Download Epidemiology and Prevention of Hepatitis A in Travelers

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Epidemiology and Prevention of Hepatitis A in Travelers
Dong Wu, MD and Chuan-Yong Guo, PhD
Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
DOI: 10.1111/jtm.12058
Background. Hepatitis A is the second most common vaccine-preventable travel-associated infectious disease and hepatitis A
virus (HAV) is the most common cause of viral hepatitis. The incidence of infection is closely related to sanitary conditions and
the level of economic development.
Methods. We evaluated HAV incidence, infection-related risk factors, and HAV vaccination rates in international travelers
through retrospective analyses using major databases, such as CENTRAL, MEDLINE, EMBASE, and the current literature
describing epidemiological data for HAV infection in recent years.
Results and Conclusions. We found that the incidence of HAV infection in developed countries is very low. As international
travel increases, the incidence of hepatitis A among travelers remains high and likely leads to regional outbreaks. Travelers should
visit the Centers for Disease Control and Prevention website or Infectious Disease Prevention Center of their countries to learn
about the incidence of infectious diseases associated with their destination before going abroad to determine if they should be
vaccinated.
H
epatitis A is the second most common infectious
disease in travelers and the most common cause of
viral hepatitis.1 The hepatitis A virus (HAV) is a small
nonenveloped single-stranded RNA virus that replicates
in hepatocytes and interferes with liver function,
promoting an immune response that causes liver
inflammation. In approximately 0.2% of clinical cases,
infection results in acute liver failure and death, and this
risk increases with age and the presence of chronic
liver disease.2 HAV is transmitted through direct
person-to-person contact, exposure to contaminated
water or shellfish, or the consumption or handling of
contaminated uncooked fruits and vegetables.
The average incubation period for HAV is 28 days,
and the clinical manifestations vary. For example, some
people may be asymptomatic, some show mild clinical
symptoms, and some present with severe hepatitis.
HAV infection symptoms may include the abrupt onset
of fever, malaise, loss of appetite, nausea, abdominal
discomfort, and jaundice, and these can last from weeks
to several months. In children younger than 6 years
Corresponding Author: Professor Chuan-Yong Guo, PhD,
Department of Gastroenterology, Shanghai Tenth People’s
Hospital, Tongji University School of Medicine, Shanghai,
200072, China. E-Mail: [email protected]
© 2013 International Society of Travel Medicine, 1195-1982
Journal of Travel Medicine 2013; Volume 20 (Issue 6): 394–399
infected with HAV, more than 50% are generally
asymptomatic and the remaining present with mild
symptoms. Although 10% of infected individuals have
prolonged or relapsing symptoms over 6 to 9 months,
chronic HAV infection does not occur.3 The overall
case-fatality ratio (CFR) is 0.3%; however, among
adults over 50 years, the CFR is 2.7%. The CFR is
also higher in individuals with chronic liver disease,
including chronic viral hepatitis.4 Diagnosis of hepatitis
A depends primarily on the detection of serum antiHAV IgM antibodies, which are detectable 5 to
10 days postexposure and gradually disappear 6 months
postinfection. However, anti-HAV IgG can also develop
in the early stages and last a lifetime. Because HAV
vaccines are not widely used, most individuals develop
anti-HAV IgG-acquired immunity through infection.5
The Epidemiology of HAV Globally
Approximately 1.5 million clinical cases of HAV
infection occur worldwide annually, but the rate of
infection is probably as much as ten times higher.6 The
HAV endemicity level for a population is determined
by the results of age-seroprevalence surveys. In 2010,
the World Health Organization published a systematic
review of the global prevalence of and susceptibility to
HAV infection.7 Worldwide, geographical areas can be
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Epidemiology and Prevention of Hepatitis A in Travelers
Figure 1 Estimated prevalence of hepatitis A virus.
characterized with high, intermediate, low, or very low
levels of endemicity for hepatitis A8 (Figure 1).
