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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
infected with HAV, more than 50% are generally
asymptomatic and the remaining present with mild
symptoms. Although 10% of infected individuals have
nonenveloped single-stranded RNA virus that replicates prolonged or relapsing symptoms over 6 to 9 months,
in hepatocytes and interferes with liver function, chronic HAV infection does not occur.3 The overall
promoting an immune response that causes liver case-fatality ratio (CFR) is 0.3%; however, among
inflammation. In approximately 0.2% of clinical cases, adults over 50 years, the CFR is 2.7%. The CFR is
infection results in acute liver failure and death, and this also higher in individuals with chronic liver disease,
risk increases with age and the presence of chronic including chronic viral hepatitis.4 Diagnosis of hepatitis
liver disease.2 HAV is transmitted through direct A depends primarily on the detection of serum anti-
person-to-person contact, exposure to contaminated HAV IgM antibodies, which are detectable 5 to
water or shellfish, or the consumption or handling of 10 days postexposure and gradually disappear 6 months
contaminated uncooked fruits and vegetables. postinfection. However, anti-HAV IgG can also develop
The average incubation period for HAV is 28 days, in the early stages and last a lifetime. Because HAV
and the clinical manifestations vary. For example, some vaccines are not widely used, most individuals develop
people may be asymptomatic, some show mild clinical anti-HAV IgG-acquired immunity through infection.5
symptoms, and some present with severe hepatitis.
HAV infection symptoms may include the abrupt onset
The Epidemiology of HAV Globally
of fever, malaise, loss of appetite, nausea, abdominal
discomfort, and jaundice, and these can last from weeks Approximately 1.5 million clinical cases of HAV
to several months. In children younger than 6 years 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
Corresponding Author: Professor Chuan-Yong Guo, PhD, by the results of age-seroprevalence surveys. In 2010,
Department of Gastroenterology, Shanghai Tenth People’s the World Health Organization published a systematic
Hospital, Tongji University School of Medicine, Shanghai, review of the global prevalence of and susceptibility to
200072, China. E-Mail: guochuanyong@hotmail.com HAV infection.7 Worldwide, geographical areas can be

© 2013 International Society of Travel Medicine, 1195-1982

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 Epidemiology and Prevention of Hepatitis A in Travelers 395

Figure 1 Estimated prevalence of hepatitis A virus.

characterized with high, intermediate, low, or very low occur in adolescents and young adults. Infections in
levels of endemicity for hepatitis A8 (Figure 1). these developed countries occur in specific settings and
The seroprevalence of antibodies to HAV (total are mainly associated with travel.1,4
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 The Travel-Associated Risk of HAV Infection
and sanitary conditions in each area. The estimates In developed countries, there is a general lack of
demonstrate that all high-income regions have very immunization against HAV, although it is considered
low HAV endemicity levels, all low-income regions an important travel-associated infection. A systematic
have high endemicity levels, and most middle-income review of HAV seropositivity rates in Canada, a
regions have a mix of intermediate and low endemicity. country with low endemicity, demonstrated that
In developing or underdeveloped countries, such as the seroprevalence in Canadian-born children was
Africa, parts of South America, the Middle East, and approximately 1% in ages 8 to 13, 1% to 6% in 20
India, HAV infection is very common. Most infections to 24 years, 10% in 25 to 29 years, and 17% in 30
are acquired during early childhood. Infections that to 39 years, with subsequent age-associated increases.
occur at an early age are often asymptomatic. Therefore, Compared with Canadian-born individuals, subjects
reported rates of infection in these areas are relatively born outside Canada were approximately six times more
low, and outbreaks are not common. In countries likely to be seropositive. Furthermore, travel to high-
with intermediate endemicity, such as China, some risk areas by individuals aged 20 to 39 was associated
Eastern European countries, and some Southeast Asian with a significant increase in anti-HAV seropositivity.
countries, community-wide outbreaks may occur. For This study indicated that HAV infection occurred more
example, in Shanghai, China in 1988, 30 million often in adults, and the increase in HAV prevalence
people were infected with HAV owing to consumption among young adults coincided with disease importation
of contaminated shellfish.9 In developed countries, and an increased frequency of risk factors, most likely
such as North America, Western Europe, Scandinavia, behavioral-related ones.10 Epidemiological studies have
Australia, and Japan, HAV infection is less common. demonstrated that in Germany in 2007 and 2008
Infection rates in children are generally low, though approximately 60% of people infected with HAV had
peak rates of infection and reported disease tend to no travel history to endemic areas. Additionally, young

