Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Use of oseltamivir in 12 European countries between 2002 and 2007 – lack of association with the appearance of oseltamivir-resistant influenza A(H1N1) viruses

Use of oseltamivir in 12 European countries between 2002 and 2007 – lack of association with the... R e s e a r c h a r t i c l e s U s e o f o s e lt a m i v i r i n 1 2 e U r o p e a n c o U n t r i e s b e t w e e n 2 0 0 2 a n d 2 0 0 7 – l a c k o f a s s o c i a t i o n w i t h t h e a p p e a r a n c e o f o s e lt a m i v i r - r e s i s t a n t i n f l U e n z a a ( h 1 n 1 ) v i r U s e s 1 1 1 2 1 P Kramarz (Piotr.Karamarz@ecdc.europa.eu) , Dominique Monnet , A Nicoll , C Yilmaz , B Ciancio 1. European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden 2. Ministry of Health of the Republic of Turkey, Ankara, Turkeyl Variable levels of oseltamivir resistance among seasonal influenza NAIs, especially the oral drug oseltamivir, became increasingly A(H1N1) isolates have been reported in Europe during the 2007-8 important after a sudden increase in adamantane resistance among northern Hemisphere influenza season. It has been questioned seasonal influenza A viruses between 2004 and 2006 [5,10,11]. whether oseltamivir use could have driven the emergence and NAIs have also been preferred in recommendations to amantadine predominance of resistant viruses. This study aimed at describing (the most commonly used adamantane) since they show lower the levels of use of oseltamivir in 12 European Union (EU) Member levels of adverse neurotoxic reactions [12]. Before the 2007-8 States and European Economic Area (EEA)/European Free Trade influenza season, resistance to the NAIs among transmitting Area (EFTA) countries. The data were converted into prescription seasonal influenza A viruses was extremely rare in Europe and rates and compared with the national proportions of resistant elsewhere [13-15] and higher proportions of resistance had been reported only in children: up to 18% of children infected with inu fl enza A(H1N1) viruses through regression analysis. Overall use of oseltamivir in European countries between 2002 and 2007 was inu fl enza A(H3N2) and treated with oseltamivir shed virus resistant to oseltamivir [16-17]. However, NAI-resistant viruses detected low compared to e.g. the use in Japan. High variability between the countries and over time was observed. In eight of the 12 countries, before 2007-8 showed in most cases a poor ability to transmit from human to human. there was a peak of prescriptions in 2005, coinciding with concerns about a perceived threat from an influenza pandemic which might have lead to personal stockpiling. Ecological comparison between This situation changed abruptly during the 2007-8 northern national levels of use of oseltamivir in 2007 and the proportions Hemisphere inu fl enza season when inu fl enza A(H1N1) virus isolates of A(H1N1) viruses that were resistant to oseltamivir showed no highly resistant to oseltamivir were detected as part of surveillance statistical association. In conclusion, our results do not support the in the Europe through the networks of the European Influenza hypothesis that the emergence and persistence of these viruses in Surveillance Scheme (EISS)/European Surveillance Network for 2007-8 was related to the levels of use of oseltamivir in Europe. Vigilance against Viral Resistance (VIRGIL) [13,18]. Laboratory Further investigation is needed to elucidate the reasons for different analyses showed that up to 67.4% of all inu fl enza A(H1N1) viruses level of use between the countries. isolated from specimens collected between November 2007 and April 2008 in Europe either carried the mutation H274Y which Introduction is associated with high levels of oseltamivir resistance or tested Annual epidemics of human seasonal influenza are associated positively in the IC50 phenotypic examination for oseltamivir with a substantial burden of morbidity and mortality, which resistance (Figure 1) [19]. This was the first indication that cumulates in certain groups of the population such as older influenza A(H1N1) virus resistant to oseltamivir could readily people and those with chronic medical conditions [1-3]. Annual transmit between humans. vaccination remains the mainstay of influenza prevention, and antiviral medications, including the neuraminidase inhibitors The question arises whether current levels of oseltamivir use in (NAIs) oseltamivir and zanamivir, and M2 protein inhibitors (the European countries could have been associated with the emergence adamantanes amantadine and rimantadine) play an auxiliary role and sustained transmission of resistant inu fl enza A(H1N1) viruses. in the prevention or treatment of influenza infection. They can be The aim of the study was thus to describe, using all available especially helpful in controlling outbreaks in nursing homes, in data (including data from prescription surveys and databases), individuals who cannot be immunised or in situations in which oseltamivir usage at population level in several EU Member vaccine has not been given or in which vaccination is not optimally States and EEA/EFTA countries and to determine if there was any effective due to a poor match between the vaccine strain and the correlation between the level of use and the observed proportions circulating strains [4-9]. of A(H1N1) viruses that were resistant. E U R O S U R V E I L L A N C E Vol . 14 · I ss u e 5 · 5 F eb r u a r y 2 0 0 9 · w w w . e u r o s u rv e i ll a n c e . o r g 1 Methods these data into prescription rates (number of prescriptions per We used several sources of information on oseltamivir 1,000 inhabitants per year) using Eurostat population data [20]. prescriptions as a proxy measure for oseltamivir utilisation in EU Four other countries monitored by IMS Health, the Netherlands, Member States and EEA/EFTA countries. Portugal, Switzerland and the United Kingdom (UK), had only negligible prescription levels for oseltamivir. Information on oseltamivir use from a prescription survey We used data from a continuing survey of a panel of office- Information on oseltamivir use from population prescription based physicians in EU Member States and EEA/EFTA countries databases from databases maintained by Intercontinental Marketing Services In Denmark and Norway, data on the number of patients having (IMS) Health, an independent commercial company providing used oseltamivir at least once each year between 2002 and 2007 information on the use of pharmaceuticals. IMS Health attempts and between 2004 and 2007, respectively, were extracted from to achieve a high level of representativeness of their panels for the national, publicly available databases on redeemed prescriptions population of all physicians in the involved countries. Participating [21,22]. These numbers of prescriptions were converted into rates physicians are being surveyed for two consecutive workdays per of redeemed prescriptions per 1,000 inhabitants per year. In both quarter