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Hepatitis C Epidemiology and Prevention Globally and for the United States

Hepatitis C Epidemiology and Prevention Globally and for the United States . Division of Viral Hepatitis National Center for HIV/AIDS, Viral Hepatitis, STD & TB Prevention Centers for Disease Control and Prevention. National Center for HIV/AIDS, Viral Hepatitis, STD & TB Prevention.

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Hepatitis C Epidemiology and Prevention Globally and for the United States

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  1. Hepatitis C Epidemiology and Prevention Globally and for the United States Division of Viral Hepatitis National Center for HIV/AIDS, Viral Hepatitis, STD & TB Prevention Centers for Disease Control and Prevention National Center for HIV/AIDS, Viral Hepatitis, STD & TB Prevention Division of Viral Hepatitis

  2. Learning Objectives • Understand the natural history of hepatitis C virus (HCV) infection • Understand the trends in HCV transmission, disease, and mortality • Understand the health benefits of HCV testing, care, and treatment • Understand the testing algorithm and strategies to screen patients for HCV infection

  3. Hepatitis C Virus • Discovered in 1989, RNA virus, genus Hepcivirus, family Flaviviridae • 9600 nucleotide genome- single polyprotein • Structural proteins- envelope E1, E2- cell entry • Non-structural proteins- targets of therapy • NS3/NS4A- proteases- cleaves polyprotein • NS4A- viral assembly • NS5B- polymerase- replication of viral RNA • High genetic diversity – intra-host variants- “quasispecies” • Major-7 genotypes- 30% heterogeneity • No vaccine candidates

  4. Serologic Profile of HCV Infection—Chronic

  5. Serologic Profile of HCV Infection—Resolved

  6. HCV-Infected Persons Are at Risk for Serious Morbidity and Mortality • Acute HCV infection • 30%-40% mild moderate symptoms; rare mortality from acute HCV • ~70% become chronically infected • Chronic HCV infection- cause of almost all morbidity/mortality • After 25-30 years of HCV infection • Cirrhosis: 15-35%1 • HCC: 1-3% annual incidence2 • HCV infection increases HCC risk 17-fold1 • 31-61% of HCC cases with markers of HCV infection3 • Mortality • Lifetime risk of HCV-related death: 37%4 1 Freeman AJ et al, Hepatology 2001; 2Norderstedt, et al. Dig Liv Dis 2010; 3 Hassan MM, et al. J Clin, Gastroenterol 2002; 4 Rein et al, Dig Liver Dis 2011; Am J Epidemiology 2002; 5 Perz et al, J Hepatology 2006.

  7. Global Hepatitis C Burden Is Large and Highest in Asia and Africa 3–4 million new infections per year 180 million chronic infections Liver International pages 1-3, 8 JUN 201 2WHO unpublished data; 3 Perz JF, et al. J Hepatol. 2006;4 Zhuang X et al. Drug Alcohol Depend 2012; 5Serano L etal. J intAssoc Physicians AIDS Care ( Chic) 2012 Jul 24; 6Pltt L et al. Eur J Public Health 2009 .; 76P

  8. Six HCV Genotypes and Sub-genotypes Vary by Region Important Predictor of Treatment Response 1b 2,3 1b,3 1a,1b, 2,3 1b,2 1b,6 4 1b,3 3 5 1b,3 1a,1b, 2,3 WHO.org

  9. Hepatitis C Is a Leading Cause of Infectious Disease Deaths Worldwide, 2010 Disease Lower respiratory tract infections HIV/AIDS Diarrheal diseases Tuberculosis Malaria Hepatitis B virus Hepatitis C virus Meningitis Measles Hepatitis A virus Est. Deaths per Year ~2.8 million ~1.5 million ~1.4 million ~1.2 million ~1.2 million ~786,000 ~499,000 ~422,000 ~125,000 ~103,000 Lozano. Lancet. Vol 380. 2012

  10. A Large Number of Persons Are Living with Hepatitis C in the United States; Many Are Unaware of Their infection * National Vital Statistics System ; CDC MMWR, August 2012

