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Widespread Tamiflu Resistance in Human H1N1 Matches H5N1

Recombinomics Commentary 14:24
January 30, 2008

"That's quite a surprise," the lab's scientific director, Dr. Frank Plummer, said, noting the resistance mutation spotted in the Winnipeg testing is the same one that has been reported over the past few days from Norway, several other European countries and the United States.

Eight of 81 H1N1 viruses tested carry the H274Y mutation - one each from British Columbia and Newfoundland and Labrador, and six from Ontario. Plummer said that total includes one virus (from British Columbia) recovered from a child who is believed to have been infected in Sudan.

His surprise is shared by experts with the World Health Organization's Global Influenza Program, which convened a teleconference of about 50 scientists from leading influenza laboratories around the world Tuesday to try to get a handle on how far this virus has spread, how common it is in places where it is being found and what is driving the spread.

The above comments provide additional detail on the frequency of H1N1 seasonal flu with Tamiflu resistance marker, H274Y.  In public sequences at Los Alamos, the change suddenly appeared in 2007 at multiple locations in the United States.  The above comments suggest the frequency has grown this season and the polymorphism is widespread in Europe and North America.

In the United States the change was in the Solomon Islands variant, which links back to Asia, where the identical change has been seen in H5N1 from patients treated with Tamiflu, as well as birds, including wild birds in Astrakhan in 2005.

Like the wild birds, most of the recent human isolates are from hosts that have not been treated with oseltamivir.  The widespread appearance of H274Y in such hosts indicates the change does not create a selective disadvantage, and is analogous to the sudden appearance of another NA polymorphism in N1, which is G743A in various genetic backgrounds of clade 2.2 H5N1.  That change is silent and doesn’t offer an obvious selective advantage, yet it was appended onto at least eleven different genetic backgrounds in 2007.

These polymorphism are appended via recombination, and the widespread use of a Tamiflu blanket provides a selective environment for the acquisition of H274Y in human H1N1 co-infected with H5N1 patients.

Evidence is accumulating for mild human cases of mild H5N1, which are largely going undetected.  A recent study of patients in Cambodia identified H5N1 antibodies in patients who were asymptomatic.  Similarly H5N1 was isolated from patients with mild infections in Egypt.  These cases did not develop pneumonia, and similar cases would likely be mistaken for seasonal flu, and H5N1 testing would not be done.

The sudden appearance of H274Y in seasonal H1N1 after Tamiflu blankets had been applied extensively in recent preceding years is not a coincidence.

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