VIRAL HEPATITIS A mkolar@med.muni.cz EPI; Autumn 2019 A“Infectious” “Serum” Viral hepatitis Enterically transmitted Parenterally transmitted other E “NANB” B D C VIRAL HEPATITIS HISTORICAL PERSPECTIVE HEPATITIS A VIRUS HEPATITIS A (Hepatitis A virus) - Case definition Clinical Criteria ◼ Any person with a discrete onset of symptoms (e.g. fatigue, abdominal pain, loss of appetite, intermittent nausea and vomiting) ◼ AND ◼ At least one of the following three: ◼ — Fever ◼ — Jaundice ◼ — Elevated serum aminotransferase levels Laboratory Criteria ◼ At least one of the following three: ◼ — Detection of hepatitis A virus nucleic acid in serum or stool ◼ — Hepatitis A virus specific antibody response ◼ — Detection of hepatitis A virus antigen in stool Epidemiological Criteria ◼ At least one of the following four: ◼ — Human to human transmission ◼ — Exposure to a common source ◼ — Exposure to contaminated food/drinking water ◼ — Environmental exposure Case Classification ◼ A. Possible case NA ◼ B. Probable case ◼ Any person meeting the clinical criteria and with an epidemiological link ◼ C. Confirmed case ◼ Any person meeting the clinical and the laboratory criteria HEPATITIS A VIRUS ◼ RNA Picornavirus • Single serotype worldwide • Acute disease and asymptomatic infection ◼ No chronic infection • Protective antibodies develop in response to infection - confers lifelong immunity HEPATITIS A - CLINICAL FEATURES •Jaundice by <6 yrs <10% age group: 6-14 yrs 40%-50% >14 yrs 70%-80% •Rare complications: Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis •Incubation period: Average 30 days Range 15-50 days •Chronic sequelae: None 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Week Response Clinical illness ALT IgM IgG HAV in stool Infection Viremia EVENTS IN HEPATITIS A VIRUS INFECTION CONCENTRATION OF HEPATITIS A VIRUS IN VARIOUS BODY FLUIDS Source: Viral Hepatitis and Liver Disease 1984;9-22 J Infect Dis 1989;160:887-890 Feces Serum Saliva Urine 100 102 104 106 108 1010 BodyFluids Infectious Doses per mL GEOGRAPHIC DISTRIBUTION OF HEPATITIS A VIRUS INFECTION ACUTE HEPATITIS A CASE DEFINITION FOR SURVEILLANCE ◆ Clinical criteria An acute illness with: • discrete onset of symptoms (e.g. fatigue, abdominal pain, loss of appetite, intermittent nausea, vomiting), and • jaundice or elevated serum aminotransferase levels ◆ Laboratory criteria • IgM antibody to hepatitis A virus (anti-HAV) positive ◆ Case Classification • Confirmed. A case that meets the clinical case definition and is laboratory confirmed or a case that meets the clinical case definition and occurs in a person who has an epidemiologic link with a person who has laboratory-confirmed hepatitis A (i.e., household or sexual contact with an infected person during the 15-50 days before the onset of symptoms). • Close personal contact (e.g., household contact, sex contact, child day-care centers) • Contaminated food, water (e.g., infected food handlers) • Blood exposure (rare) (e.g., injection drug use, rarely by transfusion) HEPATITIS A VIRUS TRANSMISSION Unknown 46% Contact of day- care child/employee 6% Other Contact 8% Child/employee in day-care 2% Food- or waterborne outbreak 4% Injection drug use 6% Sexual or Household Contact 14% Men who have sex with men 10% International travel 5% RISK FACTORS ASSOCIATED WITH REPORTED HEPATITIS A, 1990-2000, UNITED STATES Source: NNDSS/VHSP PREVENTING HEPATITIS A • Hygiene (e.g., hand washing) • Sanitation (e.g., clean water sources) • Hepatitis A vaccine (pre-exposure) • Immune globulin (pre- and post- exposure) PREPARATION OF INACTIVATED HEPATITIS A VACCINES • Cell culture adapted virus grown in human fibroblasts • Purified product inactivated with formalin • Adsorbed to aluminum hydroxide adjuvant • Highly immunogenic • 97%-100% of children, adolescents, and adults have protective levels of antibody within 1 month of receiving first dose; essentially 100% have protective levels after second dose • Highly efficacious • In published studies, 94%-100% of children protected against clinical hepatitis A after equivalent of one dose HEPATITIS A VACCINES HEPATITIS A VACCINES Age Volume 2-Dose Schedule Vaccine (yrs) Dose (mL) (mos) HAVRIX ® # 1-18 720 (EL.U.