HCV Epidemiology, Screening, Natural History, and Extra-Hepatic Manifestations Paul Y. Kwo, MD, FACG Professor of Medicine Director of Hepatology Stanford University Hepatitis C Virus Page 1 of 22
The Scope of The Problem US Prevalence: 1.0 % are chronically infected with Hepatitis C virus (HCV) World Health Organization. Hepatitis C: Fact Sheet. http://www.who.int/mediacentre/factsheets/fs164/en/index.html. June 2011. HCV Genotypes and Subtypes Developed countries 2 Americas + Western Europe South Africa Middle East North Africa 4 5 1 IVDU 3 Simmonds P, Journal of Hepatology, 1999 Asia 6 Page 2 of 22
Global Distribution and Prevalence of HCV Genotypes Messina JP et al, Hepatology, 2015; 61: 77-87. HCV is Nearly 4 Times as Prevalent as HIV and HBV 4 Prevalence of Chronic Viral Infections 2.7 to 3.9 Million 1 75% Unaware of Infection Total No. Infected (millions) 3 2 1 1.1 Million 1 21% Unaware of Infection ~800,000 to 1.4 Million 1 65% Unaware of Infection Undiagnosed Diagnosed 0 HIV HBV HCV A 2011 study estimated that as many as 5.2 million persons are living with HCV in the United States 2, 3 Based on a 2015 literature search that takes into account populations excluded from NHANEs, the number of US residents who have been infected with HCV is ~4.6 million (range 3.4 million-6.0 million) 4 HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus. 1. Institute of Medicine. Washington, DC: The National Academies Press; 2010; 2. Chak E, et al. Liver Int. 2011;31(8):1090-1101; Gish R et al., Hepatology. 2016: DOI 10.1002/hep.28026; 4. Edlin BR et al. Hepatology. 2015;62(5):1353-63. Page 3 of 22
Deaths From HCV Surpassed Those From HIV Change in Mortality Rates From 1999 to 2007 1 Rate per 100,000 People 7 6 5 4 3 2 1 0 HIV Hepatitis C Hepatitis B 1999 2000 2001 2002 2003 2004 2005 2006 2007 Year 15,106 12,734 The number of HCV-related deaths has since continued to increase; HCV-related deaths rose to 19,659 in 2014 2 1,815 1. Ly KN, et al. Ann Intern Med. 2012;156(4):271-278. 2. Available at : http://www.cdc.gov/hepatitis/statistics/2014surveillance/commentary.htm. Accessed May 10, 2016. Hepatitis C-Related Cirrhosis Is Projected to Peak Over Next 10 Years Number of patients 1,200,000 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;138:513-521. Page 4 of 22
Indications for OLT over 12 years: HCV still most common indication for OLT 9 SRTR Annual report 2011 (http://srtr.transplant.hrsa.gov) Estimated 29,700 estimated cases of acute hepatitis C: 2013 http://www.cdc.gov/hepatitis/statistics/index.htm Page 5 of 22
HCV/HIV Co-Infection Outbreak in Indiana 84% Co-infected with HCV Page 6 of 22
States With Increases in Acute HCV Infection, 2010-2014 > 50% increase 1%-50% increase Insufficient or missing data No change or decline CDC. Viral hepatitis surveillance. 2014. Risk Factors for Acute Hepatitis C Injection Drug Use 43.0% Other High Risk* 30.0% *Other High Risk 16% drug related 11% previous drug use not within last 6 months 5% intranasal cocaine use 4% history of STDs 1% prison 9% lower socio-economic status (fewer years of education) Unknown 1.0% Household 3.0% Occupational 4.0% Transfusion** 4.0% **None in 1995 Sexual (MSM and Multiple Partners) 15.0% Page 7 of 22
