Zobair M. Younossi M.D., M.P.H., FACG

HCV Epidemiology and Cohort Screening Guidelines Zobair M. Younossi, MD, MPH, FACG Consultant or Advisor: Conatus, Enterome, Gilead, Merck, Salix, Vertex, J & J HCV Epidemiology and Cohort Screening Guidelines Zobair M. Younossi M.D., M.P.H., FACG Chairman, Department of Medicine Inova Fairfax Hospital Vice President for Research Inova Health System Falls Church, VA 1

Disclosures Dr. Younossi is a consultant or Advisor to Gilead, Merck, Enterom, Coneautus, Vertex, Salix and J & J This presentation does not include off-label discussion of any medication The Impact of HCV Epidemiologic Impact of HCV: True prevalence of HCV Natural history-the wave of HCV-related liver disease HCV-infected cohorts at higher risks Factors affecting progression of liver disease Economic burden of HCV HCV Screening: Awareness of HCV infection: Effectiveness of risk based screening An alternative screening program: Birth Cohort Screening Other barriers 2

HCV Epidemiology and Cohort Screening Guidelines Zobair M. Younossi, MD, MPH, FACG Consultant or Advisor: Conatus, Enterome, Gilead, Merck, Salix, Vertex, J & J Prevalence of Hepatitis C: United States 185 million people are infected with HCV globally Based on CDC National Health and Nutrition Examination Survey III (NHANES III), 2.7 3.9 million people in U.S. have HCV 1 1.3% - 1.9% of U.S population ever infected with HCV 1 Question: Was the initial estimation of HCV prevalence correct? 2 1. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/hepatitis/hcv/statisticshcv.htm. Accessed 10/26/10. 2. Edlin BR. Hepatology 2005;42(Suppl 1):213A. 3

Has the Prevalence of Hepatitis C Infection in the US Been Underestimated? Population Reported Prevalence Range Estimated Number in US Estimated Range of HCV Cases Homeless 22.2-52.5% 643,067 142,761-337,610 Incarcerated 23.1-41.2% 1,613,656 372,754-664,826 Veterans 5.4-10.7% 22,915,943 1,237,461-2,452,006 Chronic Hemodialysis Hemophiliacs with Transfusions before 1992 Chak E et al. Liver Int 2011, 1478-3231 7.8% 263,820 20,578 76.3-100% 17,000 12,971-17,000 Has the Prevalence of Hepatitis C Infection in the US Been Underestimated? (cont) Population Reported Prevalence Range Estimated Number in US Estimated Range of HCV Cases Nursing Home Residents 4.5% 1,413,540 63,609 Active Military Duty 0.48% 1,417,747 6,805 Healthcare Workers 0.9-3.6% 7,200,950 64,809-259,234 Unaccounted number of HCV positive 1,921,748-3,821,668 Chak E et al. Liver Int 2011, 1478-3231 4

Chronic Hepatitis C Infection in the United States Estimated Hepatitis C Cases Cases (in millions) Number of 8 7 6 5 4 3 2 1 0 5.2 Total 7.1 Chak E, et al. Liver Int. 2011; 31:1090-1101. http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#section2. 1.9 Conservative estimate Upper limit of estimate The Initial HCV Prevalence Rates Underestimated the True Burden of HCV 3.8 Not Included in NHANES 3.2 NHANES The Impact of HCV Is There an Age Group Contributing to the Burden of HCV Disease? 5

Two-Thirds of Those With Chronic HCV in the U.S. Were Born Between 1946 and 1964 (The Birth Cohort) 1,600,000 1,400,000 Estimated Prevalence by Age Group Individuals (n) 1,200,000 1,000,000 800,000 600,000 400,000 200,000 0 <1920 1920-1929 1930-1939 1940-1949 1950-1959 Birth Year Group 1960-1969 1970-1979 1980-1989 Pyenson B, et al. Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease. New York, NY: Milliman, Inc; 2009. 1990+ The Impact of HCV What is the Natural History of Hepatitis C? 6