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immigrant patients who had recently visited family in of acute HAV infection, 311 cases of acute hepatitis B
areas with a high HAV infection risk accounted for most virus (HBV) infection, and 362 cases of acute hepatitis C
imported disease cases.11 virus (HCV) infection were reported from five Mexican
In the past, the risk of HAV infection in unvaccinated and two US locations. Mexican HAV infection cases
travelers was considered to be 3 per 1,000 individuals most frequently reported close personal contact with
per month of travel to a developing country in good a known case, whereas US cases most often reported
quality accommodations. Those who ate and drank cross-border travel.20 Case–control studies conducted
under poor hygienic conditions had a higher risk (20 per in Italy have shown that the incidence of acute hepatitis
1,000 individuals per month traveled).12,13 Currently, A declined from 4 cases per 100,000 people in 1991
with improvements in sanitary conditions, the risk of to 1.4 cases per 100,000 people in 2006, and the
infection for nonimmune travelers who visit high- and incidence of acute HAV infection was highest among
medium-endemic areas has been reduced to 6 to 30 per persons aged 15–24 years. The CFR was 2.9 deaths per
100,000 individuals per month traveled.14 Interestingly, 10,000 people. Presently, most acute HAV infections
the risk to travelers differs from one area to another. An are due to contaminated shellfish consumption, travel
analysis of 636 cases of travel-related hepatitis between to endemic areas, and contact with patients with acute
1997 and 2005 demonstrated that the areas associated HAV infection.21 For those who live or visit rural areas,
with the highest incidence of disease were East Africa, the risk of acute HAV infection is highest in those who
the Middle East, and the Indian subcontinent. Visiting travel long distances to remote areas or eat and drink
friends and relatives (VFR) travelers represented 83, 91, in poor sanitary conditions.22 In developing countries,
and 70% of the cases to these three regions; the highest travelers who follow the ‘‘standard’’ itineraries with
incidence was found in children 0 to 14 years where respect to accommodations and eating behavior may
88% of the cases were VFR travelers. So travelers, also develop travel-related hepatitis.
especially children, who are VFR in endemic areas In addition, a study by Heudorf and colleagues
constitute a high-risk group for acquiring hepatitis A.14 showed that there were no significant differences in
Travel to areas endemic for HAV infection constitutes incidence of hepatitis A between business travelers
a considerable risk; our research shows the importance and tourist travelers.23 Some special groups, such as
of improving the environment and developing health those with human immunodeficiency virus (HIV) and
policies. Vaccination before traveling to a medium- or immunocompromised travelers appear to be more
high-endemic area could be a safe and effective means susceptible to hepatitis A than immunocompetent
of preventing travel-related HAV infection. travelers; however, a recent study has a different
Sporadic cases are reported frequently. For example, conclusion. One study by Mikati and colleagues24
since September 2008, 26 cases of HAV infection with a included 149 travelers of whom 70 travelers (47%) were
history of travel to Egypt have been reported in France. immunocompromised. Immunocompromised travelers
Investigations indicated that the most likely source of had similar infectious diseases exposure risks to hepatitis
infection was a Nile river cruise that was common to the A as immunocompetent travelers. Most of the reported
majority of cases.15 In 2004, 351 tourists who traveled travel-related illnesses were of minor nature.
to Egypt from nine European countries were infected
with HAV, which was likely due to consumption of
Prevention of Travel-Related HAV Infection
contaminated orange juice.16 Therefore, it is important
to provide appropriate preventive information to HAV infection prevention measures for travelers
travelers VFR in high infection risk areas, especially include education regarding infectious diseases and food
individuals raised in developed countries who lack and water precautions as well as vaccination.
immunity.17,18 In the United States in 2007, among Table 125 summarizes the main types of HAV
cases for which exposure information was collected, vaccine available, the volume per dose, and the
the most common risk factor for HAV infection was vaccination schedule across the world. Monovalent
international travel (approximately 18% of cases).19 vaccines are made of inactivated HAV adsorbed to
About 85% of travel-related cases were associated aluminum hydroxide as an adjuvant. A full vaccination
with travel to Mexico, Central America, or South series includes two doses. The first dose provides
America. The spread of HAV infection in the United protective anti-HAV titers for at least 12 months,
States continues to decline; however, cases among and the second dose increases the duration of
nonimmunized travelers to HAV-endemic countries protection. Combination vaccines include combination
have accounted for any increase in HAV infection. hepatitis A-hepatitis B vaccine (Twinrix Junior, Twinrix,
For US residents traveling abroad, the risk of HAV GlaxoSmithKline, Rixensart, Belgium) and combination
infection is associated with living conditions, duration hepatitis A-typhoid vaccine (Vivaxim, Sanofi Pasteur,
of travel, and the incidence of HAV infection in the Lyon, France). The HAV-HBV combination vaccine
destination country. The US–Mexico Border Infectious generally consists of three doses given on a 0-, 1-,
Disease Surveillance Project, a study that analyzed and 6-month schedule. For travelers to HAV endemic
characteristics of acute viral hepatitis cases from January areas, there is a rapid vaccination schedule given on
2000 to December 2009, demonstrated that 1,437 cases a 0-, 7-, and 21-day schedule, and an additional dose

