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Global Spread of Tamiflu Resistant Pandemic H1N1
Recombinomics Commentary 20:35
August 8, 2009

The release of a full set of sequences from a patient in Hunan, China raises concerns that oseltamivir resistance is widespread and circulating at much higher frequencies than indicated by the eight detail isolates.  The sequence from China, A/Hunan/SWL3/2009, was released yesterday, a day after the CDC released a sequence, A/Singapore/57/2009 at GISAID, which was a day after the sequence from Denmark, A/Denmark/528/2009, was released.  All three isolates have H274Y appended onto a different pandemic H1N1 genetic background, and all three backgrounds were distinct from earlier sequences from Osaka, Yamaguchi, and Hong Kong.  H274Y was also reported in isolates from patients in Quebec and Tokushima. 

This pattern of H274Y on multiple H1N1 backgrounds was also seen in seasonal flu and recently released 2009 seasonal sequences from Central and South American countries also have H274Y, providing a large reservoir of H274Y, which can jump from N1 in seasonal H1N1 to N1 in pandemic H1N1.

Although details of the cases in Hunan and Singapore have not been released, most of the other cases involved patients who were on prophylactic Tamiflu.  In Denmark and Tokushima, the patients developed symptoms on the 5th day of prophylactic treatment, raising doubts that the H274Y was due to a de novo mutation.  The incubation period for wide type influenza is 2-4 days, so symptoms 5 days after the start of Tamiflu treatment are not likely to be due to de novo mutation, because the incubation period would be significantly longer than wild type, because the newly mutated virus would take longer than five days to grow to a level that would produce symptoms.

In addition, the repeated identification of the same polymorphism, H274Y, and the lack of detection of another resistant polymorphism, N294S, decreases the likelihood that random mutations are generating the resistance.

Instead, it is more likely that H274Y is circulating as a minor population, leading to a shorter incubation period than would be expected for de novo mutation, and a higher frequency of detection.  The May 30 isolate date  of  the Singapore isolate coupled with the release date of August 6, raise concerns that the number of isolates with H274Y that either have not been sequenced or have not had sequences released, may be significant.

The concern was increased by recent reports on multiple resistant isolates along the Texas / Mexican border.  Although the claims of confirmed cases were denied, the detail associated with the cases suggests that there is some indication of resistance in this area.  Similarly, earlier reports of patients who remained H1N1 positive after extended treatment with Tamiflu raises additional concern of resistant H1N1 that has not been isolated or sequenced.

The rapid spread of H274Y in pandemic H1N1 would not be a surprise. H274Y spread in seasonal flu has been described in detail, and the level rapidly increased to 100%.  The co-circulation of H1N1 seasonal flu with H274Y and widespread use of Tamiflu for treatment or prevention, increases the likelihood of rapid spread of H274Y in pandemic H1N1. 

The recently released sequences, which contain H274Y on six different genetic backgrounds, including at least one patient who was not treated with Tamiflu, significantly increases concerns of additional worldwide spread in the near term.

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