Hepatitis C: Update on Testing and Treatment 10/23/12 Karla Thornton, MD, MPH Division of Infectious Diseases Department of Internal Medicine UNM Health Sciences Center kthornton@salud.unm.edu Learning Objectives • Recognize the magnitude of the HCV epidemic and the consequences of not addressing the problem • Understand the CDC’s new screening guidelines for HCV • Become familiar with the new drugs approved for HCV and the future of HCV therapy Hepatitis C Prevalence, U.S. • Overall prevalence of anti-HCV in the U.S. population from NHANES III (1988-1994) 3.9 million (1.8%) • Prevalence of chronic infection 2.7 million (1.3%) • Correcting for patient groups under-represented in NHANES (incarcerated, homeless, hospitalized, active duty military, and nursing home residents) 5 million (~2.4%) • Infection is most prevalent among those born during 1945–1965 Alter et al. N Engl J Med. 1999;341(8):556-562. Edlin, B. R. Hepatology 42, 213A (2005). Source: National Notifiable Diseases Surveillance System (NNDSS) HCV is a Neglected Disease Edlin B. Nature 2011; 474:S18-19. Prevalence of Anti-HCV, United States, 1999-2002 (NHANES) Overall prevalence: 1.6% (4.1 million) 8% Men Prevalence of anti-HCV 7% Women 6% 5% 4% 3% 2% 1% Age Group (years) Armstrong, et al, Ann Intern Med. 2006;144:705-714. 55+ 50-54 45-49 40-44 35-39 20-34 6-19 0% HCV in AI/AN Populations Seroprevalence Studies 1. Alaska native population – estimated prevalence 0.8% 2. Pregnant women in Arizona 3% 3. Urban Native American Clinic in Nebraska 11.5% 1. McMahon, Epidemiology and Risk Factors for Hepatitis C in Alaska Natives, Hepatology, February 2004. 2. Wilson, Hepatitis C Infection and Type 2 Diabetes in American-Indian Women, Diabetes Care, September 2004. 3. Neumeister, Hepatitis C Prevalence in an Urban Native-American Clinic, Journal of the National Medical Association, April 2007. Source: National Notifiable Diseases Surveillance System (NNDSS) Wise, et al. Changing Trends in Hepatitis C-Related Mortality in the United States, 1995-2004. Hepatology Vol.47, No. 4, 2008. Projected Morbidity and Mortality Forecasting HCV Morbidity and Mortality • Incident HCV infections peaked in the 1980’s (300,000-400,000/year) • Large cohort of currently asymptomatic patients who are approaching the years when they will develop complications • Mathematical model which forecast future cases of end-stage liver disease, transplants, and deaths from 2010 to 2060. Rein, DB, Wittenborn, JS, Weinbaum, CM Sabin, M, Smith, BD, Lesesne, SB. Forecasting the Mortality and Morbidity Associated with Prevalent Cases of Pre-Cirrhotic Chronic Hepatitis C Infections in the United States. Journal of Digestive Liver Diseases 2010. Forecasting HCV Morbidity and Mortality • Of 2.7 M HCV infected persons in primary care — 1.47 M will develop cirrhosis — 350,000 will develop liver cancer — 897,000 will die from HCV-related complications Rein, DB, Wittenborn, JS, Weinbaum, CM Sabin, M, Smith, BD, Lesesne, SB. Forecasting the Mortality and Morbidity Associated with Prevalent Cases of Pre-Cirrhotic Chronic Hepatitis C Infections in the United States. Journal of Digestive Liver Diseases 2010. Forecasted Annual Incident Cases of Decompensated Cirrhosis (DCC), Hepatocellular Carcinoma (HCC), Liver Transplants, and Deaths Associated with Persons with Chronic Hepatitis C Infection and No Liver Cirrhosis in the United States in 2005 Rein, DB, Wittenborn, JS, Weinbaum, CM Sabin, M, Smith, BD, Lesesne, SB. Forecasting the Mortality and Morbidity Associated with Prevalent Cases of Pre-Cirrhotic Chronic Hepatitis C Infections in the United States. Journal of Digestive Liver Diseases 2010. IOM Report and DHHS Guidelines Institute of Medicine : Hepatitis and Liver Cancer A National Strategy for Prevention and Control of Hepatitis B and C • Viral hepatitis “cause(s) substantial morbidity and mortality