Two Vietnamese patients have died after developing strains of bird flu that were resistant to Tamiflu, the antiviral drug that nations around the world are stockpiling in the hope of saving lives if a global pandemic occurs.

Their deaths, which took place in January, were reported Thursday in The New England Journal of Medicine. A third patient, a 14-year-old Vietnamese girl whose case was reported in Nature in October, also developed resistance but survived.

Health officials had predicted that the bird flu virus, H5N1, would evolve into resistant forms, which happens often with virus-fighting medications. But experts also say the deaths are a warning that countries are not yet prepared to deal with a pandemic.

Experts are unsure whether a flu pandemic is imminent, but they fear that the H5N1 virus could trigger one if it becomes highly contagious.

Fifty countries are stockpiling Tamiflu, which can be used to treat and prevent infections. Tamiflu’s maker, Roche, announced Wednesday that U.S. regulators would allow it to market the drug to prevent flu in children ages 1 through 12, Reuters reported.

Roche can now produce enough of the drug to treat 65 million people but will make enough for 300 million patients by the end of 2006, says David Reddy, leader of Roche’s influenza pandemic task force.

It still makes sense for countries to stockpile the drug because most patients respond to Tamiflu, says Arnold Monto, a professor of epidemiology at the University of Michigan School of Public Health. The New England Journal article said four of eight Vietnamese patients treated with Tamiflu survived.

But the study suggests doctors might need to use higher doses to prevent resistance, Reddy says. Roche plans to work with the World Health Organization and the National Institutes of Health on a trial that would give patients twice the standard dose of Tamiflu.

If that dose proves effective, nations might need to double their planned stockpiles, says Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota. For now, he says, doctors just don’t know the ideal dose.

Doctors might need to find other ways to treat bird flu should there be a pandemic. The same genetic changes that make the virus more contagious also could make it less deadly, Reddy adds.

Beyond Tamiflu, the Infectious Diseases Society of America recommends stockpiling another antiviral, Relenza, says Andrew Pavia, a member of the group’s task force on pandemic flu. Unlike Tamiflu, which is in pill form, Relenza is given through an inhaler and is harder to administer, especially to patients who are unconscious. Researchers are testing an injectable form.

People who misuse Tamiflu or stockpile it themselves could waste the drug or harm themselves by developing resistance, say doctors Allan Brett and Abigail Zuger in an editorial accompanying the New England Journal article.

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