of a year and provide information on each patient encounter countries, data included corporate prescriptions, i.e. medicines during this period. The manufacturer of oseltamivir, F.Hoffmann-La purchased by business organisations for their employees. The data Roche Ltd., provided the European Centre for Disease Control and did not include any supply of antiviral medications to countries for Prevention (ECDC) with the data from IMS Health on the numbers national or corporate stockpiles. of oseltamivir prescriptions in Austria, Belgium, Finland, France, Germany and Greece for the years 2002 to 2007. We then converted Quarterly prescription information The initial analysis consisted in computing annual figures for oseltamivir prescriptions per 1,000 inhabitants. To examine trends in oseltamivir use over time in more detail, we also obtained F i g u r e 1 quarterly prescription numbers and converted them into prescription Nati ona l prop or ti ons of antiv ir a l resistance in A(H1N1) rates. Quarterly data were available for eight countries: Austria, inf lu enza v ir us es for EU/EEA Memb er States, 2007-8 Belgium, Finland, Germany, Greece, the Netherlands, Portugal, Switzerland, and the UK. Norway 67.4% Investigation of the relationship between oseltamivir use and Belgium 53.1% levels of resistance France 46.6% Linear regression analysis was performed to determine whether Netherlands 26.9% there was any relationship between the use of oseltamivir and Luxembourg 26.0% the levels of oseltamivir resistance. Proportions of oseltamivir Finland 23.1% resistance during the 2007-8 inu fl enza season among all A(H1N1) 20.7% Portugal tested strains expressed on the web sites of ECDC, EISS and the World Health Organization (WHO) were regressed on the levels of Switzerland 18.9% Germany 13.1% 11.1% Sweden Ireland 11.1% F i g u r e 2 United Kingdom 11.0% Pres cripti ons of os eltamiv ir p er 1,000 in habitants in eig ht Greece 10.8% Europ e an countri es*, 2002-2007 Poland 10.0% Romania 8.2% 6 2002 Austria 7.3% Denmark 4.4% 2004 Slovenia 3.6% 1.9% Spain Italy 0.9% Slovakia 0.0% 0.0% Latvia Hungary 0.0% Czech Republic 0.0% Austria Belgium Germany Denmark† Greece Finland France Norway† 0.0 10 20 30 40 50 60 70 80 Data (available as of 6 August 2008) were provided by European Influenza * Data only include patient prescriptions. They do not include stockpiles Surveillance Scheme www.eiss.org/index.cgi and the VIRGIL Project at national /regional level or by hospitals/institutions. Data for Denmark www.virgil-net.org. and Norway include corporate prescriptions. Countries with fewer than 10 test results (Bulgaria, Estonia) are not Netherlands, Portugal, UK and Switzerland: data not presented due to shown in the graph. ‘negligible’ number of prescriptions. EU/EE A/EF TA countries in the EISS network for which no test results were † Denmark and Norway: the data are based on the number of patients, available: Cyprus, Lithuania, Malta. which may slightly underestimate the number of prescriptions. EU: European Union; EE A: European Economic Area EF TA: European Free Trade Source: IMS Health data provided by F. Hoffmann – La Roche Ltd., Basel Area; EISS: European Influenza Surveillance Scheme; VIRGIL: European except for: Denmark;,data provided by Danish Medicines Agency, and Surveillance Network for Vigilance against Viral Resistance. Norway: data provided by Norwegian Institute of Public Health. 2 E U R O S U R V E I L L A N C E Vol . 14 · I ss u e 5 · 5 F eb r u a r y 2 0 0 9 · w w w . e u r o s u rv e i ll a n c e . o r g Prescriptions per 1,000 inhabitants oseltamivir use in the countries in 2007. STATA (STATA/SE 10 for It was noticeable that the peak of oseltamivir use observed Windows, STATA Corporation) was used for statistical analyses. in 2005 in Austria, Belgium, Finland and Germany (Figure 2) concentrated mostly during the first quarter of that year. Results Annual oseltamivir prescription rates No correlation of prescription data and resistance development As shown in Figure 2, the overall prescription rates for oseltamivir We have analysed oseltamivir resistance in 2007-8 because a remained under six prescriptions/1,000 inhabitants/year in the sharp increase in resistance was observed during that season. We eight EU Member States for which such data was availabe. This is regressed it against oseltamivir use in 2007 assuming this was low compared to those reported, for example, in Japan where the a good proxy for oseltamivir use in 2008. However, regression reported prescription rate in 2005 was 70.9/1,000 inhabitants/ analysis for twelve countries (Figure 4) did not show any statistical year [23]. association between the levels of oseltamivir resistance during the influenza season 2007-8 and oseltamivir prescriptions in 2007 After a substantial peak in prescriptions in 2005, when (R2 = 0.02). three countries exceeded three prescriptions/1,000 inhabitants/ year (Austria, Belgium and Norway) and one country exceeded Discussion five prescriptions/1,000 inhabitants/year (Germany), the use of We found overall low levels of oseltamivir use in EU Member oseltamivir decreased to under two prescriptions/1,000 inhabitants/ States in the period between 2002 and 2007, compared to the use year in 2006 and 2007 in all included countries. However, the of oseltamivir in Japan, a country with the world’s highest per capita trends from 2006 to 2007 differed: an increase occurred in Austria, use of oseltamivir (70.9/1,000 inhabitants/year), but relatively low Belgium, Finland and France, a small decrease in Germany, Greece levels (3%) of oseltamivir resistance during the 2007-8 season and Norway, and the rates remained stable in Denmark. [23,24]. In the most recent year with available data (2007), we observed a There was a common peak in prescriptions in 2005 in eight substantial variation in oseltamivir prescription rates in EU Member countries. One possible explanation for this phenomenon is the States, with an almost tenfold differences in those countries with concern over ‘bird flu’ influenza A(H5N1) in 2005 when spread any significant use of oseltamivir. The highest rates were seen in of these viruses from Asia towards Europe received considerable Belgium and the lowest in Greece. Countries with negligible use attention in the media. Many of these prescriptions to individuals that are not shown in the figure are the Netherlands, Portugal, and families may therefore have gone to form a source of medication Switzerland and the UK. Greece exhibited a different prescription for the future (“personal stockpiling”). A similar spike of influenza pattern with high use in 2003 and 2004. antiviral medication sales, was observed in October 2005 in New York [25] and, in general, in the autumn and winter of 2005 accross the United States [26]. It did not coincide with influenza In summary, our analysis showed low prescription rates of oseltamivir with substantial variation between analysed countries activity itself, but rather with the beginning media coverage of avian