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Drug-resistant flu virus emerges in untreated patients

April 3, 2007 By Terry Devitt

Flu viruses with reduced sensitivity to the front-line drugs used to thwart and treat infection have been found in patients who were not treated with the drugs, according to an international team of researchers.

The finding, reported April 4, 2007 in the Journal of the American Medical Association (JAMA), provides evidence that flu viruses are evolving resistance to oseltamivir, better known by its trade name Tamiflu, and are spreading via human-to-human contact.

The emergence of drug-resistant influenza was documented in a study of Japanese patients. It is a clear early warning that flu viruses may be beginning to outwit what are now highly effective drugs, says Yoshihiro Kawaoka, a University of Wisconsin–Madison virologist and the senior author of the new JAMA study.

“There is urgent need to develop new kinds of antivirals,” says Kawaoka, an internationally recognized authority on influenza. “This is the first report that drug-resistant influenza B virus may be transmitting in the community.”

Tamiflu is a widely prescribed drug in Japan. The study looked at drug sensitivity in viruses obtained from 74 children treated with the drug and from 348 untreated patients during the last flu season. Of the untreated patients, seven were found to have a virus with a mutation that made them less sensitive to antiviral medication.

The goal of the study was to assess the prevalence and transmissibility of drug-resistant influenza B virus, a strain that is milder than the pandemic-causing influenza A viruses, but nonetheless a serious disease, especially for the very young and the very old.

Tamiflu works by suppressing neuraminidase, an enzyme produced by the virus that helps it reproduce. By interfering with the neuraminidase, the drug prevents new viruses from emerging from cells and stops the chain of infection. Taken soon enough, the drug can be used to prevent or mitigate infection.

Scientists and clinicians fear the emergence of drug-resistant strains of influenza as there are very few antiviral drugs on the market. If flu viruses manage to evolve resistance, key lines of defense will have been effectively removed. More worrisome, says Kawaoka, is that the same resistance will emerge in influenza A viruses, which include highly pathogenic strains such as H5N1 avian influenza.

“We don’t know if this will happen with A viruses,” Kawaoka explains, “but it is sending us a signal that it may happen with A viruses.”

The finding that drug-resistant viruses were being found in patients who had not been treated with antiviral drugs means they “were likely to have been infected with such variants in a community setting” or through contact with family members shedding the mutant viruses.

“We don’t know how extensive that transmission is because we don’t know the history of those patients,” according to Kawaoka. “But we do know that some of the patients in the study were not treated with Tamiflu, but shed Tamiflu-resistant viruses. If you find Tamiflu-resistant viruses in patients not treated with Tamiflu, and there is no animal reservoir for the virus, where else could they get it?”

Viruses, including influenza viruses, mutate constantly in order to stay one step ahead of immune responses, vaccines and drugs. Their ability to readily recombine and exchange genes with other viruses gives them an evolutionary edge that helps them survive.

That same ability worries scientists and doctors as new strains emerge capable of evading host defenses and antiviral defense systems constructed by humans. Viruses capable of thwarting key drugs could conceivably confer that ability on other viruses, dashing a key line of defense and sending scientists and pharmaceutical manufacturers scurrying to develop new medicines.

The new study was funded by a CREST grant from the Japanese Science and Technology Agency; the Japanese Ministry of Education, Culture, Sports, Science and Technology; and the U.S. National Institutes of Health.