Hepatitis B and C virus (HBV and HCV) cause significant morbidity and mortality worldwide. With the rise in international travel over the last three decades, many travelers are at risk of HBV and HCV infection.
Hepatitis B and C virus (HBV and HCV) cause significant morbidity and mortality worldwide. With the rise in international travel over the last three decades, many travelers are at risk of HBV and HCV infection.
This review focuses on the epidemiology of HBV and HCV in international travelers, the modes of transmission, and the prevention of infection in travelers.
The risk of HBV and HCV infection varies widely and depends on the prevalence of the destination country, the duration of travel, and the activities undertaken while abroad. Travelers commonly undertake high-risk activities that place them at risk of both HBV and HCV infection. Poor uptake of preventative health measures and poor adherence to health recommendations are also common. The monthly incidence of HBV infection for long-term travelers to endemic countries ranges from 25 to 420 per 100,000 travelers. HBV infection can be prevented through timely vaccination of travelers. HBV vaccination is safe and efficacious with protective levels of antibodies achieved in >90% of recipients. Information regarding the risk of HCV acquisition is scarce and until recently was limited to case reports following medical interventions.
This review demonstrates international travelers are at risk of HBV and HCV infection and provides evidence-based information enabling health practitioners to provide more appropriate pre-travel advice. HBV vaccination should be considered in all travelers to countries with a moderate to high HBV prevalence (HBsAg ≥ 2%) and the risk and benefits discussed with the individuals in consultation with the health practitioner. There is no duration of travel without risk of HBV infection. However, it is apparent that those travelers with a longer duration of travel are at greatest risk of HBV infection (ie, expatriates). Travelers should also receive advice regarding the modes of transmission and the activities that place them at risk of both HBV and HCV infection.
Over the last three decades, the number of international travelers has risen dramatically. In 2011, the number of international tourist arrivals was 983 million worldwide up from 799 million arrivals in 2005 and 435 million arrivals in 1990. Worldwide, an estimated 350 to 400 million people are living with chronic hepatitis B virus (HBV) infection and 170 million with chronic hepatitis C virus (HCV) infection, placing a large number of travelers at risk of both HBV and HCV infection.
While the incidence of HBV infection in long-term travelers (expatriates) has been reasonably well described, there is minimal information available to guide health practitioners on the risks of HBV infection among short-term travelers or of travel-associated HCV infection. This review focuses on the epidemiology of HBV and HCV in international travelers, the modes of transmission, and the prevention strategies. Evidence-based information is crucial to facilitate informed decision making and support health practitioners in providing more appropriate pre-travel advice.
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.
|Country||Year universal hepatitis B vaccination of children implemented|
|United Kingdom||Targeted vaccination to high-risk groups|
|United States of America||1991|
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]
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.
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%).
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.
Twinrix (GlaxoSmithKline) contains inactivated HAV and recombinant HBsAg. The immunogenicity of the combination vaccine is at least as good as the monovalent vaccines[54, 55] and is particularly useful as many travelers also require hepatitis A vaccination. Ambrix (inactivated HAV and recombinant HBsAg) is licensed in Europe as a two-dose schedule in children aged 1 to 15 years.
HCV is a member of the Hepacivirus genus within the Flaviviridae family.[57-59] It is estimated that 3% of the world's population is chronically infected. The prevalence is estimated to be 3.2% in China, 4.8% in Pakistan, and up to 15% in parts of Asia and Africa. The highest prevalence of HCV is in Egypt (15%–22% of the population)[61-64] (Figure 2).
HCV transmission generally results from parenteral exposure to contaminated blood via injecting drug use (IDU), blood transfusions, unsafe injections, medical procedures, body piercing, or tattooing. It may also occur via perinatal transmission. Sexual transmission of HCV has been described among HIV-positive men who have sex with men, and is associated with high-risk sexual behaviors.[58, 65, 66] In approximately 20% of people no cause of infection can be established. The risk of occupational transmission of HCV needlestick injuries is around 0.3%. Perinatal transmission from HCV-infected mothers occurs in 2.7% to 8.4% of births.
