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The ABC’s of Hepatitis Ian Williams, PhD, MS Division of Viral Hepatitis Centers for Disease Control and Prevention Viral Hepatitis – Historical Perspective “Infectious” Viral hepatitis “Serum” A Enterically E transmitted NANB B D Parenterally C transmitted F, G, ? other Classification of Hepatitis Viruses Virus Family DNA or RNA Envelope HAV Picornaviridae RNA* no HBV Hepadnaviridae DNA** yes HCV Flaviviridae RNA* yes HDV Deltavirus (genus) RNA*** yes RNA* no HEV ? (Previously classified as a calicivirus) *linear, single strand; ** circular, double strand; *** circular, single strand Basic Features of Hepatitis Viruses Incubation Period* Chronic Infection Virus Transmission A fecal-oral B parenteral 8-12 (6-24) Yes C parenteral 6-9 (2-24) Yes D parenteral ? (2-10) Yes E fecal-oral * Weeks 4 (2-6) 4-5 (2-9) No No Acute Viral Hepatitis, United States, 1991-1998 63% 28% 8% 1% Source: Sentinel Counties Study, CDC Hepatitis A Hepatitis B Hepatitis C Non-ABCDE Mechanism of Injury • Hepatotropic viruses • Acute infection: direct cytotoxicity vs. immune response to infection vs. combination of the two • Chronic infection: immune response probably more important Clinical Manifestations of Acute Viral Hepatitis Asymptomatic Symptomatic Fulminant liver failure and death Typical Signs and Symptoms • • • • • Fever Malaise Anorexia Nausea Vomiting • Jaundice • Scleral icterus • Abdominal/RUQ pain • Hepatomegaly • Arthritis Laboratory Findings in Acute Viral Hepatitis Laboratory indicators of liver pathology • Elevated ALT (SGPT) and AST (SGOT) • Elevated bilirubin • Elevated alkaline phosphatase Laboratory indicators of infection • Increased WBC All non-specific with regard to making an etiologic diagnosis Differential Diagnosis of Acute Hepatitis Viral infections hepatitis A, B, C, D, and E, CMV, EBV, HSV, VZV, yellow fever Bacterial infections typhoid fever, Q fever, RMSF, leptospirosis, secondary syphillis, sepsis toxocariasis, liver flukes Parasitic infections Toxins ASA, acetaminophen, INH, rifampin, oral contraceptives, anti-seizure meds, carbenicillin, sulfonamides Alcohol, carbon tetrachloride Autoimmune diseases Autoimmune hepatitis, SLE Drugs Immunologic Markers Used for Serologic Diagnosis Immune globulin of the M sublcass (IgM): • Produced in early infection Immune globulin of the G subclass (IgG): • Produced in later infection Total immune globulin (Total Ig): • Combination of IgM and IgG • Early infection - primarily IgM • Late infection - primarily IgG Hepatitis A Virus (HAV) Clinical Features of Hepatitis A Incubation period Mean:28-30 days Range:2-6 weeks Jaundice <6 years: 10% 6-14 years: 40-50% >14 years: 70-80% Case fatality Overall: 0.3% >50 years: 1.8% Chronic infection No Transmission of HAV Virus transmitted from person to person Primarily through fecal-oral route – short period of viremia – occasional bloodborne transmission Virus shed in feces of infected persons (both symptomatic and asymptomatic persons) Greatest period of communicability: 2 weeks before onset of jaundice Virus in environment for months Modes of Transmission of HAV Close personal contact - household Ingestion - sexual of contaminated food and water - Fresh produce - ice - food contaminated after cooking Blood exposure (rare) - blood transfusion -injection drug use Reported Risk Factors for Hepatitis A in the United States Household or sexual contact (12%) Unknown* (51%) Day care related (11%) Male homosexual activity (7%) Injection drug use (14%) Travel (4%) * Most "unknowns" probably related to person-to-person transmission Source: Sentinel Counties Surveillance