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Epidemiology and Natural History of Hepatitis C Virus Infection

Epidemiology and Natural History of Hepatitis C Virus Infection. Miriam J. Alter, Ph.D., MPH Infectious Disease Epidemiology Program Institute for Human Infections and Immunity University of Texas Medical Branch Galveston, Texas. May 5, 2009. Topics. History of discovery

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Epidemiology and Natural History of Hepatitis C Virus Infection

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  1. Epidemiology and Natural History of Hepatitis C Virus Infection Miriam J. Alter, Ph.D., MPH Infectious Disease Epidemiology Program Institute for Human Infections and Immunity University of Texas Medical Branch Galveston, Texas May 5, 2009

  2. Topics • History of discovery • Virus and clinical characteristics • General population characteristics • Prevalence • Incidence • Natural history and role of co-factors • Alcohol • Metabolic factors • HIV co-infection • Current and future morbidity and mortality

  3. Viral Hepatitis - Overview • Primary infection of the liver caused by at least five unrelated viruses: A, B, C, D, E • HAV and HEV • Fecal-oral route • Acute self-limited disease; no chronic infection • HBV, HCV, HDV • Percutaneous or mucosal exposures to blood • Chronic infection – major causes of cirrhosis and hepatocellular carcinoma worldwide

  4. Viral Hepatitis – Historical Perspective Enterically transmitted “Infectious” A E Viral hepatitis NANB Parenterally transmitted “Serum” B D C F, G, ?other Non-pathogenic false-report

  5. Clinical Features of Hepatitis • jaundice • abdominal pain • hepatomegaly Common • malaise • anorexia • nausea & vomiting • fever Less Common • diarrhea • arthralgias • pruritis • rash

  6. Hepatitis C Virus InfectionBefore Discovery • First identified as a clinical entity (non-A, non-B hepatitis) in transfused patients late 1960s • Most risk factors identified before 1990 from cohort and case-control studies of acute disease dx by exclusion • Whole blood transfusion, clotting factors • IDU • Iatrogenic (dialysis, unsafe injection techniques) • Occupational (needlesticks, frequent expos to blood) • Perinatal • Sex • “High” rate of chronic infection • Persistence of abnormal ALT in NANB cohorts followed from onset • High rate of transfusion-transmitted NANB hepatitis from apparently healthy donors

  7. Hepatitis C Virus • RNA Flavivirus (Hepacivirus) • Discovery using recombinant DNA technology reported in 1989 • Clinical entity (non-A, non-B hepatitis) in transfused patients reported late 1960s • Target organ liver • Bloodborne (primarily) and sexually-transmitted • No vaccine • Mutations occur during viral replication • Substantial heterogeneity (quasispecies) prevents effective neutralization

  8. Hepatitis C Virus InfectionAfter Discovery • RNA Flavivirus • Mutations occur during viral replication • Substantial heterogeneity (quasispecies) prevents effective neutralization • No vaccine • Serologic (Ab) followed by NAT (RNA) • Clinical symptoms of acute disease <20% • Chronic infection 60-85% • Chronic hepatitis 70% • Cirrhosis and liver cancer 5-20% • Mortality 5%/year • Most common indication for liver transplantation in US

  9. ABO and anticoagulants Hypodermic needle invented by Sir Christopher Wren, 1660 Blood banking <20% of patients received IV therapy 1st human-human blood transfusion, 1834 Transfusions, AHF, plasmapheresis, commercial IV solutions, single use disposables, vaccination Injection drug use HCV – A Product of The Twentieth Century 1850 1650 1800 1900 1950 2000

  10. HCV Accomplishments During Past 15 Years • Determined burden of infection and morbidity in the general population • Eliminated transfusion-associated infections • Documented >80% decline in incidence • Characterized the epidemiology • Implemented community-based prevention

  11. 5-15% 20% All infections; many never come to medical attention including those that resolve Broader spectrum of disease severity; but milder cases may not be referred 30-50% High proportion severe disease Natural History of HCV Infection How Selection of Study Population Affects Conclusions Regarding Disease Progression Cirrhosis Pathologic Evidence of Disease if Detected Signs and Symptoms of Disease Medical Care Sought Diagnosis by Referral Biologic Onset of Disease

  12. Natural History of HCV in Patients Referred for Medical Care ~20 Years After Infection Tx UK IDU Exposure 30-50% transfused All transfused 50% transfused

