HBV is part of the Hepadnaviridae family in the genus Orthohepadnavirus. It is the leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide resulting in 500,000 to 1.2 million deaths per year.[2, 3]
The prevalence of HBV infection varies widely, so the risk of HBV infection to travelers will alter depending on destination. There are areas of low prevalence (0.1%–2%) including Australia, the United States, Canada, and Western Europe; areas of intermediate prevalence (2%–7% HBsAg+ve) in parts of central Asia, Central and South America, and Eastern Europe; and areas of high prevalence (≥8% HBsAg+ve) in China, Africa, and countries within the Middle East and Southeast Asia (Figure 1).[4, 5] It is estimated that 88% of the world's population live in intermediate- to high-prevalence countries and >2 billion people have been infected worldwide.
The global prevalence of HBV infection and the risk to travelers are likely to decrease as universal vaccination of infants is progressively introduced[7, 8] (Table 1). The estimated global coverage rate of HBV vaccination in infants has increased from <1% in 1990 to 69% in 2008. For example, in Taiwan, 18 years after universal HBV vaccination of children began, the prevalence of chronic HBV infection (HBsAg+ve) in university students has decreased from 14.5% to 1.9%.[6, 10] However, some low-prevalence countries (eg, UK) have not implemented a universal vaccination policy. Thus, many adult travelers born before the implementation of childhood immunization programs (or from countries where such programs do not exist) remain susceptible to HBV infection.
Modes of Transmission of HBV
Transmission of HBV is through percutaneous or mucosal exposure to HBV-infected blood or bodily fluids including saliva or semen. It may also occur from mother to infant (perinatal), between children (horizontal), via sexual contact, contaminated blood products, contaminated medical equipment, and via sharing needles and injecting apparatus.[13, 14]
Clinical Features of HBV
The incubation period for HBV may be up to 180 days. Acute HBV infection results in symptomatic illness in approximately 30% to 80% of adults (1% fulminant hepatitis), whereas children under 1 year are usually asymptomatic. Symptoms include malaise, fever, jaundice, dark urine, pale stools, right upper quadrant pain, anorexia, and nausea.
The risk of chronic disease after HBV infection depends on the age of acquisition. About 90% of infected neonates, 30% to 50% of children aged 1 to 4 years, and 1% to 10% of acutely infected adults develop persistent infection.[14, 15] Approximately 15% to 40% with persistent infection develop advanced liver disease, cirrhosis, and/or HCC.
Epidemiology of HBV in Travelers
Apart from hepatitis A and influenza, HBV infection is among the commonest vaccine-preventable infections in travelers.[16-18] HBV acquisition during travel is associated with travel duration, the immune status of the traveler, and the prevalence of HBV in the destination country. Additionally, specific populations of travelers may be at greater risk including expatriates, those visiting friends and relatives, and travelers engaging in casual sex, dental surgery, and medical procedures.[16, 19-23] Emerging data suggest that travelers seeking urgent, unforeseen medical or dental care are common, which places travelers at risk of HBV infection. The unpredictable nature of emergency care makes it difficult to target advice according to traveler characteristics. While there is little evidence to quantify the risk, travelers may also be exposed to HBV via activities including tattoos, piercings, and acupuncture.
HBV infection has been associated with travel. Nine percent of all HBV cases reported in the Netherlands between 1992 and 2003 were travel-related with an estimated incidence of HBV infection of 4.5 per 100,000 travelers. Fifty-one cases of HBV infection were identified from a cohort of ill travelers presenting to GeoSentinel clinics between 1997 and 2007, with HBV acquisition independently associated with older age and male sex (41 of 51 cases), possibly reflecting risk-taking behavior including unsafe sex while abroad. However, given the long incubation period, we were unable to exclude acquisition of acute HBV infection cases prior to travel. Studies of travelers have demonstrated that new sexual partners and unprotected intercourse are relatively common,[24, 26] particularly in the setting of excessive alcohol intake.
