Journal of Occupational & Environmental Medicine:
Special Section on Health and the Corporate Traveler
Risk and Burden Associated With the Acquisition of Viral Hepatitis A and B in the Corporate Traveler
Bunn, William B. III MD, JD, MPH
From Navistar, Inc, Warrenville, Ill.
Address correspondence to: William B. Bunn, III, MD, JD, MPH, International Truck and Engine Corporation, 4201 Winfield Road, Warrenville, IL 60555; E-mail: firstname.lastname@example.org.
As the number of international business travelers continues to grow, so does the list of destinations, many of which are endemic for both hepatitis A and B. Generally, travelers are unaware of the risks of acquiring viral hepatitis when traveling; many are unsure of modes of transmission and do not seek pretravel advice or do not follow the recommendations of travel health professionals. Infected employees can result in increased health care costs and reduced productivity in the workplace. Safe and efficacious monovalent vaccines and a combined hepatitis A and B vaccine are available. Successful corporate health and immunization programs can prevent hepatitis A and B when employees are abroad on business. This article examines the distribution, risks, costs, burden, and prevention of hepatitis A and B in the international business traveler.
Hepatitis A virus (HAV) is one of the most common vaccine-preventable infections acquired abroad.1 HAV is highly endemic in Africa, the Middle East, Asia (excluding Russia), certain areas of the Caribbean, and South America. Areas with intermediate prevalence include Russia and Eastern Europe (Fig. 1).1,2 In the United States there were 4488 acute clinical hepatitis A cases reported to the Centers for Disease Control and Prevention (CDC) in 2005.3 When unreported cases and asymptomatic infections were considered, it was estimated that as many as 19,000 acute clinical cases and 42,000 new HAV infections occurred in 2005.4 The rate of reported acute HAV infections declined by about 88% from 1995 to 2005. The implementation of childhood vaccination programs in communities and states with rates of hepatitis A higher than the national average may have contributed to the decreased number of reported cases.3 Many US travelers continue to be susceptible to infection, and up to 15% of reported hepatitis A cases are associated with international travel.3 A similar trend has also been observed in Canada, as the number of HAV infections reported in Ontario declined from 1998 to 2004, while the number of travel-related infections held steady during this period. From January 1998 to December 2004, 1381 cases of hepatitis A were reported in Ontario. Of which, 594 cases (43%) were travel related, and the most commonly reported travel destination was Asia, specifically Pakistan and India.5
Worldwide, 350 million persons are chronically infected with hepatitis B virus (HBV), the cause of up to 80% of hepatocellular carcinomas.6 Chronic HBV infection prevalence is highest in Africa, Asia (including China, Korea, Indonesia, and the Philippines), most of the Middle East, Southern and Western Pacific islands, the interior Amazon River Basin, Honduras, Guatemala, and certain parts of the Caribbean.1 Areas of intermediate endemicity (2% to 7%) include Japan, Eastern and Southern Europe, Russia, South Central and Southwest Asia, and parts of the Middle East (Fig. 1).1 For international travelers, the CDC regards the risk of HBV infection as generally low, except for those traveling to high or intermediate endemic countries.1
In 2005, there were 5494 reported cases of acute clinical hepatitis B in the United States.3 When accounting for unreported cases, it was estimated that as many as 15,000 acute clinical cases and 51,000 new infections occurred in 2005.3,4 Similar to hepatitis A, acute hepatitis B rates reported to the CDC have declined. The number of reported acute clinical hepatitis B cases declined by 79% from 1990 to 2005. The greatest decline in HBV infection was observed in children and adolescents, for which routine immunization is recommended. However, the incidence of HBV remains high among some adult groups, and increases as certain high-risk behaviors continue. Persons whose occupation, lifestyle, or environment places them in frequent contact with the HBV-infected blood, such as emigrating from high endemic areas, household contacts of infected persons, and injection drug users, have been identified as having the highest risk for infection.6
HAV is a picornavirus, a small RNA virus, which has tropism exclusively for hepatocytes.2 Transmission occurs through the fecal-oral route via ingestion of contaminated food or water, or by close personal contact, including sexual contact, with infected individuals.2 HAV can be highly stable outside the body in favorable environments (ie, low pH or moderate temperatures) for months.2 Approximately 10 to 12 days after initial exposure, HAV can be detected in the blood.2 The incubation period for HAV is 15 to 50 days, with a mean incubation of 28 days. After replication in the liver, enzyme resistant viral particles are transported in the bile to the intestine before being shed in the feces.2 Virions are present in the feces for 1 to 2 weeks before illness, and for at least 1 week after the onset of symptoms. During this time, infected individuals are highly contagious.2,7
HBV is an enveloped hepadnavirus with a double-stranded DNA genome, also replicating in the liver.6 Virions are found primarily in the blood, saliva, semen, vaginal secretions, and menstrual blood of infected individuals. In addition, smaller concentrations can be found in sweat, breast milk, tears, and urine.6 HBV is transmitted primarily through sexual contact.6 Additional modes of transmission include contact with the blood of an infected person.6 Transmission can occur when receiving contaminated blood products, sharing needles during intravenous drug use, tattooing, piercing ears, and receiving acupuncture, as well as through accidental exposure to poorly sterilized needles or other contaminated sharp instruments in health care facilities.6 Transmission of HBV has not been attributed to kissing (although biting can transmit the virus), nor through contact with an infected person's sweat, urine, or stool.6 HBV virions can remain infectious on inanimate surfaces, at room temperature, for more than 7 days,6 and HBV is transmitted approximately 100 times more easily than HIV.8 Incubation periods range from 60 to 150 days (90 days on average), and at least 50% of infections are asymptomatic,6 though the development of clinical manifestations are age dependent.9
Consequences of Infection
