Public health authorities are reporting three cases of the pandemic H1N1 influenza in which the virus was resistant to a key antiviral drug.
Until now, all tested strains of the novel H1N1 flu have been susceptible to oseltamivir, known by the brand name Tamiflu, an antiviral drug that can be used to prevent or treat influenza.
But the three cases of a drug resistant virus -- one each in Hong Kong, Denmark, and Japan -- suggest that resistance could arise.
Although most experts say they are not alarmed so far, they note that if widespread resistance to oseltamivir arises, it could take an important weapon out of the hands of doctors.
"Tamiflu has been the main stockpiled drug to be used for treatment and prevention of pandemic influenza, and obviously rapidly developing resistance would be a problem if it were to occur," said Dr. Christopher Ohl, associate professor of medicine at Wake Forest University School of Medicine's Section on Infectious Diseases in Winston-Salem, N.C. "A Tamiflu-resistant virus would not respond to Tamiflu treatment or preventive administration."
What is worrying some is that one of the cases of resistance occurred in a woman in Hong Kong who had not been treated with the drug. In the other two cases, the patients had been given the drug as a preventive measure, according to Dr. Keiji Fukuda of WHO.
Fukuda said the agency is monitoring the situation closely, but no other cases have yet turned up. Moreover, he said, there's no evidence that a resistant strain is beginning to circulate.
"Right now this looks like spontaneous mutation in these patients," Fukuda said at a press conference Tuesday. He said all three patients had the same mutation, and all three had "uncomplicated" disease from which they made full recoveries.
He added there's also no evidence of a resistant strain in any of the contacts of the three patients.
Resistant Strains of Flu Virus Not Uncommon
However, drug resistance is an issue with other strains of flu. The U.S. Centers for Disease Control and Prevention said that nearly all of the tested strains of seasonal H1N1 flu this season were resistant to oseltamivir, although there was less resistance among circulating strains of H3N2 influenza A or influenza B.
For that reason, the CDC in June recommended that physicians treat all suspected flu cases, whether seasonal or pandemic, with the other approved member of the same class of drugs, zanamivir (Relenza), wherever possible.
Until the three cases of the pandemic H1N1 virus emerged, there had been no sign of oseltamivir resistance in that strain. Fukuda said there is still no evidence that a resistant strain is being transmitted.
Even so, "The emergence of drug-resistant viruses is not unexpected," said David Topham of the University of Rochester, "especially in light of the increased use of influenza antivirals in the context of this recent pandemic."
Topham cautioned, "Overuse of the antivirals will almost certainly hasten the emergence of resistant strains, which will leave us fewer options for treating those who truly are in need."
Unfortunately, many physicians are using oseltamivir in a way calculated to generate resistance, according to Dr. Len Horovitz of Lenox Hill Hospital in New York city.
"It is my observation that all too many physicians -- mostly pediatricians -- are treating mild cases," he said. In addition, he said, they're using the drug as a preventive measure to fight the effects of household contacts with patients.
"It is not surprising that resistance is being seen," said he added, saying he'd be concerned "if there is a second wave of a more virulent mutated strain [this fall]."
Resistance to oseltamivir is more frequent in people treated with the drug, according to Dr. Daniel Hinthorn of the University of Kansas Hospital and Medical Center in Kansas City, Kansas.
Mutation May Have Made H1N1 Resistant to Tamiflu
If it shows up in a person who hasn't been exposed to the drug, it could be that it was transmitted from a person who had been given oseltamivir, he said.
The virus might also have undergone a genetic change to become resistant -- the "spontaneous mutation" Fukuda mentioned.
Or, the virus might have recombined with other strains -- something that influenza viruses do frequently –--and derived its resistance that way, Hinthorn said.
That's not very likely right now, he said, since the pandemic virus is just about the only strain in circulation.
"This is certainly potentially important," he said, but "only time will tell if this is a rare or a common event."
Oseltamivir is a member of a class of drugs known as neuraminidase inhibitors: neuraminidase in the "N" in H1N1. It's widely used because it is an oral drug. Its companion drug, zanamivir is inhaled, making it difficult to use for people with respiratory conditions. It is also not approved for children.
If oseltamivir resistance becomes widespread in the pandemic flu, it could create difficult treatment choices for physicians, according to Dr. Jeffrey Boscamp of Hackensack University Medical Center in Hackensack, N.J.
"We struggled during the seasonal flu outbreak this past winter with the emergence of Tamiflu-resistant influenza A and had to come up with some difficult antiviral combinations, particularly for children who couldn't take Relenza," he said.
"It is highly likely that we will see Tamiflu resistance here [in the pandemic strain] and it will limit our treatment options," he said. "It will be a very big problem if we see this novel virus becoming more virulent than it currently is."
All of this makes predicting what influenza will do a "dangerous game," according to Marc Lipsitch of the Harvard School of Public Health.
Even if it turns out that a resistant strain has been transmitted from one person to another, "it could be an unlucky, one-off event, and we need to watch and see how much more it spreads," he said.
Tamiflu Still Useful, Experts Say
And even if that's not so, it will take a while for resistance to become widespread, Lipsitch said.
"The use of oseltamivir will continue to have benefits for quite a while, because there are so many more drug-sensitive cases out there than drug-resistant ones," he said, "and we would expect it to be months at least -- maybe more -- before a resistant strain became a majority of cases."
"But predictions are hazardous and careful surveillance is critical," he added.
This article was developed in collaboration with ABC News.