Prevalence of HCV in Select Populations Incarcerated ~151,600 to 500,000 Illicit drug users ~300,000 (80%-90%) 2,3 Alcoholics ~240,000 (11%-36%) 4 Homeless ~175,000 (22%) 5 (11.1%- 36.6%) 1 Coinfected with HIV ~300,000 (30%) 6 Living below the poverty level ~940,000 (3.2%) 8 Women 39% Men 9 61% Veterans ~280,000 (8%) 7 Children (6-18 years) ~100,000 (0.1%) 9 Adapted from 1.Varan AK, et al. Pub Health Rep. 2014;129:187-195; 2. Edlin BR. Hepatology. 2002;36:S210-9; 3. SAMHSA. www.oas.samhsa.gov/nhsda/2k3nsduh/2k3results.htm. 2004. Accessed February 4, 2010; 4. LaBrecque DR, et al. In: Hepatitis C Choices. 4th ed. 2008; 5. Nyamathi AM, et al. J Gen Intern Med. 2002;17:134-43; 6. Singal AK and Anand BS. World J Gastroenterol. 2009;15:3713-3724; 7. Brau N, et al. Am J Gastroenterol. 2002;97:2071-8; 8. Alter MJ, et al. N Engl J Med. 1999;341:556-62; 9. Jonas MM. Hepatology. 2002;36:S173-8; 9. CDC. Available at: http://www.cdc.gov/hepatitis/statistics/2014surveillance/index.htm#tabs-1170600-4. Prevalence by age of Hepatitis C in US Chronic HCV prevalence, US (all persons per CDC) 1.3% (3.2 million) 65.6% of all infected persons in the U.S. were born between 1945-1964 Overall prevalence, 4.3% Men 6.2% Black Americans, 9.4% Black American men, 13.6% Higher incidence in Hispanics too Armstrong, et al. Ann Intern Med. 2006. Page 8 of 22
Natural History of HCV Infection ~15% ~85% Resolved Exposure (Acute Phase) ~80% Stable Chronic ~ 20-year progression rate may be accelerated with HIV, HBV, alcohol use, and steatosis ~20% Cirrhosis Time, years ESLD = end-stage liver disease; HCC = hepatocellular carcinoma. ~75% ~6%/year ~4%/year Slowly Progressive ESLD HCC ~3%-4%/year Transplant/Death 10 20 30 NIH Consens State Sci Statements. 2002;19:1-46; NIH Consens State Sci Statement. 1997;15:1-41; Di Bisceglie AM. Hepatology. 2000;31:1014-8; Bialek SR, et al. Clin Liver Dis. 2006;10:697-715; Alter MJ. Semin Liver Dis. 1995;15:5-14. Chronic HCV Infection 1000 HCV RNA + + + + + + + + + + + + + ALT (U/L) 800 600 400 Anti-HCV Symptoms (25%) Chronic Hepatitis C 200 0 0 2 4 6 8 10 12 24 1 2 3 4 5 6 Weeks Months Time After Exposure Hoofnagle JH. Hepatology.1997;26:15S-20S. Page 9 of 22
Immune-Mediated Clearance in Hepatitis C TNF α IFN γ Infected Hepatocyte CD8 TCR CD8 CTL Class I MHC Apoptosis Clearance of Infected Hepatocytes Liver Inflammation due to HCV Page 10 of 22
Histologic Staging Stage 0 Stage 1 Stage 2 No Fibrosis Portal Fibrosis Few septa Stage 3 Numerous septa Cirrhosis Stage 4 Stages of Fibrosis In Chronic Hepatitis Page 11 of 22
Why Do We Treat Chronic HCV? 1000 HCC ALT (U/L) 800 600 400 ALT 2+ 1+ Anti-HCV HCV RNA 4+ 3+ Fibrosis Cirrhosis 200 0 0 0.5 1 2 5 10 15 20 25 30 35 40 45 50 Years After Exposure Hoofnagle JH. Hepatology 2002;36:S21-S29. Disease Progression in HCV is Not Linear: Importance of Early Treatment Probability of Progression 10 15% cirrhosis at 20 years ~50% cirrhosis at 40 years Poynard T, et al. J Hepatol. 2001;34:730-739. Page 12 of 22
Risk Factors Associated with Faster Fibrosis Progression in Chronic HCV Disease state factors Fibrosis stage HCV onset after 40 years of age Persistently elevated ALT Host factors Male gender Age >45 years Obesity/steatosis Diabetes HIV, HBV coinfection Immune system compromise Iron overload Life style (ETOH, smoking) Viral factors Genotype 3 Poynard T, Afdhal NH. Antivir Ther. 2010;15:281-291. Poynard T, et al. Lancet. 1997;349:825-832. ALT=alanine transaminase HCV Infection Associated with Significantly Higher Prevalence of Comorbidities Incidence of Comorbidities (%) Employees w/ HCV (n=1329) Employees w/out HCV (n=26,580) Neoplasm 19* 13 Metabolic abnormality (eg, diabetes) 34* 27 Mental disorder 20* 10 Systemic Disorders Nervous 31* 24 Circulatory 36* 28 Digestive 42* 18 Genitourinary 35* 28 *P<0.0001 vs. employees without HCV infection Significantly higher prevalence of comorbidities in the HCV-infected vs. non-infected cohort Retrospective claims data from Human Capital Management Services Research Reference Database (2001-2007). Su HCV J, et status al. Hepatology. by ICD-9 2010;52:436-442. codes. Controls matched on demographic characteristics. Page 13 of 22