Serological testing is needed to distinguish between the different types of acute viral hepatitis infections. Symptoms of acute HAV infection include jaundice, fatigue, abdominal pain, loss of appetite, nausea, diarrhea, and fever.2 Most (70%) infected children under the age of 6 years are asymptomatic, yet those over 6 years of age are usually symptomatic and about 70% develop jaundice.2 Although chronic infections do not occur, approximately 15% of HAV-infected patients experience relapses for 6 months.2 Most patients show complete recovery within 2 months of onset.2 The case-fatality ratio for acute hepatitis A is about 0.3% across all age groups, although individuals over the age of 40 have an increased risk of death.2
Outbreaks of hepatitis A have a significant financial impact. The estimated cost for acute hepatitis A in 1997, which included direct medical costs, lost workdays and salary, and incurred housekeeping expenses, was $7715 per patient.10 During a hepatitis A outbreak in Spokane, Washington, from 1997 to 1998, the average cost per case was $3837.11 During this outbreak, respondents reported missing between 2 and 155 days of work (average 9.1 day) due to HAV infection. Of those surveyed, three claimed workers' compensation for lost wages, which ranged from $1700 to $2000 from occupations in sales and teaching, respectively.11
Another hepatitis A outbreak in Ohio from November 1998 to May 1999 involved 136 cases.12 The average cost per case of the outbreak was $2894. Approximately 40% of the total cost was attributed to direct medical costs, 51% attributed to lost wages, and 9% attributed to health department costs. Employers incurred 29% of these outbreak costs.12 Of the 86 case-patients who were employed, 97% lost at least 1 day of work due to illness, with an average number of 12 workdays lost (range, 0 to 42 days). Average lost wages due to hepatitis A infection were $1675 among full-time workers. Employers paid an estimated $840 per case-patient through sick-leave reimbursement, and case-patients incurred an average of $633 of non-reimbursed lost wages.12 International travel increases the risk for HAV infection.2 Companies that require frequent travel to high endemic areas could experience a higher number of employees acquiring, or returning, with an HAV infection, resulting in unnecessary illness-associated costs.
Symptoms of acute HBV infection can include jaundice, fatigue, abdominal pain, loss of appetite, nausea and vomiting, and joint pain.6 As with HAV infections, asymptomatic HBV infections do occur. Approximately 30% of HBV-infected individuals remain asymptomatic.13 Fulminant hepatitis, the most severe form of acute infection, occurs in about 1% to 2% of cases of acute infection, and has a case-fatality ratio of 63% to 93%.6 Chronic HBV infection can lead to cirrhosis, liver failure, and liver cancer.6 Approximately 15% to 25% of persons chronically infected with HBV die from chronic liver disease.6
Hepatocellular carcinoma (HCC) is a well-described consequence of HBV infection and usually appears 25 to 30 years after the initial infection.9 Individuals with chronic HBV infection are 12 to 300 times more likely to develop HCC than noncarriers, resulting in an estimated 1000 to 1500 deaths annually in the United States.6 Primary liver cancer rates associated with HBV remained constant in the United States from 1993 to 1998.14 Approximately 3000 to 4000 mortalities per year in the United States occur from HBV-related cirrhosis.6 Patients with chronic HBV have significantly higher health care costs than other patients.15 A retrospective analysis of health care costs in a Health Maintenance Organization database revealed that patients with chronic HBV infection had health care costs 3.3 times higher than uninfected individuals in the 7 months surrounding the identification of their first diagnostic markers. These individuals continued to have monthly health care costs 2.9 times higher than uninfected individuals, after the first 7 months.15 In the United States, the estimated annual cost for a case of chronic HBV, without complications, is $761. Furthermore, the estimated annual cost for a case of HBV-related cirrhosis and HBV-related HCC is $11,459 and $7533, respectively (adjusted to US dollars in the year 2000).16 These two forms of vaccine-preventable hepatitis account for nearly 8 of 10 new viral hepatitis infections in the United States.4
Impact of Corporate Medical Programs
As international business continues to grow into developing countries, corporations must expand their travel medicine programs. Many international business trips are frequently executed by a small and highly skilled set of employees, making the productivity of this group a major concern during the trip and upon return. The evacuation of a traveler can cost up to $100,000 in addition to the health care costs. An effective vaccine program for travelers can essentially eliminate this risk and the costs of lost productivity and health care.
At any given time, large US-based international corporations can have as many as 100 to 5000 US expatriates and short-term assignees (3 to 6 months) abroad. Some multinational corporations can have as many as 200,000 expatriates and short-term assignees traveling with families, all of whom require appropriate pretravel measures.17
In addition to costs associated with medical expenses and lost productivity, the illness-induced repatriation of a key employee and his or her family can cost more than $500,000 for the employer.17 A comprehensive vaccination and health screening program for all employees destined for remote areas costs approximately $500 per employee.17 Of 100 employees sent abroad, six are expected to be repatriated per year, with a cost of $500,000 per employee ($3 million in total).17 The total cost of an effective vaccination and screening program ($50,000 for 100 employees) can cost less than 2% of the total incurred costs if 6% of the employees contract a travel-related illnesses and require repatriation.17 A similar analysis for travelers with evacuation costs reaching $100,000 and major costs of lost productivity will show cost-effectiveness.
In addition, employers are legally required to provide a standard of health care similar to that of their home country, including preventative medicine, irrespective of the geographic location of the employee at the time.17 Workers' compensation laws usually apply since travelers and expatriates are at increased risk for acquiring an infection. Tort liability is also a consideration for other workers, close contacts, and family members who may contract the disease.