influenza A (H5N1) and the potential for an influenza pandemic and over time. [23]. Quarterly oseltamivir prescription rates Figure 3 shows a more detailed comparison of oseltamivir It is more difficult to explain the observation that most of the prescription rates in eight countries for which data were available oseltamivir use in EU Member States in 2005 concentrated in the at the level of periods of three months. r fi st quarter of the year. Inu fl enza activity during the season 2004-5 F i g u r e 3 Prescriptions of oseltamivir per 1,000 inhabitants in eight European countries*, 2002-2007, by quarter of a year 2002/Q3 2004/Q1 2005/Q3 2007/Q1 2002/Q4 2004/Q2 2005/Q4 2007/Q2 2003/Q1 2004/Q3 2006/Q1 2007/Q3 2003/Q2 2004/Q4 2006/Q2 2007/Q4 2003/Q3 2005/Q1 2006/Q3 2008/Q1 2003/Q4 2005/Q2 2006/Q4 Portugal Switzerland United Kingdom Austria Belgium Finland Germany Greece Netherlands Turkey Source: IMS Health data provided by F. Hoffmann – La Roche Ltd., Basel except for: Denmark;,data provided by Danish Medicines Agency, and Norway: data provided by Norwegian Institute of Public Health. E U R O S U R V E I L L A N C E Vol . 14 · I ss u e 5 · 5 F eb r u a r y 2 0 0 9 · w w w . e u r o s u rv e i ll a n c e . o r g 3 Prescriptions per 1,000 inhabitants only partially explains this peak. Although the media paid some A(H1N1) in Europe in the 2007-8 season. The H274Y point attention in early 2005 to ongoing outbreaks of avian influenza mutation, which confers oseltamivir resistance is most likely a among poultry in Indonesia, Thailand, and Vietnam and possibly random event, and potential factors influencing its occurrence are also in Cambodia and Lao People’s Democratic Republic, it was not known [32]. the outbreaks of avian influenza in Turkey, Romania, Croatia and the UK in October 2005 which spiked most of the media reports Our study had several limitations, apart from being restricted that year [26]. At the time there were public statements in many to an ecological level of analysis. Firstly, we obtained information countries about national antiviral stockpiles being purchased by on antiviral medication prescriptions which do not necessarily governments [28,29]. represent all medications consumed. Indeed, it is possible that some of the purchased medications were not consumed but stored It should be noted that some countries had significant levels in “private stockpiles”. This seems especially likely for the antivirals of prescribing even before 2005, which could be an indication acquired in the peak year of 2005. Secondly, the IMS Health data for therapeutic or prophylactic application by physicians. The are based on a sample of physicians who may not necessarily be contrasting prescription pattern in Greece with high use in 2003 representative for all physicians in the analysed countries. Thirdly, and 2004, may represent the seasonal inu fl enza activity pattern in data were only available for a limited number of EU Member States that country with the highest activity in February-April 2003, and and EEA/EFTA countries, and the situation could be quite different then from December 2003 to the first months of 2004. in the countries that we could not study. Moreover, for several countries we only had data on oseltamivir resistance for the first We also found a substantial variation in prescription rates quarter of 2008. between the analysed countries, which is hard to justify on any scientific grounds. Reasons may be differences in national Conclusion guidelines, clinical practice patterns, marketing strategies or While the precise relationship between oseltamivir use and insurance companies’ reimbursement [30]. Among the countries resistance of influenza A(H1N1) to oseltamivir remains uncertain, with negligible use of anti-influenza drugs, the UK and the the available data do not suggest a link between the rapid rise in Netherlands have medical guidelines on when antiviral medications the proportion of the resistant A(H1N1) and the use of oseltamivir are indicated that restrict their widespread use [4,12,31], while in Europe. in Switzerland, most insurance companies do not reimburse the use of antivirals (D. Koch, personal communication). Exploring The use of influenza antiviral medication in EU Member States this phenomenon in more detail would warrant a separate study should be closely monitored in the future. More studies are needed and would be justified because the wide variations in the use of to assess how the influenza prescription rates reflect the actual antivirals for inu fl enza does at present not ree fl ct observed patterns use of the medication by patients, in order to explore the potential of influenza-like illness/influenza and cannot be seen as having a causes of the large variation in the number of prescriptions in EU scientific basis. Member States and EEA/EFTA countries. In addition, a scientific discussion is needed about what are the right indicators for use of Although the analyses had to be restricted to ecological analyses, these drugs. Virological studies are needed to better understand these preliminary data do not point towards any correlation between the mechanism behind the development of oseltamivir resistance a higher prevalence of resistance and higher rates of antiviral use. among A(H1N1) seasonal influenza viruses, and to monitor the Hence, it seems very unlikely that oseltamivir use has driven the possible emergence and spread among other influenza viruses. rise and persistence of ‘fit’ oseltamivir-resistant influenza viruses Epidemiological studies are needed to understand the determinants of resistance development, in order to be able to design targeted interventions and to assess the impact on transmission and clinical outcome. F i g u r e 4 Reg ressi on of the prop or ti on of resistant str ains on the numb er of pres cripti ons of os eltamiv ir p er 1,000 in habitants in Europ e an countri es A k n ow le d ge m e n t s 80 We wish to thank David Reddy and James Smith (F.Hoffmann-La Roche Ltd) for making available the data on oseltamivir use in the analysed countries. ECDC would like to thank all countries, virologists, clinicians and others for contributing data. Funding for the VIRGIL project comes from the European Union FP6 Research Programme http://ec.europa.eu/ research/health/inu fl enza/proj13_en.html and EISS is supported by ECDC. Laboratories in EISS contribute to the Global Influenza Surveillance Network managed by WHO. R e fe re n c e s 1. Nichol KL. Complications of influenza and benefits of vaccination. Vaccine. 1999;17 Suppl 1:S47-52. 0 0.5 1 1.5 2. Simonsen L. The global impact of influenza on morbidity and mortality. Vaccine. 1999;17 Suppl 1:S3-10. Oseltamivir prescriptions per 1,000 inhabitants 2007/Q1 3. Fleming DM, Elliot AJ. The impact of influenza on the health and health care Source as in Figure 3. utilisation of elderly people. Vaccine. 2005;23 Suppl 1:S1-9. 4 E U R O S U R V E I L L A N C E Vol . 