Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::
Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::
From Eurosurveillance Weekly:
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(1a) [ESWI, ANTIVIRALS, SEASONAL INFLUENZA] Observed oseltamivir resistance in seasonal influenza viruses in Europe interpretation and potential implications (
http://www.eurosurveillance.org/edition/v13n05/080131_1.asp)
A Nicoll and P Kramarz on behalf of the Influenza Project Team (influenza@ecdc.europa.eu)*, European Centre for Disease Prevention and Control, Stockholm, Sweden
*B Ciancio, P Kreidl, H Needham, A Nicoll, C Varela, A Würz, K Fernandez de la Hoz, F Plata, C Yilmaz
In this week’s issue of Eurosurveillance, Zambon and colleagues describe the first findings of the European Union-funded European Surveillance Network for Vigilance Against Viral Resistance (VIRGIL) of some seasonal influenza viral isolates resistant to the antiviral drug oseltamivir in Europe [1]. Since the winter of 2004-5, a sample of influenza viral isolates have been routinely monitored by VIRGIL for antiviral resistance in a number of EU member states and other European countries [2]. Testing of the isolates for the 2007-8 season began in late January, with the finding that in the specimens for the first 10 countries, four countries had a proportion of seasonal influenza A/H1N1 with a mutation that confers a high level of resistance to the drug oseltamivir. The proportion of A/H1N1 isolates that were resistant was especially high in Norway [1], both in genome sequencing and phenotypical testing.
An interim risk assessment was published by the European Centre for Disease Prevention and Control (ECDC) on 27 January based on these preliminary findings and the available science [3].
As of January 31, resistant isolates have been found in nine out of 18 of the European countries whose specimens were tested (Denmark, Finland, France, Germany, the Netherlands, Norway, Portugal, Sweden and the United Kingdom (UK) [1].
Although a high proportion of isolates have been found resistant (overall figure of approximately 14%), the sample size was relatively small, meaning this may not accurately reflect the proportion that are resistant among all infections.
Norway and VIRGIL alerted the World Health Organization (WHO) and all 27 EU and the other 2 EEA countries (Iceland and Liechtenstein) through the International Health Regulations and Early Warning Response System.
Further testing has begun in the laboratories of the Centre of Infections of the UK’s Health Protection Agency as well as the WHO Influenza Collaborating Centre in London, and through sequencing and phenotypic testing in national influenza centres.
The WHO has held international consultations, and testing in WHO Collaborating Centres has identified similar findings in some other parts of the world, although not all.
It is not yet clear from where these viruses emerged, or why.
However, as they are in Europe, we must address them.
The fact that the first findings came from Europe may simply be a reflection of the surveillance methods used here and the timeliness of the work.
They should not be taken to imply that they emerged in Europe.
The WHO is now coordinating further investigations at a global level, while the ECDC, working with the WHO European Region and the European Commission, is coordinating investigations in the EU and EEA/EFTA countries.
The oseltamivir resistance investigation is still in its early stages, with a small number of samples from several countries tested.
A more accurate picture will only emerge when many more specimens have been tested and more epidemiological information is available.
Influenza activity this season has only recently begun to significantly increase in Europe and A/H1N1 has been the predominant strain circulating so far [4].
From the samples examined to date, the proportions of the new virus A/H1N1 with the H274Y mutation appear to be low [1].
Oseltamivir is seemingly not frequently used in Europe, although better data needs to be acquired on this and the use of other antivirals.
There has been no evidence to date that any of the Norwegian patients were exposed to the drug before their infection.
Therefore, the resistance is unlikely to be related to antiviral medication use in individual patients in Europe.
For the same reason, these findings have fewer clinical implications for routine clinical treatment of mild influenza infections than if oseltamivir was used more widely.
The ECDC’s interim risk assessment also emphasised that the findings are not related to avian influenza (the similarly named A/H5N1), pandemics or pandemic preparedness.
However, they are a timely reminder of the ability of influenza viruses to develop antiviral resistance and the fact that it cannot be guaranteed that any novel influenza virus emerging will be sensitive to any particular antiviral medication [5,6,7,8].
Influenza seasons in which H1N1 viruses predominate are typically associated with less severe illness and lower overall mortality than seasons in which other influenza A viruses predominant.
There is currently no evidence that the mutated H1N1 strain is any more virulent than other strains of seasonal influenza (all the Norwegian patients had typical influenza illnesses), but any influenza A can nevertheless cause severe disease or be fatal for vulnerable people, including infants, the elderly and those with chronic debilitating disease.