Risk to Travelers
In 2005, international travel was the most frequently identified risk factor for HAV infection among Americans, and was associated with 15% of cases reported to the CDC that year (Fig. 2).3 In Canada, 40% of reported HAV cases between 2000 and 2002 were associated with international travel.18 In the United States, in 1996, 4% of reported acute viral hepatitis cases in the CDC Sentinel Counties Study were associated with international travel, primarily due to travel to Mexico, Central, or South America.19 The risk of acquiring HAV for nonimmune travelers is 6 to 300 per 100,000 person-months abroad.20,21 Travelers' risks are dependent upon their destination, and risk increases with length of stay and potential for consumption of contaminated foods or beverages.1 Foods frequently contaminated with HAV include unpeeled or uncooked fruits and vegetables, tap water that has not been boiled, ice or shellfish from sewage-contaminated water, and ice cream.1 HAV foodborne outbreaks are not isolated to poor sanitary conditions, as outbreaks have been attributed to hotels and resorts in well-developed areas.22
When visiting endemic regions, travelers may be at risk for HBV exposure through unprotected sexual contact with local residents, or unanticipated medical treatment, including post-trauma emergency care, in facilities where needles may not be properly sterilized or where poorly screened blood transfusions are used.6 Additionally, certain activities, such as tattooing, intravenous drug use, and acupuncture, increase the risk for infection. Other risky activities include body piercing and sharing razor blades or toothbrushes.23–25 Up to 10% to 15% of travelers are exposed to blood or other bodily fluids when traveling abroad.21 The number of hepatitis B cases directly resulting from specific high-risk activities while traveling is unknown. However, a 2006 survey revealed that 8% of US travelers put themselves at high risk for infection when visiting endemic areas for HBV through sexual activity, dental treatment, sporting activities (such as horseback riding), and skin-perforating cosmetic practices.26 A comprehensive survey involving over 9000 respondents from nine countries revealed that a significant proportion of European travelers also placed themselves at high (6.6% to 11.2%) or potential (60.8% to75.8%) risk for contracting HBV when traveling to endemic regions.27 Less than 25% of these travelers were vaccinated against HBV.27
One analysis of three retrospective studies estimated the overall risk of acquiring a symptomatic HBV infection in vacationers traveling to Asia, Africa, and Latin America (n = 463). The exact duration of their stay was not known, and was estimated to be 1 month. The overall risk for acquiring a symptomatic HBV infection per journey was 1 in 2500 months (or 40 per 100,000 months), varying between 20 in 100,000 months in Africa and Latin America and 60 in 100 months abroad in Asia.28 Another prospective study29 showed that only 2 of 7887 travelers to developing countries were diagnosed with hepatitis B, both of whom worked abroad (n = 97). No vacationers (n = 7317) acquired HBV. The incidence rate per month for symptomatic hepatitis B was therefore estimated to be 25 in 100,000. As the estimated risk was based on only 2 cases of hepatitis B, it should be noted that the range for risk of infection would vary greatly.
A European consensus panel recently concluded that the risk of contracting HAV and HBV is significant enough to consider vaccination against both viruses for European travelers heading to the Eastern European Union destinations of Armenia, Azerbaijan, Belarus, Bosnia and Herzegovina Bulgaria, Georgia, Kazakhstan, Kosovo, Kyrgyzstan, Moldova, Romania, Russia, Serbia and Montenegro, Tajikistan, Turkmenistan, and Ukraine.30 HAV and HBV vaccinations should also be considered when traveling to Albania, Egypt, FYROM, Israel, Jordan, Lebanon, Libya, Morocco, Syria, Tunisia, and Turkey.30
In many developing countries, lack of regulations and inspections of health care facilities and provider practices increase the risk of HBV transmission. Injections in health care settings in developing countries that use improper infection-control procedures and unsanitary injection equipment have been identified as major sources of HBV transmission.31 Post-travel surveys revealed that 64% of US travelers visiting developing countries became ill, 8% of whom sought medical care.32 Of those who sought medical care, 17% received injections.32 Furthermore, 31.7% of international Canadian travelers seeking medical attention underwent parenteral injections, including medication, intravenous therapy, blood transfusion, or anesthesia, or had blood extracted for laboratory samples.23 Even in the United States where government regulations and recommendations are well-known and enforced, an HBV outbreak in a private medical office performing unnecessary injections and inadequate sanitation measures was recently documented.33
In 2000, an analysis of epidemiological studies and surveys on sterilization practices in regions of the world with high HBV disease burdens showed that an estimated 39.3% (1.2% to 75% depending on region) of administered injections involved reused equipment. This resulted in an estimated 21 million new HBV infections because of needle reuse (31.9% of all new HBV infections).34,35 Global modeling estimates suggest that approximately 8 to 16 million HBV infections will result from unsafe injections each year.36 Reuse of injection equipment occurs in almost one in three injections in developing and transitional countries.35 India, Afghanistan, Egypt, Iraq, Pakistan, Sudan, and Yemen had the highest injection needle reuse rates.35 Analysis of injection practices in developing countries indicates that ill or hospitalized adults are often exposed to 10 to 100 times as many injections, many of which may be unnecessary, compared with the 1.5 injections that their healthy counterparts receive annually.37
Injuries sustained abroad may result in emergency dental or surgical procedures. When abroad, travelers are more likely to be injured in an accident or violent act than they are to contract an exotic illness.38 Travelers visiting developing countries should be particularly wary of traffic, both drivers and pedestrians, as traffic laws in these countries are often limited or inadequately enforced. Road signs may be written in unfamiliar languages, lighting may be poor or nonexistent, residential driving habits may be dangerous, and traffic may be a mix of many different vehicles, pedestrians, and animals.38 Additionally, injury can occur through intentional violence, as criminals often target business travelers, making violence a significant risk in many developing countries.1,38