14 · I ss u e 5 · 5 F eb r u a r y 2 0 0 9 · w w w . e u r o s u rv e i ll a n c e . o r g % resistance 2008 4. National Institute for Clinical Excellence (NICE).Guidance on the use of 27. World Health Organization (WHO). H5N1 avian influenza: timeline of major events. Geneva: World Health Organization. Available from: http://www.who. oseltamivir and amantadine for the prophylaxis of inu fl enza. London: National int/csr/disease/avian_inu fl enza/ai_timeline/en/index.html. [Accessed 3 June, Institute for Clinical Excellence; 2003 Sep. Technolog y Appraisal Guidance 67. 2008]. Available from: http://www.nice.org.uk/nicemedia/pdf/67_Flu_prophylaxis_ guidance.pdf 28. Trakatellis A. A high level policy report. Pandemic Inu fl enza in the EU: Are we 5. Moscona A. Oseltamivir resistance--disabling our influenza defences. N Engl sufficiently prepared?. Brussels: European Parliament; 2007. Available from: J Med. 2005;353(25):2633-6. http://www.atrakatellis.gr/Events/19/Final%20report%20(3).pdf 29. Meijer A, Lackenby A, Hay A, Zambon M. Influenza antiviral susceptibility 6. Jefferson T, Demicheli V, Di Pietrantonj C, Rivetti D. Amantadine and rimantadine monitoring activities in relation to national antiviral stockpiles in Europe for influenza A in adults. Cochrane Database Syst Rev. 2006;2:CD001169. during the winter 2006/2007 season. Euro Surveill. 2007;12(4):pii=698. Available 7. Fleming DM. Managing influenza: amantadine, rimantadine and beyond. Int J from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=698 Clin Pract. 2001;55(3):189-95. 30. Stephenson I, Clark TW, Pareek M. Antiviral treatment and prevention of 8. von Itzstein M. The war against influenza: discovery and development of seasonal inu fl enza: A comparative review of recommendations in the European sialidase inhibitors. Nat Rev Drug Discov. 2007;6(12):967-74. Union. J Clin Virol.2008;42(3):244-8. 9. Jefferson TO, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D. Neuraminidase 31. Centre for Infectious Diseases Control Netherlands (CIb). Inu fl enza. Bilthoven: inhibitors for preventing and treating influenza in healthy adults. Cochrane National Institute for Public Health and the Environment (RIVM). Available Database Syst Rev. 2006;3:CD001265. from: http://www.rivm.nl/cib/infectieziekten/Influenza/Influenza.jsp. 10. Hayden FG. Antiviral resistance in influenza viruses – implications for [Accessed 25 January 2009]. management and pandemic response. N Engl J Med. 2006;354(8):785-8. 32. Ives JA, Carr JA, Mendel DB, Tai CY, Lambkin R, Kelly L, et al. The H274Y mutation 11. Bright RA, Medina M, Xu X, Perez-Oronoz G, Wallis TR, Davis XM, et al. Incidence in the influenza A/H1N1 neuraminidase active site following oseltamivir of adamantane resistance among inu fl enza A (H3N2) viruses isolated worldwide phosphate treatment leave virus severely compromised both in vitro and in from 1994 to 2005: a cause for concern. Lancet. 2005;366(9492):1175-81. vivo. Antiviral Res. 2002;55(2):307-17. 12. National Institute for Clinical Excellence (NICE). Guidance on the use of zanamivir, oseltamivir and amantadine for the treatment of inu fl enza. London: National Institute for Clinical Excellence; 2003 Feb. Technolog y Appraisal This article was published on 5 February 2009. Guidance 58. Available from: http://www.nice.org.uk/nicemedia/pdf/58_Flu_ fullguidance.pdf Citation style for this article: Kramarz P, Monnet D, Nicoll A, Yilmaz C, Ciancio B. Use of oseltamivir in 12 European countries between 2002 and 2007 – lack of association 13. Lackenby A, Hungnes O, Dudman SG, Meijer A, Paget WJ, Hay AJ, et al. Emergence with the appearance of oseltamivir-resistant inu fl enza A(H1N1) viruses . Euro Surveill. of resistance to oseltamivir among inu fl enza A(H1N1) viruses in Europe. Euro 2009;14(5):pii=19112. Available online: http://www.eurosurveillance.org/ViewArticle. Surveill. 2008;13(5):pii=8026. Available from: http://www.eurosurveillance.org/ aspx?ArticleId=19112 ViewArticle.aspx?ArticleId=8026 14. McKimm-Breschkin J, Trivedi T, Hampson A, Hay A, Klimov A, Tashiro M, et al. Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrob Agents Chemother. 2003;47(7):2264-72 15. Monto AS, McKimm-Breschkin JL, Macken C, Hampson AW, Hay A, Klimov A, et al. Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob Agents Chemother. 2006;50(7):2395-402. 16. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al. Resistant inu fl enza A viruses in children treated with oseltamivir: descriptive study. Lancet. 2004;364(9436):759-65. 17. Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother. 2005;55 Suppl 1:i5-i21. 18. Nicoll A, Ciancio B, Kramarz P, on behalf of the Inu fl enza Project Team. Observed oseltamivir resistance in seasonal inu fl enza viruses in Europe interpretation and potential implications. Euro Surveill. 2008;13(5):pii=8025. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=8025 19. European Centre for Disease Control and Prevention (ECDC). Percentage oseltamivir resistance in A(H1N1) seasonal influenza virus detected in Europe. Stockholm: European Centre for Disease Control and Prevention; 2008. Available from: http://ecdc.europa.eu/Health_topics/influenza/antivirals_ graph.html. 20. EUROSTAT website. Population and social conditions. European Commission. Available from: http://epp.eurostat .ec.europa.eu/portal/page?_ pageid=0,1136184,0_45572595&_dad=portal&_schema=PORTAL. [Accessed 3 June 2008]. 21. Norwegian Prescription Database. Oslo: Norwegian Institute of Public Health. Available from: http://www.fhi.no/eway/default.aspx?pid=238&trg=MainArea_ 5811&MainArea_5811=5903:0:15,4440:1:0:0:::0:0. [Accessed 3 June, 2008]. 22. Danish Prescription Database. Statistics. Copenhagen: Danish Medicines Agency. Available from: http://www.dkma.dk/1024/visUKLSArtikel.asp?artikelID=1672. [accessed 3 June, 2008]. 23. Yasui K, Amano Y, Minami I, Nakamura S, Akazawa Y, Uchida N. Recent changes in the trends of seasonal inu fl enza outbreaks in the Nagano Prefectural area of Japan: an oseltamivir effect? J Infect Chemother. 2007;13(6):429-31. 24. World Health Organization (WHO). Influenza A(H1N1) virus resistance to oseltamivir. Geneva: World Health Organization. Available from: http://www. who.int/csr/disease/inu fl enza/oseltamivir_summary/en/index.html. [Accessed 3 June, 2008]. 25. Centers for Disease Control and Prevention (CDC). Increased antiviral medication sales before the 2005-06 influenza season--New York City. MMWR Morb Mortal Wkly Rep. 2006;55(10):277-9. 26. Ortiz JR, Kamimoto L, Aubert RE, Yao J, Shay DK, Bresee JS, et al. Oseltamivir prescribing in pharmacy-benefits database, United States, 2004-2005. Emerg Infect Dis. 2008;14(8):1280-3. E U R O S U R V E I L L A N C E Vol . 14 · I ss u e 5 · 5 F eb r u a r y 2 0 0 9 · w w w . e u r o s u rv e i ll a n c e . o r g 5 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Eurosurveillance Unpaywall

Use of oseltamivir in 12 European countries between 2002 and 2007 – lack of association with the appearance of oseltamivir-resistant influenza A(H1N1) viruses

EurosurveillanceFeb 5, 2009

Loading next page...
