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Fitness Of Oseltamivir-Resistant A/H1N1/2009

 

 

 

# 4952

 

 

Last night CIDRAP posted a summary of a PLoS Pathogens study in their nightly newsscan that has the potential, at some point, to become a significant story.

 

A brief excerpt, followed by some comments on my part.

 

Study: Tamiflu-resistant 2009 H1N1 passes fitness tests


Trials to assess the pathogenicity and transmissibility of oseltamivir-resistant 2009 H1N1 viruses in mice and ferrets suggest that the resistant strain is as fit as counterparts that are sensitive to the drug, according to Japanese researchers. The group, which includes Dr Yoshihiro Kawaoka, a virologist from the University of Wisconsin at Madison, reported their findings in PLoS Pathogens . .  .  .

Aug 26 PLoS Pathogens abstract

 

 

The entire study is titled:

 

Characterization of Oseltamivir-Resistant 2009 H1N1 Pandemic Influenza A Viruses

Kiso M, Shinya K, Shimojima M, Takano R, Takahashi K, et al. (2010) Characterization of Oseltamivir-Resistant 2009 H1N1 Pandemic Influenza A Viruses. PLoS Pathog 6(8): e1001079. doi:10.1371/journal.ppat.1001079

 

And as the CIDRAP piece explained, the authors looked a the fitness (ability to replicate, compete, and transmit) of oseltamivir (Tamiflu) resistant novel H1N1 viruses compared to non-resistant strains.

 

For now, the good news is that the 2009 H1N1 virus remains overwhelmingly sensitive to Tamiflu.

 

But of course, the same could have been said about the old seasonal H1N1 virus back in 2006-2007, when 99% of isolates tested showed good sensitivity to oseltamivir.

 

Resistance is generally caused by a mutation, known as H274Y, where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 274.

 

Back in 2007, the belief was that the mutation that made the virus resistant to Tamiflu (H274Y), also reduced its biological fitness – suggesting that mutated versions of the viruses were unlikely to spread widely.

 

But those hoped dimmed when, by the end of the 2007-2008 flu season,  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).   

 

The `replacement’ 2009 pandemic virus, that supplanted the largely resistant seasonal strain, was fortunately both relatively mild and sensitive to Tamiflu. 

 

But over the past 16 months, several hundred scattered cases of Tamiflu resistance have been detected, including in a couple of clusters, raising the specter that someday this new strain of H1N1 could become resistant as well.

 

Earlier this summer, part of the mystery of how the old seasonal H1N1 developed resistance and still managed to transmit efficiently was revealed when researchers identified two "pre-adaptive mutations” that helped pave the way for the H274Y strains to spread (see Caltech: How Seasonal Flu Gained Tamiflu Resistance).

 

Today’s study shows that while still limited in the wild, the mutated 2009 H1N1 virus demonstrates biological fitness, and replicates and spreads efficiently in mice and ferrets.

Post mortem exams of ferrets used in this study also show no reduction in pathogenicity of the mutated virus.

 

Leading the authors to state:

 

Our findings highlight the possibility that NA H274Y-possessing oseltamivir-resistant 2009 H1N1 pandemic viruses could supersede oseltamivir-sensitive viruses, as occurred with seasonal H1N1 viruses.

 

Since novel H1N1 is already resistant to the older amantadine-class (M2 ion channel blockers) antivirals, the loss of these newer neuraminidase (NA) inhibitors (oseltamivir and zanamivir) would be a serious blow.


But not as serious as it would have been before a vaccine was available. Today, unlike a year ago, we have the ability to substantially (not 100%, of course) protect against this virus. 

 

And it is almost always better to prevent a disease than to try to treat one.

 

Antibiotics and antivirals are fleeting victories against rapidly evolving pathogens at best, since from the minute they are introduced, nature begin to work on ways to defeat them.

 

Once again, from the study’s text:

 

The widespread administration of oseltamivir, and to a lesser extent zanamivir, will clearly contribute to the emergence of NA inhibitor-resistant viruses that retain optimal replication fitness and transmissibility in humans. 

 

The authors note that in vitro and in vivo experiments on two experimental drugs- CS-8958 and favipiravir – suggest these may be candidates to deal with 2009 H1N1 line of viruses in the future.

 

For some earlier essays on the H274Y mutation, you might wish to check out:

 

NIH: Rapid Development Of Antiviral Resistance In Two Cases
WER Review: Oseltamivir Resistance In Pandemic H1N1
NEJM: Community Cluster Of Tamiflu Resistant H1N1

Related Post:

H1N1
Mutation
Resistance

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