Commentary
H1N1
Tamiflu Resistance Levels in US Raise Concerns
Recombinomics Commentary
16:58
November 27, 2008
Only one state has reported local influenza activity during the 2008-09 season in the United States to date, thus the number of virus specimens available for antiviral resistance testing is limited in both overall number tested and in the number of states that have submitted specimens. Currently, data on antiviral resistance, as well as the limited information on which influenza virus types or subtypes will circulate during the season, are insufficient to provide an indication of the prevalence of oseltamivir or adamantane (amantadine and rimantadine) resistance at a national or regional level. CDC has solicited a representative sample of viruses from WHO collaborating laboratories in the United States, and more specimens are expected as influenza activity increases.
The above comments continue to delay announcements on anti-viral resistance levels and suggest that the levels of 100% resistance to amantadimes in H3N2 ,and 100% resistance to oseltamivir in clade 2B H1N1 ignore the recent history of these two seroptypes.
The high level of resistance to amantadines in H3N2 has been widespread for several years, and all reported results in Europe and the United States this season reflect 100% resistance. The same is true for oseltamivir resistance in clade 2B. In addition to the high levels in the United States, the initial data in Europe and Canada support levels at or near 100%, so the limited testing in the United States is unlikely to represent an unusual frequency for clade 2B.
However, the finding of H274Y in 20/21 isolates in the United States, which appear to be largely from Hawaii, raise concerns that levels of Tamiflu resistance in clade 2C may be spiking higher. Last season all reported H274Y in the United States was in clade 2B and most clade 2C was in western states, with highest levels in Hawaii. Thus, the high frequency in this weeks report suggests there is a high level in clade 2C, if that sub-clade was well represented in the initial testing.
Of the 101 H1N1 isolates reported to date, 75 are in the Pacific region, and the highest level of influenza in the United States is Hawaii, suggesting most of the H1N1 reported to date is from Hawaii. The level of clade 2C can be determined from the amantadine resistance levels, since last season all clade 2C was resistant, but only six of the initial H1N1 isolate have been tested for amantadine resistance this season.
These high levels of H274Y in H1N1 in initial reports from the United States, Canada, and Europe are not likely to decline in the near term, and the high frequency of H1N1 in the United States in general, and the western states in particular, indicate more rapid testing of the existing isolates would be useful for predicting near term levels of H274Y in clade 2B and clade 2C.
In addition to concerns over physicians treating H1N1 patients with oseltamivir, there are concerns that the H274Y in H1N1 will be acquired by H5N1, either through reassortment or recombination. One reported clade 2C isolate in Hong Kong has acquired N1 with H274Y via reassortment. Moreover, that polymorphism has jumped to multiple clade 2C, clade 1, and clade 2B backgrounds, suggesting recombination between these sub-clades is common, which may also drive an increase level of H274Y in clade 2C, as well as new sub-clades which may develop in the future.
Moreover, this dramatic rise in H274Y in H1N1 seasonal flu increases the likelihood of dual infections with H5N1 infected patients, leading to an increase in the level of H274Y in H5N1.
In Indonesia, the number of such individuals controlled with oseltamivir may be markedly higher than the reported cases, and widespread H274Y in H5N1 could significantly increase the likelihood of a catastrophic pandemic.
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