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A perspective article in the December 22 New England Journal of Medicine by NewYork-Presbyterian Hospital/Weill Cornell Medical Center's Dr. Anne Moscona explores why personal stockpiles and improper use of oseltamivir (Tamiflu) may cause drug-resistant strains of influenza to surface. This report is troubling news as Tamiflu, one of only two neuraminidase inhibitors available to combat seasonal as well as avian influenza, is beginning to appear less than infallible.

Neuraminidase inhibitors oseltamivir and zanamivir, marketed as Tamiflu and Relenza, respectively, are preferable to the older line of antiviral drugs known as adamantanes because they are less toxic, are effective against many more types of influenza, and curb the disease without being as prone to cause the influenza virus to mutate into a drug-resistant strain.

This makes Tamiflu and Relenza particularly valuable in a pandemic situation, and with fears of avian flu looming, doctors have been flooded with requests from patients interested in building personal stockpiles of the drugs. Tamiflu, over Relenza, has been the preferred drug because it can be taken orally. Relenza is a powder that needs to be inhaled, which can be problematic for people with respiratory ailments, and for children.

There are some obvious advantages to personal stockpiling. Neuraminidase inhibitors are more effective when taken at the onset of symptoms, so having them at home could lead to better treatment. And, home use keeps the sick out of waiting rooms and pharmacies, where influenza can be spread to others. According to Dr. Moscona, the disadvantage, and the reason that physicians should be strongly discouraged from prescribing these drugs for healthy persons, is that self-dosing may lead to inadequate use, either in dosage or duration, and inadequate use can allow the influenza virus to mutate into a drug-resistant strain. In a pandemic, inadequate use would likely intensify as keepers divided their stockpiles amongst a larger-than-anticipated group of people.

"This problem was actually predicted several years ago when scientists found that aspects of the chemical structure of Tamiflu, different than the structure of Relenza, could facilitate the development of resistance," says Dr. Moscona, professor of pediatrics, professor of microbiology and immunology, and vice chair for research of pediatrics at Weill Cornell Medical College, and attending pediatrician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. "This prediction is now being validated by clinical data."

In two Japanese studies, where children with seasonal influenza (not avian influenza) were given lower doses of Tamiflu than are typically given in the United States, 16 percent of children in one study and 18 percent in another shed drug-resistant strains of influenza. In a U.S. study with significantly higher doses, none of the treated children shed resistant viruses.

Now, in another troubling development, Dr. Menno de Jong and colleagues report in the same issue of the New England Journal of Medicine that in several patients infected with avian influenza, the viruses developed resistance to Tamiflu even though the patients were being treated with the recommended doses of the drug. As Dr. Moscona's article explains, this new study should galvanize us into taking the necessary steps to avoid drug resistance. These steps include resisting the temptation to prescribe drugs for personal stockpiling.

"What has become even more urgent with this news," says Dr. Moscona, "is that new antiviral drugs need to be developed." She says that drug combinations that can target influenza at several points in its viral cycle simultaneously will reduce the likelihood that a resistant virus will develop.

"We need more than two neuraminidase inhibitors to work with," concludes Dr. Moscona. "The future is just too uncertain and the stakes are too high."