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H1N1 Tamiflu Resistance Lesson Not Learned
Recombinomics Commentary 00:20
December 30, 2009

Dr. Nancy Cox isn't convinced H3N2 is going away. But the head of the influenza division of the U.S. Centers for Disease Control would be happy with a one-for-one exchange, with the pandemic H1N1 replacing the seasonal virus of the same name.

That's because seasonal H1N1 viruses are resistant to oseltamivir (Tamiflu), the main drug used to fight flu.

The pandemic H1N1 viruses are susceptible to Tamiflu, though they are resistant to two older flu drugs, amantadine and rimantadine. Those two drugs aren't widely used anymore because resistance to them develops easily.

Swapping viruses that are immune to Tamiflu for ones the drug works against would be a bargain, Cox suggests. "Getting rid of resistance in circulating H1N1 viruses would be a real silver lining."

The above comments on replacing seasonal H1N1 where H274Y is fixed, with pandemic H1N1 where H274Y is becoming fixed, signals a lesson not learned.  H274Y in seasonal H1N1 went from 0% to 100% in one season in several countries.  In the US it went from 10% to 100%.  Although the process began in 2006 when H274Y was first identified in seasonal H1N1 in patients who had not been treated with Tamiflu.  H274Y jumped from one seasonal flu genetic background to another via recombination, as did severall additional polymorphism which jumped from clade 2C to clade 2B to create the strain that emerged in 2008. 

The repeat in pandemic H1N1 may be much quicker because the widespread use of Tamiflu creates additional selection pressure for H274Y to pair with receptor binding domain changes that also drive selection.  The recent reports of H274Y transmission in Vietnam and hospitals in North Carolina and Wales, along with an explosion in the detection of H274Y worldwide, suggest that the fixing of H274Y may be well on its way in the next wave, which may begin in the upcoming weeks.

The latest CDC weekly report on influenza does provide support for the crowding out of seasonal H1N1, as well as seasonal H3N2.  No isolates of either sero-type were identified, and there were only 3 influenza B isolates.  In contrast, a year earlier there were 103 isolates, most of which were H1N1, but even influenza B was 10 fold higher than this year.

However, most flu cases usually appear in the winter, when the virus is stable and host resistance is compromised by cold weather and other respiratory diseases.  Thus, it is likely that an influenza virus will emerge, but seasonal flu is virtually absent throughout the northern hemisphere.  Thus although swine H1N1 in the US and across the northern hemisphere is declining, there are still high levels of pandemic H1N1 in circulation.  In the US the week 50 levels of swine H1N1 were still three fold higher than seasonal flu last year, and 100 fold higher than seasonal flu this year.  In Ukraine, deaths have spiked higher raising concerns of multiple pockets of pandemic H1N1 that can fill the seasonal flu void in the upcoming months.

Thus, the potential for H274Y to become fixed in the next wave is quite real because competing seasonal flu strains are not circulating, and competing swine H1N1 that is Tamiflu sensitive is on the decline.  However, not only can swine H1N1 fill the upcoming void with H274Y, there are additional signs that receptor binding domain changes at position 225 are also emerging.  Mill Hill has reported H1N1 with D225G as a low reactor, signaling a selective immunological advantage over wild type.  Both D225G and D225N have been associated with severe and fatal cases, so the emergence of swine H1N1 with H274Y and D225G/N could be catastrophic.

This, the silver-lining in the replacement of seasonal H1N1 with pandemic H1N1 may lead to a result that contains no silver lining, other than another example of influenza evolution via recombination, instead of the random mutation explanation of the detection of D225G/N on multiple H1N1 genetic backgrounds.

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