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Tamiflu Resistance Startles Influenza Experts

Recombinomics Commentary 15:55
February 17, 2008

Influenza experts admitted Monday they have been startled by the discovery this season of an unexpectedly high number of human flu viruses that appear to be naturally resistant to Tamiflu

The above comments describe the reaction of influenza experts to the sudden and widespread appearance of Tamiflu resistance marker, H274Y, in H1N1 seasonal flu.  Although H274Y has been reported previously in seasonal H1N1 in Japan, where oseltamivir dosages for children were somewhat lower than other countries, the earlier outbreaks in Japan were not limited to H1N1.  Other Tamiflu resistance markers appeared in H3N2, and these marker increases were many years ago, and quickly faded away.

The current outbreak has appeared suddenly, and has not been reported in Japan (the first 71 H1N1 isoaltes tested did not have H274Y).  Reported levels are highest in several countries in Europe, but the recent report of  ten cases in Chicago, including eight at one facility, suggest the 16 previously reported cases in the United States this season will rise markedly in the upcoming days.

The experts are startled because H274Y was viewed previously as an adaptive mutation that could compete in the presence of Tamiflu, since wild type H1N1 would be inhibited by the drug, but could not compete in teh absence of Tamiflu.  H274Y was thought to create a fitness penalty, which would limit the spread of H274Y in populations where wild type H1N1 was present, and Tamiflu was not.

However, the countries with high levels of H1N1 do not commonly use Tamiflu, and the patients harboring H274Y were not being treated with Tamiflu.  Thus, the H274Y in circulation is able to effectively compete in an environment with wild type H1N1, and spreading in the absence of Tamiflu.

Moreover, the “fit” H274Y is not limited to a particular H1N1 strain.  Earlier isolates in the US were the older New Caledonia strain, while more recent strains in the US and Europe were the newly emerging Brisbane/59 strain.  Moreover, the resistance is limited to H1N1.

The change in human N1 is identical to the N1 change in avian H5N1, which has been treated with Tamiflu blankets.  However, Tamiflu blankets can allow for undetected spread of H5N1, especially in mild human cases, which could lead to transfer of H274Y in avian N1 to human N1 in patients co-infected with H5N1 and H1N1. 

The movement of H274Y onto human N1 along with additional markers which improved the human N1 fitness would create an human H1N1 which had H274Y and could compete.  This new entity could then spread via human to human spread in countries that did not use Tamiflu.

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