Oseltamivir-Resistant Influenza Virus A (H1N1), Europe, 2007–08 Season

[hat-tip Ironorehopper. Also, included in this post, is excerpts from the document]
DOI: 10.3201/eid1504.081280
Suggested citation for this article: Meijer A, Lackenby A, Hungnes O, Lina B, van der Werf S, Schweiger B, et al.
Oseltamivir-resistant influenza A (H1N1) virus, Europe, 2007–08 season. Emerg Infect Dis. 2009 April; [Epub ahead of print]


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In Europe, the 2007–08 winter season was dominated by influenza virus A (H1N1) circulation through week 7, followed by influenza B virus from week 8 onward.
Oseltamivir-resistant viruses A (H1N1) (ORVs) with H275Y mutation in the neuraminidase emerged independently of drug use.
By country, the proportion of ORVs ranged from 0% to 68%, with the highest proportion in Norway. The average weighted prevalence of ORVs across Europe increased gradually over time, from near 0 in week 40 of 2007 to 56% in week 19 of 2008 (mean 20%).
Neuraminidase genes of ORVs possessing the H275Y substitution formed a homogeneous subgroup closely related to, but distinguishable from, those of oseltamivir-sensitive influenza viruses A (H1N1).
Minor variants of ORVs emerged independently, indicating multiclonal ORVs.
Overall, the clinical effect of ORVs in Europe, measured by influenza-like illness or acute respiratory infection, was unremarkable and consistent with normal seasonal activity.
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From above paper. Excerpts.

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Discussion

Unexpectedly, influenza viruses A (H1N1) with a single amino acid substitution H275Y in the NA, which caused a several hundred-fold selective reduction in susceptibility to oseltamivir, emerged and were sustained in circulation in Europe during 2007–08, despite low antivirual drug use (Figure 1).

Before the 2007–08 season, <1%>100 nmol/L for NAI drugs (A. Lackenby et al., unpub. data), in concordance with results from worldwide surveillance (8,9).

In 2007–08, influenza viruses A (H3N2) and B circulating in Europe remained sensitive to NAI drugs.

This emergence of oseltamivir-resistant influenza virus A (H1N1) in Europe coincided with the dominant circulation of this virus subtype during the 2007–08 winter in Europe and the emergence of a new drift variant, A/Brisbane/59/2007 (30).

Of the last 12 influenza seasons, influenza viruses A (H1N1) were dominant only in 2000–01, which included a new drift variant, A/New Caledonia/20/99 (20).

In the other 10 seasons, influenza viruses A (H1N1) played a minor role, with influenza viruses A (H3N2) dominant in 9 seasons.

Compared with 2000–01, peak incidence rates for ILI or ARI in 7 of 13 countries were similar or lower in 2007–08 (Table).

In 6 countries, the peak incidence rates were significantly higher in 2007–08 than in 2000–01, but with a 2-fold difference in 5 countries and, in Spain only, a 4.8-fold difference. Both the 2000–01 and 2007–08 seasons were unremarkable in the overall clinical impact of influenza, with normal seasonal activity as measured by comparison of peak incidence rates for all seasons since 2000–01.

Sporadically occurring A/New Caledonia/20/99-like ORVs with H275Y were detected during the 2006–07 season in the United Kingdom and United States but did not become epidemiologically important.

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Indeed, the genetic background plays a role in retaining the replication efficiency and pathogenicity of recombinant influenza viruses A (H5N1) and A (H1N1) after introduction of tyrosine at position 275 (33).

Furthermore, other previously analyzed influenza viruses A (H1N1) with the H275Y mutation showed impaired replicative ability in cell culture and reduced infectivity and substantially compromised pathogenicity in animal models, compared with the corresponding wild-type virus (34,35).

The coincidental emergence of H275Y with the circulation of the A/Brisbane/59/2007 drift variant may have favored the emergence of fit transmissible ORVs.