  13. Age at infection Years followed 17 15-20 8-20 Median age at FU 20 40 67 Exposure Transfusion Anti-D; IDU Transfusion References Losasciulli ‘97 Kenny-Walsh ’99; Wiese ‘00 DiBisceglie ‘91 Vogt ’99; Casiraghi ‘04 Thomas ‘00; Rodger ‘00 Seeff ‘01 Natural History of HCV in Cohorts Followed for 20 Years by Age at Infection

  14. Co-factors Affecting Natural History • Persistence • Older age at infection • Male gender • Black race • Immunosuppression • Progression • Older age at infection • Immunosuppression • Co-infection (HIV, HBV) • Metabolic syndrome • Heavy alcohol intake • Diabetes • Obesity • Male gender • Genotype?

  15. Metabolic and Other Co-Factors in Liver Disease Progression -- Independent and Synergistic for Cirrhosis and HCC Obesity 38.6% Metabolic syndrome 23% Diabetes 9.3% Heavy Alcohol 7-15% NAFLD 6-14% HCV infection 3-14% Prevalence US Factor Adult Gen Pop

  16. Annual hepatitis C mortality rates (95% CI) for selected age groups, United States, 1995-2004. Wise M et al., Hepatology;47:1128-1135

  17. Estimated Future HCV-Related Disease Burden Davis GL et al. 2009 unpublished data

  18. Predicted HCV-Related Deaths USA 2005-2025 UK 1996-2004 Sweeting MJ, et al. J Viral Hepatitis, 2007, 14, 570–576 Note: Similar trends predicted for France by same authors S. Deuffic-Burban,et al. J Viral Hepatitis, 2007, 14, 107–115 Australia 1990-2020 Greece 1990-2030 Sypsa V et al. Journal of Viral Hepatitis, 2005, 12, 543–550 Law MG. Intern J Epidemiology 2003;32:717–724

  19. Total Deaths 563,000 366,000 Cirrhosis 235,000 211,000 Liver Cancer 328,000 155,000 Viral Hepatitis-Related ESLD Mortality Worldwide DeathsHBV-related HCV-related Perz J et al. Journal of Hepatology 45 (2006) 529–538

  20. Hepatitis C Virus Infection United States New infections per year 1985-89 242,000 2006 20,000 Deaths from acute liver failure Rare Persons ever infected (1.6%) 4.1 million (3.4-4.9)* Persons with chronic infection 3.1 million (2.5-3.7)* HCV-related chronic liver disease 40% - 60% Deaths from chronic disease/year 8,000-10,000 * 95% confidence interval (data from 1999-2002)

  21. Risk Factors Associated With Acquiring HCV Infection Cohort and Acute Case Control Studies • Transfusion, transplant from infectious donor • Injecting drug use • Occupational blood exposure (needle sticks) • Birth to an infected mother • Infected sex partner • Multiple heterosexual partners

  22. HCV InfectionEstimated Past Incidence and Future Prevalence Decline in cases among IDUs Incidence Overall prevalence Infected 20+ years Armstrong GL et al. Hepatology 2000;31

  23. ALT/Anti-HBc Anti-HCV HCV RNA Posttransfusion Hepatitis All volunteer donors HBsAg NANB Donor Screening for HIV Risk Factors Anti-HIV 3rd generation HBsAg HBV Adapted from HJ Alter

  24. Injecting Drug Use and HCV • Accounts for most (50-80%) infections in Western countries, particularly in persons <50 yrs old. • Cumulative infection rates have slowed • 30% prevalence after 2-3 years (vs. 80% in 1989) • Incidence remains high in new users in many countries • 15%-20% annual rate • Associated with sharing cookers and cotton independent of needles/syringes. • Need to include in harm reduction messages

  25. Prevalence and Incidence of HCV Infection in IDUs, 1995-2001 Age <30 yearsPrevalenceIncidence/100 PY New York City 40-50% 9-34 Chicago 27% 10 Vancouver, BC 46% 37 Italy (Veneto region) 37% -- UK 13-20% Any age Seattle 86% 21 Italy (Veneto region) 74% -- Ireland 66% 24.5 UK 48-76% 14 Diaz T Am J Pub Health 2003; Des Jarlais DC Am J Epi 2003; Thorpe L Am J Epi 2002; Hahn JA JID 2002; Miller Hepatology 2002; Hagan H Am J Epi 1999; Quaglio J Viral Hep 2003; Bird SM J Epi Biostat 2001; Grogan L Irish J Med Sci

