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Explosion of Swine Flu Tamiflu Resistance in the United States
Recombinomics Commentary 13:29
November 23, 2009

The majority of 2009 influenza A (H1N1) viruses are susceptible to the neuraminidase inhibitor antiviral medication oseltamivir; however, rare sporadic cases of oseltamivir resistant 2009 influenza A (H1N1) viruses have been detected worldwide. A total of 21 cases of oseltamivir resistant 2009 influenza A (H1N1) viruses have been identified in the United States since April 2009. In specimens collected since September 1, 2009, 11 cases have been identified in the United States, including seven newly identified cases since last week and one case reported during a previous week that was reclassified. All tested viruses retain their sensitivity to the neuraminidase inhibitor zanamivir. Of the 21 cases, 12 patients had documented exposure to oseltamivir through either treatment or chemoprophylaxis, eight patients are under investigation to determine exposure to oseltamivir, and one patient had no documented oseltamivir exposure.

The above comments from the week 45 CDC update, describe an explosion of oseltamivir resistant cases in the United States.  Moreover, a linkage to Tamiflu has not been established for these cases, raising concerns that an evolutionarily fit H1N1 is circulating in the US.  Reports of four seriously ill patients at Duke developing resistance also was disclosed Friday.  However, these four cases were said to have developed over a six week period and some media reports indicated the patients were taking prophylactic Tamiflu, which would suggests that those four patients were not included the above tally.  In addition an outbreak at a Wales hospital was also describe Friday, which followed a cluster at Edinburgh increasing concerns that H274Y is transmitting and detection is becoming increasingly common.

Although Roche and others have maintained that the H274Y was due to a spontaneous mutation,  there is little evidence to support this interpretation.  Like seasonal H1N1, all resistance involved the same genetic change which coded for H274Y.  Moreover, the rapid appearance of H274Y indicated it was not due to a spontaneous de novo mutation, but was circulating as a minor species which was more easily detected after Tamiflu treatment.

However, reports of H274Y in patients who were not treated with Tamiflu suggested an easily detected fit version was also circulating, an the number of new cases without a demonstrated link to Tamiflu treatment raised concern that the more easily detected H274Y was becoming more common. The more easily detected H274Y was described for seasonal flu and the appearance on multiple genetic backgrounds suggested the movement form one genetic background to another was due to recombination.  Recombination was supported by similar jumps by other important changes from clade 2C to clade 2B, including at least one silent change.

Similarly, the detection receptor binding domain change D225G on multiple backgrounds indicates that key change  is "in play" also and is moving from one background to another via recombination, although statements have been made that the polymorphism was "spontaneous" and not transmitting, which, like H274Y, is not supported by the data.

Release of sequences from these recent cases would be useful to determine if a dominant H274Y species is emerging.

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