2013;22:21-25 doi: !0.2478/vi0i62-0i2-0026-z Current status of human papillomavirus vaccination implementation in central and eastern Europe Katja Seme1, Polona J. Maver S Tina Korac1, Amalia Canton2, Jitka Častkova3, Goran Dimitrov4, Irina Filippova5, Helena Hudecova6, Ermina Iljazovic7, Bernard Kaic8, Vesna Kesic9, Nerija Kuprevičiene10, Dragan Lauševic11, Zsuzsanna Molnar12, Jurijs Perevoščikovs13, Marek Spaczynski14, Venera Štefanova15, Veronika Učakar16, Mario Poljak1 13 Abstract We present a review of the current implementation status of vaccination against human papillomaviruses (HPV) and available data concerning the burden of HPV infection and HPV type-specific distribution in 16 central and eastern European countries: Albania, Bosnia and Herzegovina, Bulgaria, Croatia, the Czech Republic, Estonia, Montenegro, Poland, Romania, Serbia, Slovakia, Slovenia, and The Former Yugoslav Republic of Macedonia. At least one current HPV prophylactic vaccine is registered in all central and eastern European countries except Montenegro. Six counties-Bulgaria, the Czech Republic, Latvia, Romania, Slovenia, and Former Yugoslav Republic of Macedonia-have integrated the HPV vaccination into their national immunization program and currently provide routine vaccination free of charge to the primary target population. Ten countries have not integrated HPV vaccination into the national immunization program. The key reasons for lack of implementation of HPV vaccination into the national immunization program are the high vaccine cost and negative public perception. Vaccination of males is not recommended in any country in the region. Received: 5 March 2013 | Returned for modification: 10 March 2013 | Accepted: 14 March 2013 Introduction Two prophylactic HPV vaccines have been available since 2006 and can be used as efficient and powerful tools for primary prevention of cervical cancer and other HPV-associated diseases (1-5). The quadrivalent vaccine (Gardasil/Silgard®, Merck & Co., Whitehouse Station, NJ, USA) and bivalent vaccine (Cervarix®, GlaxoSmithKline Biologicals, Rixensart, Belgium) have each been licensed in over 100 countries worldwide. By the beginning of 2012, HPV vaccination had been introduced into national immunization programs in at least 40 countries (6). In 2011, when we started preparing the central and eastern European regional report for the HPV Vaccines Monographs (7), we realized that published data concerning current HPV vaccination implementation in central and eastern European countries are scant, available for only a limited number of countries, or out of date (8-10). Therefore a detailed survey with 28 questions was conducted by the authors of this review from August to October 2011 and used as the main data source. Due to limited space, not all data collected could be included in the manuscript written for the regional report. Thus we decided to separately publish an extended manuscript on this topic, and we updated the survey in January 2013. In this paper, we review the current implementation status of vaccination against human papillomaviruses (HPV) in each of the 16 central and eastern European countries: Albania, Bosnia and Herzegovina, Bulgaria, Croatia, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Montenegro, Poland, Romania, Serbia, Slovakia, Slovenia, and The Former Yugoslav Republic (FYR) of Macedonia. The key data obtained by survey are summarized in Tables 1 and 2. Albania Only the bivalent vaccine is currently registered in Albania (11). It has been licensed since 2009. The HPV vaccination is not integrated into the national immunization program and there are currently no issued recommendations for the use of HPV vaccines. There are initiatives by the Albanian Ministry of Health regarding HPV vaccination, described in the National Cancer Control Program, which includes a number of specific recommendations and actions. The recommendations include the step-by-step building of a national program for vaccination against HPV and emphasize health education (12). Bosnia and Herzegovina Both HPV vaccines, quadrivalent and bivalent, have been registered in Bosnia and Herzegovina: the bivalent vaccine since July 2007 and the quadrivalent one since October 2008. In 2011, the Ministry of Health of the Federation of Bosnia and Herzegovina prepared a document entitled Strategy of Prevention, Treatment and Control of Malignant Disease in which HPV vaccination was mentioned for the first time as a possible prevention of cervical cancer. No further explanation or recommendations regarding the use of HPV vaccination were included in the document. The current cost of HPV vaccines is €100 for the bivalent vaccine and €125 to €165 for quadrivalent HPV vaccine, and this depends on the supplier. •institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. 'Ministry of Health, Bucharest, Romania. 