System for Acute Viral Hepatitis, CDC 45 40 35 30 25 20 15 10 5 0 2000 98 96 94 92 1990 88 86 84 82 1980 78 76 74 72 1970 68 66 64 62 1960 58 56 54 52 Reported cases per 100,000 population Reported Incidence of Hepatitis A United States (1952-2001) Source: CDC Year Estimated Incidence of Acute Hepatitis A in the United States (1982-2001) Number Estimated Acute Cases Estimated Acute Infections 400,000 350,000 300,000 250,000 200,000 150,000 100,000 50,000 0 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 Year Immune Globulin (IG) Prepared from pooled human plasma Mechanism of action: passive transfer of neutralizing antibodies Prevents infection or clinical expression of disease Prevention of Hepatitis A with IG Pre-Exposure Prophylaxis • Protection lasts 3-5 months • Used for travelers Post-Exposure Prophylaxis • Must be given within 14 days of exposure • Used for household and sexual exposures • Sometimes used for common source exposures (e.g., infected food handler) Prevention of Hepatitis A with Hepatitis A Vaccine Used for pre-exposure prophylaxis Given as 2-dose series Licensed for use for persons >2 years old Duration of protection: at least 20 years – possibly lifelong Unresolved issues: – use for post-exposure prophylaxis – use in community-wide outbreaks Recommendations for Hepatitis A Vaccination Travelers to HAV endemic countries Homosexual and bisexual men Drug users (IDU and other street drugs) Persons with chronic liver disease (disease more server in these persons – not necessarily at higher risk) Children living in states with high rates of hepatitis A Transmission of Bloodborne Viral Infections Route Percutaneous Apparent Inapparent Permucosal Mode injection drug use needle stick injury blood/ serous fluid sex perinatal Relative Transmission Efficiency of Bloodborne Viral Infections HBV HCV HIV Injection drug use +++ ++++ ++ Sexual +++ + ++ Perinatal ++++ + ++ Occupational +++ +/- +/- Risk Factors for Transmission of Hepatitis Viruses and HIV Proportion of Infections Risk Factor HBV HCV HIV Injection drug use 14% 60% 31% MSM 15% 1% 47% Heterosexual partners 40% 20% 10% Transfusion rare Past 7- 20% Past 2% Occupational 5-7% (past) <<1% <<1% No Identified Risk 30% 10% 9% Disease Burden from Bloodborne Viral Infections Outcome Chronic infections New infections /yr Deaths /yr HBV HCV HIV ~1.2 ~2.7 ~0.8 (million) (million) (million) ~120,000 ~40,000 ~40,000 5,000 8,000 18,000 Hepatitis B Virus (HBV) Clinical Features of Hepatitis B Incubation period Average: 60-90 days Range: 45-180 days Clinical illness (jaundice) < 5 years: <10% >5 years: 30-50% Case-fatality rate 0.5-1.0% Chronic infection YES <5 years: 30-90% 5 years: 6-10% 100 100 80 80 Chronic Infection 60 60 40 40 20 20 Symptomatic Acute Hepatitis B 0 Birth 1-6 months 7-12 months Age at Infection 1-4 years 0 >5 years Symptomatic Infection (%) Chronic Infection (%) Outcome of HBV Infection by Age at Infection Outcome of HBV Infection Liver cancer and cirrhosis Chronic infection Asymptomatic acute hepatitis B Resolved & immune Asymptomatic carrier Infection Liver cancer and cirrhosis Chronic infection Symptomatic acute hepatitis B Asymptomatic carrier Resolved & immune Chronic HBV Infection, Vietnam Geographic Distribution of Chronic HBV Infection HBsAg Prevalence >=8% - High 2-7% - Intermediate <2% - Low Concentration of HBV in Body Fluids High blood serum wound exudate Moderate semen vaginal fluid saliva Low/not Detectable urine feces sweat tears breast milk Modes of Transmission of HBV Percutaneous and permucosal – e.g., IDU, needle stick injuries Sexual – homosexual and heterosexual Perinatal – From mother to child