Learning Objectives. Upon completion, participants should be able to:

Transcription

1 Learning Objectives Upon completion, participants should be able to: Understand the magnitude of the HCV problem and the natural history and consequences of HCV infection Implement guideline-recommended HCV screening based on risk and birth cohort Describe the virologic characterization of HCV and the assessment of the severity of liver disease 1

2 Prevalence of HCV Infection in the US Despite its high prevalence and increasing disease burden, chronic HCV has not been diagnosed in most Americans with this disease, and few cases have been treated 2.7 to 5.2 million living with chronic HCV in the US Denniston M, et al. Ann Intern Med. 2014;160: ; Chak E, et al. Liver Int. 2011;31: ; Zalesak M, et al. PLoS One. 2013;8:e More Than 5.2 Million People Living With Chronic HCV in the US Number of HCV Cases, millions NHANES Estimate Conservative estimate Upper limit of estimate HCV Cases Not Included in NHANES* *Homeless (n = 142, ,610); incarcerated (n = 372, ,826); veterans (n = 1,237,461-2,452,006); active military (n = 6,805); healthcare workers (n = 64, ,234); nursing home residents (n = 63,609); chronic hemodialysis (n = 20,578); hemophiliacs (n = 12,971-17,000) Estimated Total HCV Cases Chak E, et al. Liver Int. 2011;31:

3 Prevalence of HCV in Select Populations Incarcerated ~151,600 to 500,000 (11.1%- 36.6%) 1 Coinfected with HIV ~300,000 (30%) 6 Living below the poverty level ~940,000 (3.2%) 8 Illicit drug users Alcoholics ~300,000 ~240,000 (80%-90%) 2,3 (11%-36%) 4 Women 39% Men 9 61% Homeless ~175,000 (22%) 5 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: ; 2. Edlin BR. Hepatology. 2002;36:S210-9; 3. SAMHSA 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: ; 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. Global Distribution and Prevalence of HCV Genotypes Messina JP, et al. Hepatology. 2015;61:

4 Natural History of HCV Infection Resolved Exposure (Acute Phase) ~15% ~85% ~80% Stable Chronic ~ 20-year progression rate may be accelerated with HIV, HBV, alcohol use, and steatosis ~20% Cirrhosis Time, years ~75% Slowly Progressive ~6%/year ESLD ~3%-4%/year Transplant/Death ~4%/year HCC ESLD = end-stage liver disease; HCC = hepatocellular carcinoma. 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: ; Alter MJ. Semin Liver Dis. 1995;15:5-14. Extrahepatic Manifestations of Chronic HCV Infection Arthralgia Arthritis 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; ; Gill K, et al. Hepatol Int. 2016;10:

5 Projected Prevalence of Chronic HCV, Cirrhosis, and Complications Estimates by Year of Prevalent HCV Cases Prevalence of Cirrhosis at the Time of Initial HCV Infection Total HCV Infected, millions Cirrhosis Ever infected Acute hepatitis Chronic HCV Number of Cases, millions Cirrhosis M 50+ yrs Cirrhosis M yrs Cirrhosis M 0-30 yrs Cirrhosis F 50+ yrs Cirrhosis F yrs Cirrhosis F 0-30 yrs Peak Incidence Year Peak Cirrhosis Year F = female; M = male. 40 Years Davis GL, et al. Gastroenterology. 2010;138: Projected Prevalence of Chronic HCV, Cirrhosis, and Complications Projected Number of Patients With Decompensated Cirrhosis and HCC 160, ,000 Number of Cases 120, ,000 80,000 60,000 40,000 HCC Decompensated cirrhosis 20, Year Davis GL, et al. Gastroenterology. 2010;138:

6 In the US, Deaths Due to HCV Exceed Those Due to HIV 7 Rate per 100,000 Persons HIV HCV HBV 15,106 12, Year Ly KN, et al. Ann Intern Med. 2012;156: The Problem: Only One-Half (or Fewer) of Those Infected With HCV Are Aware of Their Infection 49% Unaware of their infection 51% Aware of their infection Adapted from Volk ML, et al. Hepatology. 2009;50:

7 Underdiagnosis and Undertreatment 60% 50% 40% 30% 20% 10% 0% 50% (1.6 M) 32%-38% ( M) 7%-11% (220, ,000) 5%-6% (170, ,000) Diagnosed Referred to Care Treated Successfully Treated Holmberg SD, et al. N Engl J Med. 2013;368: Burden of Bloodborne Chronic Viral Infections in US and Patient Awareness Prevalence 4,000, ,000, ,000, ,000, Unaware of infection Aware of infection ~1,100,000 ~1,100, , , , ,000 ~3,300,000 HIV/AIDS HBV HCV 2,475, ,000 Adapted from Colvin HM, et al; Institute of Medicine. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C r [90]1

8 Reasons for Lack of Treatment for Patients With Chronic HCV 49% Unaware of infection 12% Received treatment 9% Did not follow up with a doctor after learning they were infected 6% Refused treatment 24% Doctor recommended no treatment Adapted from Volk ML, et al. Hepatology. 2009;50: Patient Knowledge About HCV Is Poor Semistructured interviews of baby boomers in the emergency department in a large public hospital in New York City Interviewed 81 patients 52% were born outside of the US but most had lived in US for 26 years or more 69% had a highschool diploma or lower level of education 37% were unemployed Topic Transmission by infected needles Association with injection drugs, even if drug use was many years ago Percent of Patients Able to Recognize Correct Response 93% 90% Liver failure 81% Chronic nature of HCV 71% HCC 57% Asymptomatic nature of 61% disease Sexual transmission 68% HCV is curable 51% Prevalence in baby boomers 29% Allison WE, et al. J Emerg Med [epub ahead of print]. 8

9 Rural Health Communities Evaluation of medical providers who prescribed antiviral therapy in Wisconsin in 2012 revealed: 1 treatment provider for every 340 residents with HCV 51 of 72 Wisconsin counties had no providers Durham County Health Department goal to cure every patient in Durham Screened 2,000 residents, used a bridge counselor to facilitate care at Duke or University of North Carolina Despite our efforts, we have also found that some patients have been unwilling or unable to attend clinics at the academic centers. It has become clear that we must facilitate treatment in the Durham community and away from the academic center if we expect to achieve our goal to cure all. Westergaard RP, et al. J Prim Care Comm Health. 2015:6:215-7; Muir AJ, et al. Clin Gastroenter Hepatol. 2015;13: Acute or Incident HCV Infections Are Increasing in the US Sexual transmission of HCV among HIV-infected MSM New York City, 2005 to 2010 Acute HCV infections attributed to unsafe injection practices at an endoscopy clinic Nevada, 2007 HCV infection among adolescents and young adults Massachusetts, 2002 to 2009 Transition to injection heroin after prescription narcotic abuse HCV infection rising among injection drug users central Appalachia rural areas, 2015 MSM = men who have sex with men. CDC. MMWR Morb Mortal Wkly Rep. 2008;57:513-7; CDC. MMWR Morb Mortal Wkly Rep. 2011;60:945-50; CDC. MMWR Morb Mortal Wkly Rep. 2011;60:537-41; CDC. MMWR Morb Mortal Wkly Rep. 2015;64:

10 States With Increases in Acute HCV Infection, > 50% increase 1%-50% increase Insufficient or missing data No change or decline CDC. Viral hepatitis surveillance Increases in HCV Infection Related to IDU Among Persons Aged 30 Years Kentucky, Tennessee, Virginia, and West Virginia, No. of Cases per 100,000 Population Nonurban Urban *

11 HCV/HIV Coinfection Outbreak in Indiana 84% Coinfected With HCV Potential Barriers to HCV Identification Patient-Related Barriers Patients reluctant to discuss HCV risk factors Clinician-Related Barriers Healthcare professionals may be unaware of or reluctant to ask about HCV risk factors Systemic Barriers Stigmatization of HCV infection in healthcare system and community Colvin HM, et al; Institute of Medicine. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. 2010; USDHHS. Combating the Silent Epidemic of Viral Hepatitis: Action Plan for the Prevention, Care, and Treatment of Viral Hepatitis