Chronic Hepatitis C Progression Acute Hepatitis C Chronic Hepatitis 50 85% A 10 30 years Cirrhosis 20 30% Decompensation 6 10% HCC 5 10% Liver Transplant (1,915 transplants due to CHC in 2007) Death 5 10% (~12,000 Annually) Alberti A et al. Aliment Pharmacol Ther 2005;22(Suppl 2):74-78. Gallegos-Orozco JF, Vargas HE. Med Clin North Am 2009;93:931-950. A Centers for Disease Control and Prevention. Available at http://www.cdc.gov/hepatitis/hcv/statisticshcv.htm. Accessed 05/21/12. The Impact of HCV Combining the High Prevalence of HCV in the Birth Cohort and the Natural History of HCV, What is Wave of HCV-related Liver Disease? 7

The HCV Birth Cohort will be Responsible for Increasing Cases of Decompensation and HCC 160,000 140,000 ber of cases Num 120,000 100,000 80,000 60,000 40,000000 20,000 0 Birth Cohort Infection Decompensated cirrhosis Hepatocellular cancer 1950 1960 1970 1980 1990 2000 2010 2020 2030 Year Davis GL, et al. Gastroenterology. 2010;138(2):513-521 Hepatitis C-Related Cirrhosis Is Projected to Peak Over the Next 10 Years Num mber of patients 1,200,000 000 1,000,000 800,000 600,000 400,000 200,000 25% of patients with HCV currently have cirrhosis 37% of patients with HCV are projected to develop cirrhosis by 2020, peaking at 1 million 0 1990 2000 2010 2020 2030 Year Davis GL, et al. Gastroenterology 2010 8

Projected Disease Burden of HCV and Complications as Infected Population Ages HCV infection Cirrhosis Decompensated Cirrhosis Hepatocellular Carcinoma Liver-related death 2,940,678 2,870,391 2,281,556 2,433,709 2,177,089 472,103 720,807 858,788 879,747 828,134 65,294 103,117 134,743 146,408 142,732 7,271 11,185 13,183 13,390 12,528 13,000 27,732 36,483 39,875 39,064 Davis GL et al. Liver Transpl 2003;9:331-338. Advanced Liver Disease in Chronic HCV-Infected US Population, 2009-20282028 Individuals 250,000000 200,000 150,000 100,000 50,000 0 2009 2012 2015 2018 2021 2024 2027 Year Liver transplant Hepatocellular carcinoma Decompensated cirrhosis Assuming no changes in SOC, the total number of patients with advanced liver disease in 20 yrs is projected to be > 4-fold greater The Milliman Report. Consequences of Hepatitis C Virus (HCV): May 2009. http://www.milliman.com/expertise/healthcare/publications/rr/pdfs/consequences-hepatitis-c-virus-rr05-18-09.pdf. 9

The Impact of HCV Are we Seeing the Consequences of the Wave of HCV-related Complications? Mortality Annual age-adjusted adjusted mortality rates Ly KN et al. Ann Intern Med 2012 10

The Impact of HCV Are we Seeing the Consequences of the Wave of HCV-related Complications? Hepatocellular Carcinoma (HCC) Hepatocellular Carcinoma and HCV HCC is one of most rapidly increasing solid cancers in the United States 80%-90% of HCC cases occur in cirrhotic livers A large proportion of HCC in the U.S is related to viral hepatitis C International Agency for Cancer Research. Globocan 2002. McGlynn KA et al. Int J Cancer. 2001;94:290-296; McGlynn KA et al. Cancer Epidemiol Biomarkers Prev. 2006;15:1198-1203; El-Serag HB. Gastroenterology. 2004;127:S27-S34. 11

Presumed Etiology of HCC in the U.S. Hepatitis C is the Predominant Cause 33% 47% 15% 5% HCV HBV + HCV HBV Neither Poynard eel-serag H. Gastroenterology 2004;127:S27. HCV HBV Alcohol Cryptogenic Other Snowberger N, et al. Alim Pharm Ther 2007;26:1187. The Impact of HCV Can We Take Care of HCV-related Complication (Cirrhosis and HCC) with Liver Transplantation? 12

Demand for Livers Much Greater Than Organ Supply 20000 18000 16000 14000 12000 10000 8000 6000 4000 2000 0 Waiting List Additions to List Deceased Donors Liver Transplants 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 The Impact of HCV Over the next two decades HCV-related complications will increase 13

The Impact of HCV Are There Certain Populations at Even Higher Risks? Chronic Hepatitis C in Special Populations Special populations in this context refer to individuals with: Increased prevalence of HCV Challenges related to access to care Therapeutic difficulties Suboptimal response to therapy, etc 14