3National institute of Public Health, Prague, Czech Republic. 'University Clinic of Gynecology and Obstetrics, Skopje, Macedonia. 5Department of CD Surveillance and Control, Health Board, Tallinn, Estonia. 6Public Health Authority of the Slovak Republic, Bratislava, Slovakia. 'University Clinical Center, Tuzla, Bosnia and Herzegovina. 8Croatian institute of Public Health, Zagreb, Croatia. 9Medical Faculty, University of Belgrade; Department of Obstetrics and Gynecology, Clinical Center of Serbia, Belgrade, Serbia. "Public Health institute, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. "Na- tional institute of Public Health, Podgorica, Montenegro. "National Center for Epidemiology, Budapest, Hungary. *3Centre for Disease Prevention and Control of Latvia, Riga, Latvia. •'Poznan University of Medical Sciences, Poznan, Poland. *5National Centre of infectious and Parasitic Diseases, Sofia, Bulgaria. l6National institute of Public Health, Ljubljana, Slovenia. h Corresponding author: mano.poljak@mf.um-lj.si < < Vi < < < V-I < < < ta < ra (p C c 0 ro re c c E (N E T-t a. O a. E CN JE ™ 0 0 <4— < 4— iñ O C > ra TD *C c C "O TD N E > O C C T-* m Si > > S E I ra ° I o à C iO o ¡ f J '§ > o O (N o ^ (P O ' C O ra > (U > OL JD _o UÏ Bulgaria Both vaccines are currently in use in Bulgaria; the quadrivalent one was introduced in 2007, and the bivalent one in 2008. In 2007, an expert advisory body, including members from the Ministry of Health and National Center for Infectious and Parasitic Disease Control, issued official recommendations for the use of HPV vaccines in Bulgaria for girls 12 to 18 years old before first sexual contact, with catch-up vaccinations up to age 26. In June 2009, the Ministry of Health included the HPV vaccine in the recommended vaccination list. In 2012 the National Program for Primary Prevention of Cervical Cancer was approved by the council of ministers. To enable implementation of the program, the parliament approved 2 million leva (about €1 million) for the first year for reimbursement of HPV vaccine for the target population of 12-year-old girls. Catch-up vaccinations up to age 26 are recommended, but are based on personal initiative and are not free of charge. The vaccine is delivered through health centers or primary care providers and the informed consent of parents or guardians is required. Because the program is in its initial stage, it is still early for the vaccination coverage data, but most recent data from the media have shown that in the first 3 to 4 months of the program about 14% of the target population has been vaccinated (Y. Panay-otova, personal communication). Croatia Both HPV vaccines have been registered in Croatia: the quadrivalent vaccine since 2007, and the bivalent one since 2008. In 2008, the Croatian Institute of Public Health prepared official recommendations for the use of HPV vaccines and revised the recommendations in 2009. In addition to the institute, several professional medical associations published recommendations for HPV vaccination. According to the recommendations, HPV vaccination is recommended as individual protection to girls and women between ages 9 and 26, preferably before sexual debut. Immunization of schoolgirls and higher-education students is performed at school medical departments affiliated with the county institutes of public health, and working women can be vaccinated by their gynecologist, family physician, or at epidemiology departments at the county institutes of public health. Due to the financial constraints of the Health Insurance Institute, HPV vaccination is not reimbursed. Since 2008, the health administrations of a few cities and counties have funded vaccination campaigns for schoolage children, ensuring that all three doses are free of charge to 13-year-old girls. Vaccination response rates have varied from 10% to 70%, depending mostly on the parents' attitudes towards HPV vaccination. The vaccination of males is not currently recommended. Czech Republic Both HPV vaccines have been registered and are on the market in the Czech Republic: the quadrivalent vaccine since 2006, and the bivalent one since 2007. In 2006, the Ministry of Health prepared official recommendations for the use of HPV vaccines for females 9 to 25/26 years old. Financial coverage was from personal funds, self-supported. Recommended HPV vaccination has been integrated into the national immunization program since April 2012 by a decision of Ministry of Health on the basis of National Immunization Committee (NIKO) recommendation. HPV vaccination is covered by general health insurance for the target population of adolescent women, 13 years of age. Written informed consent of the girl's parent or guardian is required for vaccination. The bivalent vaccine has been used in the national immunization program and is delivered through pediatricians. A catch-up program has not been implemented in the Czech