  26. HCV by Frequency of IDU among 5282 College and University Students, US IDU history (% total) HCV Prevalence Never injected (98%) 0.5% Ever injected (2%) 22.6% Once or twice 9.0% Daily, regular, sporadic * 29.0% * Sporadic = more than once or twice but not long term

  27. Occupational Transmission of HCV • Inefficient by occupational exposures • Incidence <0.5%-2% following needle stick from HCV-positive source • Associated with hollow-bore needles, deep injury • Case reports of transmission from blood splash to eye; one from exposure to non-intact skin • Prevalence 1-2% among health care workers • Lower than adults in the general population • 10 times lower than for HBV infection

  28. Perinatal Transmission of HCV • Only from women HCV-RNA pos. at delivery • Average rate of infection 4-6% • Higher (17%) if woman co-infected with HIV • Role of viral titer unclear • Threshold for transmission not consistent among studies • Risk factors • Internal fetal scalp monitoring (7-fold increased risk) • Prolonged rupture of membranes (9-fold increased risk) • No association • Delivery method • Breastfeeding

  29. Perinatal Transmission of HCV No. Infants % Infants Potential risk factorTestedInfected Type of Delivery Vaginal 336 10% C-section 107 8% Type of Feeding* Breast-fed 157 5% Bottle-fed 74 8% * Includes only infants born to HIV-negative mothers

  30. Exposures Not Associated With Acquiring HCV Case Control Studies of Acute Hepatitis C, U.S., 1979-85 Cases Controls Exposure (prior 6 months)n=148n=200 Medical care procedures 30.4% 29.5% Dental work 24.3% 23.5% Health care work (no blood contact) 4.1% 5.0% Ear piercing 2.7% 3.0% Tattooing 0.7% 0.5% Acupuncture 0 1.0% Incarceration 4.1% 1.0% Foreign travel 4.1% 2.5% Military service 1.3% 4.9% Sources: JID 1982;145:886-93; JAMA 1989;262:1201-5.

  31. Identification of Rare Events Associated with HCV Transmission • Healthcare procedures in the U.S. • Patient-to-patient and HCW-to-patient • Difficult to detect • Identified in in-patient, out-patient, dialysis and home-therapy • Increasingly recognized in context of outbreaks • Mostly due to unsafe injection practices • Re-use of syringes and needles • Contaminated multiple dose medication vials • HIV-positive MSM through high risk sexual activities

  32. HCV Prevalence by Age, NHANES, U.S. General Population, 1988-94 vs. 1999-02 (1.8%) (1.6%) 3.9 million 4.2 million Alter MJ, NEJM 1999;341:556-562; Armstrong GL, Ann Intern Med 2006;144:705-714

  33. HCV Prevalence by Gender, Age and Race, NHANES, U.S. General Population, 1999-2002 Males Females Armstrong GL, Ann Intern Med 2006;144:705-714

  34. Distribution of HCV Genotypes in the General Population, 1990 vs. 2000, US * Nainan OV. Gastroenterol 2006;131:478-484 *CDC, preliminary unpublished data

  35. HCV Genotypes in the US General Population by Percentage US-Born, 1988-1994 All US-born Blacks All Asian-born Nainan OV. Gastroenterol 2006;131:478-484

  36. Demographics Independently Associated with HCV Infection among Participants Age 20-59 VariableAdjusted OR (95% CI) Ethnicity Non-Hispanic white 1.0 Non-Hispanic black 1.9 (0.9–3.8) Mexican American 2.6 (1.2–5.8) Place of birth Within United States 1.0 Outside of United States 0.2 (0.08–0.7) Ratio of income to poverty threshold 2.0 1.0 1.0–1.9 3.5 (1.9–6.4) 0.0–0.9 9.1 (4.5–18.2) Armstrong GL, Ann Intern Med 2006;144:705-714

  37. Risk Factors Independently Associated with HCV Infection among Participants Age 20-59 VariableAdjusted OR (95% CI) Blood transfusion before 1992 No 1.0 Yes 2.6 (0.9–7.3) Drug Use Never 1.0 Non-injection drug use 3.7 (1.7–7.9) Injection drug use 148.9 (44.9–494) Lifetime number of sexual partners 0–1 1.0 2–19 1.4 (0.3–6.0) >20 5.2 (1.5–18.2) Armstrong GL, Ann Intern Med 2006;144:705-714