The circulating A/H1N1 viruses, including the oseltamivir-resistant ones, are well matched with the current seasonal influenza vaccine, meaning that those who have been vaccinated are already at a lower risk of contracting the disease or developing severe complications than those who have not yet been immunised.
The tests conducted so far have also shown that the mutated viruses are fully susceptible to the other currently available antiviral drugs, zanamivir and the adamantanes (amantadine and rimantadine) [1].
However, it is agreed that there is currently insufficient evidence for authorities to consider changes to clinical guidelines.
Resistant viruses carrying the same mutation have been seen in previous seasons but, as with most resistant viruses, were few in number, ‘unfit’ and transmitted poorly.
Consequently, ‘fitter’ non-resistant viruses eventually predominated.
The cautious use of antiviral medication may have contributed to this.
These A/H1N1 isolates with the H274Y mutation are fitter.
They are in several countries and are transmitting in the community [1].
The specimens tested to date are from early in the season and it may be that as the season progresses ordinary A/H1N1s predominate.
Equally, the resistant viruses may come to predominate, as did the adamantane-resistant viruses in other H-types in some parts of the world, notably North America [5].
Careful virological and epidemiological surveillance should continue for the rest of this and other seasons.
The ECDC will revise its assessment as more information on this issue emerges and comments are received.
In collaboration with VIRGIL and the European Influenza Surveillance Scheme (EISS), the Centre will also regularly update the figures on resistance in Europe, initially on a weekly basis.
More information about seasonal influenza can be found on the websites of the ECDC (
http://www.ecdc.europa.eu) and the WHO (
http://www.who.int).
References
1-Lackenby A, Hungnes O, Dudman SG, Meijer A, Paget WJ, Hay AJ, Zambon MC. Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. Euro Surveill 2008;13(5). Available from: LINK
2-Meijer A, Lackenby A, Hay A, Zambon M. Influenza antiviral susceptibility monitoring activities in relation to national antiviral stockpiles in Europe during the winter 2006/2007 season. Euro Surveill 2007;12(4)[Epub ahead of print]. Available from: LINK
3-Interim ECDC Risk Assessment. Emergence of seasonal influenza viruses type A/H1N1 with oseltamivir resistance in some European countries at the start of the 2007-8 influenza season. 27 January 2008. Available from: LINK
4-Arkema JMS, MeijerA, Paget WJ, van Casteren V, Hungnes O, Mazick A and van der Velden J. The influenza season has started in a number of European countries. Euro Surveill 2008;13(4). Available from: LINK
5-Deyde VM, Xu X, Bright RA, Shaw M, Smith CB, Zhang Y, Shu Y, Gubareva LV, Cox NJ, Klimov AI. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J Infect Dis. 2007 Jul 15;196(2):249-57. Epub 2007 Jun 7.
6-Bright RA, Shay DK, Shu B, Cox NJ, Klimov AI. Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. JAMA. 2006 Feb 22;295(8):891-4. Epub 2006 Feb 2.
7-Bright RA, Medina MJ, Xu X, Perez-Oronoz G, Wallis TR, Davis XM, Povinelli L, Cox NJ, Klimov AI. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet. 2005 Oct 1;366(9492):1175-81. Epub 2005 Sep 22.
8-Fiore AE, Shay DK, Haber P, Iskander JK, Uyeki TM, Mootrey G, Bresee JS, Cox NJ. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. Centers for Disease Control and Prevention (CDC). MMWR Recomm Rep. 2007 Jul 13;56(RR-6):1-54.
9-European Centre for Disease Prevention and Control. Seasonal influenza information. Available from: LINK
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(1b) [ESWI, ANTIVIRALS, SEASONAL INFLUENZA] Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe (
http://www.eurosurveillance.org/edition/v13n05/080131_2.asp)
A Lackenby1, O Hungnes2, SG Dudman2, A Meijer3,4, WJ Paget3, AJ Hay5, MC Zambon (Maria.Zambon@HPA.org.uk)1
1. Health Protection Agency, Centre for Infection, London, United Kingdom
2. Norwegian Institute of Public Health, Oslo, Norway
3. EISS Coordination Centre, Nivel Institute, Utrecht, the Netherlands
4. National Centre for Public Health and the Environment, Bilthoven, the Netherlands
5. WHO Collaborating Centre, MRC National Institute of Medical Research, London, United Kingdom
Surveillance of the antiviral susceptibility of influenza viruses circulating in Europe has been established since 2004 through the European Union-funded European Surveillance Network for Vigilance against Viral Resistance (VIRGIL), in collaboration with the European Influenza Surveillance Scheme (EISS), the World Health Organization (WHO) and national influenza centres. Results from analysis of early winter (November 2007 – January 2008) A(H1N1) virus isolates has revealed that a significant proportion, approximately 14% of these European strains (see Table), are resistant to oseltamivir (Tamiflu), the most widely used anti-influenza drug, but retain sensitivity to zanamivir (Relenza) and amantadine/rimantadine.