during labor and delivery (in utero transmission rare) Reported Risk Factors for Acute Hepatitis B in the U.S. (1991-2000) IDU (20%) MSM (12%) Other1 (5%) Heterosexual (43%) 1 Unrecognized (14%) Other: Household contact, institutionalization, hemodialysis, blood transfusion, occupational exposure Source: Sentinel Counties Study of Acute Viral Hepatitis, CDC Who is at Risk for HBV Infection? High-risk heterosexual men and women Sexually active homosexual men Injection drug users Health care workers Household and sex partners of persons with chronic infection Hemodialysis patients Recipients of blood products Clients and employees of institution for developmentally disabled Families of adoptees from HBV endemic countries Inmates of correctional facilities High-Risk Heterosexual Men & Women >1 sex partner in the past 6 months STD clinic patients Recently acquired STD Commercial sex workers HBV Prevalence Among Various Risk Groups General population (4.9%) >10 sex partners (6%) >50 sex partners (12%) MSM (20-40%) IDU (60-80%) 0 20 40 60 80 100 Percent Infected (Anti-HBc positive) Prevention of HBV Infection Hepatitis B Immune Globulin (HBIG) • Post-exposure prophylaxis Hepatitis B Vaccine • Pre-exposure prophylaxis • Post-exposure prophylaxis Hepatitis B Immune Globulin (HBIG) Prepared from plasma containing high titers anti-HBs Used for post-exposure prophylaxis to prevent infection from: - Perinatal exposure - Sexual exposure - Occupational exposure Must be given soon after exposure to be effective Does not protect against future exposures Hepatitis B Vaccine Primary component of vaccine is HBsAg – HBsAg elicits devolvement of anti-HBs – anti-HBs protective antibody Worldwide, plasma-derived and recombinant formulations available Only recombinant available in U.S. Given as a 3-dose series Highly immunogenic – seroconversion ~95% Protection long-lasting – booster doses of vaccine not recommended Elimination of HBV Transmission in the United States Current Strategy Routine vaccination of infants Routine vaccination of adolescents not vaccinated in infancy Vaccination of high-risk children, adolescents, and adults Coverage, % HepB3, DTP3, and Hib3 Coverage, Among 19-35 Month-Old Children, 1992-2000 100 90 80 70 60 50 40 30 20 10 0 DTP3 Hib3 Routine HepB vaccination recommended 1990 HepB3 1991 1992 1993 1994 1995 Year 1996 1997 1998 1999 2000 Reported Cases of Acute Hepatitis B in Children United States, 1985-2000 1 to 4 yrs 5 to 9 yrs Reported Cases 200 150 100 50 Routine HepB vaccination recommended 0 00 20 99 19 98 19 97 19 96 19 95 19 94 19 93 19 92 19 91 19 90 19 89 19 88 19 87 19 86 19 85 19 Year Estimated Incidence of Acute Hepatitis B in the United States (1982-2001) Estimated Acute Cases 350,000 300,000 Vaccine licensed Estimated Acute Infections Infant immunization recommended Number 250,000 200,000 150,000 100,000 50,000 0 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 Year Features of HCV Infection Incubation period Average, 6–7 wk Range, 2–26 wk Acute illness (jaundice) Mild (20%–30%) Persistent infection 75%–85% Chronic hepatitis 70% Immunity No protective antibody response identified Risk of Fatal Outcome in Persons Who Develop Hepatitis C Infection Time 100 85% Chroni c 20% Cirrhosis 85 80% 17 25% 15% Resolv e 15 75% Stable 68 Courtesy of Seeff, LB and Alter, HJ. Stabl e 13 Mortality 4 Etiology of Chronic Liver Disease United States Birmingham, AL CDC, unpublished data HBV& Cryptogenic Alcohol 3% 17% HBV 11% Other 5% Harlem, NYC Frieden et al. Hepatology 1999 HBV & Alcohol 6% Other 6% HCV 11% Alcohol 24% HCV 26% HCV & Alcohol 14% HCV & Alcohol 46% Alcohol 29% HBV, HCV & Alcohol 2% Prevalence of HCV Infection by Age United States, 1988-1994 Average Prevalence = ~1.8% Prevalence of Anti-HCV (%) 4 # Infected Nationwide = ~3.9 million 3 2 1 0 6–11 12–19 20–29 30–39 40–49 50–59 60–69 70–79 Age (yr) Alter MJ. N Engl J Med. 1999;341:556 (NHANES III, 1988–1994). 