Arthralgia Arthritis Extrahepatic Manifestations of Chronic HCV Infection Behçet disease Canities Cerebral vasculitis Cryoglobulinemia Depression Diabetes Fatigue Fibromyalgia Hypertrophic cardiomyopathy Immune thrombocytopenic purpura Insulin resistance Lichen myxedematosus and planus Lung abnormalities Membrane nephropathy Membranoproliferative glomerulonephritis Mooren corneal ulceration Multiple myeloma Neutropenia Non-Hodgkin lymphoma Paresthesia Porphyria cutanea tarda Pruritus Raynaud syndrome Sialadenitis Sjögren syndrome Spider nevi Systemic lupus erythematosus Thrombocytopenia Thyroid disease Vasculitis Vitiligo Waldenstrom macroglobulinemia Jaobson IM, et al. Clin Gastroenterol Hepatol. 2010;8;1017-29; Gill K, et al. Hepatol Int. 2016;10:415-23. Be Careful Using Fibrosis as the Only Indication for Therapy: REVEAL C Cumulative Mortality (%) 35 30 25 20 15 10 5 Anti-HCV+, HCV RNA detectable All Causes (n=2394) 12 30.1%* 10 12.8% 12.4% 0 0 2 4 6 8 10 12 14 16 18 20 Follow-Up (Years) 8 6 4 2 Anti-HCV ( ) Liver Cancer (n=115) 10.4%* 1.6% 0.3% 0 0 2 4 6 8 10 12 14 16 18 20 Follow-Up (Years) 20 18 16 14 12 10 8 6 4 2 23,800 adults, 16.2 y f/u Extrahepatic Diseases (n=2199) 19.8%* 12.2% 11.0% 0 0 2 4 6 8 10 12 14 16 18 20 Follow-Up (Years) Lee M-H, et al. J Infect Dis. 2012;206:469-477 Page 14 of 22
Cure of Hepatitis C Reduces Liver Related Complications in those with hepatitis C Van der Meer, et al. JAMA 2012:308:2584-2593. 29 Benefits of Diagnosis Prevent Transmission Avoid sharing objects with blood Stop illicit drugs or sharing needles Discuss risk of sexual transmission with unsafe sex Other Recommendations Avoid alcohol consumption Discuss available treatments Vaccinate for hepatitis A and B Test for HBV, HIV Consider family member screening Page 15 of 22
Screening/Diagnostic Tests Hepatitis C ELISA: detects hepatitis C antibodies HCV RNA by RT-PCR detects virus in the bloodstream Liver Biopsy/Fibrosis Assessment: determines the extent of liver injury but cannot alone establish a diagnosis Some payors use as guide for therapy Screening Test for HCV ELISA Screening Tests Serologic assays to detect circulating HCV Abs Sensitivity (97%-100%) Positive predictive value 95% with risk factors + elevated ALT 50% without risk factors + normal ALT False-positive results More likely in patients with low risk of HCV infection False-negative results More likely in severely immunocompromised patients ELISA = enzyme-linked immunosorbent assay. Kamili S, et al. Clin Infect Dis. 2012;55:S43-8. Page 16 of 22
HCV RNA Assays Use sensitive quantitative assay When to test? If anti-hcv Ab test result is positive Diagnostic Test for HCV If antiviral treatment is being considered If unexplained liver disease is present, anti-hcv Ab test result is negative, and person is immunocompromised If acute HCV infection is suspected Pawlotsky JM. Hepatology. 2002;36:S65-S73; Options for Liver Fibrosis Assessment No single test is accurate enough Liver biopsy: Gold standard Elastography: Approved in US Serum Biomarkers Serum Markers of Fibrosis: FIBROSpect, FibroSURE, APRI, FIB-4 34 Axial CT/MRI, US can demonstrate cirrhotic morphology, portal hypertension Page 17 of 22
Importance of Confirming Viremia Anti-HCV Antibody Positive HCV RNA Positive HCV Genotype Consider Liver Biopsy Vaccinate for HAV / HBV* Negative Negative No Further Testing No Active Disease Who Should Be Tested For HCV? One-time HCV testing is recommended for persons born between 1945 and 1965*, without prior ascertainment of risk. Rating: Class I, Level B Birth cohort screening Other persons should be screened for risk factors for HCV infection, and 1-time testing should be performed for all persons with behaviors, exposures, and conditions associated with an increased risk of HCV infection. Risk Behaviors Exposures Other Injection-drug use (current or ever, including those who injected once) Intranasal illicit drug use