up years *Cumulative mortality by serostatus of antibodies against HCV (anti HCV) and serum HCV RNA level at study entry. RNA, ribonucleic acid. Lee MH, et al. J Infect Dis. 2012;206:469 77. 9

Patients with HCV and CKD have a higher comorbidity burden and worse outcomes than those with HCV alone US patients with HCV and renal impairment had a higher risk of clinical outcomes during 1 year follow up than HCV patients without renal impairment Adjusted odds ratio (Log scale) 10.0 8.0 6.0 5.0 4.0 3.0 2.0 1.0 HCV alone without renal impairment HCV and CKD stages 2 4 HCV and ESRD (CKD 5) Patients aged 65 years (N=10,608) Results are consistent with those seen in patients <65 years Diagnosis of HCV, CKD, and ESRD identified via ICD 9 and CPT code. CKD defined as GFR between 15 90 ml/min. ESRD is defined as GFR <15 ml/min. AMI, acute myocardial infarction; CPT, current procedural technology; ICD, International Classification of Diseases. Senaka P, et al. Hepatology. 2015;62(Suppl):1120A. Metabolic 10

Type 2 diabetes and insulin resistance are more prevalent in HCV patients than in healthy individuals 1,2 HCV is associated with disturbances to the metabolic role of the liver, and possibly leading to insulin resistance and Type 2 diabetes mellitus 3 Patients with HCV have a 2.3 fold increased risk of Type 2 diabetes 2 Insulin resistance parameters are higher in patients with HCV than healthy controls* 1 Insulin C peptide 12 P=0.002 1000 P<0.001 Insulin (µu/ml) 10 8 6 4 2 0 HCV (n=121) Control (n=137) *Colored bars indicate the mean, error bars indicate standard deviation. 1. Hui JM, et al. Gastroenterology. 2003;125:1695 704; 2. Tang L, et al. Infect Agents Cancer. 2016;11:29; 3. Antonelli A, et al. World J Diabetes. 2014;5:586 600. C Peptide (pmol/l) 800 600 400 200 0 HCV (n=121) Control (n=137) Type 2 diabetes is an independent risk factor for cirrhosis in patients with chronic HCV Cumulative incidence of cirrhosis 0.22 0.20 0.18 0.16 0.14 0.12 0.10 0.08 0.06 Incidence of cirrhosis was significantly higher among patients with new onset diabetes New onset diabetes (n=424) P<0.001 0.04 0.02 Non diabetes (n=1708) 0.00 0 1 2 3 4 5 6 7 8 9 10 11 Years of follow up Large cohort study: 2132 patients with HCV (424 patients with new onset diabetes and 1708 patients without diabetes) were evaluated for development of cirrhosis or decompensation 1 1. Huang YW, et al. Hepatology. 2014;60:807 14. 11

Cardiovascular HCV is a risk factor for the development of cardiovascular disease 1 HCV infection is associated with multiple cardiovascular disorders 2 HCV Brain Cerebrovascular events Arterial Atherosclerosis Arterial stiffness Peripheral artery disease Heart Cardiovascular events Myocardial injury Increased risk of cerebro cardiovascular mortality 1. Cacoub P, et al. Dig Liver Dis. 2014;46:S165 73; 2. Petta S. J Adv Res. 2017;8:161 8. 12

Chronic HCV infection is associated with an increased risk of cardiovascular mortality Community based cohort study of 23,820 individuals aged 30 65 years enrolled from 1991 to 1992 and followed until December 2008 Cumulative risk (%) 6 5 4 3 2 Active HCV infection Previous HCV infection Never infected with HCV P=0.005 for comparison among 3 groups P=0.36 for active HCV vs. previous HCV 5.0% 3.5% 2.9% 1 0 0 2 4 6 8 10 12 14 16 18 20 Follow up (years) Lee MH, et al. J Infect Dis. 2012;206:469 77. HCV is associated with an increased the risk of stroke A population based cohort study of 4094 patients with newly diagnosed HCV and 16,376 age and gender matched controls monitored for incidence of stroke between 2002 2008 Cumulative risk of stroke 4% 3% 2% 1% Cumulative risk of stroke in HCV infected and uninfected populations 2.5% P<0.0001 1.9% After controlling for conventional risk factors, patients with HCV were more likely to experience a stroke than control subjects 0% HCV positive (n=4094) HCV negative (n=16,376) Liao CC, et al. PLoS ONE. 2012;7:e31527. 13