 
/lp/unpaywall/use-of-oseltamivir-in-12-european-countries-between-2002-and-2007-lack-NUXyHqe25w

References

References for this paper are not available at this time. We will be adding them shortly, thank you for your patience.

Publisher
Unpaywall
ISSN
1025-496X
DOI
10.2807/ese.14.05.19112-en
Publisher site
See Article on Publisher Site

Abstract

R e s e a r c h a r t i c l e s U s e o f o s e lt a m i v i r i n 1 2 e U r o p e a n c o U n t r i e s b e t w e e n 2 0 0 2 a n d 2 0 0 7 – l a c k o f a s s o c i a t i o n w i t h t h e a p p e a r a n c e o f o s e lt a m i v i r - r e s i s t a n t i n f l U e n z a a ( h 1 n 1 ) v i r U s e s 1 1 1 2 1 P Kramarz (Piotr.Karamarz@ecdc.europa.eu) , Dominique Monnet , A Nicoll , C Yilmaz , B Ciancio 1. European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden 2. Ministry of Health of the Republic of Turkey, Ankara, Turkeyl Variable levels of oseltamivir resistance among seasonal influenza NAIs, especially the oral drug oseltamivir, became increasingly A(H1N1) isolates have been reported in Europe during the 2007-8 important after a sudden increase in adamantane resistance among northern Hemisphere influenza season. It has been questioned seasonal influenza A viruses between 2004 and 2006 [5,10,11]. whether oseltamivir use could have driven the emergence and NAIs have also been preferred in recommendations to amantadine predominance of resistant viruses. This study aimed at describing (the most commonly used adamantane) since they show lower the levels of use of oseltamivir in 12 European Union (EU) Member levels of adverse neurotoxic reactions [12]. Before the 2007-8 States and European Economic Area (EEA)/European Free Trade influenza season, resistance to the NAIs among transmitting Area (EFTA) countries. The data were converted into prescription seasonal influenza A viruses was extremely rare in Europe and rates and compared with the national proportions of resistant elsewhere [13-15] and higher proportions of resistance had been reported only in children: up to 18% of children infected with inu fl enza A(H1N1) viruses through regression analysis. Overall use of oseltamivir in European countries between 2002 and 2007 was inu fl enza A(H3N2) and treated with oseltamivir shed virus resistant to oseltamivir [16-17]. However, NAI-resistant viruses detected low compared to e.g. the use in Japan. High variability between the countries and over time was observed. In eight of the 12 countries, before 2007-8 showed in most cases a poor ability to transmit from human to human. there was a peak of prescriptions in 2005, coinciding with concerns about a perceived threat from an influenza pandemic which might have lead to personal stockpiling. Ecological comparison between This situation changed abruptly during the 2007-8 northern national levels of use of oseltamivir in 2007 and the proportions Hemisphere inu fl enza season when inu fl enza A(H1N1) virus isolates of A(H1N1) viruses that were resistant to oseltamivir showed no highly resistant to oseltamivir were detected as part of surveillance statistical association. In conclusion, our results do not support the in the Europe through the networks of the European Influenza hypothesis that the emergence and persistence of these viruses in Surveillance Scheme (EISS)/European Surveillance Network for 2007-8 was related to the levels of use of oseltamivir in Europe. Vigilance against Viral Resistance (VIRGIL) [13,18]. Laboratory Further investigation is needed to elucidate the reasons for different analyses showed that up to 67.4% of all inu fl enza A(H1N1) viruses level of use between the countries. isolated from specimens collected between November 2007 and April 2008 in Europe either carried the mutation H274Y which Introduction is associated with high levels of oseltamivir resistance or tested Annual epidemics of human seasonal influenza are associated positively in the IC50 phenotypic examination for oseltamivir with a substantial burden of morbidity and mortality, which resistance (Figure 1) [19]. This was the first indication that cumulates in certain groups of the population such as older influenza A(H1N1) virus resistant to oseltamivir could readily people and those with chronic medical conditions [1-3]. Annual transmit between humans. vaccination remains the mainstay of influenza prevention, and antiviral medications, including the neuraminidase inhibitors The question arises whether current levels of oseltamivir use in (NAIs) oseltamivir and zanamivir, and M2 protein inhibitors (the European countries could have been associated with the emergence adamantanes amantadine and rimantadine) play an auxiliary role and sustained transmission of resistant inu fl enza A(H1N1) viruses. in the prevention or treatment of influenza infection. They can be The aim of the study was thus to describe, using all available especially helpful in controlling outbreaks in nursing homes, in data (including data from prescription surveys and databases), individuals who cannot be immunised or in situations in which oseltamivir usage at population level in several EU Member vaccine has not been given or in which vaccination is not optimally States and EEA/EFTA countries and to determine if there was any effective due to a poor match between the vaccine strain and the correlation between the level of use and the observed proportions circulating strains [4-9]. of A(H1N1) viruses that were resistant. E U R O S U R V E I L L A N C E Vol . 14 · I ss u e 5 · 5 F eb r u a r y 2 0 0 9 · w w w . e u r o s u rv e i ll a n c e . o r g 1 Methods these data into prescription rates (number of prescriptions per We used several sources of information on oseltamivir 1,000 inhabitants per year) using Eurostat population data [20]. prescriptions as a proxy measure for oseltamivir utilisation in EU Four other countries monitored by IMS Health, the Netherlands, Member States and EEA/EFTA countries. Portugal, Switzerland and the United Kingdom (UK), had only negligible prescription levels for oseltamivir. Information on oseltamivir use from a prescription survey We used data from a continuing survey of a panel of office- Information on oseltamivir use from population prescription based physicians in EU Member States and EEA/EFTA countries databases from databases maintained by Intercontinental Marketing Services In Denmark and Norway, data on the number of patients having (IMS) Health, an independent commercial company providing used oseltamivir at least once each year between 2002 and 2007 information on the use of pharmaceuticals. IMS Health attempts and between 2004 and 2007, respectively, were extracted from to achieve a high level of representativeness of their panels for the national, publicly available databases on redeemed prescriptions population of all physicians in the involved countries. Participating [21,22]. These numbers of prescriptions were converted into rates physicians are being surveyed for two consecutive workdays