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 Epidemiology and Prevention of Hepatitis A in Travelers 397

Table 1 Inactivated hepatitis A vaccines available: recommended dosages and schedules

Age (years) Volume per dose Vaccination schedule

Monovalent HAV
Avaxim (Sanofi Pasteur) >2 0.5 mL (160 ELISA units of inactivated HAV 0, 6–12 months
antigens)
Havrix Junior (GlaxoSmithKline, Zeist, The Netherlands) 2–16 0.5 mL (720 ELISA units of inactivated HAV 0, 6–12 months
antigens)
Havrix 1440 (GlaxoSmithKline, Rixensart, Belgium) >16 1 mL (1440 ELISA units of inactivated HAV 0, 6–12 months
antigens)
VAQTA Paed (CSL/Merck Sharp & Dohme) 1–18 0.5 mL (25 units of inactivated HAV protein) 0, 6–18 months
VAQTA Adult (CSL/Merck Sharp & Dohme) >18 1 mL (50 units of inactivated HAV protein) 0, 6–18 months
Combination: hepatitis A-hepatitis B vaccine
Twinrix Junior (GlaxoSmithKline, Rixensart, Belgium) 1–16 0.5 mL (360 ELISA units of HAV antigens and 10 μg 0, 1, 6 months
recombinant hepatitis B surface antigen protein)
Twinrix 720/20 (GlaxoSmithKline, Rixensart, Belgium) >16 1.0 mL (720 ELISA units of HAV antigens and 20 μg 0, 1, 6 months
recombinant hepatitis B surface antigen protein)
Twinrix 720/20 1–16 1.0 mL 0, 6–12 months
Twinrix 720/20 >16 1.0 mL 0, 7, 21 days, 12 months
Combination: hepatitis A-typhoid vaccine
Vivaxim (Sanofi Pasteur)* ≥16 1.0 mL(160 ELISA units of HAV antigens) 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 Pregnancy is not currently a contraindication for using
immunity. The combination hepatitis A-typhoid vaccine Ig treatment. Thus, all susceptible people traveling
Vivaxim is made of formaldehyde-inactivated HAV for any purpose, frequency, or duration to countries
and typhoid Vi capsular polysaccharide. Each 1.0 mL with high or intermediate HAV endemicity should be
dose of mixed vaccine contains 160 enzyme-linked vaccinated or receive Ig before departure. The first dose
immunosorbent assay (ELISA) units of inactivated of hepatitis A vaccine should be administered as soon as
HAV antigens and 25 μg purified typhoid Vi capsular travel to countries with high or intermediate endemicity
polysaccharide strain Ty2. A single dose of Vivaxim is confirmed.
should be given on day 0 (day of vaccination), and a Children born in developed countries often lack
second dose of monovalent hepatitis A vaccine should protection against HAV and can be easily infected.
be given between 6 and 36 months after the first dose. Therefore, they should be vaccinated. Children older
The immunogenicity of the combination vaccine is than 2 years develop protective antibodies in 97 to 100%
equivalent to that of the monovalent hepatitis vaccines of cases 1 month after the first injection. In infants
when tested after completion of the licensed schedule. younger than 12 months, acquired maternal antibodies
Anti-HAV antibodies persist for at least 20 years. For a can interfere with the immune response induced by
person exposed to HAV, the HAV vaccine can provide HAV vaccines.28 In these cases, Ig is an option, but is
