3 Avian Flu Patients Were Resistant to Tamiflu

2 Who Died From Avian Flu in Vietnam Were Resistant to an Antiviral Drug
December 22, 2005
By LAWRENCE K. ALTMAN

Two patients who died from avian influenza in Vietnam had developed resistance to the antiviral drug Tamiflu, scientists are reporting today.

The cases bring to three the number of Tamiflu-resistant cases among 138 people known to have been infected with the A (H5N1) avian influenza virus, according to the World Health Organization. Of these, 71 have died.

All cases of human infection have been reported from Southeast Asia and with rare exception are believed to have resulted from contact with infected birds. All three Tamiflu-resistant cases occurred in Vietnam.

The findings, which are being reported in The New England Journal of Medicine, show that the virus can rapidly mutate in certain patients to become Tamiflu resistant. Tamiflu might need to be given in larger amounts and for longer than currently recommended for human influenza viruses, the report said. It also said Tamiflu might need to be used in combination with other drugs in some cases.

There is no evidence that any kind of resistant avian influenza virus is being spread from person to person. Rather, there may have been some particular reason why these individuals developed resistance.

"An urgency" exists to do more research to determine the most effective antiviral treatment for any strain that might mutate to cause a human pandemic of influenza, an influenza expert at the health organization said.

But the findings do not mean that governments around the world should stop stockpiling hundreds of millions of doses of Tamiflu for use in the event of an influenza pandemic caused by the A (H5N1) avian influenza virus, said the organization expert, Dr. Keiji Fukuda.

Scientists have predicted that the A (H5N1) strain would become resistant to Tamiflu in an unknown percentage of cases. Three is too small a number of cases to determine how often the virus will become resistant to Tamiflu and to draw conclusions about the wider use of that drug at this time, Dr. Fukuda said.

Despite resistance, Tamiflu can still be useful for many people, Dr. Fukuda said in a telephone interview from his office in Geneva.

Of the eight patients being reported today, four survived and four died. Among survivors, the amount of A (H5N1) influenza virus dropped rapidly to levels where tests could not detect it, presumably accounting for the patients' recovery. In two of the fatal cases, the virus rapidly mutated to become Tamiflu resistant and overwhelm the body. The remaining two patients died, possibly because they received Tamiflu too late to stop the virus from multiplying and causing its damage.

"The presence of detectable virus after the completion of treatment is associated with a poor outcome," said the team, which was headed by Dr. Menno D. de Jong of the Hospital for Tropical Diseases in Ho Chi Minh City.

The team said its observations suggested that treatment with the recommended dose of Tamiflu, also known as oseltamivir, in some cases incompletely suppressed multiplication of the virus. "Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop," Dr. de Jong's team reported.

Dr. David Reddy, an official of Roche, the Swiss manufacturer of Tamiflu, 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 avian influenza, Dr. Reddy said.

"We have to learn how to manage" A (H5N1) avian influenza in people, Dr. 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, Md., to study people infected with A(H5N1), Dr. Reddy said.

Roche announced yesterday that United States officials approved expanded marketing of Tamiflu to include preventing the usual seasonal influenza among children ages 1 through 12. In the past, Tamiflu has been approved for preventing infection in people ages 13 and older and for treating the infection in anyone 1 year old and older.

Andrew Pollack contributed reporting from Los Angeles for this article.