Republic. As for all other vaccines, vaccination coverage data for HPV vaccination will be collected in all regions manually each year and the results sent to the center. The vaccination of males is not currently recommended. Estonia Both HPV vaccines have been registered in Estonia: the quadrivalent vaccine since 2006, and the bivalent one since 2007. The Ministry of Social Affairs issued official recommendations for the use of HPV vaccines in 2009. According to the recommendations, HPV vaccination is recommended for females age 12 and older. Due to the high vaccine cost and lack of the country's cost-effectiveness data, HPV vaccination has not been integrated into the national immunization program and there are no plans to do this in the near future. Hungary Both HPV vaccines, the quadrivalent and the bivalent, have been registered in Hungary since 2006 and 2007, respectively, but the vaccination advisory board has not yet produced recommendations for the introduction of HPV vaccination or integrated it into the national immunization program. Two recent modeling studies have confirmed the cost effectiveness of adding either of the available vaccines to the current national screening program in Hungary (13,14), but due to the high cost HPV vaccination has not been integrated into the national immunization program and there are no plans to do so in the near future. Latvia Both HPV vaccines are available in Latvia. In 2009, the state immunization board prepared official recommendations for introducing HPV vaccines in the national immunization schedule. This decision was accepted by the Ministry of Health and the cabinet of ministers, and since September 2010 HPV vaccination has been integrated into the national immunization schedule. In general, routine HPV vaccination is provided free of charge to 12-year-old girls by general practitioners and also at several schools in the capital Riga if the parents or guardians have given written informed consent to allow vaccination of their daughters in school. So far, the bivalent vaccine has been used in the national immunization program. A catch-up program has not been implemented in Latvia. According to data from a vaccination monitoring system, the coverage for one dose in Latvia increased from 47.4% in 2010 to 61.4% in 2011, and was 58.7% in 2012. Vaccination coverage for three doses was 60.6% in 2011 and 53.4% in 2012. Currently, vaccination of males is not recommended. Lithuania Both HPV vaccines are currently registered in Lithuania: the quadrivalent one since 2006, and the bivalent one since 2007. The cost of the quadrivalent vaccine per dose is approximately €122, and the cost of the bivalent vaccine per dose is approximately €110. HPV vaccination is not part of the official national immunization scheme and there are currently no official recommendations for the use of HPV vaccines. However, there are plans to introduce HPV vaccination into the national immunization program in the near future. Montenegro None of the existing HPV vaccines have been registered in Montenegro yet, but the registration of both vaccines is in progress. According to the working plan of the newly established National Immunization Technical Advisory Group (NITAG), official recommendations for the eventual integration of HPV vaccination into the national immunization program will be prepared by the end of November 2013. Recommendations will be based on the results of an ongoing study evaluating the prevalence and distribution of HPV genotypes in women with pre-cancerous cervical lesions and cervical cancer. The end of the study is planned for October 2013. The NITAG recommendation for the Ministry of Health is to implement these vaccines into the national immunization program, and the HPV vaccination will be introduced at the beginning of the new school year in 2014, provided that this probable introduction is financially feasible and sustainable. Poland The bivalent vaccine has been registered since 2007 and the quadrivalent one since 2009. The price is the same for both vaccines: €60. Official recommendations for the use of HPV vaccines were issued by the Polish Gynecological Society in 2009. The vaccination is recommended for girls 11 to 12 years old and also for girls age 13 to 18 that were not vaccinated previously (15). HPV vaccination is not part of the national immunization program, mainly due to the high cost. There are currently no initiatives to include the HPV vaccination in the national immunization program. Local authorities in some regions have introduced HPV immunization projects for girls age 12 to 13. No central registry of vaccinated women is currently available, nor is there any information on whether all three doses were administered. Romania In Romania, both the bivalent and the quadrivalent vaccine have been registered since 2008. There are official recommendations for the use of these