HCV is more prevalent in stroke patients Case controlled study of 820 patients admitted in 2010 2012 (123 patients with ischemic stroke vs. 697 matched controls) were evaluated for HCV infection HCV prevalence 50% 40% 30% 20% 10% 0% Prevalence of HCV in stroke patients vs. controls 26.8% Stroke patients (n=123) P=0.0001 6.6% Matched controls n=697) HCV was more prevalent in stroke patients than in control patients Adinolfi LE, et al. Atherosclerosis. 2013;231:22 6. Presumed mechanism of Type 2 diabetes and CV disease development in HCV infected patients 1 Interference with insulin signaling Secretion of soluble mediators Insulin resistance Type 2 diabetes Liver fibrosis HCC HCV Chronic inflammation Endothelial damage Atherosclerosis Cardiovascular and cerebrovascular outcomes The pro inflammatory environment leading to fibrosis of the liver may also lead to atherosclerosis 2 CV, cardiovascular. 1. Negro F. J Hepatol. 2014;61:S69 S78; 2. Negro F, et al. Gastroenterology. 2015;149:1345 60. 14

Malignancies HCV is associated with higher incidence of extra hepatic malignancies In the United States (2006 2010), incidence and age adjusted mortality of several extra hepatic malignancies were higher in patients with chronic HCV infection than in general population 1 Malignancy Incidence, SSR (95% CI) CI, confidence interval; RR, relative risk; SSR, standardized rate ratio. *Significantly greater in patients with chronic HCV infection vs. the general US population. 1. Allison RD, et al. J Hepatol. 2015;63:822 8; 2. Fiorino S, et al. World J Gastroenterol. 2015;21:12896 953. Age adjusted mortality, RR (95% CI) Pancreas 2.5 (1.7 3.2)* 1.6 (1.6 1.7)* Oral 2.5 (0.9 4.1) 5.2 (5.1 5.4)* Rectum 2.1 (1.3 2.8)* 2.6 (2.5 2.7)* Kidney 1.7 (1.1 2.2)* 0.5 (0.4 0.5) NHL 1.6 (1.2 2.1)* 2.3 (2.2 2.3) Lung 1.6 (1.3 1.9)* 1.0 (1.0 1.0) In addition, chronic HCV infection has been associated with B cell NHL, intrahepatic cholangiocarcinoma, and pancreatic cancer 2 15

HCV infection is strongly associated with hematologic malignancies, including B cell NHL 1 Mixed cryoglobulinemia may be a precursor to B cell NHL 2 Most patients with HCV associated B cell NHL have mild liver disease at diagnosis 3 Patients with cryoglobulinemia have a 35x greater risk of developing B cell NHL 2 In a single center study of 89 patients with HCV associated B cell NHL, 82% of patients had mild to moderate fibrosis at time of diagnosis 3 NHL, non Hodgkin lymphoma. 1. Cacoub P, et al. Dig Liver Dis. 2014;46:S165 73; 2. Tang L, et al. Infect Agents Cancer. 2016;11:29 3. Torres HA, et al. Liver Int. 2015;35:1661 1664. Other Extra Hepatic Manifestations 16

Neurocognitive morbidity is associated with HCV infection 1 ~50% of patients with HCV report neuropsychiatric symptoms 2 Depression is commonly reported in patients with HCV 3,4 HCV Brain Syndrome 3 Fatigue has been reported in 20 80% of patients with HCV 3,5 Cognitive impairment has been reported in patients with HCV 3,5 Quality of life is impaired, even in the absence of significant liver disease 3 1. Cacoub P, et al. Dig Liver Dis. 2014;46:S165 73; 2. Mathew S, et al. World J Hepatol. 2016;8:545 56; 3. Yarlott L, et al. J Adv Res. 2017;8:139 48; 4. Younossi Z, et al. Gastroenterology. 2016:150:1599 608; 5. Monaco S, et al. World J Gastroenterol. 2015;21:11974 83. Additional EHMs associated with HCV Thrombocytopenia 1,2 most frequent cytopenia associated with HCV: 10x higher in HCV+ vs. HCV Monoclonal gammopathies 1,3 are strongly associated with HCV and can progress to B cell NHL Sjögren's (Sicca) syndrome 1 eye or mouth symptoms reported in 20 30% of patients with HCV Autoantibody 1 prevalence is high in patients with chronic HCV Arthralgia/myalgia 1 reported in 40 80% of patients with mixed cryoglobulinemia Hypothyroidism 1,4 prevalence is 3 times higher in patients with chronic HCV Polyarthritis/fibromyalgia 1,5 widespread pain is reported by 2 57% of patients with chronic HCV PCT 1,6 reported in <5% of patients with HCV; 66% of patients with PCT have HCV LP 1,6 reported in 2% of patients with HCV; 4 24% of patients with LP have HCV 1. Cacoub P, et al. Dig Liver Dis. 2014;46:S165 73; 2. Ferri C, et al. Autoimmun Rev. 2016;15:1145 60; 3. Mihăilă RG. World J Gastroenterol 2016;22:6214 23; 4. Shen Y, et al. J Gastrointestin Liver Dis. 2016 Jun;25(2):227 234. 5. Palazzi C, et al. World J Gastroenterol 2016;22:1405 10; 6. Dedania J Clin Trans Hepatol 2015;3:127 133. 17

