Large numbers of Europeans travel frequently to

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1 181 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 Hans Dieter Nothdurft, MD, * Atti-La Dahlgren, MD, Elizabeth A. Gallagher, MD, Herwig Kollaritsch, MD, David Overbosch, MD, Maija-Liisa Rummukainen, MD, Pamela Rendi-Wagner, MD, Robert Steffen, MD, and Pierre Van Damme, MD, # ad hoc Travel Medicine Expert Panel for ESENEM * Department of Infectious Diseases and Tropical Medicine, University of Munich, Munich, Germany ; WHO Collaborating Centre for Travellers Health, Institute for Social and Preventive Medicine, University of Zürich, Zürich, Switzerland ; Travel Health Centre, Department of International Health and Tropical Medicine, Royal College of Surgeons in Ireland, Dublin, Republic of Ireland ; Institute for Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Vienna, Austria ; Travel Clinic Havenziekenhuis, Rotterdam, The Netherlands ; Jyväskylä Central Hospital, Jyväskylä, Finland ; # Centre for the Evaluation of Vaccination, WHO Collaborating Centre for Control and Prevention of Viral Hepatitis, Unit of Epidemiology and Social Medicine, University of Antwerp, Antwerp, Belgium DOI: /j x Large numbers of Europeans travel frequently to destinations both near and far, and there is a growing trend toward shorter but more frequent trips. 1 Traditional destinations for European (EU) travelers, such as France, Italy, and Spain, have shown only limited tourism growth in recent years, with these countries experiencing growth of 2.4, 0.6, and 3.3%, respectively, in 2000 to Many more Europeans now visit non-eu Mediterranean destinations, for example, Morocco, Egypt, and Turkey (which experienced growth of 17, 49, and 29%, respectively, in 2004), and newly emerging travel destinations in Eastern and Southern Europe, Eastern and Southern Europe and non-european Mediterranean (ESENEM) countries: Albania, Baltic States (Estonia, Latvia, Lithuania), Bosnia Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Egypt, FYROM (Former Yugoslav Republic of Macedonia), Greece, Hungary, Israel, Italy, Jordan, Kosovo, Lebanon, Libya, Malta, Morocco, Poland, Romania, Russia and the CIS, Serbia and Montenegro, Slovakia, Slovenia, Spain, Syria, Tunisia, Turkey, and Ukraine. Corresponding Author: Hans Dieter Nothdurft, MD, Department of Infectious Diseases and Tropical Medicine, University of Munich, Leopoldstr. 5, D Muenchen, Germany. hd.nothdurft@t-online.de Guest Editor : Herbert L. DuPont, MD for example, Croatia (which experienced growth of 6% in 2004). 2 Importantly, travel to such destinations is not generally perceived as a potential health risk 3 in the same way as travel to more exotic destinations (eg, Thailand, Mexico). Many Europeans traveling to Turkey or to North Africa, for example, do not consider themselves to be at major risk of infection with the hepatitis A virus (HAV) or hepatitis B virus (HBV). 4,5 There is a need to ensure that international vaccination recommendations reflect these changing travel trends and address uncertainties about the risk of HAV and HBV, particularly in newer travel destinations. Furthermore, the development and adoption of standardized HAV vaccination statements is an important public health issue. In January 2005, a panel of EU travel medicine, public health, and epidemiology experts met in Vienna, Austria. The aim of the meeting was to provide a responsible assessment of currently available data regarding HAV and HBV epidemiology and vaccination recommendations for nonimmune travelers visiting specific Eastern and Southern Europe and non-eu Mediterranean (ESENEM) destinations. Countries considered by the panel were Albania, Baltic States (Estonia, Latvia, Lithuania), Bosnia Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Egypt, Former 2007 International Society of Travel Medicine, Journal of Travel Medicine, Volume 14, Issue 3, 2007,

