Global Alert and Response (GAR)

Hepatitis A


Surveillance and Control

- Endemicity
- Incidence / Epidemiology
- Trends
- Costs
- Immune prophylaxis
- Vaccines

Surveillance and control procedures should include

  • providing safe drinking water and proper disposal of sanitary waste

  • monitoring water beds where shellfish are harvested

  • monitoring disease incidence

  • determining sources of infection

  • identifying contacts of case-patients for postexposure prophylaxis

  • detecting outbreaks

  • containing spread

Endemicity
Geographic areas can be characterized by high, intermediate, or low levels of endemicity patterns of HAV infection. The levels of endemicity correlate with hygienic and sanitary conditions of each geographic area.18, 21, 31, 41, 45

  • high:
In developing countries with very poor sanitary and hygienic conditions (parts of Africa, Asia and Central and South America), infection is usually acquired during early childhood as an asymptomatic or mild infection. Reported disease rates in these areas are therefore low and outbreaks of disease are rare. Reported disease incidence may reach 150 per 100 000 per year.
  • intermediate:
In developing countries, countries with transitional economies and some regions of industrialized countries where sanitary conditions are variable (Southern and Eastern Europe, some regions in the Middle East), children escape infection in early childhood. Paradoxically, these improved economic and sanitary conditions may lead to a higher disease incidence, as infections occur in older age groups, and reported rates of clinically evident hepatitis A are higher.
  • low:
In developed countries (Northern and Western Europe, Japan, Australia, New Zealand, USA, Canada) with good sanitary and hygienic conditions, infection rates are generally low. In countries with very low HAV infection rates, disease may occur among specific risk groups such as travellers.


Click here for: Worldwide endemicity of HAV infection (table)


Incidence/Epidemiology

Hepatitis A occurs sporadically and epidemically worldwide, with a tendency to cyclic recurrences.22

Epidemics are uncommon in developing countries where adults are generally immune. Improved sanitation and hygiene conditions in different parts of the world leave large segments of the population susceptible to infection, and outbreaks may result whenever the virus is introduced.22, 31, 37

Common-source epidemics, related to contaminated food or water, may evolve explosively, as did the largest mollusc-linked epidemic in Shanghai, in 1988, involving about 300 000 people.31

Worldwide, HAV infections account for 1.4 million cases annually.45

Click here for: Estimated number of cases (table)


Trends

As nations develop public sanitation, the age at which individuals will become infected is delayed until adulthood, at which time the likelihood of developing symptomatic illness is considerably higher.16, 18, 31

In the United States, nationwide outbreak cycles appear every decade, as observed in 1961, 1971 and 1989.

Hepatitis A appears to follow a minor cyclic phase, with a peak occurring during fall and winter, possibly as a result of exposure during summer holidays spent in endemic countries. Smaller epidemics are present in different parts of the world, with cases increasing slightly during the past several years. Decreasing are cases in Greece and Italy.28, 31

The rate in males is about 20% higher than in females.18

Costs
Although most infected persons recover completely and a significant proportion remain asymptomatic, HAV infection causes considerable morbidity and mortality and imposes a large economic burden throughout the world.7, 43

On average, adults miss 30 days of work. Young children tend to suffer only flu-like symptoms, if any, but infection of children can initiate and perpetuate community-wide outbreaks.

Both medical treatment and work loss account in the United States for an estimated annual US$ 500 million (1997) costs for 63 500 cases of acute hepatitis A. For each hospitalized case, medical care costs sum up to about US$ 6900.7

Worldwide, an estimated 1.4 million cases of acute hepatitis A annually cost
US$ 1.5 to US$ 3 billion.4, 18, 40

An HAV antibody screening test and its subsequent evaluation are estimated to cost US$ 43 per case.43

The costs of vaccination are estimated to be US$ 40 for one 720 EL.U. dose plus US$ 15 for the administration. Two doses are required for a complete vaccination.43

For passive immunization, the purchase and administration of one IG dose is estimated at US$ 41.43

