Flu Virus Reported To Resist Drug Envisioned For Pandemic

Scientists from the University ofWisconsin-Madison, working with colleagues in Vietnam and Japan, reportin a brief communication in next week's edition (Oct. 20, 2005) of thejournal Nature that a young girl, provided with a prophylactic dose ofthe drug after experiencing mild influenza symptoms, developed a strainof the virus that was highly resistant to the drug.

The findingsuggests that health officials - now stockpiling millions of doses ofthe drug to forestall a global outbreak of influenza and buy time todevelop and mass produce a vaccine - should also consider otheroptions, according to Yoshihiro Kawaoka, an international authority oninfluenza and the senior author of the Nature paper.

Recentreports indicate the federal government may spend billions of dollarsto stockpile as much as 81 million courses of Tamiflu to forestall apossible influenza pandemic. The government has already stockpiled anestimated 12 to 13 million courses.

"This is the first line ofdefense," says Kawaoka, a professor in the UW-Madison School ofVeterinary Medicine who holds a joint appointment at the University ofTokyo. "It is the drug many countries are stockpiling, and the plan isto rely heavily on it."

The drug would be used to slow the spread of influenza until a vaccine is developed, which may take up to six months.

Tamifluis delivered orally and works to impede the spread of the virus bybinding to and inhibiting one of the surface enzymes the virus uses toexit infected cells of a host. Once inside a host cell, the viruscommandeers the cell's reproductive machinery to make new infectiousparticles that go on to take over other cells. When the drug is atwork, Kawaoka explains, "the virus is still able to replicate inside acell, but is unable to get out and infect other cells."

Oseltamivir,which Kawaoka describes as an "amazing drug," is one of three compoundsproven to be effective against influenza. One class, derivatives of thecompound adamantine, would be less effective, as some flu viruses havealready evolved resistance to it. The other drug, zanamivir, which wasdeveloped prior to oseltamivir, is effective, but is formulated as apowder and requires that a clinician provide instructions for use.Thus, it is more cumbersome to administer than the orally deliveredTamiflu.

These flu-fighting drugs, says Kawaoka, are by no meansa replacement or alternative to a vaccine. Effective vaccines canconfer immunity, preventing the virus from gaining a toehold in thebody. But it is unlikely sufficient quantities of a vaccine can beproduced and stockpiled prior to the emergence of a new virus in humanpopulations.

If avian influenza does emerge and becomesinfectious from human to human - and nearly all experts agree that willhappen at some point in the future - an outbreak similar to the 1918influenza pandemic could occur. That pandemic killed as many as 50million people, more than died on all the battlefields of World War I.Scientists and vaccine manufacturers would be in a race against time toproduce enough doses to forestall disaster. Drugs like Tamiflu, used incombination with quarantine, would be intended to slow the spread ofthe disease until a vaccine is produced.

Kawaoka says there maynot be enough Tamiflu to go around even though countries arestockpiling it. The Wisconsin scientist says that will create a risk ofpatients sharing the drug and using smaller doses, which couldaccelerate the emergence of virus resistant to the drug and hamperefforts to contain the spread of the disease.

He says healthofficials should consider stockpiling zanamivir and recommending thatonly the therapeutic dosages of Tamiflu be administered to patients.

"We'vebeen watching for this change (in the virus)," Kawaoka says. "This isthe first, but we will see others. There's no question about it."