To reduce the risk of acquiring bloodborne diseases or aggravating previously existing medical conditions or those acquired abroad, international business travelers should travel with adequately supplied medical kits. Based on the destination and duration of journey, a travel medicine specialist should determine the specific contents of the medical kit.39 Travel medical kit supplies are readily available and can be easily obtained through the internet. In addition to the standard fist aid items, needles, syringes, emergency dental kits, and suturing supplies can be included in medical kits, as well as water purification items and intravenous fluids (rehydration packs) for those traveling to developing countries. Consistent inclusion of medical kits in the business traveler's luggage will require well-implemented corporate medical education programs.40
Travelers' Knowledge, Attitudes, and Practices
Although awareness of transmissible diseases may be increasing among travelers, this level of knowledge is not reflected in actual behavior. It is estimated that almost 45% and 16% of individuals infected with HAV and HBV, respectively, are unable to identify the source of their infection or may deny or conceal participation in high-risk behaviors.2,6 In total, 17% to 28% of travelers correctly recognized hepatitis A as one of the highest risks among vaccine-preventable diseases.41,42 Most travelers recognized the protective effect of vaccines, though less than 24% of those surveyed were vaccinated against hepatitis A, and even fewer against hepatitis B.41–43 In addition, there appears to be incomplete knowledge among travelers about the modes of transmission for HAV and HBV. More than 60% of Canadian travelers did not know that hepatitis A could be contracted by eating contaminated food or through sexual contact, and only 42% identified sexual activity as a mode of transmission for hepatitis B.44 Data collected from airport surveys in Europe and the United States revealed that only 15% to 26% of travelers intended to completely restrict their consumption of potentially dangerous foods, whereas the majority (59% to 70%) did not plan to drink local tap water.41,42,45
Although international travelers may not consider engaging in sexual activity, surveys have found that sexual contact between travelers and local inhabitants is not uncommon.46 Up to 55% of international travelers reported casual sex, particularly with local residents, and a significant percentage (30% to 65%) did not use condoms, or were inconsistent with condom use.46–50 A survey of travelers visiting Lima, Peru revealed that 12.2% had new sex partners during their stay; 67.3% of partners were local inhabitants, 34.6% were other travelers, and 7.7% were sex workers.47 Sexual activity among US travelers (15.2%) was greater than that among travelers from other countries (10.6%). Condoms were consistently or sometimes used in 24% and 20% of the respondents, respectively.47
Although similar data from US travelers are unavailable, a survey of patients attending two Glasgow genitourinary medicine clinics revealed that 19.6% of women, 31% of heterosexual men, and 42% of homosexual men had sexual contact with a new partner while abroad.49 Of those who had had a new sexual contact abroad, 50% of women who had sex with a new partner and 59% of heterosexual men who had sex with a new partner used condoms inconsistently. In total, 24% of those traveling for personal reasons had a new sexual contact, whereas 41% of those traveling for business had a new sexual contact. Of heterosexual male travelers who had a sexual contact abroad, 22.6% on vacation or visiting friends and relatives had sexual contact with a local inhabitant compared with 92% of those on business or working abroad.49 However, these data should not be used as a literal representation of all business travelers. It is also not known whether the reported sexual activity resulted in HBV infection.49 Lack of awareness about the modes of transmission combined with failure to protect against vaccine-preventable diseases will continue to put business travelers at unnecessary risk for the development of serious and costly infections. Routine corporate education and vaccination programs lead by physicians can reduce these risks and minimize economic and wellness costs.51 In 1995, the CDC reported survey results, which stated 36% of responding primary-care physicians provided pretravel advice. When presented with three travel scenarios, 0.5% of physicians gave appropriate advice in all three scenarios, 40% did not give any correct advice, and 22% had no opinion.52 Corporate travel program directors should not assume that adequate pretravel advice is consistently given by primary care physicians.
Vaccines to Prevent Hepatitis A and B
Vaccines against HAV have been available in the United States since 1995. Both Havrix (GlaxoSmithKline; Rixensart, Belgium) and VAQTA (Merck; Whitehouse Station, New Jersey) are inactivated HAV virus vaccines, licensed for administration in the United States. Individuals are vaccinated by intramuscular injection, with a primary immunization and a booster dose 6 to 12 months later (up to 18 months later for VAQTA).53,54 The CDC and World Health Organization (WHO) recommend HAV vaccination for adults in high-risk groups, including persons traveling to endemic areas. CDC recommendations were updated in 2006 to include all children beginning at 1 year of age.55–57 Physicians often follow current CDC and WHO vaccination recommendations. Integrated databases, such as Travax™ (Shoreland, Inc., Milwaukee, WI), are frequently used by multinational industries for travel medicine recommendations. Shoreland expands on these recommendations to state that even individuals staying at deluxe hotels in intermediate to high HAV endemic areas, who do not exhibit risky eating habits, should not overlook vaccination.58
Protective antibody responses are generated within as little as 2 weeks after the first dose of HAV vaccine.59 Immunity is generally long lived, and if patients miss the second scheduled dose they can receive a booster injection years later without reduced immunity.58
Because a single dose of HAV vaccine results in rapid seroconversion, anti-HAV immunoglobulin (IG) therapy is generally not used as a prophylactic measure for travelers to endemic areas. Composite data from three clinical studies that compared immunization with a single dose of HAV vaccine to the prophylactic administration of IG in over 400 healthy adults, 18 to 50 years of age, showed that a single immunization results in strong and sustained antibody responses when compared with IG. Postvaccination geometric mean titers of immunized seroconverters (≥20 mIU/mL) ranged from 264 to 339 mIU/mL at day 15 and increased to 335 to 637 mIU/mL at month 1. Study participants receiving two and a half to five times the standard dose of IG (standard dose = 0.02 to 0.06 mL/kg) had a geometric mean titer of 146 mIU/mL at 5 days postadministration, 77 mIU/mL at month 1, and 63 mIU/mL at month 2.53 Planned pretravel vaccination is a more practical approach to HAV prophylaxis.