80+ Prevalence of HCV Infection by Age and Race, United States, 1988-1994 7 Anti-HCV+ (%) 6 Black 5 Mexican American 4 3 White 2 1 0 6–11 12–19 20–29 30–39 40–49 50–59 Age (yr) Alter MJ. N Engl J Med. 1999;341:556 (NHANES III, 1988–1994). 60–69 70+ Prevalence of HCV Infection by Age and Gender, United States, 1988-1994 Percent Anti-HCV Positive 6 Males 5 4 Total 3 2 Females 1 0 6-11 12-19 20-29 30-39 40-49 50-59 60-69 Source: CDC, NHANES III Age in Years 70+ HCV Infection - Estimates of Past Incidence and Future Prevalence 140 Decline in cases among IDUs Infections per 100,000 120 100 80 Incidence 60 40 20 0 Prevalence 2.0% Overall prevalence 1.5% 1.0% Infected 20+ years 0.5% 0.0% 1960 1970 1980 1990 2000 2010 Source: Armstrong GL et al. Hepatology 2000;31 2020 2030 Future Hepatitis C Mortality and Costs Future HCV-related mortality may double over the next 10 to 20 years $10.7 billion in direct medical care expenditures $ 75.5 billion in societal (indirect) costs Wong JB, et al. AJPH 2000; 90(10): 1562-1569. Relative Importance of Risk Factors for Remote and Recent HCV Infection Remote (>15 yr ago) Recent (<15 yr ago) Injection Drug Use Injection Drug Use Transfusion Unknown Other* Sexual Transfusion Sexual *Nosocomial, occupational, perinatal Unknown Other* Posttransfusion Hepatitis, United States Alter HJ and Houghton M. Hepatitis C virus and eliminating posttransfusion hepatitis. Nature Medicine 2000;6:1082-6. Risk of HCV, HBV, and HIV Infection Among Injection Drug Users Baltimore 1983–1988 100 Seroprevalence (%) HCV 80 HBV 60 40 HIV 20 0 0 6 12 18 24 30 36 42 48 Duration of Injecting (mo) Garfein RS. Am J Public Health. 1996;86:655. 54 60 66 72 Risk of HCV Infection Among Injection Drug Users Seroprevalence (%) 100 Baltimore: 1983-1988 80 60 40 20 0 0 6 12 18 24 30 36 42 48 54 60 66 Duration of Injection (months) Garfein RS Am J Public Health 1996; 86:655. Thorpe LE JID 2000;182:158894. Diaz T Am J Public Health 2001; 91(1): 23-30. 72 78 84 Sexual Transmission of HCV Case-control, cross sectional studies – infected partner, multiple partners, early sex, non-use of condoms, other STDs, sex with trauma – MSM no higher risk than heterosexuals Partner studies – low prevalence (1.5%) among long-term partners – infections might be due to common percutaneous exposures (e.g., unsafe injections, drug use) – male to female transmission more efficient – more indicative of sexual transmission Sexual Transmission of HCV- II Occurs, but efficiency is low – Rare between long-term steady partners – Factors that facilitate transmission between partners unknown (e.g., viral titer, other STDs) Accounts for 15-20% of acute and chronic infections in the United States – Sex is a common behavior – Large chronic reservoir provides multiple opportunities for exposure to potentially infectious partners Other Potential Exposures to Blood No or insufficient data showing increased risk – intranasal cocaine use, tattooing, body piercing, acupuncture, military service Limited number of studies showing associations that cannot be generalized – convenience or highly selected groups (mostly blood donors) No associations in acute case-control or population-based studies Other Potential Exposures to Blood - II Biologically plausible but no data showing these practices, procedures, or histories alone place persons at increased risk for HCV May be