Prevalence of Antibody to HCV by Ethnicity: United States Characteristic (Participants tested, n) All participants (n=15,079) Non-Hispanic white (n=5,991) Non-Hispanic black (n=3,530) Mexican American (n=4,422) Prevalence of Antibodies to HCV, % (95% CI) 1.6 (1.3-1.9) 15(1119) 1.5 (1.1-1.9) 3.0 (2.4-3.9) 1.3 (0.8-2.1) Estimated Persons Ever Infected Nationwide, n (95% CI) 4,060,000 (3,410,000 4,850,000) 2,610,000 (2,020,000 3,380,000) 920,000 (720,000 1,170,000) 260,000 (150,000 430,000) HCV Infection in Blacks/African Americans High Prevalence of HCV The Milliman Report. Consequences of Hepatitis C Virus (HCV): May 2009. 15

Weighted Percentage 100 90 80 70 60 50 40 30 20 10 HCV Infection in Blacks/African Americans High Prevalence of HCV Genotype 1 0 91 70 71 20 11 White Non-Hispanic (n = 60) Nainan OV, et al. Gastroenterology. 2006;131:478-484. 8 1 Black Non-Hispanic (n = 125) 14 15 Mexican American (n =71) Genotype 1 Genotype 2 Genotype 3 African-Americans Americans are Less Likely to Have Hepatitis C Virus (HCV) Infection Cleared NHANES (2005-2008) 2008) cohort (N=14,750) Of these, 192 (1.32±0.11%) were anti-hcv+ with 76% having detectable HCV RNA. HCV Clearance HCV Ab (+) and HCV RNA (-) The rate of HCV clearance was lowest among African- Americans (9.25±3.47%) as compared to both Caucasians (27.21±6.49%) 21±6 and Hispanics 31.21±9.09% (p<0.05). 05) In multivariate analysis, the only independent predictor of HCV non-clearance (Active HCV infection) was African American race: OR (95% CI) = 3.80 (1.31-11.06), 11.06), p = 0.01 H Mir, M Stepanova, M Afendy, M Kugelmas, ZM Younossi J of Clin Gastro 2012 16

HCV Infection in Blacks/African Americans Negative prognostic considerations Appear to be unable to clear HCV as efficiently compared with Whites Impaired CD4 cell cytokine response Higher incidence of HCC (histologically documented): 6.1 and 2.8 per 100,000 persons in Blacks/African Americans and Whites, respectively HCC-associated mortality rate is twice that of Whites Positive prognostic considerations More likely to have lower ALT levels than other populations Lower piecemeal necrosis scores May have less fibrosis than Whites Fewer cases of cirrhosis Jeffers LJ. Liver Int. 2007;27:313-322. The Impact of HCV What Are Some of Other Factors That Affect Disease Progression? 17

Factors Associated with Fibrosis in HCV Age at infection Duration of infection Metabolic factors (steatosis steatosis, obesity, DM) Excessive alcohol use Compromised immune system Genetic factors HIV co-infection HBV co-infection Normal liver Cirrhosis Poynard T, et al. Lancet.1997;349:825-832. Monto A, et al. Hepatology. 2002;36:729-736. Marcolongo M, et al. Hepatology. 2009;50:1038-1044. Cecil Medicine 23 rd edition. Saunders Elsevier, Philadelphia, PA 2008. Metabolic Syndrome and HCV Variable Mild-moderate fibrosisi (Scheuer 1-2) Severe fibrosis (Scheuer 3-4) Univariate analysis P value Multivariate analysis OR (95% CI) P N=130 N=40 Age (years) 40.6 ± 10.2 48.8 ± 8.2 0.002 1.080 (1.028-1.136) 0.002 Gender: Male vs. female 86/44 35/5 0.009 0.329 (0.103-1.045) 0.06 IR or HOMA >2.7: Absent/present 87/43 13/27 <0.001 2.640 (1.110-6.281) 0.02 Histologic Steatosis <10% vs. 10% Grade of inflammation 1 vs. 2-3 89/41 15/25 <0.001 3.375 (1.394-8.171) 0.007 41/89 2/38 0.001 8.988 (1.853-43.593) 0.006 Petta S et al. Liver Int 2010 18