Prolonged duration of travel is associated with an increased likelihood of HBV infection. In susceptible expatriates residing in countries of high HBV endemicity, the estimated monthly incidence of HBV infection ranges from 25 per 100,000 for symptomatic infections to 80 to 420 per 100,000 for all HBV infections. Volunteers, aid workers, and missionaries are at increased risk of HBV infection as a result of extended travel and close contact with the local population. A study of North American missionaries between 1967 and 1984 with prolonged periods abroad (average 7.3 years) in tropical and subtropical regions identified anti-HB core (anti-HBc) antibody seroconversion in 5.5% of study subjects. A study of Swedish expatriates demonstrated that the prevalence of anti-HBc antibody was 5%, double that of the general population. A Japanese study identified 72 cases of acute HBV infection (0.68%) in 10,509 Japanese volunteers traveling to tropical and subtropical countries between 1978 and 1993. The incidence of HBV infection dropped dramatically following the introduction of vaccination in conjunction with providing education on the risk factors for HBV infection to the volunteers prior to travel.
The precise risk for short-term travelers is not known but is estimated to be significantly lower.[16, 17, 30, 31] A study of Danish travelers demonstrated that the monthly incidence of HBV infection was 10.2 per 100,000 with 62% of cases traveling for <4 weeks. Many studies rely on travelers becoming unwell following travel in order for testing to occur so will underestimate the incidence of HBV infection.
We recently reported the incidence of HBV and HCV infection in a retrospective cohort study of 361 Australian travelers to Asia. This cohort was composed of predominantly short-term travelers with a median travel duration of 21 days (range 7–326), 74% of whom traveled for <30 days. Fifty-six percent of the travelers (202 of 361) were HBV immune [anti-HB surface (anti-HBs) antibody ≥ 10 mIU/mL], with the majority (106 of 202) having anti-HBs antibody titers between 10 and 200 mIU/mL. Analysis of pre- and post-travel sera demonstrated HBV seroconversion in a male traveler to China, representing an incidence density of new HBV infections in nonimmune travelers of 2.19 per 10,000 travel days (95% CI: 0.07–12.19). Of note, 59% of HBV nonimmune travelers attended a pre-travel clinic at least 21 days prior to departure to Asia. This would have provided sufficient time for HBV vaccination (accelerated schedule) and indicates a missed opportunity for vaccination.
A number of studies have identified that travelers have low baseline knowledge of travel-related infections and place themselves at risk of HBV infection through their actions while abroad.[20, 34-36] A Danish study of >11,000 travelers identified that 5% of nonimmune and 5% of short-term travelers were placed at high risk of HBV acquisition through activities such as injections, operations, or tattoos. The percentage of high-risk activities increased to 41% for those traveling for >6 months. Most of the risk behaviors were involuntary or unanticipated. In a retrospective study of 503 Australian travelers, 281 (56%) had visited a country with medium to high prevalence of hepatitis B, of whom only 43% had been vaccinated and 162 (33%) undertook activities associated with potential HBV exposure. Another survey of 309 Australian travelers to Southeast Asia and East Asia identified that 54% sought pre-travel advice, 28% received HBV vaccine, and 49% undertook a high-risk activity.
Medical Tourism is a burgeoning industry estimated to be worth $60 billion in 2006. Organ transplantation and medical tourism have repeatedly been identified as risk factors for both HBV and HCV infection,[38, 39] highlighting that screening for transmissible infections cannot universally be assured. Kennedy and colleagues reported that 2 of 16 Australian patients who traveled overseas for commercial kidney transplantation developed fulminant hepatitis related to HBV infection and died. Among a cohort of Saudi patients receiving renal transplants in India, there was a significantly higher incidence of HBV infection compared with a similar cohort transplanted in Saudi Arabia (8.1% vs 1.4%).