*) 0.5 0, 6-12 >18 1,440 1.0 0, 6-12 VAQTA ® ## 1-18 25 (U**) 0.5 0, 6-18 >18 50 1.0 0, 6-18 * EL.U. – Enzyme-linked immunosorbent assay (ELISA) units ** Units # has 2-phenoxyethanol as a preservative ## has no preservative Recommended Dosages of Hepatitis A Vaccines SAFETY OF HEPATITIS A VACCINE • Most common side effects − Soreness/tenderness at injection site - 50% − Headache - 15% − Malaise - 7% • No severe adverse reactions attributed to vaccine • Safety in pregnancy not determined – risk likely low • Contraindications - severe adverse reaction to previous dose or allergy to a vaccine component • No special precautions for immunocompromised persons DURATION OF PROTECTION AFTER HEPATITIS A VACCINATION ◼ Persistence of antibody • At least 5-8 years among adults and children • Efficacy ◆ No cases in vaccinated children at 5-6 years of follow-up ◼ Mathematical models of antibody decline suggest protective antibody levels persist for at least 20 years ◼ Other mechanisms, such as cellular memory, may contribute • Decreased antibody concentration: − Concurrent administration of IG − Presence of passively-transferred maternal antibody − Age − Chronic liver disease • Decreased seroconversion rate: − HIV infection − May be related to degree of immunosuppression − Liver transplantation FACTORS ASSOCIATED WITH DECREASED IMMUNOGENICITY TO HEPATITIS A VACCINE USE OF HEPATITIS A VACCINE FOR INFANTS • Safe and immunogenic for infants without maternal antibody • Presence of passively-acquired maternal antibody blunts immune response • all respond, but with lower final antibody concentrations • Age by which maternal antibody disappears is unclear • still present in some infants at one year • probably gone in vast majority by 15 months COMBINED HEPATITIS A HEPATITIS B VACCINE • Approved by the FDA in United States for persons >18 years old • Contains 720 EL.U. hepatitis A antigen and 20 μg. HBsAg • Vaccination schedule: 0,1,6 months • Immunogenicity similar to single-antigen vaccines given separately • Can be used in persons > 18 years old who need vaccination against both hepatitis A and B • Formulation for children available in many other countries ◼ Considerations: ◆ cost of vaccine ◆ cost of serologic testing (including visit) ◆ prevalence of infection ◆ impact on compliance with vaccination ◼ Likely to be cost-effective for: ◆ persons born in high endemic areas ◆ Older U.S. born adults ◆ Older adolescents and young adults in certain groups (e.g., Native Americans, Alaska Natives, Hispanics, IDUs) PRE-VACCINATION TESTING • High response rate among vaccinees • Commercially available assay not sensitive enough to detect lower (protective) levels of vaccine-induced antibody POST-VACCINATION TESTING Not recommended: ◼ Pre-exposure ◆ travelers to intermediate and high HAV-endemic regions ◼ Post-exposure (within 14 days) Routine ◆ household and other intimate contacts Selected situations ◆ institutions (e.g., day-care centers) ◆ common source exposure (e.g., food prepared by infected food handler) HEPATITIS A PREVENTION IMMUNE GLOBULIN HEPATITIS A VACCINATION RECOMMENDATIONS: GUIDING PRINCIPLES ◼ Need comprehensive strategy to reduce overall rates ◆ Routine vaccination of children likely to be most effective ◼ Need creative approaches ◆ Formulation not available that would allow integration into infant schedule ACIP RECOMMENDATIONS PERSONS AT INCREASED RISK OF INFECTION, 1996 • Men who have sex with men • Illegal drug users • International travelers • Persons who have clotting factor disorders • Persons with chronic liver disease