In circumstances where passive protection against HAV is required either postexposure or in persons requiring both immediate and long-term protection, HAV vaccine is approved to be administered concomitantly with IG with different syringes and at different injection sites.53,58 Clinical studies conducted during 10 HAV outbreaks in Slovakia showed that when direct contacts of confirmed HAV cases received either a single dose of HAV vaccine (n = 2171) or IG (n = 3837), the number of confirmed hepatitis A cases dropped within the first seven weeks in the IG group, whereas the number of HAV cases dropped within the first 4 weeks after immunization in the vaccinated group.60 Among contacts with HAV-infected individuals, 16 cases (0.7%) of hepatitis A were reported in the vaccine group and 51 cases (1.3%) were reported in the IG group (P < 0.05) during the maximum incubation period of 45 days. After 2 or 3 years, volunteers who received a booster dose showed a significant increase in anti-HAV geometric mean concentrations; however, the time difference between primary vaccination and booster administration did not seem to impact the magnitude of the booster response. In the United States, a randomized, double-blinded, placebo-controlled trial conducted during an HAV outbreak in Monroe, New York, among susceptible healthy children and adolescents aged 2 to 16 years (n = 1037), showed that a single dose of HAV vaccine had 100% efficacy (P < 0.001).61 No clinically confirmed cases of HAV were detected in recipients of the vaccine at 16 days postvaccination.62 Protective immune responses were shown to persist for at least 9 years after the booster.63 These studies demonstrate that postexposure immunization with a single dose of inactivated HAV vaccine can confer high and long-term protection and effectively control viral hepatitis A outbreaks.60–63 Also, considering the incubation period of HAV (average, 2 to 4 weeks), the WHO recommends that HAV vaccine can be administered up to the day of departure and still protect travelers. The WHO further states that the use of IG is virtually obsolete for travel prophylaxis,56 as IG is not commonly available for prophylactic or acute treatment. CDC recommendations were recently modified to state that healthy persons between 12 months and 40 years of age should be given the age appropriate dose of vaccine instead of IG for postexposure prophylaxis.64 However, the CDC still prefers IG for persons over 40 years of age or those with underlying medical conditions; due to a lack of available data, neither postexposure treatment has been evaluated more than 2 weeks after exposure.64 Shoreland recommends that travelers be immunized as soon as travel is considered (at least 4 weeks before departure), but vaccination is still recommended anytime before departure, as it is likely to provide adequate protection in the absence or unavailability of prophylactic IG.58 Furthermore, the Canadian National Advisory Committee on Immunization recommends HAV vaccination over IG for postexposure prophylaxis in persons greater than 1 year of age.58
Two monovalent HBV vaccines are available in the United States: Engerix-B (GlaxoSmithKline; Rixensart, Belgium) and Recombivax HB (Merck; Whitehouse Station, New Jersey). Both vaccines, which are based on recombinant DNA technology, have demonstrated efficacy and are well-tolerated. The CDC, WHO, and Shoreland recommend HBV vaccination for all infants, children, and adolescents under 19 years of age,1,65 as well as unvaccinated adults at risk for exposure, including travelers visiting intermediate to high endemic areas1,56,65 and all travelers who engage in high-risk activities.1,56,65 Both HBV vaccines are administered by three intramuscular injections at 0, 1, and 6 months.66,67 Should a lapse occur in the dosing schedule, HBV protection (serum antibodies ≥10 mIU/mL for seroprotection) can be assessed upon completion of the recommended vaccination schedule.65 Monovalent hepatitis vaccines can be interchanged between manufacturers without a lapse in protection.58,65
There is much overlap among areas highly endemic for HAV and HBV (Fig. 1).68 Travelers who require protection from both viruses can be vaccinated with the bivalent vaccine, Twinrix (GlaxoSmithKline; Rixensart, Belgium), which can be given to travelers 18 years of age and older.69 For those traveling to areas endemic for both HAV and HBV, the CDC, WHO, and Shoreland recommend vaccination against HAV and HBV.56–58,70 Twinrix can be administered via three intramuscular injections at 0, 1, and 6 months.69 In adults, immunization with Twinrix is well tolerated and was shown to have similar or fewer adverse events when compared with concomitant immunization with equivalent monovalent vaccines.71 Twinrix was recently approved for an accelerated dosing schedule with injections at 0, 7, and 21 to 30 days, followed by a booster immunization at 12 months.69 The combination of fewer immunizations when compared with HAV and HBV immunizations administered separately, as well as the decreased time between dosing with the accelerated schedule, could facilitate increased compliance in protecting business travelers against HAV and HBV. In the following studies, rates of seroconversion and seroprotection are accepted efficacy endpoints for HAV and HBV vaccination studies, respectively.69 In subjects 18 years and older, immunization with Twinrix on the accelerated schedule or concomitant immunization with monovalent vaccines on the standard immunization schedule resulted in ≥98% seroconversion for HAV by day 37 (Table 1).72 However, immunization with Twinrix on the accelerated schedule resulted in a 63% seroprotection rate against HBsAg after 37 days, whereas concomitant monovalent immunization resulted in a seroprotection rate of approximately 44% (Table 1).72 An earlier study reported HAV seroconversion rates of 91% and 98%, and HBsAg seroprotection rates of 18% and 8%, 30 days after volunteers (mean age of 40 years) were immunized once on the standard schedule with Twinrix and concomitant monovalent vaccines, respectively (Table 1).71 Furthermore, a combined analysis of 11 clinical trials showed that individuals immunized with Twinrix on the standard schedule had HAV seroconversion and HBsAg seroprotection rates of 94% and 31%, respectively, 30 days after the first immunization.69 It should be noted, however, that by 60 days, immunization with Twinrix on the accelerated schedule or standard administration of concomitant monovalent vaccines was shown to have comparable HAV seroconversion (99.5% and 98.9%, respectively) and HBV seroprotection (85.0% and 84.9%, respectively) rates.73 When immunized with Twinrix on the accelerated schedule, business travelers with only 1 month's notice before their departure date can still receive a level of protection against both HAV and HBV if high levels of HBsAg antibodies are obtained at 30 days postvaccination. Full implementation of the combined HAV and HBV vaccine may be limited by the high efficacy observed with the monovalent formulations.6 Before an experiential departure date, further assessments are needed to evaluate protection and compliance rates for combination and monovalent vaccination, as well as a comparison of four doses of Twinrix with an extra dose of HBV vaccine in the concomitant immunization group.