Cost-effective analyses performed in Ireland showed that where HAV immunity is 45% or less, vaccination is the strategy of choice, and when immunity is greater than 45%, then screening followed by vaccination should be used.34

Immune prophylaxis
Until recently, passive immunization with pooled IG was the only option available for preventing hepatitis A. HAV research has led to the development of inactivated vaccines. Their use is being encouraged and preferred to the administration of IG for preexposure prophylaxis when repeated exposure is anticipated.21

  • passive immunization:

The administration of IG can reduce the incidence of hepatitis A up to 90%, and it is most effective if given before exposure. Its use is declining now that HAV vaccines are being used more widely.21

IG is still used for postexposure prophylaxis. If administered within two weeks of exposure it will either prevent development or reduce the severity of the disease.21, 22, 39

Passive immunization is safe for adults and children, pregnant or lactating women and immunosuppressed persons, but it only provides a limited duration of protection after a single IG dose of 100 IU (6 months), leaving susceptibles available for infection following another exposure.

Because of its short duration of action, IG must be readministered on a regular basis to maintain its effectiveness and ensure continuous protection. It is therefore expensive, logistically complicated and unreliable to supply long-term protection, and considered obsolete, except for situations in which immediate protection is required. Moreover, IG can interfere with immune response to live, attenuated vaccines (measles, mumps, rubella (MMR) and varicella). The administration of MMR should be delayed at least 3 months and 5 months for varicella after administration of IG. On the other hand, IG should not be administered within 2 weeks after administration of live, attenuated vaccines.

  • active immunization:

At least four inactivated vaccines (Havrix®, Vaqta®, Epaxal®, and Avaxim®) are presently commercially available in some parts of the world.

Inactivated HA vaccines are safe, highly immunogenic, and provide long-term protection from HAV infection (20 years). They can be administered simultaneously with a number of other vaccines (diphtheria, polio, tetanus, oral typhoid, cholera, Japanese encephalitis, rabies, yellow fever and hepatitis B) without affecting the rates of seroconversion.12

Hepatitis A is the most common immunization-preventable infection in travellers.41, 47

Click here for: Recommendations for use of hepatitis A vaccine and IG
Click here for: Recommended doses of IG

Vaccines
The use of IG has provided passive, short-term protection. Vaccines give active and long lasting protection against hepatitis A.16, 19, 23, 27

Inexpensive, live, attenuated vaccines have been produced in China, and millions of Chinese may have been vaccinated, although little information about these preparations is currently available. The H2-strain vaccine does not induce seroconversion if given orally, but nearly all of the individuals that were given the vaccine subcutaneously developed antibodies. This attenuated HAV is not transmitted orally although it is shed in stools in little amounts. The vaccine gave 100% protection against HAV infection during a 4 year period at 11 primary schools.4, 18, 21, 28, 40

The first inactivated HAV vaccine (Havrix®, SmithKline Beecham) became available for i.m. injection in Europe in 1991 and was approved in the United States in 1995. The second inactivated vaccine came in 1995 (Vaqta®, Merck). Both are whole-virus preparations, produced by growth of attenuated HAV strains in cell culture, inactivated with formalin, adsorbed to aluminium as adjuvant. Havrix® is preserved in 2-phenoxyethanol. Both vaccines are highly effective and provide seroconversion rates of more than 99.4% when given as a single primary immunisation, followed by a booster dose 6-12 months later.18, 19, 21, 23, 27, 45

A third vaccine (Epaxal®, Berna) developed in Switzerland and currently marketed in Switzerland and Argentina, incorporates immunogenic formalin-inactivated HAV particles within immunopotentiating reconstituted influenza virosomes that facilitate antigen delivery to immunocompetent cells.3, 18, 21, 26, 33, 45

Another inactivated vaccine (Avaxim®, Pasteur Mérieux) has given excellent results since its introduction in France, the Netherlands, Sweden and the United Kingdom in 1997.45