  11. HCV Transmission risks Globally

  12. Unsafe Injections Are the Major Risk for HCV Transmission • Injection drug use • High HCV prevalence globally1: ~64 % (95% CI, 63.4-64.7%) • 60-70% of new infections in US and other countries • HCV incidence is highest among new injectors2-48-25% per year • Health-care exposures 5-11 • 2 million infections annually • Poor infection control (e.g., dialysis, anesthesia, chemotherapy) • Illicit drug diversion 1Hagan, et al. Int J Drug Policy. 2007; 2Hagan, et al. Amer J Public Health. 2001; 3Lucidarme, et al. Epid and Infect. 2004; 4Mehta. J Infect Dis. 5-2011; Ezzati M, et al. Lancet. 2002; -6Guerra J, et al. J Viral Hepat. 2012; -7Miller FD, Abu-Raddad LJ. Proc Natl Acad Sci USA. Aug 17, 2010; 8-Bosan A, et al. J Pak Med Assoc. 2010; -9Baatarkhuu O, et al. Liver Int. 2008; 2-10Thompson ND, et al. 2009; -11Perz JF, et al. Hepatology. 2012.

  13. Outbreak Detection in Healthcare Settings • Residential care facility- North Dakota • 35 HCV cases identified; >25% prevalence • Highly related HCV quasispecies • Infection control improved

  14. Other Exposures Are Associated with Transmission of HCV Non-injecting drug use (e.g., cocaine); 0-17% HCV+ Perinatal- Infants born to HCV infected mothers ~4% risk if mother HCV+ ~25% if mother HCV/HIV+ Heterosexual transmission is rare Household transmission is possible, two fold increased risk 1Scheinmann, et al , Drug and Alcohol Dependence, 2006; 2 Weinbaum MMWR 2003;3 Gough et al. BMC Public Health 2010,4Mast , et al, J Infect Dis, 2005.;; 6 Marincovich B,. Sex Transm Infect. Apr 2003; 7 Yaphe S; Sex TransmInf 2012 Aug 3; 8 Bottieau, et al Eurosurveillance 2010.)9 Ackerman Z, J Viral Hepat 2000.

  15. HIV and HCV Co-infection • 4-5 million infected with HIV globally • In US, ~25% of HIV infected persons are HCV infected • HIV hastens progression of HCV related liver disease • Most HCV transmission related to injection drug use • Sexual transmission of HCV increasingly reported among HIV+ men who have sex with men (MSM) • CDC recommends • One time HCV screening of all persons with HIV • Periodic HCV screening thereafter (e.g., yearly) G Tossing, Eur J Med 2005; Ragni MV, JID 2001; DAD Study Group AIDS 2010

  16. Trends in HCV- Associated Disease and Mortality in the United States

  17. HCV Is a Major Cause of Liver Disease and Associated Health Care Costs • HCV is a major cause of liver disease • 40,000 persons (36%) on liver transplant waitlist • 50% of persons with liver cancer; 2.5% annual increase • Substantial HCV-related costs • Three-fold higher disability days (1.36  vs. 0.34) than others • $21,000 in annual health costs vs. $5,500 for others • Cure of HCV infection reduces costs ($900 vs. $1,378 per patient month) Kim WR, et al. Gastroenterology. 2009; Simard EP, et al. Ca Cancer J Clin. 2012; Kanwal F, et al. Gastroenterology. 2011; Ly K, et al. Ann Int Med. 2012; Rein, et al. Dig Liver Dis. 2010; Gordon SG, Aliment Pharmacol Ther. 2013.

  18. In the United States, at a Time of Declines in HIV Deaths, Mortality from HCV Is Increasing 16,600 deaths Ly KN, Xing J, Klevens RM, Jiles RB, Holmberg SD. Causes of death and characteristics of decedents with viral hepatitis, United States, 2010. Clin Infect Dis. 2014 Jan;58(1):40-9.

  19. In Absence of New Interventions, the Burden of Hepatitis C Is Projected to Continue to Grow in the United States • Markov model of life-time health outcomes • Of 2.7 million HCV-infected persons in primary care: • 1.47 million will develop decompensated cirrhosis (DCC) • 350,000 will develop hepatocellular carcinoma ( HCC) • 897,000 will die from HCV-related complications DCC- decompensated cirrhosis HCC-hepatocellular carcinoma Rein D, et al. Dig Liver Dis. 2010.

  20. HCV Incidence Was Highest Before HCV Discovery and Impact of Prevention Strategies - United States Anti-HCVtest licensed (1992) Casesper 100,000 HCV discovery 1989 Year Ward JW. Clin Liver Dis. 2013.

  21. Many States Reported Increases in New HCV Infection During 2007-2011 Studies to date: • ~70% IDU • Young (18-29 years) • Predominantly white • Equally female and male • Non-urban, suburban areas • Previous prescription narcotic users Viral hepatitis surveillance summary. http://www.cdc.gov/hepatitis.