2 182 Yugoslav Republic of Macedonia (FYROM), Greece, Hungary, Israel, Italy, Jordan, Kosovo, Lebanon, Libya, Malta, Morocco, Poland, Romania, Russia and the CIS, Serbia and Montenegro, Slovakia, Slovenia, Spain, Syria, Tunisia, Turkey, and Ukraine. This paper presents the findings of the expert panel and offers a consensus agreement for the recommendation of HAV and HBV vaccinations for travelers to the countries concerned. Data Sources The panel reviewed current epidemiological data, outbreak reports, and surveillance figures of imported infections with HAV and HBV (these data were largely sourced from the EU project EUROHEP.NET 6 and the World Health Organization (WHO) Regional Office for Europe). 7 Current travel immunization recommendations for selected countries that is, Austria, Belgium, Finland, Germany, The Netherlands, Ireland, and Sweden were also discussed. HAV in EU Travelers HAV infection remains the most common vaccinepreventable disease among travelers. 8,9 There has been a lack of reliable data on the incidence of HAV in travelers, with existing studies showing conflicting results Teitelbaum 13 in particular showed that the risk of acquiring HAV while traveling in certain countries is more than an order of magnitude lower than some previous estimates. However, recent research in Swiss and Swedish travelers has highlighted the continued prominence of imported HAV among returning EU travelers. In Switzerland, from 1988 to 2002, 2,565 (35%) cases of HAV from a total of 7,300 reported cases were imported into the country. 14 Many of the imported HAV cases were from destinations for which HAV vaccination is not currently recommended, particularly former Yugoslavia ( n = 226), Italy ( n = 164), Spain ( n = 147), and France ( n = 131). In Sweden, between 1999 and 2004, 384 (48%) cases of HAV from a total of 799 reported cases were imported into the country. 15 Again, several of the imported cases were from countries where vaccination is not currently recommended, particularly former Yugoslavia ( n = 32). It is likely that the incidence of imported cases of HAV is actually higher than these figures suggest because of underreporting due to, for example, missing laboratory or medical reports and cases diagnosed abroad. Nothdurft et al. Incidence and Seroprevalence of HAV Infections in Selected ESENEM Countries Recent data on the prevalence of HAV in EU countries have been collected by EUROHEP.NET, a concerted action funded by Directorate General research of the EU Commission and coordinated by the WHO Collaborating Centre for Prevention and Control of Viral Hepatitis based at the University of Antwerp, Belgium. The project was established in 2002 to collect data on surveillance, epidemiology, and prevention through vaccination, of vaccine-preventable hepatitis. One of the objectives of EUROHEP.NET is to examine the feasibility of creating a EU network for surveillance and prevention of HAV and HBV. 16 Data were collected in 22 countries for the period 1990 to 2001, including 11 Eastern EU countries. Preliminary results in those countries show that both the Czech Republic and Hungary have very low incidences of reported HAV cases, with <5 cases per 100,000 population in 2001 ( Table 1). Although it has decreased from 250 to 200 cases per 100,000 in 1990, Bulgaria still had an annual incidence rate of 50 to 100 cases of HAV per 100,000 in ( Table 1 ). The EUROHEP.NET project has highlighted the great variation in surveillance systems between different countries in Europe. Since the surveillance methods, and the case definitions used, differ so widely in Europe, comparison of epidemiological data is almost impossible. Furthermore, surveillance systems are designed for monitoring trends obtaining accurate incidence rates is often not their primary goal. 17 However, it is possible to compare different countries using standardized, age-specific seroprevalence curves, as produced by another EU project, the European Sero-Epidemiological Network 2, 18 from the serum banks of 16 EU countries. The profiles show how HAV seropositivity proportional to age increases with age, as the circulation of HAV (and therefore seropositivity) has decreased in younger age groups. For instance, in 1990, Romania had a very high incidence of HAV (>250 cases per 100,000 population) ( Table 1 ), but by 2003, it had become an area of intermediate endemicity, in which seropositivity was proportional to age, with 100% of 50- to 60-year-olds being seropositive. 19 The definition of increased endemicity is based on age-specific seroprevalence at the travel destination and the incidence of returning travelers with HAV. The national incidence of HAV disease may not be relevant because it is possible to have hyperendemic areas without a high incidence of clinical