This point is also illustrated by the emergence of A/Brisbane/59/2007-like ORVs in other parts of the Northern Hemisphere and their continued circulation during the 2008 Southern Hemisphere influenza epidemic season (36–38).

Since the last quarter of 2007, ORVs have been detected in continents other than Europe, with proportions of ORVs varying from 100% in South Africa and Australia to <5% style="margin: 5px 20px 20px;">

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The finding of a high prevalence of ORVs in the community and the overall temporal increase in resistance demonstrates that the previously documented reduced fitness of viruses bearing the H275Y mutation, ostensibly caused by structural and functional constraints (10), has been overcome in currently circulating influenza viruses A (H1N1).

The results of Rameix-Welti et al. (32) suggest that a combination of specific amino acid substitutions have increased the affinity of the NA of recent influenza viruses A (H1N1) (ORVs and OSVs) for substrate.

A better balance of NA and HA activities in ORVs compared with OSVs may have contributed to the overall fitness and transmissibility of ORVs.

However, growth curves conducted in tissue culture of pairs of ORVs and OSVs demonstrated no differences in growth kinetics or final virus yields.

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Therefore, changes in other genes also may be involved in the overall impact on the fitness of ORVs, for which whole genome sequencing is necessary.

For Europe, no focal point of initiation of spread could be identified. The spread of ORV from west to east paralleled that of influenza virus A in Europe, and there was an average delay of 5.7 weeks for the appearance of ORVs after the start of influenza virus A circulation.

However, the low R2 values for both patterns make definitive conclusions difficult to draw about the spatial spread of either influenza viruses A or ORVs.

Several independent introductions into European countries of a sensitive and a resistant strain might explain the low R2 values.

Estimating whether a global focal point exists from which ORVs emerged to spread to the rest of the world is not possible, but the fact that Japan, the country with the highest per capita use of oseltamivir (5), had relatively low levels of circulating ORVs during the 2007–08 influenza season is relevant and reflects the limited circulation of the clade 2B A/Brisbane/59/2007-like viruses belonging to the European cluster in this region (31,36).

The close relationships between the NA sequences of most of the 2007–08 European ORVs and their segregation from those of OSVs suggest that resistance results in large part from the spread of a single variant.

Phylogenetic analyses show that this is a property of clade 2B A/Brisbane/59/2007-like viruses and is not associated with emergence of another antigenic variant.

However, identification of other resistant variants in the United Kingdom, some of which are more closely related to OSVs than to most ORVs (e.g., A/England/654/2007) indicates the independent parallel emergence of multiple resistant variants.

This is emphasized by small distinct clusters of closely related ORVs in Japan that are related to European OSVs, whereas only a few of the Japanese ORVs belonged to the large European ORVs cluster (31).

Resolution of the origin and frequency of emergence of ORVs and association with drug use clearly require substantially more intimate knowledge of the genetic relationships among OSVs and ORVs worldwide.

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Our observations suggest that the new genetic background of influenza viruses A (H1N1) that appeared in 2007 enabled the virus to develop oseltamivir resistance independently at several locations in the world.

The combined effect of the relatively high level of circulation of influenza viruses A (H1N1) in Europe; the introduction of a new antigenic drift variant in a susceptible population, partly related to the lack of substantial influenza virus A (H1N1) circulation since the 2000–01 season; and the uncompromised transmissibility of the ORVs contributed to the epidemiologic success of the ORVs during the 2007–08 season.

This phenomenon shows clearly that continuation of antiviral susceptibility monitoring and increasing capacity for timely response are essential (21,39).

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In addition, the appearance of viable transmitting ORVs is a reminder that the level of resistance to oseltamivir of seasonal or pandemic virus cannot be predicted, and therefore antiviral strategies should not rely on single drugs (40).

Although oseltamivir remains a valuable influenza antiviral agent, the emergence of natural resistance shifts attention from oseltamivir to other antiviral agents and to improved vaccination (e.g., greater vaccination coverage, more immunogenic and broadly reacting vaccines) in the fight against seasonal and pandemic influenza.
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