As of week 03/2008, 16 European countries have reported significant influenza activity (Austria, Belgium, Bulgaria, France, Hungary, Ireland, Italy, Lithuania, Luxembourg, Northern Ireland, Poland, Portugal, Romania, Slovenia, Spain and Switzerland).
Of the total virus detections since week 40/2007 (N=3447), 81% have been influenza A and 19% influenza B, and the predominant viruses circulating in most countries have been A(H1N1) similar to the A/Solomon Islands/3/2007 vaccine strain [1].
The presence of oseltamivir-resistant viruses circulating in the community in several European countries (Denmark, Finland, France, Germany , Netherlands, Norway, Portugal, Sweden and United Kingdom) is in marked contrast to the previous winter seasons of 2004/2005, 2005/2006, and 2006/2007, when oseltamivir resistance was detected in <1% of circulating strains from 24 countries.
A total of 437 influenza A(H1N1) viruses, isolated during November 2007 to January 2008, were tested using measurement of neuraminidase (NA) enzyme activity in the presence of oseltamivir to determine the drug-sensitivity (IC50) of the viral enzyme (2) in conjunction with sequence analysis of the viral neuraminidase gene.
To date, oseltamivir-resistant viruses have been detected in nine countries (Table 1); in particular, 26 of 37 (70%) in Norway, 15 of 87(17%) in France, 3 of 43 (7.0%) in Germany and 8 of 162(5%) in the United Kingdom carry the same mutation, causing the substitution of histidine by tyrosine at residue 274 (H274Y) of the neuraminidase, which is known to confer a high level resistance to oseltamivir.
Viruses bearing this mutation, when tested in enzyme assays, showed a reduction of approximately 400 fold in susceptibility to oseltamivir (IC50 values increased from approximately 1nM to more than 400nM).
All these viruses remain sensitive to the other anti-neuraminidase drug zanamivir and to the anti-M2 drugs amantadine and rimantadine.
The resistant (H274Y) viruses have been isolated from both adults and children, ranging from 1 month to 61 years in age, with the majority of viruses being isolated from adults.
So far, there is no information that any of these viruses, in any country, has been obtained from a person who has either been treated or been in close contact with another individual who has been treated with oseltamivir.
We therefore conclude that the identification of these oseltamivir-resistant viruses as a substantial proportion of circulating viruses, particularly in Norway, is the first clear evidence that influenza A(H1N1) virus with the H274Y mutation can readily transmit between individuals.
More extensive surveillance within Europe and in other parts of the world is required to establish the relative prevalence and geographical distribution of these resistant viruses, and to evaluate their potential impact on the effectiveness of drug use.
The spectrum of clinical illness associated with infection by oseltamivir-resistant viruses remains to be fully determined, although limited information from initial clinical cases does not suggest unusual disease syndromes.
Although the resistant viruses have been isolated from November through January, the ability of these viruses to persist throughout the influenza season, and from one season to the next, will require continuous world-wide surveillance by the WHO Global Influenza Surveillance Network.
Determining the origins and genesis of these drug-resistant strains, which appear to have emerged in regions of the world where there is little drug pressure, will be important in understanding the emergence and persistence of oseltamivir resistance in relation to the evolution of influenza viruses and drug use.
Acknowledgements:
We would like thank all members of EISS laboratories for contributing viruses and data, particularly VIRGIL colleagues Dr Bruno Lina (Lyon) and Dr Sylvie van der Werf (Paris). Funding support from EU FP6 Programme for VIRGIL Contract No 503359.
References
1-European Influenza Surveillance Scheme. Increased influenza activity in Europe. EISS Weekly Electronic Bulletin 2008; 25 January 2008: 250. Available from:
http://www.eiss.org
2-Methodology used for testing in vitro susceptibility of influenza viruses to oseltamivir and zanamivir was described by the Neuraminidase Inhibitor Susceptibility Network (NISN) in Wetherall et al, J Clin Microl. 2003;41;742-50. Surveillance of the antiviral susceptibility of influenza viruses circulating in Europe is supported by the EU-funded VIRGIL programme (Contract No 503359), in collaboration with EISS and the WHO.
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