limited to certain settings and account for small fraction of cases – e.g., prisons, unregulated practitioners, populations with certain cultural practices, etc. Risk factor or high prevalence identified in selected subgroup cannot be extrapolated to the population National Hepatitis C Prevention Strategy • Prevent HCV infection • Detect and control chronic liver disease • Evaluate effectiveness of activities • Conduct surveillance and research Prevention Activities Primary = Prevent HCV Transmission • high risk activities - IDU, high risk sex • nosocomial, occupational, transfusions and transplant Secondary = Reduce Risk of Chronic Liver Disease • identify, test, counsel, medical management Reasons to Identify Persons with Chronic HCV Infection • Medical management – evaluate for chronic liver disease – treatment if indicated – substance abuse treatment (alcohol, drugs) if appropriate – immunization (HB, HA, influenza, pneumo) • Counsel to prevent disease transmission – household contacts – sexual contacts – drug use contacts HCV Testing Routinely Recommended Based on increased risk for infection • Ever injected illegal drugs • Received clotting factors made before 1987 • Received blood/organs before July 1992 • Ever on chronic hemodialysis • Evidence of liver disease Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCVRelated Chronic Disease. MMWR 1998; 47: RR-19 HCV Testing Routinely Recommended Based on need for exposure management Healthcare, emergency, public safety workers after needle stick/mucosal exposures to HCV-positive blood Children born to HCV-positive women Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCVRelated Chronic Disease. MMWR 1998; 47: RR-19 National Hepatitis C Prevention Strategy Communication of Information on Hepatitis C education of health care professionals public service advertising education of persons in groups at risk of infection – – transfusion recipients injection drug users Most difficult task: keeping messages factually correct Geographic and Temporal Differences in the Epidemiology of HCV Infection HCV infection is endemic in most parts of the world. Substantial geographic and temporal differences in endemicity of HCV infection – related to frequency and extent to which various risk factors contributed to transmission Estimated Prevalence of Anti-HCV WHO Global Burden of Disease Estimate, CDC, Unpublished data Geographic Patterns of Age-Specific Prevalence of HCV Infection Percent Anti-HCV Positive 50 Egypt 40 30 20 Japan, Italy 10 U.S., Australia 0 0-9 10-19 20-29 30-39 Age Group (Years) 40-49 50+ Geographic Differences in HCV Transmission Patterns Exposures among prevalent infections Importance of Exposures by HCV Endemicity Low Moderate High Injecting drug use Transfusions ++++ +++ ++ +++ + +++ Health-care related Unsafe injections Folk medicine +/+/- ++++ ++++ ++ ++++ ++++ No data Children Playing with Medical Waste, Bangladesh Relative Importance of Risk Factors for Hepatitis C and Prevention Strategies by HCV Endemicity High/Moderate Endemicity Nosocomial Transfusion Low Endemicity Injection Drug Use Other Safe blood supply Infection control Other Sexual Risk reduction counseling and services Adequate resources Identify persons at high risk for counseling, testing, and medical management Viral Hepatitis - Overview A B C D E Feces Blood* Blood* Blood* Feces fecal-oral Percutaneous Percutanous Percutaneous fecaloral Chronic infection no yes yes yes no Vaccine yes yes no yes** no pre/post (IG) post (HBIG) no no no Source of virus Route of transmission Pre/Post prophylaxis * Blood and blood-derived body fluids **Prevention of Hep B with vaccine