  22. Two of Three Americans Living with HCVWere Born During 1945-1965 • Reflects high HCV incidence in distant past • Five-fold higher prevalence than others (3.39% vs. .55%) • 81% of all HCV+ adults • 73% of all HCV-related mortality 1988–1994 1999–2002 7.0 A 6.0 5.0 4.0 Proportion Anti-HCV-Positive, % 3.0 2.0 1.0 0.0 0 10 20 30 40 50 60 70 Age at Time of Survey, y 7.0 B 1945 1965 6.0 1988–1994 1999–2002 5.0 4.0 Proportion Anti-HCV-Positive, % 3.0 2.0 1.0 0.0 1910 1920 1930 1940 1950 1960 1970 1980 1990 Year of Birth Smith, et al. AASLD Liver Meeting. San Francisco, CA. 2011; Armstrong, et al. Ann Int Med. 2006; Kramer, et al. Hepatology. 2011; Ly, et al. Ann Int Med. 2012.

  23. Limited Effectiveness of Risk-based HCV Testing Strategies • CDC recommendations since 1998 included: • Injection drug use • Blood transfusion before 1992 and other blood • Many clinicians are not aware of HCV testing guidelines. • Clinicians may be reluctant to ask about risks. • Patients may be reluctant to disclose or may not recall risks. • At least 45-60% are unaware of their HCV infection. • A birth cohort approach was considered to improve access to HCV testing, care, and treatment. Shehab TM. J Viral Hepat, 2001. Shehab TM, et al. Am J Gastroenterol, 2003. Serrante JM, et al. Fam Med, 2008. Shehab TM, et al. Hepatology, 1999. Roblin, et al. Am J Man Care 2011. Spradling, et al., Hepatology, 2012. Zapata et al, Ann Hepatology, 2010; Napper et al, AIDS Behav, 2010; Haley et al, Preven Med, 2002; Torrone et al, AIDS Pat Care, 2010; Volk et al, 2009

  24. HCV Testing of Persons Born 1945-1965 Yields Health Benefits and is Cost-effective • Reduces risks of liver cancer and mortality • 70% reduction in hepatocellular carcinoma • 90% reduction in liver related mortality • 50% reduction in all cause mortality • Can save over 120,00 HCV related deaths • Is cost-effective (CE) at typical willingness to pay thresholds • $15,700-85,300 per QALY* • CE for populations with low HCV prevalence ( >0.84%) Rein D, Ann Int Med 2012, Eckman , CID, 2013,;McEwan, Hepatology2013,;McGarry, Hepatology 2012, Liu S, Plos One 2013

  25. Proportion of HCV-infected Persons by Year of Birth: 15 Countries Wedemeyer H, J Viral Hepat. 2014

  26. New Options for HCV Testing, Care, and Treatment

  27. HCV Direct Acting Agents in Late Stages of Development • NS3-4A Protease inhibitors “pravir” • Telapravir, Bocepravir licensed since May 2011 • Simepravir approved Nov 22, 2013 • Faldaprevir- expected 2014 • ABT 450/r - expected 2014 • NS5B Polymerase inhibitor “buvir” • Nucleoside- Sofosbuvir –approval Nov-Dec 2013 • Non-nucleoside- Dasabuvir expected 2014 • NS5A inhibitor “asvir” • Daclatasvir expected 2014 • Ledipasvir expected 2014 • Ombitasvir expected 2014

  28. The Evolution of HCV Therapyfrom Interferon to Direct Antiviral Agents 1998 2001 2002 2011-13 1986 2014+ 90+% +/-INF RIBA 70-75 54-56 SVR (%) 42 39 34 16 6 PEG-IFN /RBV 12 mo PEG-IFN /RBV + PI 6-12 mo IFN 6 mo IFN 12 mo IFN/RBV 6 mo IFN/RBV 12 mo PEG-IFN 12 mo StraderDB, et al. Hepatology 2004;39:1147-71.

