Epidemiology and Natural History of Hepatitis C Virus

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

Viral Hepatitis - Overview n n 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 n HBV, HCV, HDV – Percutaneous or mucosal exposures to blood – Chronic infection – major causes of cirrhosis and hepatocellular carcinoma worldwide

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

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

Hepatitis C Virus Infection Before Discovery n n First identified as a clinical entity (non-A, non-B hepatitis) in transfused patients late 1960 s Most risk factors identified before 1990 from cohort and case -control studies of acute disease dx by exclusion – – – n 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

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

Hepatitis C Virus Infection After Discovery n RNA Flavivirus – Mutations occur during viral replication – Substantial heterogeneity (quasispecies) prevents effective neutralization – No vaccine n n n 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

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

HCV Accomplishments During Past 15 Years n n n 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

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

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

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

Co-factors Affecting Natural History n Persistence – – n 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?

Metabolic and Other Co-Factors in Liver Disease Progression -- Independent and Synergistic for Cirrhosis and HCC Factor Prevalence US Adult Gen Pop Obesity 38. 6% Metabolic syndrome 23% Diabetes 9. 3% Heavy Alcohol 7 -15% NAFLD 6 -14% HCV infection 3 -14%

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

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

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

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

Hepatitis C Virus Infection United States New infections per year 1985 -89 2006 20, 000 242, 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)

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

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

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

Injecting Drug Use and HCV n n 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) n Incidence remains high in new users in many countries – 15%-20% annual rate n Associated with sharing cookers and cotton independent of needles/syringes. – Need to include in harm reduction messages

Prevalence and Incidence of HCV Infection in IDUs, 1995 -2001 Age <30 years New York City Chicago Vancouver, BC Italy (Veneto region) UK Prevalence 40 -50% 27% 46% 37% 13 -20% Any age Seattle Italy (Veneto region) Ireland UK 86% 74% 66% 48 -76% Incidence/100 PY 9 -34 10 37 -- 21 -24. 5 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

HCV by Frequency of IDU among 5282 College and University Students, US IDU history (% total) HCV Prevalence Never injected (98%) Ever injected (2%) Once or twice Daily, regular, sporadic* * Sporadic = more than once or twice but not long term 0. 5% 22. 6% 9. 0% 29. 0%

Occupational Transmission of HCV n n Inefficient by occupational exposures Incidence <0. 5%-2% following needle stick from HCV-positive source – Associated with hollow-bore needles, deep injury n n Case reports of transmission from blood splash to eye; one from exposure to nonintact skin Prevalence 1 -2% among health care workers – Lower than adults in the general population – 10 times lower than for HBV infection

Perinatal Transmission of HCV n 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 n Risk factors – Internal fetal scalp monitoring (7 -fold increased risk) – Prolonged rupture of membranes (9 -fold increased risk) n No association – Delivery method – Breastfeeding

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

Exposures Not Associated With Acquiring HCV Case Control Studies of Acute Hepatitis C, U. S. , 1979 -85 Exposure (prior 6 months) Cases n=148 Controls n=200 Medical care procedures Dental work Health care work (no blood contact) Ear piercing Tattooing Acupuncture Incarceration Foreign travel Military service 30. 4% 24. 3% 4. 1% 2. 7% 0 4. 1% 1. 3% 29. 5% 23. 5% 5. 0% 3. 0% 0. 5% 1. 0% 2. 5% 4. 9% Sources: JID 1982; 145: 886 -93; JAMA 1989; 262: 1201 -5.

Identification of Rare Events Associated with HCV Transmission n 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 n HIV-positive MSM through high risk sexual activities

HCV Prevalence by Age, NHANES, U. S. General Population, 1988 -94 vs. 1999 -02 (1. 8%) 3. 9 million (1. 6%) 4. 2 million Alter MJ, NEJM 1999; 341: 556 -562; Armstrong GL, Ann Intern Med 2006; 144: 705 -714

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

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

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

Demographics Independently Associated with HCV Infection among Participants Age 20 -59 Variable Ethnicity Non-Hispanic white Non-Hispanic black Mexican American Place of birth Within United States Outside of United States Ratio of income to poverty threshold 2. 0 1. 0– 1. 9 0. 0– 0. 9 Armstrong GL, Ann Intern Med 2006; 144: 705 -714 Adjusted OR (95% CI) 1. 0 1. 9 (0. 9– 3. 8) 2. 6 (1. 2– 5. 8) 1. 0 0. 2 (0. 08– 0. 7) 1. 0 3. 5 (1. 9– 6. 4) 9. 1 (4. 5– 18. 2)