The seroprevalence of antibodies to HAV (total
anti-HAV), as measured in selected cross-sectional
studies among each country’s residents, is shown in
Figure 1. The levels of endemicity are related to hygienic
and sanitary conditions in each area. The estimates
demonstrate that all high-income regions have very
low HAV endemicity levels, all low-income regions
have high endemicity levels, and most middle-income
regions have a mix of intermediate and low endemicity.
In developing or underdeveloped countries, such as
Africa, parts of South America, the Middle East, and
India, HAV infection is very common. Most infections
are acquired during early childhood. Infections that
occur at an early age are often asymptomatic. Therefore,
reported rates of infection in these areas are relatively
low, and outbreaks are not common. In countries
with intermediate endemicity, such as China, some
Eastern European countries, and some Southeast Asian
countries, community-wide outbreaks may occur. For
example, in Shanghai, China in 1988, 30 million
people were infected with HAV owing to consumption
of contaminated shellfish.9 In developed countries,
such as North America, Western Europe, Scandinavia,
Australia, and Japan, HAV infection is less common.
Infection rates in children are generally low, though
peak rates of infection and reported disease tend to
occur in adolescents and young adults. Infections in
these developed countries occur in specific settings and
are mainly associated with travel.1,4
The Travel-Associated Risk of HAV Infection
In developed countries, there is a general lack of
immunization against HAV, although it is considered
an important travel-associated infection. A systematic
review of HAV seropositivity rates in Canada, a
country with low endemicity, demonstrated that
the seroprevalence in Canadian-born children was
approximately 1% in ages 8 to 13, 1% to 6% in 20
to 24 years, 10% in 25 to 29 years, and 17% in 30
to 39 years, with subsequent age-associated increases.
Compared with Canadian-born individuals, subjects
born outside Canada were approximately six times more
likely to be seropositive. Furthermore, travel to highrisk areas by individuals aged 20 to 39 was associated
with a significant increase in anti-HAV seropositivity.
This study indicated that HAV infection occurred more
often in adults, and the increase in HAV prevalence
among young adults coincided with disease importation
and an increased frequency of risk factors, most likely
behavioral-related ones.10 Epidemiological studies have
demonstrated that in Germany in 2007 and 2008
approximately 60% of people infected with HAV had
no travel history to endemic areas. Additionally, young
J Travel Med 2013; 20: 394–399
396
immigrant patients who had recently visited family in
areas with a high HAV infection risk accounted for most
imported disease cases.11
In the past, the risk of HAV infection in unvaccinated
travelers was considered to be 3 per 1,000 individuals
per month of travel to a developing country in good
quality accommodations. Those who ate and drank
under poor hygienic conditions had a higher risk (20 per
1,000 individuals per month traveled).12,13 Currently,
with improvements in sanitary conditions, the risk of
infection for nonimmune travelers who visit high- and
medium-endemic areas has been reduced to 6 to 30 per
100,000 individuals per month traveled.14 Interestingly,
the risk to travelers differs from one area to another. An
analysis of 636 cases of travel-related hepatitis between
1997 and 2005 demonstrated that the areas associated
with the highest incidence of disease were East Africa,
the Middle East, and the Indian subcontinent. Visiting
friends and relatives (VFR) travelers represented 83, 91,
and 70% of the cases to these three regions; the highest
incidence was found in children 0 to 14 years where
88% of the cases were VFR travelers. So travelers,
especially children, who are VFR in endemic areas
constitute a high-risk group for acquiring hepatitis A.14
Travel to areas endemic for HAV infection constitutes
a considerable risk; our research shows the importance
of improving the environment and developing health
policies. Vaccination before traveling to a medium- or
high-endemic area could be a safe and effective means
of preventing travel-related HAV infection.
Sporadic cases are reported frequently. For example,
since September 2008, 26 cases of HAV infection with a
history of travel to Egypt have been reported in France.