Hepatitis A and B present significant health risks to today's business travelers. Consumption of inadequately prepared food and water, unexpected sexual encounters and hospitalizations, and invasive cosmetic practices can expose business travelers to hepatitis viruses. Many business travelers remain unaware of the risks of infection or do not follow recommendations to avoid risky behavior. This is compounded by a lack of universal adult vaccination against HAV and HBV, confusing risky behavior-based vaccination recommendations, and a lack of consistency in corporate immunization policies. In addition, many travelers do not anticipate situations that would put them at increased risk for infection (eg, hospitalization or unprotected casual sex).
Hepatitis A and B place a burden on infected individuals, both clinically and financially. Financial impact results in reduced work productivity, early termination of business trips, lost wages, increased health care costs from acute or chronic hepatitis infections, and altered interpersonal interactions from sickness. The impact can affect the infected individual's employer, health care community, and family. Education and vaccination programs for all nonimmune travelers should be adopted by employers who send their employees to HAV and HBV endemic areas. Doing so could prevent employer-incurred costs associated with infections acquired abroad and may prevent additional costs related to transmission of HAV or HBV to coworkers, family members, or sexual partners.
Business travelers must be better educated about their risks of contracting HAV and HBV. For those visiting high endemic areas, the risk of infection increases with the length of stay. To this end, employee programs aimed at educating business travelers about their risk of acquiring travel-related infections would be beneficial. There are no approved vaccines for other diseases with modes of transmission similar to HBV, including the hepatitis C virus and HIV. Vaccination against HAV and HBV is more cost-effective than treating the resulting illness; therefore, corporations with international travelers to endemic areas should be vaccinating all travelers for both HAV and HBV. Universal HAV and HBV vaccination was recommended in children and infants in 2005 and 1991, respectively. Immunity to hepatitis A and B will begin to be assumed in those entering the workforce in approximately 15 and 6 years, respectively. However, expanding recommendations to include adolescents and at risk groups will make it increasingly necessary for corporate physicians to inquire about prior vaccination of employees against both viruses before these individuals enter the workforce.
Many travelers are unaware of modes of HAV and HBV transmission and do not seek pretravel advice from health care professionals. Successful corporate health programs can prevent HAV and HBV infection with vaccination. HAV vaccination has been attributed to a 35.0% to 61.8% reduction of HAV in international Swiss travelers, depending on the destination, between 2000 and 2004.20 Comprehensive vaccination regimens should be integrated into employer-sponsored health maintenance plans for groups at risk for HAV or HBV infection under preventative care. Family physicians will remain the primary source of pretravel health recommendations for many patients who do not have employer-sponsored plans; family physicians must continue to inform and educate patients about the health risks associated with HAV and HBV when traveling abroad.
2. Hepatitis A. In: Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 10th ed. Centers for Disease Control and Prevention. Washington, DC: Public Health Foundation; 2007.
3. Wasley A, Miller JT, Finelli L. Surveillance for acute viral hepatitis–United States, 2005. MMWR Surveill Summ. 2007;56:1–24.
4. The Centers for Disease Control and Prevention. Disease Burden From Hepatitis A, B, and C in the United States. Viral Hepatitis Surveillance. Washington, DC: The Centers for Disease Control and Prevention; 2006.
5. Leung TW, Vrbova L. Descriptive analysis of endemic and travel hepatitis A cases in Ontario, 1998 to 2004. Can Commun Dis Rep. 2006;32:287–296.
6. Hepatitis B. In: Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 10th ed. Centers for Disease Control and Prevention. Washington, DC: Public Health Foundation; 2007.
7. Koff RS. Hepatitis A. Lancet. 1998;351:1643–1649.
8. Centers for Disease Control and Prevention. Prevention and control of infections with hepatitis viruses in correctional settings. MMWR Recomm Rep. 2003;52: 1–36.
9. Mahoney FJ. Update on diagnosis, management, and prevention of hepatitis B virus infection. Clin Microbiol Rev. 1999;12:351–366.
10. Berge JJ, Drennan DP, Jacobs RJ, et al. The cost of hepatitis A infections in American adolescents and adults in 1997. Hepatology. 2000;31:469–473.