Interaction of HCV and Alcohol Disease Progression Meta-analysis analysis of 20 studies involving >15,000 patients with CH-C Heavy drinking (210 to 560 gram/week) increased risk of Advanced fibrosis [RR:1.63 (1.22-2.17)] 2.17)] Cirrhosis [RR:2.14 (1.45-3.17)] De-compensated cirrhosis [RR: 3.54 (2.14-5.85)] Hutchison SJ et al. Clin Gastro and Hepatology 2005 Interaction of HCV and Alcohol Mortality Data for 8,985 participant of NHANES III-mortality linked files CH-C: C: HCV Ab (+) and HCV RNA PCR (+) (N=218) Alcohol consumption was estimated as grams/day Excess alcohol consumption was defined as >20gram/day Outcomes: All cause mortality Cardiovascular mortality Liver related mortality Follow-up 162.95 mos (CH-C) C) and 178.27 mos (controls) Younossi Z et al. APT 2013 19

Interaction of HCV and Alcohol Mortality The Impact of HCV HCV patients with Metabolic Syndrome and those who drink alcohol excessively are at risk for advanced liver disease 20

The Impact of HCV What is the Economic Burden of HCV? The Economic Burden of HCV Direct medical costs associated with CH-C C have been estimated to be over $20,000 000 per patient annually, approximately $15,000 greater than those incurred by a demographically matched controls (Davis et al., 2011) Indirect costs resulting from loss of productivity from disease related morbidity and mortality have been estimated to reach $3.7 billion annually ($1,424-$1,710 $1,710 annually per patient) (Brook et al., 2011; Su et al., 2010; Leigh et al., 2001) 21

100 Annual US Medical Costs for Chronic HCV Infection from 2009-20282028 USD$, Billions 80 60 40 20 Medicare Uninsured VA Medicaid Commercial 0 2009 2012 2015 2018 2021 2024 2027 Year Total medical costs for patients with HCV infection are expected to be more than double, from $30 billion to more than $85 billion USD, over the next 20 yrs This is especially true for Medicare The Milliman Report. Consequences of Hepatitis C Virus (HCV): May 2009. The Impact of HCV Economic Burden of HCV is Tremendous and is Expected to Grow Over the Next Two Decades 22

How to Identify New Cases of HCV Infection? Screening for HCV How to Identify New Cases of HCV Infection? Risk-based screening strategy has been recommended by CDC and AASLD for years: How Effective Has it Been? 23

Risk-Based Screening Criteria The CDC and AASLD recommend screening for all patients with 1 or more risk factors for HCV HCV testing is recommended for at-risk persons who: Ever injected illegal drugs, even if only once many years ago Were recipients of clotting factor concentrates made before 1987 Were recipients of blood or blood product transfusions/solid organ transplants pre-july 1992 Ever received long-term hemodialysis Health care workers after needlesticks involving HCV-positive blood Recipients of blood or organs from a donor who later tested HCV-positive All persons with HIV infection Patients with signs or symptoms of liver disease (e.g., abnormal liver enzyme tests) Children born to HCV-positive mothers Centers for Disease Control and Prevention. Adapted from: http://www.cdc.gov/hepatitis/hcv/guidelinesc.htm. Accessed 09/07/2012 The Impact of HCV Effectiveness of Risk-based Screening for HCV If Risk Based Screening Strategy for HCV was Effective, Most HCV Infected Patients Should be Diagnosed and Aware of Their Infection: Is this true? 24

Are Most Infected Individuals Aware of Their HCV infection? ~3,300,000 individuals are infected Only 825,000 are aware of their infection 2,475,000 are unaware of their infection 825,000 AWARE (25%) 2,475,000 UNAWARE (75%) Centers for Disease Control and Prevention. Hepatitis C FAQs for Health Professionals. Available at: http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm. Accessed January 6, 2011. Institute of Medicine. Hepatitis & Liver Cancer: A National Strategy for Prevention Control of Hepatitis B and C; 2010. The Impact of HCV Effectiveness of Risk-based Screening for HCV A decade after CDC s recommendation for risk-based screening for HCV, <25% of HCV infected individuals have been identified What is an Alternative Screening Strategy? Focus on cohorts with the high prevalence Screen everyone in this cohort regardless of risk THE BABY BOOMER ARE AT HIGHER RISK FOR HCV 25