A combined hepatitis A and B vaccine (Twinrix®, SmithKline Beecham) has been introduced in Australia, Canada and some countries in Europe in 1997. In its adult formulation it contains 720 ELISA Units (EL.U.) of hepatitis A antigen (Havrix®) and 20 µg of hepatitis B surface antigen (Engerix®-B) adsorbed onto aluminium salts.45 Twinrix® is licensed for use in children aged 1 year or older in several countries and is given as a 3-dose series, using a 0, 1, 6 months schedule. The immunogenicity of the combined vaccine has been compared to the immunogenicity of simultaneously or separately applied single vaccines. The results of the study recommend the use of the combined vaccine for subjects at risk for both hepatitis A and hepatitis B.13

In the United States, IG is still recommended for protection from HAV infection in children less than 2 years of age, because residual anti-HAV passively acquired from the mother may interfere with vaccine immunogenicity.21

If not specified otherwise, manufacturers suggest that paediatric formulations contain half the antigenic mass of the adult formulation and are given to children and adolescents between 1 and 18 years of age. Immunization priorities differ between countries, as do vaccination schedules, local production capabilities, and demands for specific vaccine combinations.

The systematic use of Havrix® in Alaska in 1996, covering at least 80% of eligible persons, indicates that the vaccine can efficiently stop established outbreaks and prevent epidemics of hepatitis A in communities where cases of hepatitis A are documented.21, 30, 45

Havrix® is the only vaccine specifically licensed for active immunization against the hepatitis A virus in chronic liver disease patients.

Click here for: Recommended dosages of available vaccines
Click here for: Vaccine safety
Click here for: Vaccination strategies


Worldwide endemicity of HAV infection

 

HAV endemicity

 

Regions by epidemiological pattern

 

Average age of patients (years)

 

Most likely mode of transmission

 

Very high

 

Africa, parts of South America, the Middle East and of south-east Asia

 

under 5

 

- person-to-person

- contaminated food and water

 

High

 

Brazil's Amazon basin, China and Latin America

 

5-14

 

- person-to-person

- outbreaks/ contaminated food or water

 

Intermediate

 

Southern and Eastern Europe, some regions of the Middle East

 

5-24

 

- person-to-person

- outbreaks/ contaminated food or water

 

Low

 

Australia, USA, Western Europe

 

5-40

 

- common source outbreaks

 

Very low

 

Northern Europe and Japan

 

over 20

 

- exposure during travel to high endemicity areas,  uncommon source

Worldwide endemicity of HAV infection 5, 11, 42, 44, 45


Estimated number of cases per continental region

REGION

1990 POPULATION (in millions)

INCIDENCE (per 100,000 per year)

cases  (per year)

North America

 275

10

28,000

Central and South America

453

20-40

162,000

Europe

791

5-60

 278,000

Africa and Middle East

827

20-60

251,000

Asia

2893

10-30

676,000

Oceania

28

15-30

5,000

Total

 

 

1,399,000

From: Hadler SC. Global impact of hepatitis A virus infection changing patterns. In: Hollinger FB, Lemon SM, and Margolis HS, eds. Viral Hepatitis and Liver Disease. Baltimore, Williams & Wilkins, 1991: 14-20, with permission (http://lww.com).


Recommendations for use of hepatitis A vaccine and IG

  • preexposure prophylaxis

Hepatitis A vaccination provides preexposure protection from HAV infection. It is recommended for persons who are at increased risk for infection and for any person wishing to obtain immunity.

Persons who seek immunological protection, but are allergic to vaccine components should receive IG. The administration must be repeated if protection is required for periods exceeding 5 months. For persons who require repeated IG, screening of their immune status is useful to avoid unnecessary doses of IG.

  • postexposure prophylaxis

Persons who have been exposed to HAV and who have not previously been vaccinated should be administered a dose of IG (0.02ml/kg) within two weeks of exposure.39 Persons who have received a dose of hepatitis A vaccine at least 2 weeks before exposure to HAV do not need IG.