Investigations indicated that the most likely source of
infection was a Nile river cruise that was common to the
majority of cases.15 In 2004, 351 tourists who traveled
to Egypt from nine European countries were infected
with HAV, which was likely due to consumption of
contaminated orange juice.16 Therefore, it is important
to provide appropriate preventive information to
travelers VFR in high infection risk areas, especially
individuals raised in developed countries who lack
immunity.17,18 In the United States in 2007, among
cases for which exposure information was collected,
the most common risk factor for HAV infection was
international travel (approximately 18% of cases).19
About 85% of travel-related cases were associated
with travel to Mexico, Central America, or South
America. The spread of HAV infection in the United
States continues to decline; however, cases among
nonimmunized travelers to HAV-endemic countries
have accounted for any increase in HAV infection.
For US residents traveling abroad, the risk of HAV
infection is associated with living conditions, duration
of travel, and the incidence of HAV infection in the
destination country. The US–Mexico Border Infectious
Disease Surveillance Project, a study that analyzed
characteristics of acute viral hepatitis cases from January
2000 to December 2009, demonstrated that 1,437 cases
J Travel Med 2013; 20: 394–399
Wu and Guo
of acute HAV infection, 311 cases of acute hepatitis B
virus (HBV) infection, and 362 cases of acute hepatitis C
virus (HCV) infection were reported from five Mexican
and two US locations. Mexican HAV infection cases
most frequently reported close personal contact with
a known case, whereas US cases most often reported
cross-border travel.20 Case–control studies conducted
in Italy have shown that the incidence of acute hepatitis
A declined from 4 cases per 100,000 people in 1991
to 1.4 cases per 100,000 people in 2006, and the
incidence of acute HAV infection was highest among
persons aged 15–24 years. The CFR was 2.9 deaths per
10,000 people. Presently, most acute HAV infections
are due to contaminated shellfish consumption, travel
to endemic areas, and contact with patients with acute
HAV infection.21 For those who live or visit rural areas,
the risk of acute HAV infection is highest in those who
travel long distances to remote areas or eat and drink
in poor sanitary conditions.22 In developing countries,
travelers who follow the ‘‘standard’’ itineraries with
respect to accommodations and eating behavior may
also develop travel-related hepatitis.
In addition, a study by Heudorf and colleagues
showed that there were no significant differences in
incidence of hepatitis A between business travelers
and tourist travelers.23 Some special groups, such as
those with human immunodeficiency virus (HIV) and
immunocompromised travelers appear to be more
susceptible to hepatitis A than immunocompetent
travelers; however, a recent study has a different
conclusion. One study by Mikati and colleagues24
included 149 travelers of whom 70 travelers (47%) were
immunocompromised. Immunocompromised travelers
had similar infectious diseases exposure risks to hepatitis
A as immunocompetent travelers. Most of the reported
travel-related illnesses were of minor nature.
Prevention of Travel-Related HAV Infection
HAV infection prevention measures for travelers
include education regarding infectious diseases and food
and water precautions as well as vaccination.
Table 125 summarizes the main types of HAV
vaccine available, the volume per dose, and the
vaccination schedule across the world. Monovalent
vaccines are made of inactivated HAV adsorbed to
aluminum hydroxide as an adjuvant. A full vaccination
series includes two doses. The first dose provides
protective anti-HAV titers for at least 12 months,
and the second dose increases the duration of
protection. Combination vaccines include combination
hepatitis A-hepatitis B vaccine (Twinrix Junior, Twinrix,
GlaxoSmithKline, Rixensart, Belgium) and combination
hepatitis A-typhoid vaccine (Vivaxim, Sanofi Pasteur,
Lyon, France). The HAV-HBV combination vaccine
generally consists of three doses given on a 0-, 1-,
and 6-month schedule. For travelers to HAV endemic
areas, there is a rapid vaccination schedule given on
a 0-, 7-, and 21-day schedule, and an additional dose