Economic Burden Chronic HCV has a substantial economic burden that increases with severity of disease Estimated mean annual costs per patient ($) 160,000 120,000 80,000 40,000 0 $17,277 Non cirrhotic liver disease $22,752 Compensated cirrhosis $59,995 End stage liver disease $112,537 HCC $145,045 Orthotopic liver transplantation Gordon SC, et al. Hepatology. 2012;56:1651 60. 18

EHMs increase the economic burden of HCV 1,2 Chronic HCV has a substantial economic burden that increases with severity of disease and complications of EHMs 1 3 Based on a 2014 estimate of 2.68 million people infected with HCV in the United States, direct medical costs of associated EHMs per patient per year ranged from: $127 (lichen planus) to $71,000 (ESRD) 2 The total annual direct cost associated with HCV associated EHMs in the United States was estimated to be $1.5 billion in 2014 2 ESRD, end stage renal disease. 1. Gordon SC, et al. Hepatology. 2012;56:1651 60; 2. Younossi Z, et al. Gastroenterology. 2016;150:1599 608; 3. Cacoub P, et al. Dig Liver Dis. 2014;46:S165 73. Economic burden of EHM and liver related medical costs in HCV and non HCV patients Annual weighted mean medical costs per patient (2016 USD) $30,000 $20,000 $17,416 $10,000 $ $11,650 HCV Patient Liver related Burden HCV cohort (n=17,054), Non HCV cohort (n=85,270) AbbVie Data on File H17.DOF.06 $6,550 Non HCV Patient EHM related Burden $240 19

Summary In addition to hepatic complications, HCV is associated with many EHMs 1,2 Patients with chronic HCV are at an increased risks of complications from EHMs 1,2 Renal Increased risk of ESRD 3 Metabolic Increased risk of insulin resistance and Type 2 diabetes 4,5 Increased risk of renal and cardiovascular comorbidities in diabetics 6 Cardiovascular Increased incidence of acute coronary syndrome and stroke 3 Increased risk of cardiovascular mortality 7 Cryoglobulinemia Increased risk of mixed cryoglobulinemia and downstream associated EHMs 4,8 Malignancies Increased incidence of lymphoma 4,9 Neurologic Decreased cognitive performance 4 Increase in fatigue 4 1. Cacoub P, et al. Arthritis Rheum. 1999;42:2204 12. 2. Cacoub P, et al. Dig Liver Dis. 2014;46:S165 73. 3. Hsu YC, et al. Gut. 2015;64:495 503; 4. Negro F, et al. Gastroenterology. 2015;149:1345 60; 5. Arase Y, et al. Hepatology. 2009;49:739 44; 6. Hsu, YC, et al. Hepatology. 2014;59:1293 302; 7. Lee MH, et al. J Infect Dis. 2012;206:469 77. 8. Gragnani L, et al. Hepatology. 2015;61:1145 53; 9. Kawamura Y, et al. Am J Med. 2007;120:1034 41. 20

Summary: The importance of EHMs in HCV Up to 74% of individuals with chronic HCV also suffer from EHMs of HCV 1 EHMs strongly associated with HCV infection include mixed cryoglobulinemia, CKD, Type 2 diabetes, and cardiovascular disease 7 Renal disease is associated with a faster progression of cirrhosis in patients with HCV 2 Chronic HCV increases risk of insulin resistance, stroke, and cardiovascular mortality 3 6 EHMs of HCV have been associated with increased mortality, reduced quality of life, and increased health care spending 6,8 1. Cacoub P, et al. Arthritis Rheum 1999;42:2204 12; 2. AbbVie Inc. Data on File H17.DoF.08 3. Antonelli A, et al. World J Diabetes. 2014;5:586 600. 4. Petta S. J Adv Res. 2017;8:161 8. 5. Liao CC, et al. PLoS ONE. 2012;7:e31527 6. Cacoub P, et al. Dig Liver Dis. 2014;46:S165 73; 7. Ferri C, et al. Autoimmun Rev. 2016;15:1145 60; 8. Nuño Solinís R, et al. Infect Dis Ther. 2016;5:491 508; 21