despite being preventable and treatable.” Underlying Issues that impede current efforts: Lack of Resources Lack of Public Awareness Lack of Provider Awareness Current CDC Resource Allocation $1 Billion Total STD 15% Domestic HIV 69% TB 14% Viral Hepatitis 2% National Center for HIV/AIDS, Viral Hepatitis, Sexually Transmitted Disease and Tuberculosis Prevention Comparison of Viral Hepatitis and HIV/AIDS disease Burden Burden People Prevalence (millions infected) Dollars Undiagnosed Infections Annual Deaths Prevention Care Research (CDC) (HRSA) (NIH) (millions undiagnosed) (thousands) (millions of dollars) (billions of dollars) (billions of dollars) 5 16 800 4.5 4.5 14 700 4 4 5 3.5 3 3 10 2.5 2.5 8 2 2 6 300 1.5 1.5 4 200 0.5 0.5 0 0 3.0 600 3.5 1 3.5 2 12 1 2.5 500 2.5 1.5 2.0 400 2 100 0 0 HIV/AIDS Hepatitis B 1 1.5 Hepatitis C 1.0 0.5 0.5 0 0 Edlin BR. Nature 2011; 474: S18-9 HHS Viral Hepatitis Action Plan • Educate providers and • • • communities Improve testing, care, and treatment Increase in the proportion of persons who are aware of their HCV infection 25%reduction in the number of new HCV cases May 12, 2011 Screening Strategies Groups Recommended for HCV Testing by AASLD • Recent/past injection drug users—even if only used once • Groups with high HCV prevalence – HIV-infected individuals – Hemophiliacs treated with clotting factor concentrates before 1987 – Hemodialysis recipients – Patients with unexplained aminotransferase abnormalities • Recipients of transfusion or transplantation before July 1992 • Children born to women infected with HCV • Healthcare, public safety, and emergency medical personnel following needle injury or mucosal exposure to HCV-infected blood • Current sexual partners of individuals infected with HCV Ghany MG, et al. Hepatology. 2009;49:1335-1374. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;47:1-39. How good are we at identifying people with HCV? • Acute infection unrecognized • Lack of testing – < 10% of patients asked about HCV risk factors in initial visit to PCP* • Unpublished CDC data from large managed care organization in the Southeast screening rate 0.5% general population *Shehab, et al. Identification and Management of Hepatitis C Patients in Primary Care Clinics, AJG, March 2003 Birth-Cohort Screening Rationale for Considering Birth Cohort Screening Recommendations • 45%-85% of infected persons are undiagnosed • Limitations of current risk-based strategies • 75% of chronic infections are in persons born from 1945-1965 • Without identifying and treating the estimated 2.8 million Americans with HCV in primary care – 1.47 million will develop cirrhosis – 350,000 will develop liver cancer – 897,000 will die from complications of HCV . The Cost-Effectiveness of Birth-Cohort Screening for Hepatitis C Antibody in U.S. Primary Care Settings • Objective: To estimate the cost-effectiveness of birth-cohort screening • Design: Cost-effectiveness simulation • Data Sources: NHANES, U.S. Census, Medicare • Target Population: Adults born from 1945-1965 with 1 or more visits to a PCP annually • Intervention: One-time antibody test of 1945– 1965 birth cohort The Cost Effectiveness of Birth-Cohort Screening for Hepatitis C Antibody in U.S. Primary care Settings. Rein DB, et al. Ann Intern Med, e-378, published ahead of print November 4, 2011. Outcome Measures • Numbers of cases that were identified and treated and that achieved SVR • Liver disease and death from HCV • Medical and productivity costs • Quality-adjusted life-years (QALYs) The Cost Effectiveness of Birth-Cohort Screening for Hepatitis C Antibody in U.S. Primary care Settings. Rein DB, et al. Ann Intern Med, e-378, published ahead of print November 4, 2011. Results • Compared with the status quo, birthcohort screening identified 808,580 additional cases of chronic HCV infection • Screening cost of $2874 per