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Epidemiology and Prevention of Hepatitis A in Travelers
Table 1
Inactivated hepatitis A vaccines available: recommended dosages and schedules
Age (years)
Monovalent HAV
Avaxim (Sanofi Pasteur)
>2
Havrix Junior (GlaxoSmithKline, Zeist, The Netherlands)
2–16
Havrix 1440 (GlaxoSmithKline, Rixensart, Belgium)
>16
VAQTA Paed (CSL/Merck Sharp & Dohme)
VAQTA Adult (CSL/Merck Sharp & Dohme)
Combination: hepatitis A-hepatitis B vaccine
Twinrix Junior (GlaxoSmithKline, Rixensart, Belgium)
1–18
>18
Twinrix 720/20 (GlaxoSmithKline, Rixensart, Belgium)
>16
Twinrix 720/20
Twinrix 720/20
Combination: hepatitis A-typhoid vaccine
Vivaxim (Sanofi Pasteur)*
Volume per dose
Vaccination schedule
0.5 mL (160 ELISA units of inactivated HAV
antigens)
0.5 mL (720 ELISA units of inactivated HAV
antigens)
1 mL (1440 ELISA units of inactivated HAV
antigens)
0.5 mL (25 units of inactivated HAV protein)
1 mL (50 units of inactivated HAV protein)
0, 6–12 months
0, 6–12 months
0, 6–12 months
0, 6–18 months
0, 6–18 months
1–16
>16
0.5 mL (360 ELISA units of HAV antigens and 10 μg
0, 1, 6 months
recombinant hepatitis B surface antigen protein)
1.0 mL (720 ELISA units of HAV antigens and 20 μg
0, 1, 6 months
recombinant hepatitis B surface antigen protein)
1.0 mL
0, 6–12 months
1.0 mL
0, 7, 21 days, 12 months
≥16
1.0 mL(160 ELISA units of HAV antigens)
1–16
0, 6–36 months
ELISA = enzyme-linked immunosorbent assay; HAV = hepatitis A virus.
*Vivaxim first dose: single dose of Vivaxim on day 0; second dose: for long-term protection, a second dose of monovalent hepatitis A vaccine should be given between 6
and 36 months after the first dose.
should be given after 12 months to maintain long-term
immunity. The combination hepatitis A-typhoid vaccine
Vivaxim is made of formaldehyde-inactivated HAV
and typhoid Vi capsular polysaccharide. Each 1.0 mL
dose of mixed vaccine contains 160 enzyme-linked
immunosorbent assay (ELISA) units of inactivated
HAV antigens and 25 μg purified typhoid Vi capsular
polysaccharide strain Ty2. A single dose of Vivaxim
should be given on day 0 (day of vaccination), and a
second dose of monovalent hepatitis A vaccine should
be given between 6 and 36 months after the first dose.
The immunogenicity of the combination vaccine is
equivalent to that of the monovalent hepatitis vaccines
when tested after completion of the licensed schedule.
Anti-HAV antibodies persist for at least 20 years. For a
person exposed to HAV, the HAV vaccine can provide
effective immune protection, but this effect has not been
fully confirmed.
HAV vaccination can cause some side effects, such as
injection site pain (15%–19%), which is more common
in children, headache (14%–16%), and general fatigue
(5%).26 No serious adverse events in children or adults
have been reported that could be definitively attributed
to the vaccine. The current practice of injecting purified
immunoglobulin (Ig) intramuscularly has proved to be
safe and rarely produces side effects. Ig is a blood
product and could theoretically lead to the spread of
blood-borne diseases; however, there has been no report
of the transmission of infectious diseases, such as HBV,
HCV, HIV infections, or syphilis. The safety of the
HAV vaccine for pregnant women is uncertain, but
the vaccination-associated risk for pregnant women and
for fetal growth is very low. The decision to vaccinate
a pregnant woman with the HAV vaccine should be
based on the individual’s risk of HAV exposure.27
Pregnancy is not currently a contraindication for using
Ig treatment. Thus, all susceptible people traveling
for any purpose, frequency, or duration to countries
with high or intermediate HAV endemicity should be
vaccinated or receive Ig before departure. The first dose
of hepatitis A vaccine should be administered as soon as
travel to countries with high or intermediate endemicity
is confirmed.
Children born in developed countries often lack
protection against HAV and can be easily infected.
Therefore, they should be vaccinated. Children older
than 2 years develop protective antibodies in 97 to 100%
of cases 1 month after the first injection. In infants
younger than 12 months, acquired maternal antibodies
can interfere with the immune response induced by
HAV vaccines.28 In these cases, Ig is an option, but is
not routinely recommended.
