The World Health Organization has recently published a review of all the cases of 2009 A(H1N1) pandemic influenza viruses reported as resistant to the neuraminidase inhibitor oseltamivir as of 22 October 2009 . The information on cases was derived from published reports, notifications under the International Health Regulations and information provided by WHO collaborating centres. It covers a total of 39 cases.
Among the 32 cases for whom detailed information was available 16 were associated with antiviral treatment of influenza, 13 with antiviral prophylaxis, and three had no history of exposure to oseltamivir.
Common features of all cases were the following:
- Resistance was associated with the histidine to tyrosine point mutation at position 275 (N1 numbering) in the neuraminidase glycoprotein (H275Y).
- None of those tested by a phenotypic assay were resistant to the other neuraminidase inhibitor zanamivir.
- None has arisen as result of reassortment with the seasonal A(H1N1) influenza virus that has become naturally resistant to oseltamivir.
- There is no evidence that oseltamivir-resistant viruses transmitted beyond the close proximity of cases.
- Apart from some severely immunosuppressed patients and two children who developed pneumonia, all other cases experienced an uncomplicated influenza illness.
There are two factors that can be considered as associated with the isolation of an oseltamivir-resistant pandemic virus in this case series:
a) Immunosuppression. This was observed in seven cases and had also been previously observed for seasonal influenza viruses. Experts suggest that prolonged virus replication in immunosuppressed individuals under oseltamivir treatment favours the emergence and selection of resistant viruses .
b) Oseltamivir given for prophylaxis. This was observed in 13 cases and deserves some attention. Oseltamivir resistance has not been considered a common event during prophylaxis for seasonal influenza. However the number of individuals receiving antiviral prophylaxis during a pandemic is likely to be larger.
The WHO article recommends that antiviral resistance testing is considered for patients with persistent and complicated illness after five or more days of antiviral treatment and for patients presenting with an influenza-like illness despite having received antiviral prophylaxis.
Finally, in order to monitor antiviral resistance at community level, the selection of samples undergoing testing should be done in an unbiased way and include a sufficient number of post-treatment samples.
ECDC comment (17-11- 2009):
This article describes the first cases of 2009 A(H1N1) influenza viruses that tested resistant to the neuraminidase inhibitor oseltamivir worldwide.
In general the patients described in this article have been geographically dispersed, cases were sporadic and not linked to one another and the viruses tested by a phenotypic test were all susceptible to the other neuraminidase inhibitor zanamivir.
Extensive susceptibility testing of clinical samples and virus is ongoing in various countries and the data available so far strongly suggest that oseltamivir-resistant viruses are not circulating at community level. For the 2009–10 season starting September 2009, only three out of 1076 viruses tested in the USA as part of the routine surveillance were resistant and only two additional resistant viruses have so far been identified by other laboratories . In Canada, two out of 69 tested viruses were resistant . In Europe since the start of the 2009 pandemic more than 500 viruses have been reported to ECDC as part of antiviral resistance monitoring and none of them was resistant [5, 6]. Two sporadic cases were identified in Denmark and the Netherlands and separately reported. The Danish case involved a well patient who had received oseltamivir prophylaxis (included in the WHO report). The case from the Netherlands was a severely immunosuppressed patient who received oseltamivir treatment . In the context of the widespread circulation of 2009 A(H1N1) pandemic viruses susceptible to oseltamivir, the occurrence of oseltamivir resistance should be considered as a very rare event and almost exclusively limited to patients receiving oseltamivir as treatment or prophylaxis. This also indicates that oseltamivir-resistant viruses that have emerged so far did not efficiently transmit from person to person. However, there are conditions that may increase the likelihood of developing oseltamivir resistance such as receipt of the drug as prophylaxis and having clinical conditions that can prolong virus replication despite treatment (e.g. immunosuppression).
Therefore, WHO generally does not recommend using antiviral drugs for prophylaxis against pandemic (H1N1) 2009 influenza and suggests that clinical monitoring of contacts at risk of severe influenza illness and early start of treatment is a better option than administering antiviral prophylaxis. However, antiviral prophylaxis may still be recommended in some national guidelines in settings like nursing homes where an influenza outbreak is detected. Similarly there is no place for use of the adamantanes during this pandemic.
