Tamiflu-resistant bird flu kills 2 in Vietnam / Experts assess how findings may affect use of antiviral drug

Two teenagers who died of avian influenza in Vietnam earlier this year developed drug-resistant strains of the virus during treatment with Tamiflu, raising questions about the world's reliance on the pills as the first line of defense against a potential flu pandemic.

A report published in today's issue of the New England Journal of Medicine tells of the resistant strains and also describes how four other Vietnamese patients treated with Tamiflu, or oseltamivir, recovered after the drug appeared to have knocked down the H5N1 bird flu virus in their bloodstreams.

The report offers the most detailed clinical findings to date of Tamiflu treatment against bird flu, and it highlights both the promise and drawbacks of the drug that many nations are now stockpiling in case the H5N1 virus mutates into a form that transmits readily among people.

"This is valuable information," said University of Virginia flu researcher Dr. Frederick Hayden, a leading expert in antiviral flu treatments. "It's an important scientific contribution that points out the limits of our current therapy, but also gives hope."

The Bush administration announced plans last month for federal and state purchases of 75 million doses of Tamiflu to have on hand by 2007 -- at a $1.4 billion estimated cost.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said the development of Tamiflu-resistant strains of H5N1 was "completely predictable," and he sees no reason to back away from stockpiling the drug. "At this point in time, it's the best drug we have," he said.

In a commentary accompanying the study, Dr. Anne Moscona of Cornell University warned that the emergence of drug-resistant strains of avian influenza was "a matter of immediate concern."

"It is becoming clear that more medication than the currently recommended doses may be required for adequate treatment," she wrote.

But, with Tamiflu in short supply worldwide, each increase in the 10-pill, five-day regimen means that even less of the drug will be available from global stockpiles if more pills are required for each successful treatment.

The Vietnamese study was led by Dr. Jeremy Farrar of the Oxford University Clinical Research Unit, at the Hospital for Tropical Diseases in Ho Chi Minh City, where seven of the eight patients in the study were treated.

Much of the article focused on the case of a 13-year-old girl whose mother had just died of avian influenza. Because bird flu was suspected, the girl was treated with Tamiflu one day after she developed a fever and cough.

Although the drug has been used frequently in bird flu cases, it has seldom been prescribed until it is too late to be of much help. Animal studies suggest that the drug needs to be taken within 48 hours of the start of a flu bout to be most effective, but patients in Southeast Asia seldom reach a hospital until they've been sick for a week.

Four days into the girl's Tamiflu treatment, her health began to decline, and three days later she died. Genetic fingerprints of virus taken from her four days after treatment began showed a single mutation that makes it resistant to Tamiflu.

An 18-year-old girl also treated with the drug in January 2005 died 20 days into her illness, and she too tested positive for the resistant strain. Two other patients in the study also died despite Tamiflu treatment, but showed no signs of resistant virus.

Tamiflu resistance has been documented in one previous study -- that of a Vietnamese girl who had taken the drug while healthy in a failed bid to prevent infection with the same virus that had afflicted her family. She was sickened by a resistant strain, but fully recovered.

Four patients treated with Tamiflu in the latest study also recovered, and tests showed their improved health coincided with "rapid declines to undetectable levels" of their viral infections.

Terry Hurley, a spokesman for Tamiflu maker Roche, said viral resistance remains rare and might be controlled by adjustments in the treatments.

Another antiviral drug, Relenza, has also been shown in animal studies to suppress avian influenza -- and researchers say it has a chemical structure that makes it less prone to generate resistant strains. The federal government has ordered 84,000 doses for the stockpile.

However, Relenza is costlier to produce, and must be inhaled -- a process that is known to cause problems for patients prone to respiratory problems.