11. Bownds L, Lindekugel R, Stepak P. Economic impact of a hepatitis A epidemic in a mid-sized urban community: the case of Spokane, Washington. J Community Health. 2003;28:233–246.
12. Sansom SL, Cotter SM, Smith F, et al. Costs of a hepatitis A outbreak affecting homosexual men: Franklin County, Ohio, 1999. Am J Prev Med. 2003;25:343–346.
13. The Centers for Disease Control and Prevention. Viral Hepatitis B Fact Sheet. Washington, DC: The Centers for Disease Control and Prevention; 2006.
14. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–750.
15. Metcalf M, Brown N, Peterson S, et al. Health care costs associated with chronic hepatitis B. Am J Health Syst Pharm. 1999;56:232–236.
16. Lee TA, Veenstra DL, Iloeje UH, Sullivan SD. Cost of chronic hepatitis B infection in the United States. J Clin Gastroenterol. 2004;38:S144–S147.
17. Bunn W. Vaccine and international health programs for employees traveling and living abroad. J Travel Med. 2001;8(suppl 1):S20–S23.
18. Provost S, Gagnon S, Lonergan G, Bui YG, Labbe AC. Hepatitis A, typhoid and malaria among travelers—surveillance data from Quebec (Canada). J Travel Med. 2006;13:219–226.
19. Bell BP, Shapiro CN, Alter MJ, et al. The diverse patterns of hepatitis A epidemiology in the United States-implications for vaccination strategies. J Infect Dis. 1998;178:1579–1584.
20. Mutsch M, Spicher VM, Gut C, Steffen R. Hepatitis A virus infections in travelers, 1988–2004. Clin Infect Dis. 2006;42:490–497.
21. Steffen R, Connor BA. Vaccines in travel health: from risk assessment to priorities. J Travel Med. 2005;12:26–35.
22. Howitz M, Mazick A, Molbak K. Hepatitis A outbreak in a group of Danish tourists returning from Turkey, October 2005. Euro Surveill. 2005;10:E051201–E051202.
23. Correia JD, Shafer RT, Patel V, et al. Blood and body fluid exposure as a health risk for international travelers. J Travel Med. 2001;8:263–266.
24. de Nishioka SA, Gyorkos TW, Joseph L, Collet JP, MacLean JD. Tattooing and transfusion-transmitted diseases in Brazil: a hospital-based cross-sectional matched study. Eur J Epidemiol. 2003;18:441–449.
25. de Nishioka S, Gyorkos TW, Joseph L, Collet JP, Maclean JD. Tattooing and risk for transfusion-transmitted diseases: the role of the type, number and design of the tattoos, and the conditions in which they were performed. Epidemiol Infect. 2002;128:63–71.
26. Connor BA, Jacobs RJ, Meyerhoff AS. Hepatitis B risks and immunization coverage among American travelers. J Travel Med. 2006;13:273–280.
27. Zuckerman JN, Steffen R. Risks of hepatitis B in travelers as compared to immunization status. J Travel Med. 2000;7:170–174.
28. Steffen R. Risks of hepatitis B for travellers. Vaccine. 1990;8(suppl):S31–S32; discussion S41–S33.
29. Steffen R, Rickenbach M, Wilhelm U, Helminger A, Schar M. Health problems after travel to developing countries. J Infect Dis. 1987;156:84–91.
30. Nothdurft HD, Dahlgren AL, Gallagher EA, et al. The risk of acquiring hepatitis A and B among travelers in selected Eastern and Southern Europe and non-European Mediterranean countries: review and consensus statement on hepatitis A and B vaccination. J Travel Med. 2007;14:181–187.
31. Hutin YJ, Harpaz R, Drobeniuc J, et al. Injections given in healthcare settings as a major source of acute hepatitis B in Moldova. Int J Epidemiol. 1999;28:782–786.
32. Hill DR. Health Problems in a Large Cohort of Americans Traveling to Developing Countries. J Travel Med. 2000;7:259–266.
33. Samandari T, Malakmadze N, Balter S, et al. A large outbreak of hepatitis B virus infections associated with frequent injections at a physician's office. Infect Control Hosp Epidemiol. 2005;26:745–750.
34. Hauri AM, Armstrong GL, Hutin YJ. The global burden of disease attributable to contaminated injections given in health care settings. Int J STD AIDS. 2004;15:7–16.
35. Hutin YJ, Hauri AM, Armstrong GL. Use of injections in healthcare settings worldwide, 2000: literature review and regional estimates. BMJ. 2003;327:1075.
36. Kane A, Lloyd J, Zaffran M, Simonsen L, Kane M. Transmission of hepatitis B, hepatitis C and human immunodeficiency viruses through unsafe injections in the developing world: model-based regional estimates. Bull World Health Organ. 1999;77:801–807.
37. Simonsen L, Kane A, Lloyd J, Zaffran M, Kane M. Unsafe injections in the developing world and transmission of bloodborne pathogens: a review. Bull World Health Organ. 1999;77:789–800.
38. The World Health Organization. Chapter 4. Injuries and violence. In: International Health and Travel. Geneva, Switzerland: The World Health Organization; 2007.
39. Goodyer L, Gibbs J. Medical supplies for travelers to developing countries. J Travel Med. 2004;11:208–211.
40. Rogers HL, Reilly SM. A survey of the health experiences of international business travelers. Part one—physiological aspects. Aaohn J. 2002;50:449–459.
41. Hamer DH, Connor BA. Travel health knowledge, attitudes and practices among United States travelers. J Travel Med. 2004;11:23–26.
42. Van Herck K, Van Damme P, Castelli F, et al. Knowledge, attitudes and practices in travel-related infectious diseases: the European airport survey. J Travel Med. 2004;11:3–8.
