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Tamiflu, If Misused, Can Lose Its Benefits Bird Flu Can Adapt to Resist the Drug, a First Study Reports

Posted on: Saturday, 24 December 2005, 09:00 CST

By Elisabeth Rosenthal

The first scientific study of humans with bird flu who have received the antiviral drug Tamiflu has found that the bird flu virus can rapidly become invulnerable to the medicine.

The finding has important implications while governments around the world are stockpiling billions of doses of Tamiflu for widespread use in the event of a future influenza pandemic, caused by the H5N1 virus, and as worried citizens hoard boxes of Tamiflu in their medicine chests.

If the drug is overused, used improperly or even used very widely, the current research suggests that Tamiflu also known as oseltamivir will quickly become impotent against the disease, leaving doctors with little else to offer ill patients.

"This frightening report should inspire us to devise pandemic strategies that do not favor the development of oseltamivir- resistant strains," wrote Dr. Anne Moscona, an infectious disease specialist at the Weill Cornell Medical Center, in a commentary on the new study that appeared Thursday in the New England Journal of Medicine. "Improper use of personal stockpiles of oseltamivir may promote resistance, thereby lessening the usefulness of our frontline treatments."

Dr. Keiji Fukuda of the World Health Organization's Global Influenza Program in Geneva said: "The fact that now we actually observe resistance developing lends a new sense of urgency to dealing with the virus, since before, the threat was theoretical."

But Fukuda added that Tamiflu was "still a good and useful drug," the best among the limited options available for treating H5N1.

"What this does is to raise questions about how to use it and highlight the fact that we need more studies and more information," he said. Only about 140 humans, all in Asia, have become infected with the H5N1 virus, all of them through close contact with infected birds.

In the new study, Dr. Menno De Jong and his colleagues at Vietnam's Hospital for Tropical Diseases in Ho Chi Minh City treated eight of those patients with Tamiflu. Vietnam has had more human bird flu cases than any other country.

The good news was that in half of the patients, Tamiflu worked well, dramatically reducing the number of virus particles in the body and presumably facilitating the patient's recovery.

But the bad news, which experts said is probably more significant, is that in two patients the bird flu virus rapidly developed strong resistance to the drug. The patients died, their bodies overwhelmed by the virus.

The remaining two patients died despite treatment, although the drug may have been started too late in their illness to help them.

From a public health perspective, the development of resistance in even a quarter of cases is worrisome, since it means that such patients, before they die, can pass on a resistant form of the virus that is even harder to treat.

There is only one class of medicine that has any effect against the virus and that class contains only two drugs Tamiflu, made by Roche, and Relenza, made by GlaxoSmithKline. Relenza is hard to use because it is a powder that must be inhaled.

If resistance to Tamiflu becomes widespread, the arsenal of medical weapons is empty.

The first and most immediate implication of the new study, experts said, is that doctors should stop giving prescriptions for Tamiflu to healthy patients. Even though the World Health Organization has generally discouraged the practice, pharmacies from Paris to New York had long waiting lists to buy the drug this autumn. It is sold by prescription only.

Moscona said that, in unskilled hands, the drug may be used haphazardly. If people take antiviral drugs in too low a dose or for too short a period, they are of little benefit and give the virus an ideal opportunity to change in ways that allow it to resist the medication.

Tamiflu is effective only against illnesses caused by an influenza virus, not the common cold. It must be started within 36 hours of the first symptoms in order to have any effect. It does not cure people, but reduces the length of the illness by a day or two and decreases somewhat the severity of symptoms.

Experts have long known that influenza viruses could develop resistance to Tamiflu, especially when the drug is used in lower doses. In Japan, where the drug is commonly used to treat normal seasonal influenza, some studies have shown that as many as 10 percent of children who take Tamiflu develop a resistant virus.

The WHO will continue to recommend that countries stockpile Tamiflu for use in the event of a pandemic, Fukuda said, although he said the study might cause them to re-evaluate the doses used and the duration of therapy.

"When you look at the options for antivirals, they are very limited and you need to prepare as best you can," he said.

Dr. David Reddy, an official at Roche, told reporters by telephone that the report underscored what scientists had learned about the drug's effects from studies in ferrets and other animals. Although the report involved a small number of cases, it was "a good basis for learning" about the use of Tamiflu in cases of avian influenza, Reddy said.

Roche is conducting additional animal studies to "more closely mirror" the use of Tamiflu in outbreaks and is planning to collaborate with the WHO and the National Institutes of Health in Bethesda, Maryland, to study people infected with H5N1, Reddy said.

***

Lawrence K. Altman and Andrew Pollack of The New York Times contributed reporting for this article.

Source: International Herald Tribune

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