per of redeemed prescriptions per 1,000 inhabitants per year. In both quarter of a year and provide information on each patient encounter countries, data included corporate prescriptions, i.e. medicines during this period. The manufacturer of oseltamivir, F.Hoffmann-La purchased by business organisations for their employees. The data Roche Ltd., provided the European Centre for Disease Control and did not include any supply of antiviral medications to countries for Prevention (ECDC) with the data from IMS Health on the numbers national or corporate stockpiles. of oseltamivir prescriptions in Austria, Belgium, Finland, France, Germany and Greece for the years 2002 to 2007. We then converted Quarterly prescription information The initial analysis consisted in computing annual figures for oseltamivir prescriptions per 1,000 inhabitants. To examine trends in oseltamivir use over time in more detail, we also obtained F i g u r e 1 quarterly prescription numbers and converted them into prescription Nati ona l prop or ti ons of antiv ir a l resistance in A(H1N1) rates. Quarterly data were available for eight countries: Austria, inf lu enza v ir us es for EU/EEA Memb er States, 2007-8 Belgium, Finland, Germany, Greece, the Netherlands, Portugal, Switzerland, and the UK. Norway 67.4% Investigation of the relationship between oseltamivir use and Belgium 53.1% levels of resistance France 46.6% Linear regression analysis was performed to determine whether Netherlands 26.9% there was any relationship between the use of oseltamivir and Luxembourg 26.0% the levels of oseltamivir resistance. Proportions of oseltamivir Finland 23.1% resistance during the 2007-8 inu fl enza season among all A(H1N1) 20.7% Portugal tested strains expressed on the web sites of ECDC, EISS and the World Health Organization (WHO) were regressed on the levels of Switzerland 18.9% Germany 13.1% 11.1% Sweden Ireland 11.1% F i g u r e 2 United Kingdom 11.0% Pres cripti ons of os eltamiv ir p er 1,000 in habitants in eig ht Greece 10.8% Europ e an countri es*, 2002-2007 Poland 10.0% Romania 8.2% 6 2002 Austria 7.3% Denmark 4.4% 2004 Slovenia 3.6% 1.9% Spain Italy 0.9% Slovakia 0.0% 0.0% Latvia Hungary 0.0% Czech Republic 0.0% Austria Belgium Germany Denmark† Greece Finland France Norway† 0.0 10 20 30 40 50 60 70 80 Data (available as of 6 August 2008) were provided by European Influenza * Data only include patient prescriptions. They do not include stockpiles Surveillance Scheme www.eiss.org/index.cgi and the VIRGIL Project at national /regional level or by hospitals/institutions. Data for Denmark www.virgil-net.org. and Norway include corporate prescriptions. Countries with fewer than 10 test results (Bulgaria, Estonia) are not Netherlands, Portugal, UK and Switzerland: data not presented due to shown in the graph. ‘negligible’ number of prescriptions. EU/EE A/EF TA countries in the EISS network for which no test results were † Denmark and Norway: the data are based on the number of patients, available: Cyprus, Lithuania, Malta. which may slightly underestimate the number of prescriptions. EU: European Union; EE A: European Economic Area EF TA: European Free Trade Source: IMS Health data provided by F. Hoffmann – La Roche Ltd., Basel Area; EISS: European Influenza Surveillance Scheme; VIRGIL: European except for: Denmark;,data provided by Danish Medicines Agency, and Surveillance Network for Vigilance against Viral Resistance. Norway: data provided by Norwegian Institute of Public Health. 2 E U R O S U R V E I L L A N C E Vol . 14 · I ss u e 5 · 5 F eb r u a r y 2 0 0 9 · w w w . e u r o s u rv e i ll a n c e . o r g Prescriptions per 1,000 inhabitants oseltamivir use in the countries in 2007. STATA (STATA/SE 10 for It was noticeable that the peak of oseltamivir use observed Windows, STATA Corporation) was used for statistical analyses. in 2005 in Austria, Belgium, Finland and Germany (Figure 2) concentrated mostly during the first quarter of that year. Results Annual oseltamivir prescription rates No correlation of prescription data and resistance development As shown in Figure 2, the overall prescription rates for oseltamivir We have analysed oseltamivir resistance in 2007-8 because a remained under six prescriptions/1,000 inhabitants/year in the sharp increase in resistance was observed during that season. We eight EU Member States for which such data was availabe. This is regressed it against oseltamivir use in 2007 assuming this was low compared to those reported, for example, in Japan where the a good proxy for oseltamivir use in 2008. However, regression reported prescription rate in 2005 was 70.9/1,000 inhabitants/ analysis for twelve countries (Figure 4) did not show any statistical year [23]. association between the levels of oseltamivir resistance during the influenza season 2007-8 and oseltamivir prescriptions in 2007 After a substantial peak in prescriptions in 2005, when (R2 = 0.02). three countries exceeded three prescriptions/1,000 inhabitants/ year (Austria, Belgium and Norway) and one country exceeded Discussion five prescriptions/1,000 inhabitants/year (Germany), the use of We found overall low levels of oseltamivir use in EU Member oseltamivir decreased to under two prescriptions/1,000 inhabitants/ States in the period between 2002 and 2007, compared to the use year in 2006 and 2007 in all included countries. However, the of oseltamivir in Japan, a country with the world’s highest per capita trends from 2006 to 2007 differed: an increase occurred in Austria, use of oseltamivir (70.9/1,000 inhabitants/year), but relatively low Belgium, Finland and France, a small decrease in Germany, Greece levels (3%) of oseltamivir resistance during the 2007-8 season and Norway, and the rates remained stable in Denmark. [23,24]. In the most recent year with available data (2007), we observed a There was a common peak in prescriptions in 2005 in eight substantial variation in oseltamivir prescription rates in EU Member countries. One possible explanation for this phenomenon is the States, with an almost tenfold differences in those countries with concern over ‘bird flu’ influenza A(H5N1) in 2005 when spread any significant use of oseltamivir. The highest rates were seen in of these viruses from Asia towards Europe received considerable Belgium and the lowest in Greece. Countries with negligible use attention in the media. Many of these prescriptions to individuals that are not shown in the figure are the Netherlands, Portugal, and families may therefore have gone to form a source of medication Switzerland and the UK. Greece exhibited a different prescription for the future (“personal stockpiling”). A similar spike of influenza pattern with high use in 2003 and 2004. antiviral medication sales, was observed in October 2005 in New York [25] and, in general, in the autumn and winter of 2005 accross the United States [26]. It did not coincide with influenza In summary, our analysis showed low prescription rates of oseltamivir with