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The Path Of Increased Resistance

 

 

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If and when novel H1N1 becomes resistant to oseltamivir (Tamiflu), few scientists will be caught terribly surprised. Antivirals and antibiotics have a history of losing effectiveness over time as viruses and bacteria learn to evade them.

 

For now, the good news is that the H1N1 virus remains overwhelmingly sensitive to Tamiflu. 

 

But of course, the same could have been said about the seasonal H1N1 virus back in 2006-2007, when 99% of isolates tested showed good sensitivity to Tamiflu.   By the end of the 2007-2008 flu season, however, nearly 13% of H1N1 isolates tested the United States were resistant to the drug.


Jump ahead to December of 2008, and nearly all seasonal H1N1 isolates tested around the world carried the H274Y mutation that conferred Tamiflu resistance. 

 

The CDC was forced to issue major new guidance for the use of antivirals for the second time in just three years (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).   

 

Obviously we caught a lucky break when it was discovered that the pandemic H1N1 virus remained susceptible to oseltamivir.  It gave us a tool to fight the pandemic with while the vaccine was under development.

 

Sporadic instances of resistance have been reported, including a couple of clusters (see WER Review: Oseltamivir Resistance In Pandemic H1N1) but so far, Tamiflu largely retains its effectiveness against this new virus.

 

Today, we’ve a study out of the University of Ohio that looks at the evolution of seasonal H1N1 towards resistance, and what they believe are evolutionary pressures bearing on novel H1N1 to follow the same path.

 

Writing in the International Journal of Health Geographics, the authors – using a supercomputer to crunch phylogenetic and geographic data -  identified 53 areas of co-circulation of resistant H1N1 and novel H1N1 where reassortment could occur.

 

Selection for resistance to oseltamivir in seasonal and pandemic H1N1 influenza and widespread co-circulation of the lineages


Daniel A Janies, Igor O Voronkin, Jonathon Studer, Jori Hardman, Boyan B Alexandrov, Travis W Treseder, Chandni Valson

Abstract (provisional)
Background (EXCERPTS)

The evolution of resistance to oseltamivir in pandemic H1N1 could be due to point mutations in the neuraminidase or a reassortment event between seasonal H1N1 and pandemic H1N1 viruses that provide a neuraminidase carrying an oseltamivir-resistant genotype to pandemic H1N1.

Results

Using phylogenetic analysis of neuraminidase sequences, we show that both seasonal and pandemic lineages of H1N1 are evolving to direct selective pressure for resistance to oseltamivir. Moreover, seasonal lineages of H1N1 that are resistant to oseltamivir co-circulate with pandemic H1N1 throughout the globe.

 

By combining phylogenetic and geographic data we have thus far identified 53 areas of co-circulation where reassortment can occur. At our website POINTMAP, (http://pointmap.osu.edu) we make available a visualization and an application for updating these results as more data are released.

Conclusions

As oseltamivir is a keystone of preparedness and treatment for pandemic H1N1, the potential for resistance to oseltamivir is an ongoing concern. Reassortment and, more likely, point mutation have the potential to create a strain of pandemic H1N1 against which we have a reduced number of treatment options.

 
The complete article is available as a provisional PDF.

 

The authors of this study aren’t putting all of their viral eggs in the reassortment basket. 

 

They point out that evolutionary pressures are driving the novel H1N1 virus along the same path as seasonal H1N1 followed in 2008, and that over time we will probably see Tamiflu resistance increase in the pandemic virus as well.

 

Reassortment – at least between seasonal H1N1 and novel H1N1 – would seem less likely today than when this study was submitted (Nov 2009) for publication.  At that time the seasonal strain was on the decline, but was still circulating (along with pandemic H1N1) in some regions of the world.

 

While surveillance is wanting in many countries, where testing is being done, we see little evidence that seasonal H1N1 is circulating today. That could, of course, change. 

 

Second, during the summer and fall of last year there were obviously a lot of opportunities for seasonal and pandemic H1N1 to intermingle and exchange genetic material, yet we’ve not seen any evidence of a reassortment between them.

 

None of which is to suggest that it can’t or won’t happen sometime in the future.  

 

Only that it takes more than just putting the two viruses in the same room to spawn a hybrid. 

 

Physorg.com has a good overview of this study, with more details.

 

Pandemic flu, like seasonal H1N1, shows signs of resisting Tamiflu

March 1, 2010 by Emily Caldwell

If the behavior of the seasonal form of the H1N1 influenza virus is any indication, scientists say that chances are good that most strains of the pandemic H1N1 flu virus will become resistant to Tamiflu, the main drug stockpiled for use against it.

 

Researchers at Ohio State University have traced the evolutionary history of the seasonal H1N1 influenza virus, which first infected humans during the 1918 pandemic. It is one of three seasonal influenza A viruses that commonly infect humans. The others are H1N2 and H3N2.

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