effective immune protection, but this effect has not been not routinely recommended.
fully confirmed. For most healthy people younger than 40 years, one
HAV vaccination can cause some side effects, such as dose of the monovalent HAV vaccine administered
injection site pain (15%–19%), which is more common at any time before departure can provide adequate
in children, headache (14%–16%), and general fatigue protection. The full vaccination should be completed
(5%).26 No serious adverse events in children or adults according to the injection schedule for long-term
have been reported that could be definitively attributed protection. The seroconversion rate progressively
to the vaccine. The current practice of injecting purified increases with time after immunization, being only 80%
immunoglobulin (Ig) intramuscularly has proved to be after 2 weeks but 99% after 1 month. The combination
safe and rarely produces side effects. Ig is a blood vaccine may take longer to induce detectable antibodies
product and could theoretically lead to the spread of because of smaller vaccine doses. Cases of HAV
blood-borne diseases; however, there has been no report infection despite vaccination have been reported. One
of the transmission of infectious diseases, such as HBV, case report described a young man who was vaccinated
HCV, HIV infections, or syphilis. The safety of the against HAV with an aluminum-adsorbed vaccine
HAV vaccine for pregnant women is uncertain, but (Havrix 1440, GlaxoSmithKline) 11 days before leaving
the vaccination-associated risk for pregnant women and for Kenya and who contracted an acute symptomatic
for fetal growth is very low. The decision to vaccinate HAV infection. He was diagnosed with an HAV
a pregnant woman with the HAV vaccine should be infection after he returned home, but his symptoms were
based on the individual’s risk of HAV exposure.27 mild and he had a good recovery.29 The infection may be

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related to the short time period between immunization 81101579, 81072005, 81172312); Shanghai Science
and departure date (only 11 days); however, the mild and Technology Foundation (Grant No.11430702400);
symptoms suggest that he did acquire some level Chinese Foundation for Hepatitis Prevention and
of protection. For most people older than 40 years, Control the WBN Research Foundation(Grant
immunocompromised people, or people with chronic No.20100021); Shanghai Municipal Health Bureau
liver disease or other chronic disease, HAV infection is Foundation (Grant No. 2011287, 2012107).
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 Declaration of Interests
Ig (0.02 mL/kg) at a separate anatomic injection site
at least 1 month before travel.30 For HIV-positive The authors state that they have no conflicts of interest
travelers, hepatitis A vaccine (Epaxal, Berna Biotech Ltd, to declare.
Bern, Switzerland) was well tolerated and was at least
as immunogenic as reported for aluminium-adsorbed
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