drug resistance and bird flu (NY Times)

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Major Flu Strain Found Resistant to Leading Drug, Puzzling Scientists

January 9, 2009 By DONALD G. McNEIL Jr.

Virtually all the dominant strain of flu in the United States this

season is resistant to the leading antiviral drug Tamiflu, and

scientists and health officials are trying to figure out why.

The problem is not yet a public health crisis because this has been a

below-average flu season so far, and because the Tamiflu-resistant

strain, one of three circulating, is still susceptible to other drugs.

But infectious disease specialists are worried nonetheless.

Last winter, about 11 percent of the throat swabs from patients with

the most common type of flu that were sent to the Centers for Disease

Control and Prevention for genetic typing showed a Tamiflu-resistant

strain. This season, 99 percent do.

" It's quite shocking, " said Dr. Kent A. Sepkowitz, director of

infection control at Memorial Sloan-Kettering Cancer Center in New

York. " We've never lost an antimicrobial this fast. It blew me away. "

The single mutation that creates Tamiflu resistance appears to be

spontaneous, and not a reaction to overuse of the drug. It may have

occurred in Asia, and it was widespread in Europe last year. In

response, the disease control agency issued new guidelines two weeks

ago. They urged doctors to test suspected flu cases as quickly as

possible to see if they are influenza A or influenza B, and if they

are A, whether they are H1 or H3 viruses.

The only Tamiflu-resistant strain is an H1N1. Its resistance mutation

could fade out, an agency scientist said, or a different flu strain

could overtake H1N1 in importance, but right now it causes almost all

flu cases in the country, except in a few mountain states, where H3N2

is prevalent.

Complicating the problem, antiviral drugs work only if taken within

the first 48 hours of infection. A patient with severe flu could be

given the wrong drug and die of pneumonia before test results come in.

So the new guidelines suggest that doctors check with their state

health departments to see which strains are most common locally and

treat for them.

" We're a fancy hospital, and we can't even do the A versus B test in a

timely fashion, " Dr. Sepkowitz said. " I have no idea what a doctor in

an unfancy office without that lab backup can do. "

If a Tamiflu-resistant strain is suspected, the disease control agency

suggests using a similar drug, Relenza. But Relenza is harder to take;

it is a powder that must be inhaled and can cause lung spasms, and it

is not recommended for children under 7.

Relenza, made by GlaxoKline, is known generically as zanamivir.

Tamiflu, made by Roche, is known generically as oseltamivir.

Alternatively, patients who have trouble inhaling Relenza can take a

mixture of Tamiflu and rimantadine, an older generic drug that the

agency stopped recommending two years ago because so many flu strains

were resistant to it. By chance, the new Tamiflu-resistant H1N1 strain

is not.

" The bottom line is that we should have more antiviral drugs, " said

Dr. Arnold S. Monto, a flu expert at the University of Michigan's

School of Public Health. " And we should be looking into multidrug

combinations. "

New York City had tested only two flu samples as of Jan. 6, and both

were Tamiflu-resistant, said Dr. Annie Fine, an epidemiologist at the

city's health department. Flu cases in the city are only " here and

there, " Dr. Fine said, and there have been no outbreaks in nursing

homes. Elderly patients and those with the AIDS virus or on cancer

therapy are most at risk.

But, she added, because of the resistance problem, the city is

speeding its laboratory procedures so it can do both crucial tests in

one day.

" And we strongly suggest that people get a flu shot, " Dr. Fine said.

" There's plenty of time and plenty of vaccine. "

Exactly how the Tamiflu-resistant strain emerged is a mystery, several

experts said.

Resistance appeared several years ago in Japan, which uses more

Tamiflu than any other country, and experts feared it would spread.

But the Japanese strains were found only in patients already treated

with Tamiflu, and they were " weak " — that is, they did not transmit to

other people.

" This looks like a spontaneous development of resistance in the most

unlikely places — possibly in Norway, which doesn't use antivirals at

all, " Dr. Monto said.

Dr. Henry L. Niman, a biochemist in Pittsburgh who runs

recombinomics.com, a Web site that tracks the genetics of flu cases

worldwide, has been warning for months that Tamiflu resistance in H1N1

was spreading.

Dr. Niman argues that it started in China, where Tamiflu use is rare,

was seen last year in Norway, France and Russia, then moved to South

Africa (where winter is June to September), and back to the Northern

Hemisphere in November.

The mutation conferring resistance to Tamiflu, known in the shorthand

of genetics as H274Y on the N gene, was actually, Dr. Niman said,

" just a passenger, totally unrelated to Tamiflu usage, but hitchhiking

on another change. "

The other mutation, he said, known as A193T on the H gene, made the

virus better at infecting people.

Furthermore, Dr. Niman blamed mismatched flu vaccines for helping the

A193T mutation spread. Flu vaccines typically protect against three

flu strains, but none have contained protections against the A193T

mutation.

Dr. ph S. Bresee, chief of flu prevention at the disease control

agency, said he thought Dr. Niman was " probably right " about the

resistance having innocently piggy-backed on a mutation on the H gene

— which creates the spike on the outside of the virus that lets it

break into human cells. But Dr. Bresee said he doubted that last

year's flu vaccine was to blame, since the H1 strain in it protected

" not perfectly, but relatively well " against H1N1 infection.

Dr. Niman said he was worried about two aspects of the new resistance

to Tamiflu. Preliminary data out of Norway, he said, suggested that

the new strain was more likely to cause pneumonia.

The flu typically kills about 36,000 Americans a year, the C.D.C.

estimates, most of them the elderly or the very young, or people with

problems like asthma or heart disease; pneumonia is usually the fatal

complication.

And while seasonal flu is relatively mild, the Tamiflu resistance

could transfer onto the H5N1 bird flu circulating in Asia and Egypt,

which has killed millions of birds and about 250 people since 2003.

Although H5N1 has not turned into a pandemic strain, as many experts

recently feared it would, it still could — and Tamiflu resistance in

that case would be a disaster.

http://www.nytimes.com/2009/01/09/health/09flu.html