case identified The Cost Effectiveness of Birth-Cohort Screening for Hepatitis C Antibody in U.S. Primary care Settings. Rein DB, et al. Ann Intern Med, e-378, published ahead of print November 4, 2011. Discussion • No universally accepted standard exists to determine what level of cost-effectiveness justifies the implementation of a new strategy • Birth-cohort screening with PEG/RBV alone ranks equivalently to colorectal cancer and hypertension screening, influenza vaccination of adults age ≥ 50 yrs, pneumococcal vaccination of adults age ≥65 yrs, and vision screening of adults age ≥ 65 yrs • Birth-cohort screening with DAA plus PEG/RBV ranks equivalently to cervical cancer or cholesterol screening The Cost Effectiveness of Birth-Cohort Screening for Hepatitis C Antibody in U.S. Primary care Settings. Rein DB, et al. Ann Intern Med, e-378, published ahead of print November 4, 2011. Summary • The majority of persons infected with HCV remain undiagnosed • New screening strategies are desperately needed • Birth-cohort screening appears to be a viable screening strategy • Birth-cohort screening appears to be as cost effective as many common and recommended screening tests • CDC is planning national education campaign called Know More Hepatitis – target PCP’s as well as persons born in the birth cohort HCV Treatment Key Points • Antiviral therapy for HCV can cure an estimated 70 % • Those who are cured have a 60% reduction in mortality • Chance of cure and intensity of treatment depends on viral genotype and host genetics • Therapy is expensive and has side effects, but neither of these hurdles are insurmountable Slide courtesy of John Scott, MD Treatment Evolution of Hepatitis C Therapy 1998 2001-2004 2011 McHutchison J., et al., NEJM 1998;339:1485-92, Poynard T., et al., Lancet 1998;352:1426-32, Manns M., et al., Lancet 2001;358:958-65, Fried MW., et al., NEJM 2002;347:975-82, Hadziyannis S., et al., Ann Intern Med 2004;14:346-55. Poordad F, et al. NEJM 2011;364:11951206. Protease Inhibitors • • • • • • • Approved May 2011 Boceprevir (Victrelis) and Telaprevir (Incivek) Potent Still need pegylated interferon and ribavirin Rapid antiviral resistance if used alone More side effects, particularly rash and anemia Major drug interactions Cyp3a/4 Slide courtesy of John Scott, MD Boceprevir (VICTRELISTM) • Merck • Oral HCV protease inhibitor for genotype 1 infections • Approved by FDA on May 13, 2011 • Combined with IFN/RBV – Dosed 800 mg q8h – Resistance develops quickly if used alone SPRINT-2: Overall SVR Rates 100 P < .001 for both treatment arms vs control 80 SVR (%) 63 66 60 38 40 20 n/N = 0 233/368 4-Wk PR + Response-Guided BOC/PR Poordad F, et al. NEJM 2011;365:1195-1206 242/366 4-Wk PR + 44-Wk BOC/PR 137/363 48-Wk PR RESPOND-2: SVR in Prior Relapsers and Prior Non-Responders Prior Relapsers n/N= 15 51 72 105 77 103 PR48 BOC BOC/ RGT PR48 Bacon B, et al. N Engl J Med. 2011;364(13):1207-1217. Prior NonResponders 2 29 27 57 PR48 BOC RGT 30 58 BOC/ PR48 Telaprevir (IncivekTM) • Vertex Pharmaceuticals • Oral HCV protease inhibitor for genotype 1 infections • FDA approved on May 23, 2011 • Combined with IFN/RBV – Dosed 750 mg q8h – Resistance develops quickly if used alone ADVANCE: SVR and Relapse Rates 100 % of Patients 90 80 75 SVR 70 Relapse Rates 60 44 50 40 28 30 9 10 0 n/N= 271/363 27/314 158/361 T12PR Data from Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 64/229 PR REALIZE: SVR in Prior Relapsers, Prior Partial Responders, and Prior Null Responders Prior Relapsers 100 Prior Partial Responders Prior Null Responders 88 SVR (%) 80 54 60 40 33 24 15 20 5 0 n/N = Pbo/ PR48 LI T12/ PR48 Pbo/ PR48 LI T12/ PR48 Pbo/ PR48 LI T12/ PR48 16/68 124/141 4/27 26/48 2/37 25/75 Data from Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. What now? • 800,000 new cases identified • Newer therapies becoming available • Cure rate continues to increase Expansion of Treatment Project ECHO Hepatitis C in New Mexico Number HCV cases 30,000 In 2004 less than 5% had been treated 2400 prisoners diagnosed in corrections system– none treated before 2004 Highest rate of chronic liver disease/cirrhosis deaths in the nation 32 of 33 counties Medically Underserved Areas 20% of doctors practice in rural areas Goals Develop capacity to safely and effectively treat HCV in all areas of New Mexico and to monitor outcomes Develop a model to treat complex diseases in rural locations and developing countries Partners University of New Mexico School of Medicine: Departments of Internal Medicine, Telemedicine and CME NM Department of Corrections NM Department of Health Indian Health Service Community Clinicians with an interest in HCV Primary Care Association Method Use Technology (multipoint videconferencing and internet) to leverage scarce healthcare resources Disease Management Model focused on improving outcomes by reducing variation in processes of care and sharing “best practices” Case based learning: Co-management of patients with specialists (Learning by Doing) HIPAA compliant centralized database to monitor outcomes Arora S, Geppert CM, Kalishman S, et al: Acad Med. 2007 Feb;82(2): 154-60. Steps Train physicians, mid-levels, nurses, pharmacists, educators in HCV Conduct telemedicine clinics – “Knowledge Network” Initiate co-management – “Learning loops” Collect data and monitor outcomes centrally Benefits to Clinicians Diminishes professional isolation Enhances professional satisfaction No-cost CMEs and Nursing CEUs A mix of work and learning Access to specialty consultation with GI, hepatology, psychiatry, infectious diseases, addiction specialist, pharmacist, patient educator Arora S, Thornton K, et al. Hepatology. 2010 Sept; 52(3):1124-33. How well has the model worked for HCV? >500 HCV Telehealth ECHO Clinics have been conducted >4500 patients entered into HCV disease management program >300 prisoners treated in the Corrections Department >6,000 CME/CE hours issues to ECHO clinicians Outcomes of Treatment for Hepatitis C Virus Infection by Primary Care Providers Results of the HCV Outcomes Study Arora S, Thornton K, et al. N Engl J Med. 2011 Jun; 364:2199-207. Objectives To train primary care clinicians in rural areas and prisons to deliver HCV treatment to rural populations of New Mexico To show that such care is as safe and effective as that given in a University Clinic To show that Project ECHO improves access to HCV care for minorities Arora S, Thornton K, et al.. N Engl J Med. 2011 Jun; 364:2199-207. Results Arora S, Thornton K, et al.. N Engl J Med. 2011 Jun; 364:2199-207. SVR According to Genotype and Site of Treatment HCV Genotype ECHO sites UNM HCV Clinic P Value All Genotypes 152/261 (58.2%) 84/146 (57.5%) 0.89 Genotype 1 73/147 (49.7%) 38/83 (45.8%) 0.57 Genotype 2 or 3 78/112 (69.6%) 42/59 (71.2%) 0.83 Arora S, Thornton K, et al.. N Engl J Med. 2011 Jun; 364:2199-207. Conclusions Rural primary care clinicians deliver HCV care under the aegis of Project ECHO that is as safe and effective as that given in a university clinic Project ECHO improves access to HCV care for New Mexico minorities. Arora S, Thornton K, et al.. N Engl J Med. 2011 Jun; 364:2199-207. Summary • HCV is a prevalent disease and 50-75% of infected patients are undiagnosed • The morbidity and mortality associated with HCV will increase dramatically over the next 20 years • Greater awareness and new screening strategies are required in the primary care setting • All persons born from 1945-1965 should be screened for HCV Summary • Diagnosis can lead to potentially life saving treatment • Newer therapies will be available in 3-5 years that will cure almost all patients who receive treatment • There is a dire need to expand access to HCV treatment Questions?