Paying the price? Widespread use of an over-the-counter product containing amantadine may have caused the H3N2 influenza strain to lose its sensitivity to the drug.

Old Flu Drugs Bite the Dust

ST. JULIAN'S, MALTA--The most aggressive of the circulating human flu strains is fast becoming resistant to a widely used class of flu drugs, researchers reported here last week at the Second European Influenza Conference. Their study shows that the drugs are all but useless in the yearly battle against seasonal flu, while further deflating hopes they might be used to fight a pandemic.

Amantadine and rimantadine block a viral protein called M2. The flu virus was known to easily evolve resistance, but even after decades of use, resistance rates were low, says Rick Bright from the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia--until recently. Bright set out to determine when and where the upward trend started. He screened more than 7500 flu samples, collected all over the world since 1995, for mutations that confer resistance against both drugs.

A dramatic pattern emerged for H3N2, the most virulent of the three strains that return each winter. Until 2002, no country had resistance rates higher than 10%. But in 2003, the rate shot up to 58% in China, then jumped to 74% in 2004. Hong Kong, South Korea, and Singapore followed with similar explosions, and samples taken in the 2005 flu season in Europe and the United States show resistance up as well.

Over-the-counter sales of amantadine in China may have favored the emergence of resistant strains, Bright says. The drug is an ingredient of several anti-cold and –flu cocktails sold in China. The leading product, called Gan Kang, is widely available for about $1.50, and a recent report in China Business put its 2004 sales at $80 million, or more than 50 million courses. The SARS panic of 2003 could have increased use of such products, Bright says.

Amantadine and rimantadine are primarily used to treat seasonal flu in the United States and Japan, for instance, in nursing homes, says Arnold Monto, an epidemiologist at the University of Michigan, Ann Arbor--but their use is bound to decline now, he adds. The finding may also deal a fatal blow to plans, under way in a few countries, to add amantadine to pandemic stockpiles. That option had already become less appealing after the recent discovery that H5N1 avian flu strains isolated in Thailand and Vietnam were resistant to the drug. With a human strain showing widespread resistance as well--and the fact that pandemic viruses may arise when avian and human strains swap genes--makes it even less appealing, says Bright.

Instead, most governments are choosing another drug called oseltamivir. So far, resistance to that drug is rare, but the CDC study "shows that we should watch and worry," Monto says.

With reporting by Gong Yidong in Beijing.