Control Measures A Hepatitis A Virus

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1. General Measures

The measures generally recommended for the prevention of fecal-oral transmission of enteric pathogens are equally applicable to hepatitis A virus infection (20). These are particularly pertinent to travelers journeying to developing countries where standards of hygiene and sanitation may be poor. Water used for drinking, washing of vegetables or fruit, or brushing of teeth is a major hazard to travelers. If in doubt, water should be boiled for at least 1 minute or, at high altitudes, for a few minutes. Alternatively, proprietary chlorine tablets can be used to disinfect water (provided that the water is clear and free of contaminating organic material). Ideally, bottled water should be used for drinking. (Portable filters have not been shown to be reliable and are currently not recommended.) Ice is a common source of contamination and should not be used for drinks unless the safety of the source of the water is assured. Similar precautions would hold for iced lollipops and frozen flavored ices. Unpasteurized milk and products made from raw milk must be avoided; unpasteurized milk should be boiled before being consumed. Food must be thoroughly cooked and should be eaten while still hot and steaming; this is especially important with minced meat dishes. Street vendors should be avoided if possible, as they are a frequent source of foodborne illness among travelers. Raw fruits and vegetables that cannot be peeled should be avoided. Some vegetables, such as lettuce, are particularly difficult to clean thoroughly and are often contaminated. Hands should be washed thoroughly and frequently using soap. The old adage for travelers still remains pertinent today: "Boil it, cook it, peel it, or forget it!" Staff caring for young infants in diapers in daycare centers or institutions for the mentally handicapped should be instructed regarding appropriate hygienic precautions, particularly adequate hand washing, if there is a possibility of contact with human feces.

2. Use of Immunoglobulin for Prophylaxis—Passive Immunization

Human immunoglobulin preparations have been successfully used for some 50 years to provide passive protection against hepatitis A virus infection (28). The immunoglobulin fraction is prepared from large numbers of plasma units from blood donors (up to 1000 units) by alcohol precipitation to produce a 16% protein preparation. Immunoglobulin is administered intramuscularly into the gluteal or deltoid muscle (in infants it can be given in the anterolateral muscle mass of the thigh). The dosage varies from 0.02 to 0.06 mL/kg body weight (the latter dose giving longer-lasting protection). The injection is painful but other side effects are very uncommon. The only contraindication is selective IgA deficiency (because of the risk of development of autoantibodies). Immunoglobulin is rapidly absorbed into the bloodstream to give almost immediate protection. Protection is, however, only temporary—usually up to 3 months, as the administered immunoglobulin is degraded.

Immunoglobulin preparations can be given simultaneously with other vaccines (at different sites of the body) (13). However, following administration of immunoglobulin, there should be a delay of at least 3 months before MMR (measles, mumps, rubella) vaccine is administered and 5 months before varicella vaccine is administered because of the potential of interference with these live vaccines by antibody in immunoglobulin preparations.

Immunoglobulin can be given as preexposure or postexposure prophylaxis. Preexposure prophylaxis applies generally to travelers who urgently require protection because of imminent departure to an endemic area. Protection will be afforded for 1-2 months if a dose of 0.02 mL/kg is administered and for up to 3-6 months if a higher dose of 0.06 mL/kg is given. Immunoglobulin may be given together with vaccine to combine the advantage of immediate protection by immuno-globulin with long-term protection by vaccine. Postexposure prophylaxis immunoglobulin is maximally effective if administered as soon as possible after exposure and rapidly loses its efficacy if there is a delay in administration. If there is a lapse of greater than 2 weeks after exposure, there is no point in giving immunoglobulin. The following are the most commonly recommended indications for postexposure prophylaxis:

Close personal contact with a patient with hepatitis A virus infection, e.g., all household and sexual contacts

Staff and children of daycare centers where a case of hepatitis A occurs, especially if there are children in diapers

Hepatitis A occurring in an institutional setting including barracks, prisons, and similar living conditions

The extent of passive immunization of contacts would need to be carefully evaluated depending on epidemiological considerations. The following circumstances generally do not warrant administration of immunoglobulin:

A case of hepatitis in a day school or office environment where there is only casual contact.

Healthcare workers exposed to a case of hepatitis in a hospital setting.

In most situations of common source outbreaks—by the time the first patient who has ingested the offending food displays symptoms of hepatitis, it is usually too late for passive immunization to be effective.

3. Active Immunization—HAV Vaccine

A number of HAV vaccines have been developed following on the successful propagation of HAV virus in cell culture. Currently four vaccines are available and in widespread use internationally (10). Three of these vaccines are produced by growing cell culture-adapted strains of HAV in human fibroblasts followed by formalin inactivation and adsorption onto an aluminum hydroxide adjuvant. A fourth vaccine has been produced using a virosome (virus-like particle) design (29). The inactivated fibroblast-grown virus particles are adsorbed onto phospholipid vesicles into which have been incorporated the hemagglutinin and neuraminidase proteins of influenza virus. The viro-some is designed to target antibody-producing cells, which have been primed by previous exposure to influenza virus, and also macrophages in order to produce more rapid and effective T- and B-cell proliferative responses.

HAV vaccine is administered as a two-dose schedule by intramuscular injection. The immune response is highly satisfactory even after one dose, but a second dose given 6-12 months later is recommended for long-term immunity. Side effects are rare and usually trivial and consist mainly of allergies to one of the vaccine components. The vaccine is presently contraindicated in children less than one year of age because of doubtful efficacy due to possible neutralization by passively acquired maternal antibodies.

Specific neutralizing antibodies are produced in 95% of adults within 15 days and 100% of adults within 2 months. In children antibodies are formed in 97-100% of recipients after the first dose. Efficacy studies in Thailand and New York demonstrated protection of 94% and 100% of cases, respectively (30,31). The long-term duration of protection is not yet known, but kinetic models predict durability of protection for at least 20 years (10).

The following individuals have been targeted for routine immunization with HAV:

People who may be exposed to the virus in their occupation (doctors, nurses, daycare center personnel)

People with liver disease

Travelers (over the age of 2 years) Individuals with clotting factor dysfunction Homosexual men Illegal drug users

HAV vaccine can also be given as postexposure prophylaxis, usually together with immunoglobulin (at different sites of the body); as with immunoglobulin, it needs to be given as soon as possible after exposure.

Selective administration of vaccine to at-risk individuals is highly effective for personal protection but has little or no effect on the circulation of the virus in the population. Studies of the source of infection in cases of HAV disease have shown that 22-26% of cases of transmission occur as a result of household or sexual contact, 14-16% in daycare centers, 4-6% in international travelers, and 2-3% as a result of food- or waterborne outbreaks (32). Thus, in approximately 50% of cases there is no identified source of infection. It is therefore clear that directing immunization to the target populations "at risk" may be highly effective in protecting those individuals from infection but would have no effect on the circulation of the virus in the population. This has recently given rise to considerations for the need to institute HAV vaccination in the routine immunization program (33-35). This has been strengthened by comparisons with polio, with which HAV has much in common. For example, both viruses share similar fecal-oral transmission routes and epidemiology. Second, both are exquisitely sensitive to neutralizing antibodies. Third, in both cases immunity is directed to their outermost VP1 protein. Fourth, neither virus is shed chronically. For universal immunization to be successful, however, high routine coverage would need to be achieved, otherwise the situation may be aggravated by coverage that was only partial, causing an upward age shift of infection, resulting in the widening of the immunity gap in the vulnerable older children and young adult population. In addition, the high cost of HAV vaccine mitigates against the introduction of universal immunization at present (10).

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