The characteristics of the patients described in this report underscore the importance of monitoring antiviral resistance in patients with various clinical characteristics and in a way that is representative of the various circumstances in which antiviral resistance may occur. This is in line with the conclusion of an ECDC working group of experts which in the context of the Surveillance and Studies in a Pandemic: Fourth meeting of the SSiaP working group (14–15 July 2009)  advised that antiviral susceptibility monitoring should be conducted in the following populations:
a) general population (representative sample);
b) sentinel populations (immunocompromised persons, children, treated patients, treatment failures, and prophylaxis failures).
To ensure representativeness of antiviral resistance data, samples undergoing testing should be selected randomly or systematically and from patients covering the clinical spectrum of disease from mild to severe . In addition, samples from a number of patients should be collected both at symptom onset and after treatment. Complying with this advice may be difficult and not feasible in some countries, therefore any information on antiviral resistance, like that reported in the WHO review, adds to our understanding of the emergence and spread of resistant viruses and is highly valuable. The bottom line, however, remains the importance of offering neuraminidase inhibitors like oseltamivir and zanamivir for treatment, especially of those with severe disease according to WHO treatment guidelines, national recommendations and ECDC guidance [10-13].
- Oseltamivir-resistant pandemic (H1N1) 2009 influenza virus, October 2009. Wkly Epidemiol Rec. 2009. 84:453-9. English, French. Available at: http://www.who.int/entity/wer/2009/wer8444.pdf
- Hayden FG. Antiviral resistance in influenza viruses: clinical and epidemiological aspects. In: Mayers DL, ed. Antimicrobial drug resistance. New York, Humana Press, 2009: 1011-1034.
- U.S. Centers for Disease Control and Prevention “FluView” 2009-2010 Influenza Season Week 44 ending November 7, 2009, available at: http://www.cdc.gov/flu/weekly/
- Public Health Agency of Canada. FluWatch. November 1, 2009 to November 7, 2009 (Week 44), available at: http://www.phac-aspc.gc.ca/fluwatch/09-10/w44_09/index-eng.php
- ECDC. Weekly influenza surveillance overview, November 16, 2009 - Week 46, available at: http://ecdc.europa.eu/en/publications/Publications/091120_EISN_Weekly_Influenza_Surveillance_Overview.pdf
- ECDC. Weekly influenza surveillance overview, October 2, 2009 - Week 39, available at: http://ecdc.europa.eu/en/publications/Publications/091002_EISN_Weekly_Influenza_Surveillance_Overview.pdf
- RIVM. Resistent H1N1-virus - 3 November 2009. Available at: http://www.rivm.nl/cib/actueel/nieuws/resistent_H1N1-virus.jsp
- ECDC meeting report. Surveillance and studies in a pandemic: Fourth meeting of the SSiaP working group, available at: http://www.ecdc.europa.eu/en/publications/Publications/0908_MER_Surveillance_and_Studies_in_a_Pandemic_Meeting_Report.pdf
- Ciancio BC, Meerhoff TJ, Kramarz P, et al. Oseltamivir resistant influenza A(H1N1) viruses detected in Europe during season 2007/2008 had similar epidemiologic and clinical characteristics of co-circulating susceptible A(H1N1) viruses. Euro Surveill November 2009 (in press).
- WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses. Geneva, World Health Organization, 2009 available at: http://www.who.int/csr/resources/publications/swineflu/h1n1_use_antivirals_20090820/en/index.html accessed October 2009).
- Centers for Disease Control and Prevention. Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009–2010 season. Atlanta, GA, 2009 (http://www.cdc.gov/h1n1flu/recommendations.htm, accessed October 2009).
- ECDC. On public health use of influenza antivirals during influenza pandemics (with particular reference to the pandemic (H1N1) 2009). Available at: http://www.ecdc.europa.eu/en/healthtopics/Documents/0908_Influenza_AH1N1_On_Public_Health_Use_of_Influenza_Antivirals_during_Influenza_Pandemics.pdf
- ECDC interim guidance. Public health use of influenza antivirals during influenza pandemics. Available at http://www.ecdc.europa.eu/en/publications/Publications/0907_GUI_Public_Health_use_of_Influenza_Antivirals_during_Influenza_Pandemic.pdf
Acknowledgments: we are grateful to Dr Adam Meijer, from the National Institute for Public Health and the Environment (RIVM) in the Netherlands for having reviewed and commented on the content of this public health development.