Why Expand Hepatitis C Testing? The vast majority (>75%) of American adults with HCV are baby boomers Testing people in this age group will help identify if many undiagnosed d cases Deaths from hepatitis C are on the rise As hepatitis C-infected baby boomers age, the likelihood that they will develop serious, life-threatening complications from the disease increases--unless those infections are appropriately diagnosed and treated Current therapies can cure up to 75% of persons treated for hepatitis C Identifying silent cases of hepatitis infection has the potential to save more lives than ever before, and the research pipeline indicates that even CDC Fact Sheet. Available at http://www.cdc.gov/nchhstp/newsroom/docs/2012/hcv-testingrecsfactsheet_508.pdf. Screening for HCV Is Birth Cohort Screening Strategy Cost-effective? ti 26

Economic Model of Birth Cohort Screening for HCV Cost-effectiveness of screening individuals born 1946-1970 1970 over 5 years (birth-cohort screening) compared with current risk-based screening Markov model for natural history and eligible patients with CH- C were treated BCS leads to: 84,000 fewer cases of decompensated cirrhosis 46,000 fewer cases of HCC 10,000 fewer OLT 78,000 fewer HCV-related deaths. BCS produces an incremental cost-effectiveness ratio (ICER) of $37,700 per QALY gained vs. risk-based screening BCS was considered to be cost effective McGarry L. Pawar V, Parekh H, Rubin J, Davis GL, Younossi ZM et al. Hepatology 2011 Economic Model of a Birth Cohort Screening Program for Hepatitis C Virus Markov Model: One-time antibody test of 1945-1965 1965 birth cohort Birth-cohort screening identified 808,580 additional cases of CH-C C at a screening cost of $2874 per case identified Assuming that birth-cohort screening was followed by treatment ICER was $15,700-35,700 per QALY gained BCS was considered to be cost effective. Rein DB et al. Ann Intern Med 2012;156:263-270. 27

Screening for HCV These Data Led to 2012 CDC Recommendations for Identifying i HCV-Infected Persons 2012 CDC Recommendations for Identifying HCV-Infected Persons Recommendation 1: Adults born during 1945 to 1965 should receive 1-time testing for HCV without prior ascertainment of HCV risk Recommendation 2: All persons identified with HCV infection should receive a brief alcohol screening and intervention as clinically indicated, followed by referral to appropriate care and treatment services for HCV infection and related conditions. Please remember, birth cohort screening augments the 1998 and 1999 CDC recommendations based on risk and medical indication and are not meant to replace those. Smith BD et al. Ann Intern Med 2012;157:1-6. 28

HCV Impact In Addition to Effective Screening Strategies, t What Are Some Other Barriers for the Management of HCV? In Addition to Low Screening Rates, Other Barriers Remain Suboptimal ability to predict who will progress Insurance coverage Co-morbidities reduce the treatment candidacy Current HCV treatment (DAA-based) Good efficacy Not everyone is a candidate Lots of side effects Expensive Resource intense Future treatment regimens 29

Health Insurance and Treatment Candidacy NHANES (2005-2008) 2008) Cohort (N=10,582) 1.16 % with detectable HCV RNA Health insurance status and treatment candidacy were analyzed HCV+ patients were less likely to be insured than HCV- individuals (61.2% vs. 81.2%, P = 0.004) In multivariate analysis, HCV infection was an independent predictor of being uninsured [odds ratio = 0.43 (95% CI = 0.24-0.78)]. 0.78)]. Of all HCV+ patients, 66.7% were eligible for anti-hcv treatment. Only 36.3% of HCV+ patients were potentially eligible for treatment and had health insurance. Stepanova M, Kanwal F, El-Seraj H, Younossi ZM Hepatology 53 (3):737-45, 2011. In Addition to Low Screening Rates, Other Barriers Remain Suboptimal ability to predict who will progress Current HCV Insurance coverage Co-morbidities reduce the treatment candidacy Treatment (DAA-based) Good efficacy Not everyone is a candidate Lots of side effects Expensive Resource intense Future treatment regimens 30

Summary CHC is common and the HCV-related liver complications are on the rise Most HCV patients are unaware of their infection Clinical and economic burden of HCV will become tremendous Risk based screening has led to identifying ~20% Enhanced screening g( (BCS) will identify more HCV and is cost effective Better treatment with IFN-free regimens (higher efficacy, lower side effect) are on the horizon Some barriers will remain 31