Tamiflu Resistance in Pandemic H1N1

How Viral Evolution Makes Drugs Ineffective

Oct 12, 2009 Stephen Allen Christensen

As pandemic H1N1 sweeps through schools, communities, and countries, it is beginning to reveal its adaptability: Mutations may render drugs like Tamiflu less useful.

2009 H1N1 (“swine flu”) is demonstrating the characteristics that make influenza A such an interesting microbe... at least from a scientist’s point of view: The virus is changing its coat and acquiring new characteristics.

And some of H1N1’s new “looks” are worrisome.

In a few isolated instances, 2009 H1N1 has become resistant to the antiviral drugs that were stockpiled to treat people who fall ill from or who are exposed to the virus.

Unfortunately, the development of resistant new H1N1 strains – and their subsequent spread within the human population – may not follow the usual patterns.

Microbial Resistance Usually Follows Darwinian Patterns

Because viruses and bacteria multiply relatively quickly, mutations in their genomes occur frequently and find their way into the microbial population. Genetic mutations that confer survival benefits get passed along to succeeding generations; those that don’t are quickly weeded out.

Under the evolutionary “pressure” created by exposure to antimicrobial drugs, only those organisms that possess the genes for resistance survive to reproduce.

Thus, resistance is typically determined by selective pressure (i.e., natural selection): Organisms that outlive their companions get to pass their genes along to their progeny.

How Influenza A Alters Its Genetic Makeup

Influenza A is a virus that constantly shifts its genetic structure. This behavior not only makes vaccine development difficult; it threatens the utility of drugs that public health experts rely upon to control outbreaks.

Two principal processes are responsible for influenza A’s variability:

Genetic Drift (Antigenic Drift): Genetic drift is driven by chance mutations at various points in the viral genome (i.e., it is not driven by environmental pressures); it is a gradual, completely random process that eventually determines the relative frequency of a characteristic in the viral population. Genetic drift results in minor changes in the surface proteins of the influenza A virus.

Genetic Shift (Antigenic Shift): Major changes in the influenza A genome result in new subtypes of the virus that haven’t previously been seen in the human population. Antigenic shift can result from reassortment of viral genetic material – such as when two dissimilar influenza viruses infect the same individual (i.e., a “mixing vessel”) and exchange segments of genes – or when direct animal-to-human infection occurs.

Antigenic shift accounts for the evolution of new human subtypes of influenza A (i.e., H1N1, H3N2, H5N1, etc.), and is the process that usually accounts for pandemic strains.

The Concept of Viral Polymorphism

Polymorphism (“many forms”) simply refers to the different genetic characteristics that are present in a given population. Eye color in humans, for example, is conferred by slightly different forms of the same gene. Eye color is a polymorphism.

Similarly, influenza A exhibits different polymorphisms among subtypes and even within a single subtype. Thus, H1N1 is not a completely uniform organism: Some H1N1 influenza viruses replicate at higher temperatures than others; some are more likely to initiate a “cytokine storm” than others; some are resistant to antiviral drugs, while others are not.

H1N1 Develops Resistance to Tamiflu with No Prior Exposure to the Drug

Years ago, two antiviral drugs – amantadine and rimantadine – were the mainstays of treatment for influenza A. Unfortunately, continued use of these medications, coupled with the virus’ innate ability to rapidly alter its genetics, has led to near-universal resistance to both drugs among some influenza A subtypes.

Oseltamivir (Tamiflu), first introduced in the late 1990s, was the first neuraminidase inhibitor to hit the market that was FDA-approved for both treatment and prevention of influenza A. The drug interferes with influenza A’s ability to escape from the cells it has infected, thus preventing viral spread through the bloodstream.

Only ten years after its development, nearly 100% of all seasonal H1N1 isolates are resistant to Tamiflu. Conversely, less than 1% of 2009 pandemic H1N1 is currently resistant. (Centers for Disease Control and Prevention. 2008-2009 Influenza Season Week 39 ending October 3, 2009. October 9, 2009)

Seasonal H1N1’s Tamiflu resistance is believed to have arisen from an antigenic shift and a subsequent “hitchhiking” of a specific polymorphism, called H274Y, within circulating strains of the virus. Once this polymorphism became fixed in the viral population, it spread freely and conferred resistance to Tamiflu even in areas where the drug had never been used. (Niman H. Emergence and fixing of antiviral resistance in influenza A via recombination and hitchhiking. Nature Precedings)

Therefore, the use of Tamiflu was not the primary driving force that led to the development of drug resistance. Rather, it was polymorphism H274Y’s ability to confer survival benefit in some other way that allowed it to become fixed in the viral genome.

Scattered cases of Tamiflu resistance have been identified in 2009 pandemic H1N1. Ominously, the culprit appears to be polymorphism H274Y. Widespread Tamiflu resistance among 2009 pandemic H1N1 may be just around the corner.