12 What Does This Mean to Primary Care Clinicians? Tremendous need for improved screening and referral to treatment Clinicians must be knowledgeable about: Who should be screened for HCV How to screen for HCV Summary of Recommendations for HCV Testing and Linkage to Care Recommendations for One-Time HCV Testing One-time HCV testing is recommended for persons born between 1945 and 1965, without prior ascertainment of risk. Rating: Class I, Level B Other persons should be screened for risk factors for HCV infection, and one-time testing should be performed for all persons with behaviors, exposure, and conditions associated with an increased risk of HCV infection. 1. Risk behaviors IDU (current or ever, including those who injected once) Intranasal illicit drug use 2. Risk exposures Persons on long-term hemodialysis (ever) Person with percutaneous/parenteral exposures in an unregulated setting Healthcare, emergency medical, and public safety workers after needlesticks, sharps, or mucosal exposures to HCV-infected blood Children born to HCV-infected women Persons who were ever incarcerated Prior recipients of transfusions or organ transplants, including persons who: Were notified that they received blood from a donor who later tested positive for HCV infection Received a transfusion of blood or blood components, or underwent an organ transplant before July 1992 Received clotting factor concentrates produced before Other considerations HIV infection Sexually active persons about to start preexposure prophylaxis (PreP) for HIV Unexplained chronic liver disease and/or chronic hepatitis including elevated ALT levels Solid organ donors (deceased and living) Rating: Class I, Level B Recommendations for HCV Testing With Ongoing Risk Factors Annual HCV testing is recommended for persons who inject drugs and for HIV-seropositive men who have unprotected sex with men. Periodic testing should be offered to other persons with ongoing risk factors for exposure to HCV. Rating: Class IIA, Level C ALT = alanine aminotransferase. AASLD/IDSA. Updated July 6,

13 Baby Boomers (Those Born Between 1945 and 1965) Account for 76.5% of HCV Cases in the US Number With Chronic HCV Infection, millions < s Estimated Prevalence by Age Group 1930s 1940s 1950s 1960s Birth Year Group 1970s 1980s Up to 75% of people with HCV in the US are undiagnosed An estimated 35% of baby boomers with undiagnosed HCV currently have advanced fibrosis (F3-F4, bridging fibrosis to cirrhosis) Adapted from Pyenson B, et al. Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease Screening of Baby Boomers Could Prevent More Than 120,000 HCV-Related Deaths 1,070,840 new cases of HCV identified with birth cohort screening 552,000 patients treated 311,000 patients cured* 121,000 deaths averted t *Cured with pegylated interferon (PEG-IFN) and ribavirin (RBV) plus directacting antiviral (DAA) treatment. t Deaths due to decompensated cirrhosis or HCC within the birth cohort; 470,000 deaths under birth cohort based screening vs 592,000 deaths under risk-based screening. Rein DB, et al. Ann Intern Med. 2012;156:

14 Screening Tests 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. Screening Tests for HCV (cont.) HCV RNA Assays Use sensitive quantitative assay When to test? If anti-hcv Ab test result is positive 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:S

15 Prevalence of Antibody to HCV: NHANES ( ) General Risk Factors 57.5% ( ) Number of Sex Partners Prevalence, % 1.6% ( ) 5.8% ( ) 13.8% ( ) 7.8% Prevalence, % 0.5% 1.1% ( ) ( ) 2.6% ( ) 7.5% ( ) 12.0% ( ) General Population IDU Blood Transfusion (< 1992) HIV Dialysis >50 Number of Sex Partners Armstrong GL, et al. Ann Intern Med. 2006;144:705-14; Finelli L, et al. Semin Dial. 2005;18: Detection of Anti-HCV IgG: Immunoassays Diagnostic specificity > 99% for third-generation assays False-negative results Undergoing hemodialysis Immunocompromised patients Low positive predictive values in populations with low (< 10%) prevalence of HCV infection Signal-to-cutoff ratios Predict true Ab positive results > 95% of the time, regardless of the anti-hcv prevalence or characteristics of the population tested Signal-to-Cutoff Ratios (FDA-Approved Screening Assays, Detect Anti-HCV IgG) Ratio Enzyme immunoassay (manual) Ortho HCV Version 3.0 Abbott HCV EIA 3.0 Chemiluminescence immunoassay (automated) Vitros anti-hcv Advia Centaur HCV Microparticle immunoassay (automated) AxSYM anti-hcv 10.0 Chemiluminescence microparticle immunoassay (automated) Architect anti-hcv 5.0 IgG = immunoglobulin G. Kamili S, et al. Clin Infect Dis. 2012;55:S

