Influenza

Influenza A(H1N1) virus resistance to oseltamivir

Last quarter 2007 to first quarter 2008

Preliminary summary and future plans

13 June 2008

The detection of an increased number of A(H1N1) viruses with resistance to oseltamivir was initially reported to WHO by Norway on 25 January 2008. The viruses carried a specific neuraminidase (NA) mutation (H274Y) that confers high-level resistance to oseltamivir in N1-containing influenza viruses1 . Prior to the recent report from Norway, such resistance was rarely observed in community isolates of influenza A or B. During the previous northern hemisphere winter season (2006/2007), surveillance through the Global Influenza Surveillance and Response System (GISRS) laboratories found no oseltamivir-resistant H1N1 viruses among isolates from Japan or Europe, and less than 1% prevalence among H1N1 isolates from the United States of America.

WHO has been collecting global data about this phenomenon from multiple laboratories participating in GISN. Oseltamivir resistance data has been obtained by phenotypic and/or genotypic analysis. Data from European countries participating in the European Influenza Surveillance Scheme (EISS) has been provided by EISS and the European Surveillance Network for Vigilance against Viral Resistance (VirGil). In most northern hemisphere countries, influenza activity has now peaked for the 2007–2008 season, with activity decreasing to levels usually seen outside of the winter period. Data collection is still ongoing, however WHO has now compiled the preliminary findings from available data on the prevalence of oseltamivir resistance in H1N1 viruses.

Overall summary

The 2007–2008 northern hemisphere season saw low levels of influenza activity in general compared with the same period in recent years. In Asia and North America influenza activity began in November and increased in December–January, while in Europe activity began in December and increased in January. In most countries, influenza activity peaked between weeks 4 and 8, 2008. Influenza A(H1N1) viruses predominated in most parts of the northern hemisphere. Influenza A(H3N2) virus activity was sporadic in many countries except for the United States of America where the proportion of A(H3N2) viruses increased rapidly during January and became the predominant virus for the season overall. At the beginning of the season, influenza B viruses circulated at low levels in most countries, however, later in the season (around week 9, 2008) the proportion of influenza B viruses increased and in some countries, especially in Europe, predominated over influenza A viruses.

From the last quarter of 2007 until 13 June 2008, a total of 6978 influenza A(H1N1) viruses have been tested for oseltamivir resistance worldwide and 1077 (15%) were found to be resistant (see Table below). Fifty-two countries and territories reported on the test results, the majority of countries being from the European Region (see Map). The number of viruses tested varied considerably by country/territory, ranging from 1–1544, leading to difficulties in the interpretation of comparative data for some countries/territories or Regions.

Data from the European Region of WHO indicated that 25% of the A(H1N1) isolates tested showed resistance. Finland, France, Luxemburg, the Netherlands, Norway, the Russian Federation and Ukraine all reported a prevalence of 25% or greater of oseltamivir-resistant A(H1N1) viruses with Norway reporting the highest prevalence (67%). Some countries recorded variations in prevalence across regions. In Norway, the highest prevalence was recorded in the southern-most counties and in France, the north-west of the country. Oseltamivir use in influenza-infected patients is generally uncommon in these European countries, and no link between oseltamivir exposure and resistance at the individual patient level was noted. The preliminary analysis suggests that the resistant mutants do not share a single origin and further genotypic analysis is ongoing.

None of the H1N1 viruses from the Eastern Mediterranean Region (11 tested) or the African Region (77 tested) of WHO had the specific NA mutation (H274Y). Thailand was the only country that submitted data from the South-East Asia Region of WHO and 1 resistant virus out of 13 A(H1N1) viruses was found. In the Western Pacific Region of WHO, China, Hong Kong Special Administrative Region reported a prevalence of 11% oseltamivir resistance in A(H1N1) viruses, while Japan reported a relatively low prevalence (3%) despite having the world's largest per capita use of oseltamivir in clinical practice. Australia reported three resistant viruses, two of which were isolated from presumed imported cases. China, Guam, Malaysia, Mongolia, New Zealand, the Philippines, Singapore and the Republic of Korea did not find any resistant viruses. In the WHO Region of the Americas, Canada and the United States of America reported prevalence rates of 26% and 11%, respectively. Of the 20 viruses tested from countries in Central America, three were found to be resistant, all of which were from Monserrat.

Preliminary summary reports from countries, areas or territories

Preliminary summary reports on oseltamivir resistance by country have been submitted by several National Influenza Centres. Additional summary reports will be made available in due course.

Summary table update and future activities

The summary table will be updated on a monthly basis, unless the situation changes. WHO will continue to monitor the situation in order to address important public health questions1 with regard to the phenomenon. Global data of relevance to this issue will continue to be collated and analysed in collaboration with GISN members and other partners, such as the European Centre for Disease Prevention and Control (ECDC) which is coordinating activities in collaboration with WHO European Region Office, across the European Union and in countries within the European Economic Area where the viruses have been observed.


1 The mutation in N1 neuraminidase of human influenza virus which confers high-level resistant to oseltamivir is a single amino acid substitution of the relevant histidine (H) to tyrosine (Y) at position 275. Most of the early work on structure and inhibitor design is based on two other subtypes (N2 and N9) and the corresponding amino acid in these subtypes is at position 274. Consequently, some scientists use 'N2 numbering' (H274Y) and some use the actual 'N1 numbering' (H275Y).
2 http://www.who.int/influenza/patient_care/antivirals/oseltamivir_faqs/en/index.html

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