Antiviral resistance eliminates drug from flu arsenal

Washington -- It's fortunate that the current flu season has been relatively mild, because physicians have lost one of their prime weapons against the disease. The dominant strain of flu circulating this season has become resistant to the antiviral Tamiflu, or oseltamivir.

This newly noted resistance has raised concerns, because oseltamivir is the most commonly used drug for treating patients who are seriously ill with influenza. It also is being stockpiled by the federal government for use in the event of a pandemic flu outbreak.

The antiviral's failure to be beneficial has made prevention even more important, noted several infectious diseases specialists meeting in Washington, D.C., for a seasonal and pandemic influenza symposium Feb. 2-3. Their message: Don't stop immunizing patients.

The meeting was organized by the Infectious Diseases Society of America and was supported by grants from pharmaceutical firms Gilead, MedImmune and Roche, which manufactures Tamiflu.

About 98% of the A(H1N1) virus, which is currently circulating in the U.S., is resistant to oseltamivir, said Richard Whitley, MD, professor of pediatrics, microbiology, medicine and neurosurgery at the University of Alabama at Birmingham. Dr. Whitley was a co-chair of the meeting and is president-elect of IDSA.

The virus still can be fought with a second antiviral treatment, Relenza, or zanamivir, although that medication is inhaled and can't be used for very young children or for those prone to wheezing. Oseltamivir is taken orally.

"We've seen antiviral resistance emerge over the past two years," said Nancy Cox, PhD, director of the Centers for Disease Control and Prevention's Influenza Division. "Physicians need to be aware that these viruses are circulating and that Tamiflu may not be effective. They need to understand that there are other drugs and drug combinations that may be available."

The extent of the resistance this season led the CDC in December to issue interim recommendations directing physicians to use a combination of oseltamivir and a second antiviral, rimantadine, which is marketed as Flumadine, when treating influenza. Zanamivir is also an appropriate choice, the CDC said.

In the United States, four antivirals are approved for treatment of the flu: oseltamivir and zanamivir, which are neuraminidase inhibitors, and amantadine and rimantadine, which are adamantanes and are older drugs.

Why the resistance developed was a matter of debate at the symposium. Widespread resistance first had been seen last season in Norway, where 20% to 25% of influenza isolates were determined to be resistant. By last summer virtually all of the H1N1 strains that were circulating in South Africa were resistant to oseltamivir, Dr. Whitley said. "We are beginning to see the same thing in the United States."

The resistance is thought to have resulted from a spontaneous mutation by the virus rather than as a product of medication overuse. Antivirals were used infrequently in Norway where resistance was high but were heavily used in Japan where resistance was low, Dr. Whitley said.

Meanwhile, Roche acknowledged the CDC recommendations and noted resistance to the medication has historically been low and is continually monitored. Results from global surveillance studies indicated that the prevalence of Tamiflu-resistant viruses was less than 1% between 1999-2007, said the company in a statement.

Few options available

The resistance issue spotlights two additional problems, said Jeffrey Duchin, MD, chief of the communicable disease epidemiology and immunization section at the Seattle-King County Dept. of Public Health in Washington. "It illustrates that we don't have many good options for the treatment of influenza, which is a common serious disease."

"We've lost the preferred drug for one of the most common strains of flu and the strain that is most likely to cause complications," he noted. "To have so few drugs is not a good option."

In addition, physicians have also been "nihilistic about treating influenza," he added. "Flu has been undertreated for a long time."

But there should be opportunities remaining to treat influenza. The CDC was reporting increasing flu activity in the nation as of the end of January, with five states -- Colorado, Delaware, New York, Texas and Virginia -- registering widespread influenza and 21 states, registering regional activity. One influenza-related pediatric death had been reported.