16 Recommended Laboratory Tests for Chronic HCV Infection Test Application HCV Ab by EIA Screening for past or present HCV infection Sensitive and inexpensive PCR for HCV RNA Confirmation of positive EIA Medical evaluation and management EIA = enzyme immunoassay; PCR = polymerase chain reaction. Ghany MG, et al. Hepatology. 2009;49: Anti- HCV HCV Assays: What the Results Mean HCV RNA Interpretation + + Acute or chronic HCV depending on the clinical context + False-positive HCV Ab Resolved infection Low-level intermittent viremia + Early acute HCV infection Chronic HCV in setting of immunosuppressed state False-positive HCV RNA test Absence of HCV infection Ghany MG, et al. Hepatology. 2009;49:

17 HCV Diagnostic Process - HCV Ab + Nonreactive Reactive Not detected HCV - + RNA Detected No HCV Ab detected No current HCV infection Current HCV infection STOP Additional testing as appropriate Link to care CDC. MMWR. 2013;62: Clinical Presentation of HCV Typically very few, if any, symptoms; most patients are completely asymptomatic Visible symptoms may include nonspecific flu-like symptoms: fatigue, muscle aches, nausea (present in 25%-30% of patients) Patients may present with jaundice and abdominal pain in advanced cases Because HCV is very difficult to detect through history and physical examination, screening is critical Huffman MM, et al. J Am Board Fam Med. 2014;27: r [72]1

18 Chronic HCV Infection 1000 HCV RNA ALT, U/L Symptoms (25%) Anti-HCV Weeks Years Time After Exposure Hoofnagle JH. Hepatology.1997;26:S Four Variables Determine HCV Treatment Choice HCV genotype Cirrhosis status Previous HCV treatment Renal function AASLD/IDSA. Updated July 6,

19 Importance of Assessing Fibrosis in HCV Treatment Determines urgency of therapy Selects patients with cirrhosis in need of additional screening for: Varices HCC Allows for the selection of proper treatment plan and duration of therapy May be used by many payers as a way to restrict access to therapy or prioritize therapy AASLD/IDSA. Updated July 6, Histologic Staging METAVIR Phase Description Impact on Liver Function 0 No fibrosis Little effect on liver function 1 Fibrous portal Little effect on liver function expansion 2 Few bridges or septa Little effect on liver function 3 Numerous bridges or septa Blood flow throughout the liver is altered, fluids and bile may begin to build up 4 Cirrhosis Abnormal blood flow may lead to ascites, failure of liver cells to function may result in generalized weakness, anorexia, malaise, weight loss, and jaundice Goodman ZD. J Hepatol. 2007;47:

20 Fibrosis area: 65% Fibrosis area: 15% Courtesy of M. Pinzani, Florence. Noninvasive Methods to Assess Liver Disease in Chronic HCV Serum biomarkers FibroTest Forn index AST to platelet ratio index (APRI) FibroSpect II MP3 Enhanced liver fibrosis score (ELF) Fibrosis probability index HepaScore Fibrometers Lok index Goteborg University cirrhosis index Virahep FibroIndex FIB-4 HALT-C model AST = aspartate aminotransferase. Measurement of liver stiffness Transient elastography Acoustic radiation force impulse imaging Magnetic resonance elastography Castera L. Gastroenterology. 2012;142:

21 Transient Elastography Ziol M, et al. Hepatology. 2005;41:48-54; Castéra L, et al. Gastroenterology. 2005;128: Transient Elastography Analyzes a Larger Volume of Liver Tissue Than Liver Biopsy Elastography ~1 cm 4 cm Liver Biopsy ~0.14 cm 2-3 cm Ultrasonic Transducer Explored Volume Courtesy of Jorge Herrera, MD. 21

