Avian Flu Strains Show Resistance to Tamiflu

Additional drugs may be needed to deal with possible resistant form of the virus

WEDNESDAY, Dec. 21, 2005 (HealthDay News) -- One of the few drugs known to be effective against the potentially pandemic avian flu is the antiviral drug Tamiflu, but a new report finds further evidence that some patients may develop resistance to it.

A report issued last October outlined one such case in Vietnam. Now, a new article gives more details on two Vietnamese patients who were resistant to Tamiflu (oseltamivir) and died from the H5N1 avian flu virus despite treatment with the drug.

According to the report, six surviving patients who were also treated with the drug appeared to respond well to the therapy, which was associated with a rapid decline of viral load to undetectable levels in the blood.

The report appears in the Dec. 22 issue of The New England Journal of Medicine.

A research team from the Oxford University Clinical Research Unit and Hospital for Tropical Diseases, in Ho Chi Minh City, believes the failed cases show that in some H5N1-infected patients, the recommended dose of Tamiflu is unable to stop the virus from replicating.

In these cases, not only does the virus spread, but a viral resistance to Tamiflu may develop.

The study's lead author, Dr. Menno D. de Jong, said the resistance is unsurprising, but added, "this does not automatically extrapolate to the situation in the event of an influenza pandemic."

"While our study shows that the drug seems to be effective in suppressing viral replication in at least some patients, it also clearly shows that oseltamivir resistance in H5N1 can develop, and if this happens it may render the drug not effective," de Jong said.

"The availability of alternative antiviral drugs, which remain active against oseltamivir-resistant virus, is important," de Jong said. "One such drug is zanamivir. In addition, strategies to prevent or delay resistance development, for example, higher dosing or combination therapy needs to be explored."

"My advice to patients is to remain calm," de Jong added. "High resistance rates have been observed in human flu as well, generally without detrimental clinical effects."

The reasons for Tamiflu's ineffectiveness in some patients is unclear, however. The researchers speculated that the virus may be replicating too fast for the drug to stop it, or somehow the drug becomes altered in these patients.

One expert believes, however, that Tamiflu resistance may not be the reason the two patients died. Instead, their deaths could be due to the virulence of the particular virus.

"There is no telling that the development of resistance has anything to do with the fatal outcome of these patients," said Dr. Arnold S. Monto, a professor of epidemiology at the University of Michigan School of Public Health, Ann Arbor. "We do not suspect that with this virus that we are going to get 100 percent cure."

Monto noted that the H5N1 virus may not be able to spread easily, since it seems to take a very large amount of the virus to move from birds and then infect people. "This virus is somewhat lacking in fitness -- its ability to infect and transmit [to people]," he said. "On a population basis, this virus might not take off."

According to Monto, a new report about to be issued shows that Japan, where Tamiflu is widely used, has not seen an emergence of a resistant flu virus. "Appropriate use of Tamiflu in treating seasonal influenza should not be inhibited because you are worried that you may be enhancing the emergence of a resistant virus," he said.

Despite this, Monto believes that other antiviral drugs to treat the flu are needed. "It's an unhealthy situation to have the whole world dependent on one drug for treating a very important infection," he said. "We can't ensure that this resistance will not emerge. We need to be sure that we have a backup if it does."

Faced with the growing fear of a pandemic of deadly avian flu, the number of requests by patients for prescriptions for Tamiflu has increased dramatically. In increasing numbers, patients have been asking their doctors for Tamiflu so they can be sure they have a supply should an outbreak occur.

One expert, writing in the same journal issue, cautions doctors not to let patients stockpile Tamiflu as a way of being prepared for an outbreak of avian flu.

Physicians are receiving requests by patients to give them prescriptions for Tamiflu, and in many cases, doctors are acceding to these requests, because it's easier than arguing with patients, said Dr. Allan S. Brett, a professor of medicine at the University of South Carolina School of Medicine, Columbia.

"Physicians should not yield to requests for Tamiflu, when the purpose is personal stockpiling," Brett said. "The patient is asking it for some hypothetical event in the future that may or may not even come," he said.

Brett also cautioned that allowing patients to have the drug may encourage them to take it when they think they have the flu, but only have a bad cold. "People may say, 'This could be influenza, so I'll just start taking the drug,' and then it becomes a real waste," he said. "In addition, widespread unnecessary use will increase the chance of resistant virus."

Another expert, writing in the journal, agreed with Brett.

"I focus on the issue of the development of resistance in influenza to Tamiflu," said Dr. Anne Moscona, a professor in the departments of pediatrics and microbiology and immunology at the Weill Medical College of Cornell University in New York City. "This means that the influenza may develop to [a point] where it is no longer able to be killed, to be treated by Tamiflu."

Moscona isn't surprised that resistance to Tamiflu is developing in the H5N1 virus. "We expected resistance to develop," she said. "Resistance is developing in seasonal flu and now resistance is developing in avian flu."

"There is no pandemic flu right now," Moscona said. "Really, Tamiflu remains an effective and important drug in seasonal influenza. Physicians should not be prescribing Tamiflu to people who just want to stockpile it. We should use these drugs to treat people who are sick."

More information

For moe on avian flu, head to the U.S. Centers for Disease Control and Prevention.

SOURCES: Menno de Jong, M.D., Ph.D., Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Allan S. Brett, M.D., professor, medicine, University of South Carolina School of Medicine, Columbia; Anne Moscona, M.D., professor, Departments of Pediatrics and Microbiology and Immunology, Weill Medical College of Cornell University, New York City; Arnold S. Monto, M.D., professor, epidemiology, University of Michigan School of Public Health, Ann Arbor; Dec. 22, 2005, The New England Journal of Medicine
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