3 HAV/HBV Risk in Selected EU and Non-EU Mediterranean Countries 183 HAV. It is also difficult to compare incidences of HAV between countries due to differences in surveillance and case reporting. The age-specific seroprevalence typical of an intermediate-endemicity area for HAV was estimated at >40% in those younger than 25 years. The risk of HAV infection in areas of low endemicity may be increased by certain activities, such as eating shellfish (eg, mussels) or raw seafood. In addition, the epidemiology of HAV may change due to localized outbreaks caused by environmental events (eg, flooding), disruption of sanitation, or food contamination (eg, an infected food handler). HBV in EU Travelers Two studies have investigated the potential risk of exposure to HBV in travelers to high-endemicity destinations. In a study of over 9,000 travelers from nine EU countries, a significant proportion of those visiting high/intermediate-endemicity destinations unwittingly exposed themselves to the risk of HBV infection while visiting countries with a high/medium risk of transmission. 20 The majority of these at-risk travelers had not been vaccinated, regardless of their destination. Approximately 10% to 15% of all travelers voluntarily or inadvertently expose themselves to a theoretical risk of transmission. 21 Incidence and Seroprevalence of HBV Infections in Selected ESENEM Countries Data on hepatitis B surface antigen (HBsAg) carrier rate in EU countries have also been collected by EUROHEP.NET and WHO Europe. It should, therefore, be possible to define at-risk countries for HBV for travelers in the ESENEM regions on the basis of the HBsAg carrier rate. According to EUROHEP.NET and WHO data, Turkey, Bulgaria, and Romania have HBsAg carrier rates of 2% to 8%; low endemicity (<2%) is reported for Western Europe, Central Europe, UK, and Nordic countries. 6 These figures highlight the range of endemicity of HBV within 22 countries of the EU region (ie, the countries included within EUROHEP.NET). This information, along with data from the WHO EU region (52 countries), can be used to update recommendations for HBV vaccination, especially for travelers to ESENEM. Indeed, over 10 highly endemic countries were found within the WHO EU region, situated only a short traveling distance from Western and Northern regions. 22 The results from EUROHEP.NET surveillance showed that a significant pool of carriers remain in Bulgaria, despite the introduction of universal HBV vaccination more than 10 years ago, with the HBsAg carrier rate remaining at 6% in 2001 (annual incidence of almost 15 cases per 100,000) ( Table 1 ). In Turkey, the HBsAg carrier rate based on the total population remained high at 9% in 2001, which is likely to be a much more accurate estimation of HBV risk than the (probably under-) reported annual incidence of >8 acute cases per 100,000 ( Table 1 ). Romania continued to possess a significant pool of HBsAg carriers (6%) in 2001, while Latvia has shown a steep increase in carriers from 20 per 100,000 to >40 per 100,000, with new circulating HBV strains identified as originating from St Petersburg, Russia. Elsewhere, in Eastern EU countries such as the Czech Republic and Lithuania, there are encouragingly low numbers of HBsAg carriers (<1% on both countries). Overview of Current National Vaccination Recommendations for HAV and HBV for Selected ESENEM Countries There is a notable lack of agreement between different EU countries in their current recommendations for HAV and HBV vaccinations for travel to ESENEM destinations. The national expert bodies in all EU (which includes EU and non-eu) countries with the exception of Germany consider Italy to be a low-risk destination and do not recommend HAV immunization to travelers. The German recommendations very specifically recommend HAV vaccination for travelers to Apulia in Southern Italy if they are planning to eat shellfish (eg, mussels). Unlike most EU countries, only Belgium, Finland, and the Republic of Ireland have a nationally approved travel vaccination schedule. Travel immunization advice can, therefore, vary within a country, depending on the source of travel advice consulted. Travel advice can be accessed by travelers from a variety of sources, including family physicians, Web sites, travel clinics, and pharmacists. Specific Consensus Statement for Selected ESENEM Countries There is currently no consensus between EU countries regarding travel vaccination for HAV and HBV for travelers in ESENEM countries, resulting in a variety of recommendations and advice. The

4 184 Nothdurft et al. Table 1 HAV and HBV annual incidence (cases per 100,000 population), 1990 to HAV HBV HAV HBV HAV HBV HAV HBV HAV HBV HAV HBV HAV HBV HAV HBV HAV HBV HAV HBV HAV HBV HAV HBV Austria Belgium Bulgaria Czech Republic Estonia Germany Greece Hungary Israel Italy Latvia Lithuania Luxembourg Malta Netherlands Norway Poland Romania Slovakia Slovenia Turkey UK Empty cells indicate that data are either unavailable and/or have not yet been reported to WHO. HAV = hepatitis A virus; HBV = hepatitis B virus.