22 Elastography vs Liver Biopsy Advantages Noninvasive Safer, less expensive Can be used for serial assessment of fibrosis Disadvantages Test failure or unreliable results BMI > 30 kg/m 2 Potential for inexperienced operator Best to differentiate F0/F1 from F4 (similar to serum markers) Gives no information on inflammation or other abnormalities Cutoffs to diagnose cirrhosis vary according to the etiology HCV: 7.3 kpa suggests significant fibrosis, whereas 12.5 kpa suggests cirrhosis Tapper EB, et al. Clin Gastroenterol Hepatol. 2015;13: Use All Available Resources to Assess Fibrosis, Noninvasive Tests Should Correlate Serum markers of fibrosis AST/ALT ratio > 0.8 suggests advanced fibrosis if no alcohol (F4/F4) APRI/FIB-4 AST/ULN divided by platelet count 100; 2 suggests cirrhosis (Age AST) / (Platelet count (square root of ALT)); > 3.25 suggests F3/F4 Platelet count < 150,000 suggests portal hypertension CT/MRI/Ultrasound Splenomegaly or portal vein diameter 11 mm suggests portal hypertension Elastography 7.3 kpa suggests advanced fibrosis AASLD/IDSA. Updated July 6, 2016; Tapper EB, et al. Clin Gastroenterol Hepatol. 2015;13:

23 Positive Test for HCV: Next Steps Counsel patients on test results Conduct additional screenings (other hepatitis viruses, alcohol use) Educate patients about disease transmission Refer patients to a specialist for treatment AASLD/IDSA. Updated July 6, Linking HCV-Infected Patients to Treatment Pathways Patients Follow to Be Diagnosed and Treated for HCV Prior to Developing Symptoms of Liver Failure Patient Barriers Treatment Referral Specialist Barriers Diagnosis Primary Care Barriers Pathways patients follow to treatment Barriers to treatment Volk ML. J Antimicrob Chemother. 2010;65:

24 Stepwise Barriers to HCV Treatment HCV Infection Treatment Initiation Barriers Asymptomatic disease Poor awareness/education Lack of medical coverage MD failure to screen/test Diagnosis Referral to Specialist Barriers Patient fears/misunderstandings Stigmatization Substance abuse Psychiatric comorbidity Financial concern Transportation/logistical concerns Communication difficulties Barriers Nonadherence MD failure to identify need for referral Logistical concerns Limited specialist availability McGowan CE, et al. Liver Int. 2012;32: HCV Infection Is Associated With Significantly Higher Prevalence of Comorbidities Incidence of Comorbidities (%) Employees With HCV (n = 1,329) Employees Without 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 Significantly higher prevalence of comorbidities in the HCV-infected vs noninfected cohort *P <.0001 vs employees without HCV infection. Retrospective claims data from Human Capital Management Services Research Reference Database ( ). HCV status by ICD-9 codes. Controls matched on demographic characteristics. Su J, et al. Hepatology. 2010;52:

25 Moving Toward Eradication of HCV Non-A, non-b hepatitis is first described Pilot study using IFN in non-a, non-b hepatitis Ribavirin tested as monotherapy in HCV First three-dimensional structure of HCV serine protease is published Crystal structure of HCV RNA dependent RNA polymerase NS5B resolved Proof of concept study using an HCV protease inhibitor Protease inhibitors in combination with IFN and ribavirin are used to treat patients with HCV GT1 Simeprevir and sofosbuvir approved Ombitasvir/paritaprevir/ ritonavir and daclatasvir/sofosbuvir approved HCV ERADICATION First use of recombinant IFN for HBV Pilot study of IFN and ribavirin First clinical trial of PEG-IFN and ribavirin Pilot studies of IFNfree DAA treatment HCV identified First randomized, doubleblind, placebo-controlled trial evaluating IFN alone or in combination with ribavirin Crystal structure of domain 1 of NS5A; recombinant infectious HCV produced by tissue culture Grazoprevir/elbasvir approved; velpatasvir (first pan-genotypic DAA) approved in combination with sofosbuvir; World Health Assembly considers the first Global Hepatitis Strategy Sofosbuvir/ledipasvir and ombitasvir/paritaprevir/ritonavir and dasabuvir approved Adapted from Heim MH. Nature Rev. 2013;13: 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. Updated July 6,

26 Acknowledgment of Commercial Support This activity is supported by educational grants from AbbVie, Gilead Sciences, Inc., and Merck & Co., Inc. Contact Information Call (toll-free) Please visit us online at for additional activities provided by Med-IQ. To receive credit, click the Get Credit tab at the bottom of the Webinar for access to the evaluation, attestation, and post-test Unless otherwise indicated, photographed subjects who appear within the content of this activity or on artwork associated with this activity are models; they are not actual patients or doctors. 26