Risk Factors Independently Associated with HCV Infection among Participants Age 20 -59 Variable Blood transfusion before 1992 No Yes Drug Use Never Non-injection drug use Injection drug use Lifetime number of sexual partners 0– 1 2– 19 >20 Armstrong GL, Ann Intern Med 2006; 144: 705 -714 Adjusted OR (95% CI) 1. 0 2. 6 (0. 9– 7. 3) 1. 0 3. 7 (1. 7– 7. 9) 148. 9 (44. 9– 494) 1. 0 1. 4 (0. 3– 6. 0) 5. 2 (1. 5– 18. 2)

Factors Independently Associated with HCV Infection among Participants Age >60 Years Variable Ethnicity Non-Hispanic white Non-Hispanic black Mexican American Blood transfusion before 1992 No Yes Armstrong GL, Ann Intern Med 2006; 144: 705 -714 Adjusted OR (95% CI) 1. 0 4. 3 (1. 9– 9. 6) 1. 6 (0. 6– 4. 0) 1. 0 4. 9 (1. 7– 14. 1)

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

Summary n 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 n Less than half of HCV infected patients have been identified – Unrealistic to expect healthcare professionals to ascertain risk histories or individualize preventive services n New strategies need to be developed for efficient delivery of preventive services

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

Estimated HCV Prevalence by Region E Europe 11. 6 million N/W/S Europe 6. 2 million No. America 5 million E Med 1. 4 million So/Central America 7. 8 million Africa 29. 4 million Southeast Asia 24 million Western Pacific 41. 4 million < 1. 0% - 1. 9% 2. 0% - 2. 9% > 2. 9% Not included in a WHO region Global Anti-HCV Prevalence 2. 2% 130, 000 Positives J Perz et al. , Journal of Hepatology 45 (2006) 529– 538

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

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

Incidence of HCV Infection by Selected Geographic Areas, 1995 -2000 Mean age 35 y Gen pop 32 y Donors 50 y 40 y 60 y <20 y 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

Global Burden of Hepatitis Infections Attributable to Contaminated Health Care Injections HBV Annual number of infections (million) 21 Attributable fraction for injections Projected deaths 2000 -2030 Disability adjusted life years (million) Source: Hauri et al. , Int J STD & AIDS 2004; 15: 7 -16 32% HCV 2 40% 75, 000 24, 000 3 0. 3

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

Unsafe Injection Practices n n n 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

Children Handling Medical Waste, Bangladesh

Current and Future Issues n Identification of infected persons – Screening and testing not routinely performed – Lack effective methods for reaching those whose risk was in the remote past • Risk factor ascertainment in routine healthcare visits is rare n Therapy regimens less than ideal, especially those with genotype 1 – In US, treatment offered to low % of HCV-positives n Implications of multiple co-factors on liver disease progression and response to therapies not well understood – Impact likely to grow creating an even greater challenge n Need to be alert to changes in epidemiology

Role of Therapeutic Management in Global Control of Viral Hepatitis n n Major advances over past 5 years in therapautic management of HBV and HCV Good news: promise of further advances Bad news: COSTS, side effects, contraindications Challenge: how to extend benefits to the vast numbers of persons who could benefit – Address affordability issues head-on

Remaining Challenges: International Prevention Efforts n n n Obtaining and maintaining funding and infrastructure for vaccine program implementation Integrating into routine childhood schedules in harmony with other vaccines Delivery of vaccine to infants born out of hospital Demonstrating impact of programs Reducing transmission due to unsafe injection practices (healthcare-related and illicit drug use)

Most Common (>10%) HCV Genotypes by Region 1, 2, 3 1, 2 1, 3, 4 1, 2, 3 4 4 1, 3 3 3 SE Asia: 6 1, 3 4 1 5 1

Distribution of HCV Genotypes in France (2001) and US (1999 -2002) Payan C, J Viral Hepatitis 2005; 12: 405 -413 CDC, NHANES 1999 -2002, unpublished data

Percentage HCV Genotypes 1, 2 and 3 by Age United States and Western Europe United States Western Europe Alter MJ. NEJM 1999; 341: 556 -62; Nainan OV. Hepatology June 1996; Pawlotsky JID Source: CDC, unpublished data 1995; 171: 1607; Simmonds J Hepatol 1996; 24: 517; Zeuzem et al. J Hepatol 1996; 24: 3.

HCV Genotypes in the US General Population by US and Foreign Birth Source: Nainan OV, Gastroenterology 2006; 131: 478– 484

HCV Genotypes in French Patients by Geographic Origin Payan C, J Viral Hepatitis 2005; 12: 405 -413