vaccines, issued by the Ministry of Health in 2008. Vaccination is recommended for females age 12 to 24. HPV vaccination is performed at local public health centers and school health services. A national school-based program to vaccinate 11-year-old females was first launched in 2008, but was temporarily suspended during the first year due to low acceptance. Only about 2% of the target population was vaccinated. The government analyzed the reasons for the low uptake and subsequently implemented a novel information campaign prior to a re-launch in February 2010, which was discontinued at the end of 2011 due to a negative public reaction, lack of proper communication, and consequent low coverage of the target population (less than 5%). The program was launched for the third time in April 2013. Serbia Both the quadrivalent and bivalent HPV vaccine have been registered in Serbia since 2008. In 2008, the Serbian expert group on cervical cancer prevention prepared official recommendations for the use of HPV vaccines. Unfortunately, these recommendations have never been officially announced. HPV vaccination has not been integrated into the national immunization program. Both vaccines are on the market and are available for individual use. The stock of bivalent vaccine expired and currently it cannot be found in pharmacies. Quadrivalent vaccine can be ordered and purchased. Initial campaigns aimed at increasing awareness about HPV vaccination have ceased, and currently there is no structured education on this issue in the country. Slovakia Both HPV vaccines, the quadrivalent one and the bivalent one, have been registered in Slovakia since 2007. In 2010, the Working Group for Immunization prepared official recommendations for the use of HPV vaccines and passed these on to the Ministry of Health of the Slovakia. The recommendation was implemented into legislation, and it says that if a doctor considers there to be a need for the vaccination against infections caused by oncogenic HPV, then the vaccination should be given to 12-year-old girls. This group pays 89% of the total price of the bivalent vaccine and 92.5% of the total price of the quadrivalent vaccine. Of course, the non-official recommendation is also designed for other age groups, but these have to pay the total price of the vaccines. Neither routine HPV vaccination nor catch-up programs have been started in Slovakia. HPV vaccination coverage is not monitored, although the number of girls up to 15 years old vaccinated against HPV is monitored. Vaccination of males is currently not recommended. Slovenia Both HPV vaccines have been registered in Slovenia, the quadrivalent one since 2006 and the bivalent one since 2007. In 2007, the Slovenian expert group on HPV prepared official recommendations for the use of HPV vaccines. According to the decision of the board of health at the Slovenian Ministry of Health, HPV vaccination has been included in the National Immunization Program since the beginning of the 2009/2010 school year and has been performed in school health service networks. Routine HPV vaccination, free of charge, is provided to 11- to 12-year-old girls if their parents or guardians give written informed consent to allow vaccination of their daughters. So far, the quadrivalent vaccine has been used in the national immunization program. A catchup program has not been implemented in Slovenia. According to data from the Slovenian national vaccination coverage monitoring system, the coverage rate (full three-dose) in the target group included in the program increased from 48.7% for the 2009/2010 school year through 55.2% for the 2010/2011 school year to 54.9% for the 2011/2012 school year. Vaccination of males is currently not recommended. The Former Yugoslav Republic of Macedonia Both the quadrivalent and bivalent vaccine have been registered in FYR of Macedonia: the quadrivalent one since 2007, and the bivalent one since 2008. The official recommendations for the use of HPV vaccines were issued in 2007 by the Commission for Contagious Diseases within the Ministry of Health, the Macedonian Association of Gynecologists and Obstetricians, the HPV Society of Macedonia, and the Macedonian Society for Cervical Pathol- ogy and Colposcopy. Vaccination was recommended for females between 9 and 26 years old. By a decision of the Ministry of Health from 2008, HPV vaccination was introduced into the national immunization program in October 2009 as obligatory for 12-year-old girls. The quadrivalent vaccine has been used in the national immunization program and is delivered through a school-based program. The catch-up vaccination is provided for 13- to 26-year-old girls and woman, and is also free of charge and is delivered through healthcare facilities. HPV vaccine coverage is monitored at the national level. Coverage for three doses increased from 37% for the 2009/2010 school year to 67% for