A study of Vietnamese victims of bird flu has found further evidence that the H5N1 virus can mutate to become resistant to Tamiflu, the drug that governments across the world are stockpiling to fight the disease.

The report, published today in the New England Journal of Medicine, said that of eight bird flu patients treated with Tamiflu at the Hospital for Tropical Diseases in Ho Chi Minh City in the last year, four died, of whom two developed a resistance to treatment.

The study was published as the World Health Organisation confirmed that two people, a 39-year-old man and an eight-year-old boy, died of bird flu in Indonesia earlier this month. Eleven people are known to have died after contracting the H5N1 virus in Indonesia, all in the last six months.

Tamiflu, generic name oseltamivir, is the world's preferred drug for the treatment of the H5N1 strain of bird flu, and its manufacturer, Roche AG, is seeking to license the drug to increase production to 600 million treatment courses in 2007.

Britain has ordered 14.6 million batches of Tamiflu, which has been shown to be effective at fighting the symptoms of the disease. But because bird flu is an inherently unstable virus, which struggles to replicate itself accurately, mutation and resistance to treatment has always been deemed likely by scientists.

In the report out today, researchers from the Oxford University Clinical Research Unit wrote: "The emergence of resistant influenza A (H5N1) variants during oseltamivir treatment should not be surprising."

Of the two patients whose infections showed resistance to Tamiflu, one was a 13-year-old girl who was treated with the drug on the second day of her illness. Most of the 73 people known to have died of bird flu have received treatment when the disease is well advanced.

According to the study, the girl initially responded well to the drug, but on the fourth day of treatment her condition worsened, and her viral load increased. "These observations suggest that the development of drug resistance contributed to the failure of therapy and, ultimately, the death of this patient," the report said.

The other patient who demonstrated resistance to Tamiflu was an 18-year-old woman, who developed a second, mutant strain of the bird flu virus during her treatment. Researchers said "the emergence of resistance and this patient’s death was less clear" because she was suffering two strains of the disease but maintained that some resistance had taken place.

The report noted that other flu viruses treated with Tamiflu tend to become resistant to the drug more readily among children than in adults.

Today's study prompted scientists to recommend that governments seek a broad range of treatments to tackle bird flu. Professor Anne Moscona of Cornell University, who wrote an accompanying comment to the study, also warned that unsupervised use of Tamiflu by families that have stockpiled the drug could weaken its effectiveness.

"This frightening report should inspire us to devise pandemic strategies that do not favour the development of Tamiflu-resistant strains," she said.

"Improper use of personal stockpiles of Tamiflu may promote resistance, thereby lessening the usefulness of our frontline defence against influenza, and should be strongly discouraged."

A spokeswoman for the Department of Health said the Government was "carefully considering" the research but insisted that "the experience is the drugs do work".

"While there is some anecdotal evidence of the build-up of resistance to anti-viral drugs such as Tamiflu, at present the experience is that these drugs do work and that they should work against a pandemic strain," she said.

"They need to be used carefully and appropriately to minimise the risk of resistance. The Government is taking steps to build up a stockpile of antiviral drugs to treat those who are ill in a pandemic, and we would agree with the authors that people should not privately stockpile the drug as this risks increasing resistance."

"Tamiflu was chosen on the basis of independent expert advice that reflected its efficacy and ease of administration," she said, adding that Relenza, a flu drug that is inhaled as a spray, was also being considered as a treatment for the disease.

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