Rating: Class I, Level B Long-term hemodialysis (ever) Getting a tattoo in an unregulated setting Health care, emergency medical, and public safety workers after needlesticks, sharps, or mucosal exposures to HCV-infected blood Children born to HCV-infected women Prior recipients of transfusions or organ transplants, including persons who: o Were notified that they received blood from a donor who later tested positive for HCV infection o Received a transfusion of blood or blood components, or underwent an organ transplant before July 1992 o Received clotting factor concentrates produced before 1987 Persons who were ever incarcerated HIV infection Unexplained chronic liver disease and chronic hepatitis including elevated alanine aminotransferase levels Solid organ donors (deceased and living) Risk-based screening *Regardless of country of birth AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C. 2015. http://www.hcvguidelines.org/full-report-view. Accessed March 2, 2015. Page 18 of 22
Majority of Persons Chronically Infected With HCV Are Baby Boomers (Those Born Between 1945-1965) 1,600,000 1,400,000 1,200,000 Estimated Prevalence by Age Group Individuals, N 1,000,000 800,000 600,000 400,000 200,000 0 <1920 1920 1929 1930 1939 1940 1949 1950 1959 1960 1969 1970 1979 1980 1989 1990+ Birth Year Group Centers for Disease Control and Prevention. MMWR. 2012;61(RR-4):1-32. AASLD/IDSA HCV Guidance Document Recommendations for Screening (cont d) For patients with ongoing risk factors: Annual HCV testing is recommended for persons who inject drugs and for HIVseropositive men who have unprotected sex with men Periodic testing should be offered to other persons with ongoing risk factors for exposure to HCV Available at: www.hcvguidelines.org. Accessed April 28, 2016. Page 19 of 22
The AASLD/IDSA Recommendations for Patients with Active HCV Abstinence from alcohol Evaluation for other conditions that may lead to fibrosis (e.g. HIV, HBV, NASH) Evaluation for advanced fibrosis APRI, Fib4, imaging Vaccination against HAV, HBV and pneumococcal infection (in patients with cirrhosis) Education on avoidance of transmission Available at: www.hcvguidelines.org. Accessed April 28, 2016. CDC Recommended Testing Sequence for Identifying Current HCV Infection Available at: www.hcvguidelines.org. Adapted from Centers for Disease Control and Prevention (CDC), 2013. Page 20 of 22
The AASLD/IDSA Recommendation for Linkage to Care All persons with current active HCV infection should be linked to a practitioner who is prepared to provide comprehensive management : www.hcvguidelines.org. Current Status of HCV in the US: Screening and Linkage to Care Rates Remain Low US population with chronic HCV infection 3.2 million* HCV detected 1.6 million (50%) Referred to care 1.0 1.2 million (32%-38%) HCV RNA test 630,000 750,000 (20-23%) Liver biopsy 380,000 560,000 (12%-18%) Treated 220,000 360,000 (7-11%) Successfully treated 170,000 200,000 (5-6%) *Recent analysis estimates 5 million Holmberg SD et al, New Engl J Med. 2013; 1859-1861; Gish R et al., Hepatology. 2016: DOI 10.1002/hep.28026 Page 21 of 22
Most Patients With HCV Viremia Should Be Considered Treatment Candidates if They Can Comply With Therapy AASLD/IDSA Treatment Guidelines Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies owing to comorbid conditions AASLD/IDSA. www.hcvguidelines.org/full-report-view. Updated July 6, 2016. HCV Epidemiology Screening and Natural History - Summary Most HCV patients remain undiagnosed 75% of them were born from 1945-1965 33% of them have advanced fibrosis ticking time bombs waiting to explode (bleed) on a Friday at midnight when you are on call Therapy is more effective and safer It s time to incorporate screening into your practice! Page 22 of 22