substantial variation between analysed countries activity itself, but rather with the beginning media coverage of avian influenza A (H5N1) and the potential for an influenza pandemic and over time. [23]. Quarterly oseltamivir prescription rates Figure 3 shows a more detailed comparison of oseltamivir It is more difficult to explain the observation that most of the prescription rates in eight countries for which data were available oseltamivir use in EU Member States in 2005 concentrated in the at the level of periods of three months. r fi st quarter of the year. Inu fl enza activity during the season 2004-5 F i g u r e 3 Prescriptions of oseltamivir per 1,000 inhabitants in eight European countries*, 2002-2007, by quarter of a year 2002/Q3 2004/Q1 2005/Q3 2007/Q1 2002/Q4 2004/Q2 2005/Q4 2007/Q2 2003/Q1 2004/Q3 2006/Q1 2007/Q3 2003/Q2 2004/Q4 2006/Q2 2007/Q4 2003/Q3 2005/Q1 2006/Q3 2008/Q1 2003/Q4 2005/Q2 2006/Q4 Portugal Switzerland United Kingdom Austria Belgium Finland Germany Greece Netherlands Turkey Source: IMS Health data provided by F. Hoffmann – La Roche Ltd., Basel except for: Denmark;,data provided by Danish Medicines Agency, and Norway: data provided by Norwegian Institute of Public Health. E U R O S U R V E I L L A N C E Vol . 14 · I ss u e 5 · 5 F eb r u a r y 2 0 0 9 · w w w . e u r o s u rv e i ll a n c e . o r g 3 Prescriptions per 1,000 inhabitants only partially explains this peak. Although the media paid some A(H1N1) in Europe in the 2007-8 season. The H274Y point attention in early 2005 to ongoing outbreaks of avian influenza mutation, which confers oseltamivir resistance is most likely a among poultry in Indonesia, Thailand, and Vietnam and possibly random event, and potential factors influencing its occurrence are also in Cambodia and Lao People’s Democratic Republic, it was not known [32]. the outbreaks of avian influenza in Turkey, Romania, Croatia and the UK in October 2005 which spiked most of the media reports Our study had several limitations, apart from being restricted that year [26]. At the time there were public statements in many to an ecological level of analysis. Firstly, we obtained information countries about national antiviral stockpiles being purchased by on antiviral medication prescriptions which do not necessarily governments [28,29]. represent all medications consumed. Indeed, it is possible that some of the purchased medications were not consumed but stored It should be noted that some countries had significant levels in “private stockpiles”. This seems especially likely for the antivirals of prescribing even before 2005, which could be an indication acquired in the peak year of 2005. Secondly, the IMS Health data for therapeutic or prophylactic application by physicians. The are based on a sample of physicians who may not necessarily be contrasting prescription pattern in Greece with high use in 2003 representative for all physicians in the analysed countries. Thirdly, and 2004, may represent the seasonal inu fl enza activity pattern in data were only available for a limited number of EU Member States that country with the highest activity in February-April 2003, and and EEA/EFTA countries, and the situation could be quite different then from December 2003 to the first months of 2004. in the countries that we could not study. Moreover, for several countries we only had data on oseltamivir resistance for the first We also found a substantial variation in prescription rates quarter of 2008. between the analysed countries, which is hard to justify on any scientific grounds. Reasons may be differences in national Conclusion guidelines, clinical practice patterns, marketing strategies or While the precise relationship between oseltamivir use and insurance companies’ reimbursement [30]. Among the countries resistance of influenza A(H1N1) to oseltamivir remains uncertain, with negligible use of anti-influenza drugs, the UK and the the available data do not suggest a link between the rapid rise in Netherlands have medical guidelines on when antiviral medications the proportion of the resistant A(H1N1) and the use of oseltamivir are indicated that restrict their widespread use [4,12,31], while in Europe. in Switzerland, most insurance companies do not reimburse the use of antivirals (D. Koch, personal communication). Exploring The use of influenza antiviral medication in EU Member States this phenomenon in more detail would warrant a separate study should be closely monitored in the future. More studies are needed and would be justified because the wide variations in the use of to assess how the influenza prescription rates reflect the actual antivirals for inu fl enza does at present not ree fl ct observed patterns use of the medication by patients, in order to explore the potential of influenza-like illness/influenza and cannot be seen as having a causes of the large variation in the number of prescriptions in EU scientific basis. Member States and EEA/EFTA countries. In addition, a scientific discussion is needed about what are the right indicators for use of Although the analyses had to be restricted to ecological analyses, these drugs. Virological studies are needed to better understand these preliminary data do not point towards any correlation between the mechanism behind the development of oseltamivir resistance a higher prevalence of resistance and higher rates of antiviral use. among A(H1N1) seasonal influenza viruses, and to monitor the Hence, it seems very unlikely that oseltamivir use has driven the possible emergence and spread among other influenza viruses. rise and persistence of ‘fit’ oseltamivir-resistant influenza viruses Epidemiological studies are needed to understand the determinants of resistance development, in order to be able to design targeted interventions and to assess the impact on transmission and clinical outcome. F i g u r e 4 Reg ressi on of the prop or ti on of resistant str ains on the numb er of pres cripti ons of os eltamiv ir p er 1,000 in habitants in Europ e an countri es A k n ow le d ge m e n t s 80 We wish to thank David Reddy and James Smith (F.Hoffmann-La Roche Ltd) for making available the data on oseltamivir use in the analysed countries. ECDC would like to thank all countries, virologists, clinicians and others for contributing data. Funding for the VIRGIL project comes from the European Union FP6 Research Programme http://ec.europa.eu/ research/health/inu fl enza/proj13_en.html and EISS is supported by ECDC. Laboratories in EISS contribute to the Global Influenza Surveillance Network managed by WHO. R e fe re n c e s 1. Nichol KL. Complications of influenza and benefits of vaccination. Vaccine. 1999;17 Suppl 1:S47-52. 0 0.5 1 1.5 2. Simonsen L. The global impact of influenza on morbidity and mortality. Vaccine. 1999;17 Suppl 1:S3-10. Oseltamivir prescriptions per 1,000 inhabitants 2007/Q1 3. Fleming DM, Elliot AJ. The impact of influenza on the health and health care Source as in Figure 3. utilisation of elderly people. Vaccine. 