For most healthy people younger than 40 years, one
dose of the monovalent HAV vaccine administered
at any time before departure can provide adequate
protection. The full vaccination should be completed
according to the injection schedule for long-term
protection. The seroconversion rate progressively
increases with time after immunization, being only 80%
after 2 weeks but 99% after 1 month. The combination
vaccine may take longer to induce detectable antibodies
because of smaller vaccine doses. Cases of HAV
infection despite vaccination have been reported. One
case report described a young man who was vaccinated
against HAV with an aluminum-adsorbed vaccine
(Havrix 1440, GlaxoSmithKline) 11 days before leaving
for Kenya and who contracted an acute symptomatic
HAV infection. He was diagnosed with an HAV
infection after he returned home, but his symptoms were
mild and he had a good recovery.29 The infection may be
J Travel Med 2013; 20: 394–399
398
related to the short time period between immunization
and departure date (only 11 days); however, the mild
symptoms suggest that he did acquire some level
of protection. For most people older than 40 years,
immunocompromised people, or people with chronic
liver disease or other chronic disease, HAV infection is
more life-threatening, and the HAV vaccine may not be
as effective. Suggestions for treating these individuals
include giving an initial dose of vaccine along with
Ig (0.02 mL/kg) at a separate anatomic injection site
at least 1 month before travel.30 For HIV-positive
travelers, hepatitis A vaccine (Epaxal, Berna Biotech Ltd,
Bern, Switzerland) was well tolerated and was at least
as immunogenic as reported for aluminium-adsorbed
vaccines. Epaxal can be considered an immunogenic
and safe hepatitis A vaccine in HIV-positive patients.31
Those with an allergy to a vaccine component and
infants younger than 12 months should also receive a
single dose of 0.02 mL/kg body weight, which provides
protection against HAV for up to 3 months. If traveling
for a long time, ie, more than 3 months, an Ig dose
of 0.06 mL/kg should be administered, which must be
repeated if the duration of travel is >5 months. Immune
globulin (IG) is also recommended for postexposure
prophylaxis; a single dose of IG (0.02 mL/kg) will
provide certain protection against HAV infection.24
Decision between a monovalent vaccine or the HAVHBV combination vaccine should be made based on
serology and HBV prevalence at the destination site.
HBV is also an important infectious disease that is
transmitted mainly from mother to child and through
body fluids. Up to one in four travelers are considered
at increased risk of exposure to HBV due to sexual
activity, body piercing, tattooing, and other high-risk
activities.22 The combined HAV-HBV vaccine reduces
the number of required injections and is cost-effective.
There is no significant difference in the immunogenicity and tolerability of combined vaccine compared with
the monovalent vaccine. In addition to vaccination or
IG therapy, travelers need to be aware of the importance of drinking water safety. Prior to consumption,
drinking water should be disinfected by boiling or with
chlorine.
In conclusion, HAV is one of the most common
travel-associated infectious diseases and can be effectively prevented by vaccination. Individuals traveling
to HAV-endemic areas should take the initiative to be
vaccinated unless the inoculation schedule is unsuitable
or there are contraindications. IG also has good effect
for short-term prevention, or as a remedial measure
after exposure. Personal protection measures are also
important, such as avoiding unhealthy, contaminated
food or drinking water; boiling or cooking food and
water for ≥1 minute to 85◦ C will inactivate HAV.
Acknowledgments
This project was supported by the National Natural
Science Foundation of China (Grant No.81270515,
J Travel Med 2013; 20: 394–399
Wu and Guo
81101579, 81072005, 81172312); Shanghai Science
and Technology Foundation (Grant No.11430702400);
Chinese Foundation for Hepatitis Prevention and
Control the WBN Research Foundation(Grant
No.20100021); Shanghai Municipal Health Bureau
Foundation (Grant No. 2011287, 2012107).
Declaration of Interests
The authors state that they have no conflicts of interest
to declare.
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