Most strains of pandemic H1N1 flu virus resist Tamiflu

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Most strains of pandemic H1N1 flu virus resist Tamiflu, say scientists

2. March 2010 04:32

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.

Within H1N1, two strains of virus circulate in humans: a seasonal form and the

pandemic form of influenza known as swine flu, which has sickened millions and

killed thousands of people since it first emerged in North America last spring.

Over time, the H1N1 strain of seasonal influenza surviving around the world has

developed mutations that have caused it to become resistant to oseltamivir-based

agents. Tamiflu is the brand name for oseltamivir phosphate.

" Something happened in 2008, when drug resistance took hold, " said

Janies, associate professor of biomedical informatics at Ohio State and primary

author of the study. " The drug-resistant isolates became the ones that survived

all over the world. This is just static now. The seasonal H1N1 influenza virus

is fixed at resistant. "

Janies and colleagues have traced the history of the same mutation in the

pandemic H1N1 strain of the virus as well, with data from its emergence last

spring until December 2009. And they are starting to see the same kinds of

mutation in this virus - changes to an amino acid that allow the virus to resist

the effects of oseltamivir - that they saw in the seasonal H1N1 flu.

" It is a pretty good bet that whatever pressure is in the environment, excessive

use of Tamiflu or something else, that was driving seasonal influenza to become

resistant to Tamiflu is also going to apply to pandemic influenza, " Janies said.

" We can see it happening already.

" This has potential to indicate that we are going to have to think of something

else to use to treat pandemic H1N1 influenza. "

The same study showed that resistance to a second antiviral drug - zanamivir,

known by the brand name Relenza - is not as prevalent, suggesting this

medication might be a good alternative to Tamiflu, he said.

The research appears online in the International Journal of Health Geographics.

So far, most pandemic H1N1 strains that have been isolated from humans are

susceptible to Tamiflu. As of Feb. 3, 2010, 225 cases of pandemic H1N1 were

reported to be resistant to the drug out of the predicted millions of cases of

illnesses with swine flu across the United States and elsewhere in the world.

But those resistant cases, as well as the way mutations have led to Tamiflu

resistance in seasonal H1N1, offer clues about how the virus changes itself to

survive against the popular drug.

The two types of H1N1 virus, seasonal and pandemic, are similar on the surface,

where their proteins interact with cells in the human body. But the internal

genes of the viruses are configured differently.

The researchers zeroed in on specific points in the neuraminidase protein - this

protein is what the " N " refers to in these virus subtype names. Resistance to

oseltamivir in H1N1 can evolve as a result of a point mutation at one of several

locations on this protein, Janies said.

He and colleagues analyzed mutations in neuraminidase proteins from 1,210

seasonal H1N1 viruses isolated around the world between September 2004 and

December 2009. For pandemic H1N1, the researchers examined mutations in specific

points on neuraminidase proteins of 1,824 viruses collected between March 2009

and December 2009.

" With the rapid availability of public sequence data on pandemic influenza, we

are able to essentially watch evolution in real time, " Janies said.

Once they selected the isolates for study, the researchers used powerful

supercomputers to analyze the evolution of these proteins and their various

mutations. The computational power allows them to match similar regions on the

proteins and put the mutation data into context in time and geography.

One result of these computations is called a phylogenetic tree, which documents

the history of mutations - including those that cause drug resistance.

Phylogenetics is the study of the evolutionary relationships and features among

various biological species, genes or proteins that share a common ancestor.

In tracing the history of neuraminidase in pandemic and seasonal H1N1, the group

found that mutations in the same amino acid position in both seasonal and

pandemic H1N1 drove the viruses toward resistance to antivirals.

" Basically a change in the amino acid changes how the neuraminidase protein

folds, and the molecule in Tamiflu no longer has the ability to interfere with

the virus, " Janies said.

The researchers also used a technique in which they compared different types of

mutations - those that do cause antiviral resistance and others that don't have

that effect - to see which type of mutation is more common.

" We look at the ratio of mutations that do confer resistance vs. those that

don't, and if the ratio is higher than 1, it means that change is being promoted

by natural selection rather than chance. Something is driving the evolution of

drug resistance, " Janies said. " We could see that happening in seasonal

influenza and in the data we have so far for pandemic influenza, as well.

" A Darwinian would say that something changed that made the Tamiflu-resistant

strain more fit than the wild type, " he said.

The group also examined mutations that alter these two strains of H1N1 viruses'

responses to Relenza. Resistance to that drug is relatively rare, Janies said,

which could be attributed to less frequent use of the drug or to the possibility

that mutations leading to resistance to Relenza aren't tolerated by the virus

itself, so those strains die off.

Janies noted that there is another phenomenon with flu that could further make

the pandemic strains difficult to treat. In at least 50 geographic regions

identified by the analysis, both seasonal and pandemic H1N1 viruses are

co-circulating, including Tamiflu-resistant strains. Because the flu virus in

general is not precise when it makes copies of itself, this means that a

drug-susceptible pandemic strain might exchange a gene with a drug-resistant

viral strain and add it to the new genome.

" And then we would have drug-resistant pandemic influenza without any mutation.

It's a random swap of the whole gene, " Janies said of this phenomenon, which is

called reassortment.

" That's how we got into this situation with pandemic influenza. We have

something that's called pandemic H1N1, but all of its internal genes are

different. It underwent a few rounds of reassortment and it's a virus we've

never seen before because its genome is highly reshuffled compared to seasonal

H1N1. This same process could confer resistance to a drug, " he said.

The researchers have plotted areas where pandemic influenza and drug-resistant

seasonal influenza circulate together into Google Earth using software called

Pointmap. Regions in the United States and Japan are among those in which

pandemic flu isolates carry the Tamiflu-resistant mutation.

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