2005;23 Suppl 1:S1-9. 4 E U R O S U R V E I L L A N C E Vol . 14 · I ss u e 5 · 5 F eb r u a r y 2 0 0 9 · w w w . e u r o s u rv e i ll a n c e . o r g % resistance 2008 4. National Institute for Clinical Excellence (NICE).Guidance on the use of 27. World Health Organization (WHO). H5N1 avian influenza: timeline of major events. Geneva: World Health Organization. Available from: http://www.who. oseltamivir and amantadine for the prophylaxis of inu fl enza. London: National int/csr/disease/avian_inu fl enza/ai_timeline/en/index.html. [Accessed 3 June, Institute for Clinical Excellence; 2003 Sep. Technolog y Appraisal Guidance 67. 2008]. Available from: http://www.nice.org.uk/nicemedia/pdf/67_Flu_prophylaxis_ guidance.pdf 28. Trakatellis A. A high level policy report. Pandemic Inu fl enza in the EU: Are we 5. Moscona A. Oseltamivir resistance--disabling our influenza defences. N Engl sufficiently prepared?. Brussels: European Parliament; 2007. Available from: J Med. 2005;353(25):2633-6. http://www.atrakatellis.gr/Events/19/Final%20report%20(3).pdf 29. Meijer A, Lackenby A, Hay A, Zambon M. Influenza antiviral susceptibility 6. Jefferson T, Demicheli V, Di Pietrantonj C, Rivetti D. Amantadine and rimantadine monitoring activities in relation to national antiviral stockpiles in Europe for influenza A in adults. Cochrane Database Syst Rev. 2006;2:CD001169. during the winter 2006/2007 season. Euro Surveill. 2007;12(4):pii=698. Available 7. Fleming DM. Managing influenza: amantadine, rimantadine and beyond. Int J from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=698 Clin Pract. 2001;55(3):189-95. 30. Stephenson I, Clark TW, Pareek M. Antiviral treatment and prevention of 8. von Itzstein M. The war against influenza: discovery and development of seasonal inu fl enza: A comparative review of recommendations in the European sialidase inhibitors. Nat Rev Drug Discov. 2007;6(12):967-74. Union. J Clin Virol.2008;42(3):244-8. 9. Jefferson TO, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D. Neuraminidase 31. Centre for Infectious Diseases Control Netherlands (CIb). Inu fl enza. Bilthoven: inhibitors for preventing and treating influenza in healthy adults. Cochrane National Institute for Public Health and the Environment (RIVM). Available Database Syst Rev. 2006;3:CD001265. from: http://www.rivm.nl/cib/infectieziekten/Influenza/Influenza.jsp. 10. Hayden FG. Antiviral resistance in influenza viruses – implications for [Accessed 25 January 2009]. management and pandemic response. N Engl J Med. 2006;354(8):785-8. 32. Ives JA, Carr JA, Mendel DB, Tai CY, Lambkin R, Kelly L, et al. The H274Y mutation 11. Bright RA, Medina M, Xu X, Perez-Oronoz G, Wallis TR, Davis XM, et al. Incidence in the influenza A/H1N1 neuraminidase active site following oseltamivir of adamantane resistance among inu fl enza A (H3N2) viruses isolated worldwide phosphate treatment leave virus severely compromised both in vitro and in from 1994 to 2005: a cause for concern. Lancet. 2005;366(9492):1175-81. vivo. Antiviral Res. 2002;55(2):307-17. 12. National Institute for Clinical Excellence (NICE). Guidance on the use of zanamivir, oseltamivir and amantadine for the treatment of inu fl enza. London: National Institute for Clinical Excellence; 2003 Feb. Technolog y Appraisal This article was published on 5 February 2009. Guidance 58. Available from: http://www.nice.org.uk/nicemedia/pdf/58_Flu_ fullguidance.pdf Citation style for this article: Kramarz P, Monnet D, Nicoll A, Yilmaz C, Ciancio B. Use of oseltamivir in 12 European countries between 2002 and 2007 – lack of association 13. Lackenby A, Hungnes O, Dudman SG, Meijer A, Paget WJ, Hay AJ, et al. Emergence with the appearance of oseltamivir-resistant inu fl enza A(H1N1) viruses . Euro Surveill. of resistance to oseltamivir among inu fl enza A(H1N1) viruses in Europe. Euro 2009;14(5):pii=19112. Available online: http://www.eurosurveillance.org/ViewArticle. Surveill. 2008;13(5):pii=8026. Available from: http://www.eurosurveillance.org/ aspx?ArticleId=19112 ViewArticle.aspx?ArticleId=8026 14. McKimm-Breschkin J, Trivedi T, Hampson A, Hay A, Klimov A, Tashiro M, et al. Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrob Agents Chemother. 2003;47(7):2264-72 15. Monto AS, McKimm-Breschkin JL, Macken C, Hampson AW, Hay A, Klimov A, et al. Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob Agents Chemother. 2006;50(7):2395-402. 16. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al. Resistant inu fl enza A viruses in children treated with oseltamivir: descriptive study. Lancet. 2004;364(9436):759-65. 17. Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother. 2005;55 Suppl 1:i5-i21. 18. Nicoll A, Ciancio B, Kramarz P, on behalf of the Inu fl enza Project Team. Observed oseltamivir resistance in seasonal inu fl enza viruses in Europe interpretation and potential implications. Euro Surveill. 2008;13(5):pii=8025. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=8025 19. European Centre for Disease Control and Prevention (ECDC). Percentage oseltamivir resistance in A(H1N1) seasonal influenza virus detected in Europe. Stockholm: European Centre for Disease Control and Prevention; 2008. Available from: http://ecdc.europa.eu/Health_topics/influenza/antivirals_ graph.html. 20. EUROSTAT website. Population and social conditions. European Commission. Available from: http://epp.eurostat .ec.europa.eu/portal/page?_ pageid=0,1136184,0_45572595&_dad=portal&_schema=PORTAL. [Accessed 3 June 2008]. 21. Norwegian Prescription Database. Oslo: Norwegian Institute of Public Health. Available from: http://www.fhi.no/eway/default.aspx?pid=238&trg=MainArea_ 5811&MainArea_5811=5903:0:15,4440:1:0:0:::0:0. [Accessed 3 June, 2008]. 22. Danish Prescription Database. Statistics. Copenhagen: Danish Medicines Agency. Available from: http://www.dkma.dk/1024/visUKLSArtikel.asp?artikelID=1672. [accessed 3 June, 2008]. 23. Yasui K, Amano Y, Minami I, Nakamura S, Akazawa Y, Uchida N. Recent changes in the trends of seasonal inu fl enza outbreaks in the Nagano Prefectural area of Japan: an oseltamivir effect? J Infect Chemother. 2007;13(6):429-31. 24. World Health Organization (WHO). Influenza A(H1N1) virus resistance to oseltamivir. Geneva: World Health Organization. Available from: http://www. who.int/csr/disease/inu fl enza/oseltamivir_summary/en/index.html. [Accessed 3 June, 2008]. 25. Centers for Disease Control and Prevention (CDC). Increased antiviral medication sales before the 2005-06 influenza season--New York City. MMWR Morb Mortal Wkly Rep. 2006;55(10):277-9. 26. Ortiz JR, Kamimoto L, Aubert RE, Yao J, Shay DK, Bresee JS, et al. Oseltamivir prescribing in pharmacy-benefits database, United States, 2004-2005. Emerg Infect Dis. 2008;14(8):1280-3. E U R O S U R V E I L L A N C E Vol . 14 · I ss u e 5 · 5 F eb r u a r y 2 0 0 9 · w w w . e u r o s u rv e i ll a n c e . o r g 5

Journal

EurosurveillanceUnpaywall

Published: Feb 5, 2009

There are no references for this article.