2 Common Flu Drugs Called Ineffective Against Virus

By David Brown
Washington Post Staff Writer
Sunday, January 15, 2006

Federal health officials yesterday advised physicians not to use two common and long-standing influenza drugs because nearly all the virus in current flu outbreaks in the United States is resistant to them.

The elimination of amantadine and rimantadine from clinical use leaves practitioners with only two licensed influenza antivirals, Tamiflu and Relenza. Relenza is largely unavailable, however, because of supply shortages.

Resistance to amantadine and rimantadine has been climbing, particularly in Asia, in recent years. It has taken a huge leap this year in the United States for reasons that are unclear.

Two years ago, 2 percent of circulating flu viruses here were resistant to the two drugs, which are known as adamantanes. Last flu season, 11 percent were resistant. This season, 91 percent of virus samples tested since Oct. 1 -- 109 out of 120 -- are adamantane-resistant, said Nancy J. Cox, head of the influenza branch at the Centers for Disease Control and Prevention.

The CDC made the announcement yesterday in an urgently called news conference. Flu season is heating up, and outbreaks have been reported in nursing homes in New York, Illinois and several other states. The adamantane drugs are commonly prescribed to prevent infection in elderly or chronically ill people at high risk of complications of the infection, including death.

"We really wanted to let clinicians know so they could treat their patients appropriately," Cox said.

In the first week in January, seven states reported "widespread" flu activity; 11 reported "regional"; nine, including Virginia, reported "local"; 21 states, including Maryland (plus the District), reported "sporadic"; and two reported none.

"These were the mainstay of influenza therapy," said Anne Moscona, a pediatrician at Weill Cornell Medical Center and an expert in antiviral drugs. She said the demise of amantadine and rimantadine is not entirely unexpected.

"The evolution of virus in this direction has been inevitable. I think 91 percent resistant is probably a higher level than was anticipated," she said.

Adamantane resistance is also rising in Europe, although flu-surveillance labs there have not released their figures, Cox said.

In Asia, resistance increased from 2 percent in 2001 to 27 percent in 2004, with some countries reporting much higher rates. In China last flu season, 74 percent of virus samples were resistant to the adamantanes.

There are two ways drug resistance can increase rapidly.

Flu virus can undergo a spontaneous mutation that makes it resistant to a drug. There are five places in the influenza virus genome where the substitution of a single nucleotide or "letter" can confer resistance to both adamantane drugs. This resistant strain can then, purely by chance, become the dominant one during a flu season.

Alternatively, using an antiviral drug during an infection -- particularly if the dose is inadequate -- can put evolutionary "pressure" on a virus to develop resistance. About 30 percent of people who take amantadine once they are infected with influenza will end up excreting drug-resistant virus from their throats, Moscona said.

Which of these mechanisms was responsible for the jump in adamantane resistance is uncertain. In recent years, however, drug-resistant strains have been found widely throughout China even where antivirals are rarely used, suggesting that chance may be an important factor.

The season's dominant strain of flu virus eventually disappears as it runs out of victims; it is replaced by a new strain. Consequently, it is possible that some future flu strains may be once again susceptible to the drugs.

The new development makes it even more imperative that people prescribed Tamiflu (also known as oseltamivir) take it at the right dose for a full course, Moscona said.

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