5 HAV/HBV Risk in Selected EU and Non-EU Mediterranean Countries 185 expert panel who attended the meeting in Vienna in January 2005 aimed to draft a consensus statement for travelers to the ESENEM region, which might help in the development of recommendations by national authorities. The consensus statement was based on the panel s discussion and published information on the endemicity of HAV and the HBsAg carrier rates in different countries. 23,24 For EU countries with no national recommendations, the expert panel based its discussion on recommendations from travel medicine experts and advisory groups. HAV and HBV The panel concluded that both HAV and HBV vaccinations should be considered for the following Eastern EU destinations: Azerbaijan, Armenia, Belarus, Bulgaria, Bosnia and Herzegovina, Georgia, Kazakhstan, Kosovo, Kyrgyzstan, Moldova, Romania, Russia, Serbia and Montenegro, Tajikistan, Turkmenistan, Uzbekistan, and Ukraine. Both HAV and HBV vaccinations should also be considered in the following Mediterranean destinations: Albania, Egypt, FYROM, Israel, Jordan, Lebanon, Libya, Morocco, Syria, Tunisia, and Turkey ( Figures 1 and 2). Additional HAV The expert panel considered that there was no HAV zero-risk country. It was concluded that all travelers to countries with high and intermediate endemicity of HAV should obtain HAV vaccination. Although the duration of stay (eg, >1 month) was cited as a reason for recommending HAV vaccination in the current recommendations of some EU countries, it was concluded that a recommendation for HAV vaccination should be adhered to regardless of duration or frequency of visits. Furthermore, it was emphasized that the risk of contracting HAV was not specifically linked to the type of accommodation, with many cases of HAV reported in travelers with standard travel itineraries, living accommodation, and food. 25 Additional HBV The panel concluded that the general recommendations for HBV vaccination should, in addition to destination-specific requirements, include travelers to areas of intermediate (HBsAg >2%) or high endemicity (HBsAg > 8%), to protect against unexpected exposure (eg, unplanned medical procedures) or possible exposure due to high-risk activities (eg, unprotected sex, elective surgery, body piercings). The expert panel considered that there was no HBV zero-risk country for individuals from highrisk groups because these travelers would, whether at home in their own country or traveling, continue to be at risk due to their behavior (eg, intravenous drug use), occupation (eg, health care personnel), or lifestyle (eg, men who have sex with men). Duration of stay was not considered to be a primary risk factor and recommendations for HBV vaccination should be made independently of this. Conclusion: The Future of Travel Medicine Advice Concerning HAV and HBV At present, standardized data on HAV and HBV epidemiology are limited, with only scant information available for some countries. Special attention should be paid to local epidemiology through improved standardized surveillance systems and reporting, and to maximize the usefulness of these data, there is an urgent need to standardize the definitions of case report and outbreak so that data can be compared between different countries. It is also important that more data on the origin of cases of HAV and HBV are collated, particularly that which differentiates between imported versus domestic infections. Other suggestions are directed toward travelers, as well as physicians concerned with travel health advice and, in particular, the need to raise awareness of the risks of HAV and HBV infection in shorthaul destinations in Eastern Europe and non-eu Mediterranean countries. It appears that there is a general misconception among both travelers and some health care professionals that HAV and HBV infections are not a risk factor for short-haul destinations in Eastern Europe and North Africa but are only a concern for exotic or long-haul flight destinations. Lack of understanding of the potential risks of travel to relatively close countries has meant that many travelers do not seek medical advice or vaccinations. There is clearly a need for raised awareness in this area. National travel medicine societies and national expert bodies issuing recommendations should be invited to reconsider their current travel immunization recommendations, particularly for selected ESENEM countries that comprise 80% of destinations of all EU travelers. 1 Such vaccination recommendations should not contradict each other and should be updated at regular intervals. The epidemiology of HAV and HBV is changing over time, and the consensus statement regarding recommendations of 2005 stated here must be

6 186 Figure 1 Summary of expert panel country-specific recommendations for hepatitis A immunization. reviewed on a regular basis as it is estimated that the situation in some of the countries studied will change tremendously in the 10 years to Acknowledgments The authors wish to thank all countries that participated in the EUROHEP.NET survey for making their data available, and without whose statistics this review would not have been possible. Figure 2 Summary of expert panel country-specific recommendations for hepatitis B immunization. Declaration of Interests Nothdurft et al. GlaxoSmithKline (GSK) has sponsored the Travel Clinic of the Havenziekenhuis Rotterdam for carrying out survey on travel-related risks among vaccines attending the vaccination outpatient clinic with an unconditional grant. GSK has also provided an unconditional grant for carrying out surveys on the travel-related risks among travelers. The ad hoc Travel Expert Panel meeting was made possible through an unrestricted grant from GSK Biologicals, Rixensart, Belgium. H. D. N. received fees for speaking from GSK. E. A. G. received reimbursement for giving and attending symposia on behalf of both GSK and Sanofi- Pasteur. She attended the meeting to form this review group with reimbursement from GSK. Her spouse has shares in GSK but personally does not have any shares in any vaccine company. H. K. received fees for serving on an advisory board and reimbursement for attending a symposium. D. O. has served on the advisory board meeting concerning the risk of hepatitis A and B among travelers in Europe, which was unconditionally sponsored by GSK and from which this paper has resulted. M.-L. R. has accepted fees for speaking from GSK and Sanofi Aventis, and reimbursement for attending meetings from GSK, Roche, Schering Plough. P. R.-W. has accepted fees for speaking, and consulting and/or serving on advisory boards from GSK. There are, however, no conflicts of interest. R. S. has accepted fees for speaking, organizing and chairing education, consulting, and/or serving on advisory boards, and reimbursement for attending meetings and funds for research from Astral, Berna Biotech/Crucell, Baxter, Chiron Behring (now Novartis Vaccine), GSK, Novartis, Optimer, Salix Pharmaceuticals, and/or Sanofi Pasteur MSD. He owns shares in Novartis. P. V. D. has been principal investigator for vaccine trials, for which the University of Antwerp receives research grants from several vaccine manufacturers. References 1. IPK International, International Tourism Consulting Group World Travel Monitor Company. Available at : (Accessed 2005 Oct 31) 2. World Tourism Organization. World Tourism Barometer 2005 ; 3 : 1 4. Av ailable at : en_excp.pdf. (Accessed 2005 Oct 31) 3. Continuous Schiphol Survey. Available at : (Accessed 2005 Oct 31)

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