  38. Factors Independently Associated with HCV Infection among Participants Age >60 Years VariableAdjusted OR (95% CI) Ethnicity Non-Hispanic white 1.0 Non-Hispanic black 4.3 (1.9–9.6) Mexican American 1.6 (0.6–4.0) Blood transfusion before 1992 No 1.0 Yes 4.9 (1.7–14.1) Armstrong GL, Ann Intern Med 2006;144:705-714

  39. Chronic (Prevalent) Acute (Incident) Injection Drug Use 50% Injection Drug Use 60% Unk 10% Sexual 20% Sexual 20% Unk 10% Other* 10% Other* 10% Transfusion 10% * Other includes occupational, nosocomial, iatrogenic, perinatal Risk Factors For Persons with Acute or Chronic Hepatitis C 1999-2002, U.S. Armstrong GL, Ann Intern Med 2006;144:705-14; CDC Sentinel Counties, unpublished data

  40. Summary • Most HCV-positives can be identified based on 2-3 major characteristics • “Laundry lists” of risk factors distract attention from those that should be used for testing • Generic risks demand their own messages regardless of risk • Don’t use illegal drugs • Anything that pierces your skin should be sterile • Less than half of HCV infected patients have been identified • Unrealistic to expect healthcare professionals to ascertain risk histories or individualize preventive services • New strategies need to be developed for efficient delivery of preventive services

  41. Global Differences in HCV Transmission Patterns Contribution of exposures to disease burden by HCV prevalence Exposures among prevalent infectionsLowModerateHigh Injecting drug use++++ ++ + Transfusions before testing - +/- +++ Unscreened transfusions- - +++ Unsafe therapeutic injections + ++++ ++++ Occupational+ + + Perinatal+ + + High-risk sex++ + +/-

  42. < 1.0% 1.0% - 1.9% 2.0% - 2.9% > 2.9% Not included in a WHO region Estimated HCV Prevalence by Region E Europe 11.6 million N/W/S Europe 6.2 million No. America 5 million Western Pacific 41.4 million E Med 1.4 million Southeast Asia 24 million Africa 29.4 million So/Central America 7.8 million Global Anti-HCV Prevalence 2.2% 130,000,000 Positives J Perz et al., Journal of Hepatology 45 (2006) 529–538

  43. Geographic Patterns of Age-specific Prevalence of HCV Infection, 2000-2005 Italy/Japan (1-1.9) Taiwan (2-2.9) Turkey (1.5) US/WEur/AU (1-1.9)* * Numbers in parentheses refer to region specific prevalences

  44. Geographic Patterns of Age-specific Prevalence of HCV Infection, 2000-2005 Egypt (>2.9) Japan hyperendemic areas (1-1.9) Italy/Japan (1-1.9) Taiwan (2-2.9) Turkey (1.5) US/WEur/AU (1-1.9)* * Numbers in parentheses refer to region specific prevalences

  45. Incidence of HCV Infection by Selected Geographic Areas, 1995-2000 Mean age 35y 32y 50y 40y 60y <20y Gen pop Donors Hyperendemic communities * Background HCV prevalence differed between areas studied, 9% vs. 24%. Source: Prati, Hepatol 1997; Sun, J Med Virol 2001; Fukuizumi, Scand J Infect Dis 1997; Okayama, J Viral Hep 2002; Mohamed, Hepatol 2005

  46. Global Burden of Hepatitis Infections Attributable to Contaminated Health Care Injections HBVHCV Annual number of infections (million) 21 2 Attributable fraction for injections 32% 40% Projected deaths 2000-2030 75,000 24,000 Disability adjusted life years (million) 3 0.3 Source: Hauri et al., Int J STD & AIDS 2004;15:7-16

  47. Immunization injections Most vaccine are administered by injections Therapeutic injectionsMost medications used in primary care can be administered orally Use of Injections Worldwide Measles Eradication Source: WHO

  48. Unsafe Injection Practices • Inadequate supplies of sterile syringes • Inadequate sterilization of reusable syringes and needles • Administration by non-professionals at home • Syringes shared with others (family, neighbors) • Overuse of therapeutic injections

  49. Children Handling Medical Waste, Bangladesh

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