43. Wilder-Smith A, Khairullah NS, Song JH, Chen CY, Torresi J. Travel health knowledge, attitudes and practices among Australasian travelers. J Travel Med. 2004;11:9–15.
44. Provost S, Soto JC. Perception and knowledge about some infectious diseases among travelers from Quebec, Canada. J Travel Med. 2002;9:184–189.
45. Van Herck K, Zuckerman J, Castelli F, Van Damme P, Walker E, Steffen R. Travelers' knowledge, attitudes, and practices on prevention of infectious diseases: results from a pilot study. J Travel Med. 2003;10:75–78.
46. Mulhall BP. Sex and travel: studies of sexual behaviour, disease and health promotion in international travellers—a global review. Int J STD AIDS. 1996;7:455–465.
47. Cabada MM, Echevarria JI, Seas CR, et al. Sexual behavior of international travelers visiting Peru. Sex Transm Dis. 2002;29:510–513.
48. Cabada MM, Montoya M, Echevarria JI, Verdonck K, Seas C, Gotuzzo E. Sexual behavior in travelers visiting Cuzco. J Travel Med. 2003;10:214–218.
49. Carter S, Horn K, Hart G, Dunbar M, Scoular A, MacIntyre S. The sexual behaviour of international travellers at two Glasgow GUM clinics. Glasgow genitourinary medicine. Int J STD AIDS. 1997;8:336–338.
50. Hawkes S, Hart GJ, Johnson AM, et al. Risk behaviour and HIV prevalence in international travellers. AIDS. 1994;8:247–252.
51. Hamlyn E, Peer A, Easterbrook P. Sexual health and HIV in travellers and expatriates. Occup Med (Lond). 2007;57:313–321.
52. Blair DC. A week in the life of a travel clinic. Clin Microbiol Rev. 1997;10:650–673.
53. Havrix. Prescribing Information. Rixensart, Belgium: GlaxoSmithKline; 2005.
54. Vaqta. Prescribing Information. Whitehouse Station, NJ: Merck and Company Inc.; 2006.
55. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1999;48:1–37.
56. The World Health Organization. Chapter 6. Vaccine-preventable diseases, vaccines and vaccination. In: International Travel and Health. Geneva, Switzerland: The World Health Organization; 2007.
57. Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-7):1–23.
58. Hepatitis A and hepatitis A/B vaccines. In: Thompson RF, ed. Travel and Routine Immunizations. Milwaukee, WI: Shoreland; 2007.
59. Connor BA, Van Herck K, Van Damme P. Rapid protection and vaccination against hepatitis A for travellers. BioDrugs. 2003;17(suppl 1):19–21.
60. Kohl I, Nemecek V, Summerova M, Chlibek R, Nad'ova K, Minarikova O. Long-term protective effect of post-exposure Havrix administration during viral hepatitis Type A outbreaks. Eur J Epidemiol. 2006;21:893–899.
61. Werzberger A, Mensch B, Kuter B, et al. A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. N Engl J Med. 1992;327:453–457.
62. Werzberger A, Kuter B, Nalin D. Six years' follow-up after hepatitis A vaccination. N Engl J Med. 1998;338:1160.
63. Werzberger A, Mensch B, Nalin DR, Kuter BJ. Effectiveness of hepatitis A vaccine in a former frequently affected community: 9 years' follow-up after the Monroe field trial of VAQTA. Vaccine. 2002;20:1699–1701.
65. Hepatitis B and Hepatitis B combination vaccines. In: Thompson RF, ed. Travel and Routine Immunizations. Milwaukee, WI: Shoreland; 2007.
66. Engerix-B. Prescribing Information. Rixensart, Belgium: GlaxoSmithKline; 2005.
67. Recombivax HB. Prescribing Information. Whitehouse Station, NJ: Merck and Company Inc.; 2006.
68. Loscher T, Keystone JS, Steffen R. Vaccination of travelers against hepatitis A and B. J Travel Med. 1999;6:107–114.
69. Twinrix. Prescribing Information. Rixensart, Belgium: GlaxoSmithKline; 2007.
70. Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR-16):1–33; quiz CE1–4.
71. Joines RW, Blatter M, Abraham B, et al. A prospective, randomized, comparative US trial of a combination hepatitis A and B vaccine (Twinrix) with corresponding monovalent vaccines (Havrix and Engerix-B) in adults. Vaccine. 2001;19:4710–4719.
72. Connor BA, Blatter MM, Beran J, Zou B, Trofa AF. Rapid and sustained immune response against hepatitis A and B achieved with combined vaccine using an accelerated administration schedule. J Travel Med. 2007;14:9–15.
73. Nothdurft HD, Dietrich M, Zuckerman JN, Knobloch J, Kern P, Sanger R. Rapid protection against hepatitis A and B using an accelerated vaccination schedule: comparison of combined vaccine, Twinrix, with separate vaccines. BioDrugs. 2003;17(suppl 1):15–18.
74. Jacobs RJ, Meyerhoff AS, Zink T. Hepatitis A immunization strategies: universal versus targeted approaches. Clin Pediatr (Phila). 2005;44:705–709.
This article has been cited 1 time(s).
Expert Review of VaccinesBusiness travelers: vaccination considerations for this populationExpert Review of Vaccines
©2008The American College of Occupational and Environmental Medicine
- Articles in PubMed by William B. Bunn, III, MD, JD, MPH
- This article in PubMed
- Articles in Google Scholar by William B. Bunn, III, MD, JD, MPH
- Other articles in this journal by William B. Bunn, III, MD, JD, MPH