The copyright of the article Tamiflu Resistance in Pandemic H1N1 in General Medicine is owned by Stephen Allen Christensen. Permission to republish Tamiflu Resistance in Pandemic H1N1 in print or online must be granted by the author in writing.

Influenza Ward, Oakland, 1918

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Oct 13, 2009 2:31 PM

Guest :

An excellent article Stephen though I have to correct you on one point. Tamiflu was not the first neuroaminidase inhibitor to reach the market. That honouor goes to Relenza.
In fact, one of the reasons why Relenza is much harder for flu viruses to develop resistance to compared to Tamiflu is that GSK (who market Relenza) spent a lot of time, effort and money testing and exploring the likelihood of flu viruses developing resitance to this drug.
In contrast, Roche began work on Tamiflu around 5 years after clinical studies started on Relenza and did NO resitance testing prior to release which they managed to only a matter of months after Relenza was released onto the market. The Roche/ Gilead strategy was simply to speed-up clinical development and capture market share by producing an easy to swallow pill (Relenza is inhaled). They succeeded very well but unfortunately the chemical modification required to protect the Tamiflu active ingredient during passage through the gut also makes resistance mutrations far more likely. In addition, Tamiflu has much more severe side-effects than Relenza in the general population (in part because around 10x the concentration of the active ingredient in Relenza is required for Tamiflu to have the same effect - because the latter is swallowed).
So, even though seasonal H1N1 viruses in 2008 showed nearly 100% resistance to Tamiflu around the world and the rate of resistance in pandemic H1N1 (swine flu) in 2009 is clearly incerasing rapidly (and is much likely far, far higher than is being officially estimated) we now have a situation where Roche and the WHO (who appear to be shamelessly acting as Roche's global marketing arm) are in denial. Flu antivirals are very important and save lives but Tamiflu now has a VERY SHORT shelf-life - countries stockpiling this drug are wasting their money and endangering their populations.
Relenza and its upcoming successor in 2010 - Lanimavir - are the only fully effective flu antivirals and I suspect will be key to protecting many people from evolving dangerous flu sub-types (eg. H5N1, H9N2) where vaccines turn out to be mismatched or are otherwise are only poorly effective.

Oct 13, 2009 2:32 PM

Guest :

An excellent article Stephen though I have to correct you on one point. Tamiflu was not the first neuroaminidase inhibitor to reach the market. That honouor goes to Relenza.
In fact, one of the reasons why Relenza is much harder for flu viruses to develop resistance to compared to Tamiflu is that GSK (who market Relenza) spent a lot of time, effort and money testing and exploring the likelihood of flu viruses developing resitance to this drug.
In contrast, Roche began work on Tamiflu around 5 years after clinical studies started on Relenza and did NO resitance testing prior to release which they managed to only a matter of months after Relenza was released onto the market. The Roche/ Gilead strategy was simply to speed-up clinical development and capture market share by producing an easy to swallow pill (Relenza is inhaled). They succeeded very well but unfortunately the chemical modification required to protect the Tamiflu active ingredient during passage through the gut also makes resistance mutrations far more likely. In addition, Tamiflu has much more severe side-effects than Relenza in the general population (in part because around 10x the concentration of the active ingredient in Relenza is required for Tamiflu to have the same effect - because the latter is swallowed).
So, even though seasonal H1N1 viruses in 2008 showed nearly 100% resistance to Tamiflu around the world and the rate of resistance in pandemic H1N1 (swine flu) in 2009 is clearly incerasing rapidly (and is much likely far, far higher than is being officially estimated) we now have a situation where Roche and the WHO (who appear to be shamelessly acting as Roche's global marketing arm) are in denial. Flu antivirals are very important and save lives but Tamiflu now has a VERY SHORT shelf-life - countries stockpiling this drug are wasting their money and endangering their populations.
Relenza and its upcoming successor in 2010 - Lanimavir - are the only fully effective flu antivirals and I suspect will be key to protecting many people from evolving dangerous flu sub-types (eg. H5N1, H9N2) where vaccines turn out to be mismatched or are otherwise are only poorly effective.

Oct 13, 2009 4:30 PM

Stephen Allen Christensen :

I stand corrected!
When I reviewed my first draft of this article, I discovered a phrase that I had cut during editing. Replacing it should help with the historical accuracy.
I certainly agree with you that the World Health Organization has behaved in a questionable fashion ever since pandemic H1N1 got a toehold and took off running. Alas, the WHO seems to have become more of a political/marketing body than a true public health entity. It's a little disheartening to realize that the health and safety of individuals are subordinate to the wellbeing of economies--sort of like "Jaws" on a much wider scale--but that's the world in which we live.

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