Commentary
Spread of H1N1 Tamiflu Resistance
Recombinomics Commentary 18:41
September 3, 2008
The recently released HA sequences from Guatemala and Honduras have raised concerns that like South Africa and Australia, the level of oseltamivir (Tamiflu) resistance in H1N1 in circulation this summer is 100%. This increase to 100% has been rapid, raising questions about the mechanism underlying the increase as well as the stability of the change in future H1N1 isolates, as well as related H5N1 isolates.
Although oseltamivir was approved in 1999, the spread of resistance in patients who are not receiving oseltamivir has only been reported recently. The highest usage is in Japan, and there have been prior outbreaks of resistance in children receiving sub-optimal doses. However, these cases were being actively treated with oseltamivir and the resistance appeared in H1N1 and H3N2 and involved multiple polymorphisms. In contrast the recent cases have only involved H1N1 and have all be H274Y, encoded by the same single nucleotide polymorphism. This change matches the change linked to resistance in H5N1, which was reported initially in oseltamivir treated patients in Vietnam in 2005.
A matching sequences downstream from H274Y has been reported for H1N1 in the United States this year, A/Indiana/01/2008 (clade 2B), but the first reported human cases were in patients in China in the 2005/2006. These patients were not receiving oseltamivir, and the H1N1 was the Hong Kong strain (clade 2C). In the following season, H274Y was reported in the New Caledonia strain (clade 1). By the end of 2007, H274Y was reported in the Brisbane strain (clade 2B) in Hawaii. The downstream sequence of clade 1, 2B, and 2C match facilitating transfer of H274Y from one genetic background to another.
However, the transfer of H274Y sequence with an altered downstream region put H274Y on a subclade that was becoming dominant in the United States and Europe allowing H274Y spread to increase markedly. However, in addition to this common sub-clade, H274Y continued to be appended onto multiple clade 2B sub-clades.
Thus, there were two mechanisms of H274Y. One involved independent introductions only new clade 2B backgrounds, while a second mechanism involved spread and evolution of a common clade 2B background. These backgrounds include isolates from France, which were precursors for a subset of the resistance in South Africa, as well as the recent sequences from Guatemala and Honduras. The other sub-set in South Africa lins back to the isolates in the United States, but this sub-set in South Africa has acquire a cluster of changes in HA, These changes are in the dominate H1N1 sub-clade in South Africa, raising concerns of additional re4siatnce to the new H1N1 vaccine, which targets clade 2b (Brisbane/59).
The ability of H274Y to jump from clade to clade, as well as multiple sub-clades in 2B, as well as the rapid evolution of the 2B sub-clades, raises concerns of another vaccine mismatch, as well as the associated increase in H274Y in the H1N1 gene pool. Moreover, the match between H5N1 and the recent H1N1 isolate from Indiana raises concerns that oseltamivir resistance would develop quickly after H5N1 transmission efficiencies in humans increase, regardless of oseltamivir usage.
The rapid spread of H274Y in seasonal flu and the recent reports of increases to 100% continue to be cause for concern in seasonal and pandemic flu evolution and spread.
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