The widespread practice of paid donor blood and poor screening has led to high HCV transmission rates in the developing world. Screening for HCV in blood and blood products is not universal in many developing countries: the WHO estimates that 43% of donated blood in the developing world is inadequately screened. The frequency of reuse of injection equipment without sterilization also varies, with highest rates in Southeast Asia and the Middle East (1.2%–75%). Unsafe injecting practices in developing countries such as Egypt, India, and Pakistan led to the formation of the Safe Injection Global Network (SIGN).[67, 69] The SIGN was established in 1999 and aims to achieve safe and appropriate use of injections worldwide. The WHO through collaborations with national regulatory authorities has focused on formulating national policies for: the safe and appropriate use of injections, the quality and safety of injection devices (in particular, single-use injection devices and auto-disable syringes), facilitating access to injection equipment, and achieving cost-effective use of injections. Intervention strategies targeting these core components simultaneously have improved vaccine injection safety.[67, 69]
Acute HCV infection is usually asymptomatic and unrecognized, with <1% of HCV-positive individuals reporting an acute illness associated with jaundice. Following infection, HCV RNA begins to replicate in the human liver and is detectable in the serum within 1 to 3 weeks.
Between 15 and 50% of acute infections resolve spontaneously over 6 to 12 months resulting in 50% to 85% of individuals becoming chronically infected. Chronic infection is characterized by a prolonged asymptomatic phase. The development of hepatic fibrosis may lead to cirrhosis, end-stage liver disease (eg, ascites, hepatic encephalopathy, and esophageal varices), and HCC.
The risk of contracting HCV in travelers is thought to be low but there is a paucity of data regarding travel-associated HCV acquisition. However, in a retrospective cohort study of 361 Australian travelers to Asia, we have provided the first estimate of the incidence of HCV infection in travelers: two travelers were found to have evidence of acute seroconversion, representing an incidence density of 1.8 infections per 10,000 travel days (95% CI: 0.22–6.53).
Parenteral exposure accounts for the majority of HCV infections in highly endemic countries. Travelers often undertake activities that place them at risk of acquiring HCV infection,[24, 36] including IDU or tattooing. The magnitude of the risk will depend on the prevalence of HCV in the destination country. The prevalence of HCV antibodies in a study of 515 Danish merchant seamen who traveled was found to be 1.2% (6 of 515). In this study, five of the seamen had tattoos and one had undergone an operation abroad. In contrast, in a study of 328 American missionaries with prolonged stays in tropical and subtropical countries, the incidence of HCV was low (0.6%).
IDU travelers appear to have higher rates of needle sharing than nontravelers.[74, 75] In a recent study within the United States, IDU travelers compared with nontravelers were more likely to be HCV positive. Travel was associated with greater sharing of needles, syringes, and drug preparation equipment as well as pooling money to buy drugs, heavy alcohol consumption, polysubstance use, and more sexual and injecting partners.
A number of case reports highlight the potential for HCV acquisition in travelers when medical care is accessed overseas. Acute HCV infection has been reported in travelers who received emergency medical care in India and Pakistan,[77, 78] and a prospective surveillance study of 131 patients traveling outside the UK identified 4 cases of HCV infection in patients who received hemodialysis in either Pakistan, Slovakia, Singapore, or Bangladesh. Separate studies identified patients from hemodialysis units in the UK and Canada who acquired HCV infection from hemodialysis in Asia and India.[80, 81]
Currently, there is no vaccine available for HCV infection and immune globulin does not provide protection. Prospective travelers need to be advised about the modes of transmission and avoidance of activities associated with parenteral exposure to contaminated blood.
Travelers who acquire HBV or HCV infections are at risk of significant morbidity and mortality and are a potential source of infection to the wider community upon return from abroad. The incremental risk of these blood-borne viruses during travel is difficult to accurately ascertain, but risk-taking behaviors such as excessive alcohol, drug use, and new sexual contacts are reportedly more common during travel. Given the efficacy of HBV vaccines, vaccination in travelers to regions with a moderate to high prevalence of HBV should be considered. Although it is clear that travelers are at risk of HCV infection, the incidence of HCV infection in travelers needs to be characterized further. Unfortunately, no vaccine exists to prevent HCV infection, so prevention relies on education and behavioral modification to avoid high-risk activities.
A challenge for health practitioners is that many travelers have poor knowledge and perception of the risk of infections while traveling, poor uptake of preventative health measures including vaccines, and poor rates of adherence to health recommendations. Raising awareness about HBV and HCV infection and improving access to pre-travel advice are critical to help prevent acquisition of these viral infections in travelers, particularly in the current era of increasing medical tourism.
The authors state that they have no conflicts of interest.