the 2010/2011 school year, and then declined to 65% for the 2011/2012 school year. Conclusions As shown in Tables 1 and 2, at least one of two current HPV prophylactic vaccines is registered in all central and eastern European countries except Montenegro. Six countries (Bulgaria, the Czech Republic, Latvia, Romania, Slovenia, and FYR of Macedonia) have actually integrated HPV vaccination into their national immunization program and currently provide routine vaccination free of charge to the primary target population (Table 1). In Slovenia and FYR of Macedonia, HPV vaccination is performed in school health service networks, whereas in the other four countries HPV vaccination is performed in local public health centers and school health services. Informed consent of parents or guardians is required in all countries, and all of them except FYR of Macedonia have initiated a national HPV immunization program. All six countries declared that a vaccination monitoring system had been implemented. However, only three countries were able to provide vaccination coverage data for all three doses. Of the six countries, only FYR of Macedonia decided to implement a catch-up program for the 13 to 26 age group. In Romania, the re-launched HPV vaccination program was discontinued at the end of 2011 due to a negative public reaction, lack of proper communication, and resulting low coverage in the target population, which did not reach 5%. Ten countries have not integrated HPV vaccination into the national immunization program (Table 1), the main reasons being high vaccine cost and negative public perception (Table 2). In approximately half of these countries, national professional societies and bodies are generally supportive of the routine HPV vaccination of adolescent girls. Because there is no publicly funded vaccination program, HPV vaccination in these countries is funded by individuals or, in some countries (e.g., Croatia, Poland), by regional or county authorities; but with low coverage achieved. At the time of preparation of the review, vaccination of males was not recommended in any country in the region. References 1. The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Eng J Med. 2007;356:1915-27. 2. Paavonen J, Jenkins D, Bosch FX, Naud P, Salmeron J, Wheeler CM, et al. Efficacy of a prophylactic adjuvanted bivalent Li virus-like-particle vaccine against infection with human papilloma virus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007;369:2161-70. 3. Paavonen J, Naud P, Salmeron J, Wheeler CM, Chow SN, Apter D, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 2009^74:301-14. 4. Villa LL, Costa RL, Petta CA, Andrade RP, Paavonen J, Iversen OE, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer. 2006;95:1459-66. 5. Taira AV, Neukermans CP, Sanders GD. Evaluating human papillomavirus vaccination programs. Emerg Infect Dis. 2004;11:1915-23. 6. Markowitz LE, Tsu V, Deeks SL, Cubie H, Wang SA, Vicari AS, et al. Human papillomavirus vaccine introduction-the first five years. Vaccine. 2012;30(Suppl 5):F139-48. 7. Poljak M, Seme K, Maver PJ, Kocjan BJ, Cuschieri KS, Rogovskaya S, et al. Human papillomavirus prevalence and type-distribution, cervical cancer screening practices and current status of vaccination implementation in central and eastern Europe. Vaccine. 2013 (in press). 8. Dorleans F, Giambi C, Dematte L, Cotter S, Stefanoff P, Mereckiene J, et al. VENICE 2 project gatekeepers group. The current state of introduction of human papillomavirus vaccination into national immunisation schedules in Europe: first results of the VENICE 2 2010 survey. Euro Surveill. 2010^5:19730. 9. Obradovic M, Mrhar A, Kos M. Cost-effectiveness analysis of HPV vaccination alongside cervical cancer screening programme in Slovenia. Eur J Public Health. 2010;20:415-21. 10. Prymula R, Anca I, André F, Bakir M, Czajka H, Lutsar I, et al. Central European Vaccination Advisory Group (CEVAG) guidance statement on recommendations for the introduction of HPV vaccines. Eur J Pediatr. 2009;168:1031-5. 11. Human Papillomavirus and Related Cancers in Albania. Summary Report 2010 [Internet]. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). c2010 - [cited 2013 Feb 24]. Available from: http://www.who. int/hpvcentre. 12. The National Cancer Control Program 2011-2020 [Internet]. Republic of Albania, Ministry of Health. c2011 - [cited 2013 Feb 24]. Available from: http://www. thewpca.org/. 13. Dasbach EJ, Nagy L, Brandtmuller A, Elbasha EH. The cost effectiveness of a quadrivalent human papillomavirus vaccine (6/11/16/18) in Hungary. J Med Econ. 2010;13:110-8. 14. Vokô Z, Nagyjânosi L, Kalô Z. Cost-effectiveness of adding vaccination with the AS04-adjuvanted human papillomavirus 16/18 vaccine to cervical cancer screening in Hungary. BMC Public Health. 2012^2:924. 15. Polish Gynaecological Society Guidelines for HPV vaccination. Ginekol Pol. 2009;80:139-46.