Viruses develop resistance to flu drugs

By HELEN BRANSWELL

Wednesday, September 21, 2005 Posted at 9:02 PM EDT

Canadian Press

Toronto - Human flu viruses are becoming increasingly resistant to
the class of drugs known as adamantanes, one of only two existing
classes of flu drugs, a new study released Thursday shows.

The authors say their findings call into question the future usefulness
of the adamantane or M2 inhibitor drugs - a warning echoed by a
leading antiviral expert who was not involved in the work.

That independent expert, Dr. Frederick Hayden suggested that in light
of the findings the drugs amantadine and rimantadine should not play a
significant role in drug stockpiles put together to help a country
weather a flu pandemic.

"I think that these data present real concerns about how can we use
this class in the future. And it certainly says it makes little sense
to make it an important part of drug stockpiles for pandemic
response," said Dr. Hayden, a scientist at the University of Virginia
who is on secondment to the World Health Organization.

"It takes one of the arrows out of our quiver, as it were."

Only one of the drugs, amantadine, is sold in Canada. The Public Health
Agency of Canada has plans to add substantial quantities of the drug to
the country's pandemic stockpile.

The M2 inhibitors are off-patent and much cheaper than the only other
class of flu drugs, the patent-protected neuraminidase inhibitors
oseltamivir (Tamiflu) and zanamivir (Relenza).

The first author of the study was less definitive about the future of
the drug, saying he felt it was too soon to consider the class lost for
good.

"It's hard to tell. We don't know exactly what caused the resistance.
And it's possible that if it was caused by a spontaneous mutation the
virus could mutate and go back the other way," said Rick Bright of
the strain surveillance section of the influenza branch at the U.S.
Centers for Disease Control in Atlanta.

"I certainly wouldn't give up hope on any class of (flu) drugs at
this point."

But the paper itself warns agencies and governments purchasing pandemic
stockpiles that amantadine and rimantadine "will probably no longer
be effective for treatment or prophylaxis" - using the drugs to
ward off illness - "in the event of a pandemic outbreak of
influenza."

Dr. Bright and his co-authors analyzed human flu viruses submitted to
the CDC - in its role as a WHO influenza reference laboratory -
between Oct. 1, 1994 and March 31, 2005. The aim was to see if the
rates of resistance to the adamantane drugs changed over that period.

The scientists screened more than 7,000 human influenza A viruses
looking for specific genetic mutations known to confer resistance to
the adamantane drugs.

Rates of resistance started to rise in China in 2000 and spiked between
2002 and 2003. Additional spikes occurred in 2003 in viruses from Hong
Kong, Taiwan and South Korea.

"Viruses collected in 2004 from South Korea, Taiwan, Hong Kong and
China showed drug-resistance frequencies of 15 per cent, 23 per cent,
70 per cent and 74 per cent respectively," they wrote in the article,
published by the medical journal The Lancet.

The trend extends beyond Asia. Thirty per cent of Canadian viruses
collected in 2005 and analyzed by the team were resistant to the drugs.
Resistance rates were also significantly above historical values in a
number of countries in South, Central and North America and in Europe.

The authors can't say what is behind the increase in resistance but
they hypothesize it may either be driven by high use of the drugs in
parts of Asia, where they can be bought without prescription or because
of a spontaneous mutation.

While the development occurred almost in parallel - both timewise and
geographically - with the explosion of outbreaks of the avian
influenza strain known as H5N1, both Dr. Bright and Dr. Hayden felt the
events were unrelated.

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