  29. The Quality of HCV Management Must Improve for Patients to Benefit from HCV Therapy 50% 38% 23% 6% 11% Holmberg S, et al, NEJM, 2013)

  30. Can Antiviral Therapy Reduce HCV Prevalence among Injecting Drug Users? Martin et al. Journal of Hepatology 2011 vol. 54 j 1137–1144 • Annually treating 10 HCV infections per 1000 IDU and achieving SVR of 62.5% • Projected to result in a relative decrease in HCV prevalence over 10 years of 31%, 13%, or 7% for prevalences of 20%, 40%, or 60%, respectively

  31. CDC and USPSTF Recommendations for HCV Testing Are Based on Birth Cohort, Risk, and Medical Indications • One-time test for persons born 1945-1965 • Major risk - Past or present injection drug use • Other risks • Received blood/organs prior to June 1992 • Received blood products made prior to 1987 • Ever on chronic hemodialysis • Infants born to HCV infected mothers • Intranasal drug use • Unregulated tattoo • History of incarceration Medical • Persistently elevated ALT • HIV CDC, MMWR Aug 2012; Moyer VA, Ann Int Med 2013

  32. HCV Testing and Linkage to Care at Community Health Centers October 1, 2012 – March 31, 2014

  33. HCV Screening & Testing at Venues Serving PWIDPrevention and Public Health Fund*January 2013—March 2014 Venues Include: Syringe Exchange Programs; Drug Treatment Centers; Health Departments; Methadone Clinics; Corrections; Shelters *Preliminary Data

  34. HCV Testing in a National Commercial Laboratory 2012-2013 – United States Mark BrecherLabcorp, personal communication

  35. Recommended Testing Sequence for Identifying Current Hepatitis C Virus (HCV) Infection HCV antibody + Reactive Nonreactive - - HCV RNA Detected + Not detected Current HCV infection No HCV antibody detected No current HCV infection STOP* Additional testing as appropriate† Link to care * For persons who might have been exposed to HCV within the past 6 months, testing for HCV RNA or follow-up testing for HCV antibody is recommended. For persons who are immunocompromised, testing for HCV RNA can be considered. † To differentiate past, resolved HCV infection from biologic false positivity for HCV antibody, testing with another HCV antibody assay can be considered. Repeat HCV RNA testing if the person tested is suspected to have had HCV exposure within the past 6 months or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen. Source: CDC. Testing for HCV infection: An update of guidance for clinicians and laboratorians. MMWR. 2013;62(18).

  36. Simplifying Testing and Management of Persons Diagnosed with HCV • Point of care assays for anti-HCV • Laboratory based testing for anti-HCV and HCV RNA • Standing orders • Clinical reminders • Reflex testing for HCV RNA for all anti-HCV + specimens • Non-invasive staging of liver disease • Liver biopsy- the gold standard, use decreasing • Alternatives – • Serologic algorithms (FIB-4, APRI, Fibrotest) • Ultrasound elastrography (Fibroscan) • Sensitivity 70-80% fibrosis; 80%-90% cirrhosis Holmberg , CID 2013; Ghany M, Hepatology 2009,2011; Cho R, Ann Int Med 2013; Poynard T, J Hepat 2012; Casera L HIV Med 2013

  37. National Guidance for HCV Treatment United States - 2014* • Developed by IDSA and AASLD • Genotype 1: 12 weeks of therapy • Sofosbuvir/PEG/RIB • Sofosbuvir/Simeprevir/+RIB X 12 weeks (all-oral) • Genotype 2 or 3: Sofosbuvir/RIB X 12-24 weeks (all-oral) • Treatment guidance available at hcvguidelines.org • New agents filed at FDA- expect licensure by Dec 2014 • Cost is an issue • CDC cost-effectiveness studies in progress PEG: pegylated interferon; RIB: ribavirin * CDC supported

  38. HCV Deaths Averted with Testing by Treatment Options P: pegylated interferon; R: ribavirin; Sof: sofosbuvir; Sim: simepravir; RB: risk-based; BC: birth cohort David Rein, personal communication

  39. CDC Strategies to Improve HCV Testing, Care, and Cure • Assessment- Monitoring and investigations • Policy development • Gather and evaluate evidence • Set national priorities to prevent transmission and disease • Guide prevention programs • Mobilize partnerships • Assurance • Support and evaluate programs • Assess policy implementation in health system • Train workforce • Educate communities • Capacity building is needed to be successful

  40. Take-home Points • Blood-borne exposures to HCV are major transmission risks. • The burden of HCV-related disease is large and growing. • Many if not most persons living with HCV are undiagnosed. • Cure of HCV infection reduces transmission and mortality risks. • CDC and USPSTF recommend HCV testing for persons born 1945-1965, past or present injection drug users, and others at risk. • Access to HCV testing, care, and treatment must improve for patients to benefit from current and anticipated therapies.

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