Prevention of Hepatitis B in Travelers
Travelers should be given information regarding the modes of HBV transmission and the likelihood of infection with high-risk activities. Many national health authorities as well as the WHO recommend that HBV vaccination should be considered in nonimmune travelers to countries with a moderate to high HBV prevalence (HBsAg ≥ 2%).[14, 43, 44] Vaccination with a three-dose regimen is safe and effective with protective levels of neutralizing antibodies (anti-HBs antibody ≥ 10 mIU/mL) achieved in >90% of healthy adults and children.[4, 14]
Vaccination should be discussed with all nonimmune travelers as activities associated with HBV acquisition are often unexpected. Although the risks of exposure are likely to increase with longer travel duration, offering HBV vaccine cannot depend solely on a minimum trip duration, especially as HBV vaccine provides prolonged protection so cumulative risk from repeated trips also needs to be considered.
Allowing sufficient time for pre-travel vaccination is crucial. The standard three-dose regimen is administered at 0, 1, and 6 months. An accelerated schedule administered on days 0, 7, and 21 (booster at 12 months) is recommended for rapid protection. Two doses of the adult formulation at 0 and 4 to 6 months are safe and efficacious in adolescents (aged 11–15 years).
Recommendations for serologic testing of immunity to hepatitis B vaccination vary between countries. In Australia, serological testing is not performed after routine vaccination of adults (including travelers). However, anti-HBs antibody levels should be performed 1 to 2 months after vaccination in health-care workers, patients on hemodialysis, and individuals at risk of recurrent exposure to HBV. There is no universal agreement on how to manage nonresponders to HBV vaccination. However, the Australian Immunization Guidelines suggest offering nonresponders either a fourth double dose or another three-dose vaccine series. Persistent nonresponders should be counseled to minimize exposure and offered immunoglobulin within 72 hours if significant HBV exposure occurs.
Anti-HBs antibody levels decrease over time following a primary immunization course; however, the need for HBV boosting is controversial. The duration of protection has been estimated to be at least 15 years[46-48] and even if titers of anti-HBs fall to <10 mIU/mL, a booster dose is likely to be unnecessary because of an effective amnesic response. In the United States, HBV boosting is not recommended for otherwise healthy individuals, whereas some European countries (including the UK) recommend it. The European Consensus Group on hepatitis B immunity and a recent review by Van Damme and Van Herck concluded that there was no evidence to recommend HBV boosting in healthy individuals including travelers.[50, 51] This issue will have increasing practical relevance as cohorts immunized as infants become adult travelers.
Plasma-derived and recombinant forms of HBV vaccine are comparable in terms of efficacy and durability. Plasma-derived vaccines are prepared by concentrating and purifying plasma from HBsAg carriers and are used in developing countries. Concerns regarding the potential of plasma-derived products to transmit infections have led to the widespread use of recombinant HBV vaccines in Europe, the United States, and Australia.
Recombinant HBsAg is produced by cloning the HBV S gene in either yeast or mammalian cells. In the United States, two thimerosal free vaccines that express HBsAg [Engerix-B (GlaxoSmithKline, Brentford, UK) and Recombivax-HB (Merck, Rixensart, Belgium)] have been licensed. Engerix-B contains 20 µg of recombinant HBsAg adsorbed onto 0.5 mg of aluminum hydroxide. Recombivax-HB contains 10 µg of recombinant HBsAg protein adsorbed onto 0.5 mg of aluminum hydroxyphosphate sulfate. Recombivax-HB is available in Europe as HBVAXPRO.
In Europe, a recombinant HBsAg vaccine adjuvanted with ASO4 [Fendrix (GlaxoSmithKline)] is licensed for use in adolescents and adults with renal insufficiency. ASO4 is a novel adjuvant that contains aluminum hydroxide and monophosphoryl lipid A. The primary immunization schedule of recombinant HBsAg vaccine adjuvanted with ASO4 is four doses given at 0, 1, 2, and 6 months.