Mass postexposure vaccination to contain the spread of HAV in established outbreaks has been well documented and proven efficacious in ceasing emerging epidemics.21

Serologic screening of contacts of infected individuals for anti-HAV before they are given IG is not recommended because screening is more costly than IG and would delay its administration.

The prospective duration of antibody persistence can be estimated to last at least 20 years. However, a booster vaccination after 10 years is recommended for protection, as long as no long-term follow-up data are available.19, 21, 27


Recommended doses of IG

setting

duration of coverage

IG dose

preexposure

short-term  (1 - 2 months) 

0.02 ml/kg

 

long-term   (3 - 5 months)

0.06 ml/kg°

postexposure  

 

0.02 ml/kg

  • Doses should be given as intramuscular injections into the deltoid or the gluteal muscle. For children <2 years of age, injections should be given into the anterolateral thigh muscle.
  • Whenever possible, HAV vaccination should be the procedure of choice.

° repeat every 5 months if continued exposure to HAV occurs 9


Recommended dosages of available vaccines

Havrix® (SmithKline Beecham Biologicals)

Group

Age
(years)

Dose
(ELISA Units, EL.U.)

Volume

No. Doses

Schedule
(months)*

Children and Adolescents

2-19

720 EL.U.

0,5ml

2

0, 6-12

Children and Adolescents

1-18

360 EL.U.
(US$ 19.50)
°

0,5ml

3

0, 1, 6-12

Adults

>18

1440 EL.U.
(US$ 56.90)°

1.0 ml

2

0, 6-12

Vaqta® (Merck & Co., Inc.)

Group

Age
(years)

Dose
(Units, U)

Volume

No. Doses

Schedule
(months)*

Children and Adolescents

2-17

25 U

0.5 ml

2

0, 6-18

Adults

>17

50 U

1.0 ml

2

0, 6

* 0 months represents timing of the initial dose. Subsequent numbers indicate months after the initial dose.
° Prices are the average wholesale costs per single-unit dose in the
United
States
9

For travellers who seek medical advice less than 2 weeks before travelling, a double dose is recommended (two injections, single dose; or one injection, double dose). This induces antibodies in over 90% of individuals within 2 weeks, and will most probably protect against infection. Alternatively, a dose of IG (0.02 ml/kg body weight) may be given with the first dose of vaccine.

When hepatitis A vaccine is administered concomitantly with pooled IG for immediate protection, separate syringes and different sites must be used.

Persons allergic to vaccine components should follow the recommendations for the use of IG. Persons who have anti-HAV from prior infection do not need to be vaccinated, but do not react adversely to immunisation.

Studies for the development of safe and efficacious live-attenuated vaccines are currently in progress.

HAV vaccines are stable and can be stored for at least two years at 4°C without loss of immunogenicity.21


Vaccine safety

Havrix®, Vaqta®, Avaxim®, Epaxal® and Twinrix® have excellent safety profiles and are highly immunogenic in humans.3, 18, 19, 32 Nearly 100% of vaccinees will develop protective levels of antibody within 1 month of the first dose of vaccine.

Side effects are local, of low intensity and short duration, involving a generally clinically insignificant soreness at the injection site.

Safety of the vaccines has not been determined during pregnancy.

Because the available vaccines are inactivated, no special precautions need to be taken in vaccination of HIV-1 positive or otherwise immunocompromised persons, although they may be less responsive.21


Vaccination strategies

The best vaccination strategy for a region depends on the epidemiology of HAV, the risk groups involved, the duration of protection, the possibility of postexposure protection, and the cost of the intervention.45

Groups at high risk of HAV infection as a result of behaviour, lifestyle or occupation should be the primary target of a hepatitis A vaccination programme.45

It is important to note that for many cases of hepatitis A risk factors and sources of infection cannot be identified. Immunization programmes directed only to high risk groups would miss those with unidentified risks, and would therefore not reduce the impact of the disease or eliminate hepatitis A.17

In most developing countries hepatitis A is not a real public health priority, since it is acquired in early childhood when infections are usually asymptomatic. These countries do not at present need to consider universal hepatitis A immunization programmes.17

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