Study of flu patients reveals virus outsmarting key drug

August 26, 2004

MADISON - A drug envisioned as a front-line defense for the next flu pandemic might have a genetic Achilles' heel that results in a drug-resistant influenza virus capable of infecting new human hosts, according to a study published this week (Aug. 28) in the British medical journal The Lancet.

The study of Japanese children with influenza and treated with the antiviral drug oseltamivir was conducted by an international team of researchers led by virologist Yoshihiro Kawaoka of the University of Wisconsin-Madison and the University of Tokyo. Results of the study showed that nearly 20 percent of patients treated with the drug produced mutant drug-resistant viruses as soon as four days after treatment. Moreover, patients continued to shed significant amounts of infectious viral particles even after five days of treatment with the potent antiviral agent.

"The problem with this compound is that a single (genetic) mutation makes the virus resistant," says Kawaoka, an authority on influenza who holds an appointment at the UW-Madison School of Veterinary Medicine.

The finding is important because it provides evidence that influenza viruses can easily and quickly thwart one of the few lines of defense for a disease that claims many lives each year and that, in a pandemic, is among the world's most feared and deadly diseases.

"The importance of this work is that when a pandemic occurs with a new virus and this drug is extensively used, then we may be faced with the rapid appearance of resistant viruses," Kawaoka says.

At present, there are only two strategies for stemming the spread of influenza: vaccines and antiviral drugs. Vaccines use inactivated forms of a virus to ramp up the immune system and thwart infection. Antiviral drugs such as oseltamivir work by inhibiting key proteins on the surface of the virus, effectively locking them in their host cells and preventing the virus from escaping and infecting new cells and hosts.

In a pandemic caused by a new strain of flu virus, new vaccines would need to be developed to cope with changes the virus creates to escape immune detection in host animals. But vaccines take six months or longer to develop and produce in quantity. In the event of an influenza pandemic, when a virulent new form of the flu virus emerges and poses a global health threat, antiviral drugs are viewed as a stopgap, a way to buy time while new vaccines are developed and rushed into production.

The last flu pandemic was in 1968. The influenza pandemic of 1918 was a global tragedy, claiming 21 million lives - more than died in battle in World War I. One billion people - nearly half of the earth's population at the time - were infected.

The new study of Japanese children portrays what might happen in a pandemic as the immune system of a child, never before exposed to a flu virus, mirrors the adult human immune system exposed to the new, more virulent forms of flu virus at the root of pandemics.

"Most of the children we looked at are younger than 3 years old," Kawaoka explains. "They're encountering the flu virus for the first time. In this respect, our population of patients might be considered comparable to one experiencing pandemic influenza in the absence of pre-existing immunity."

The study of 50 Japanese children with influenza, says Kawaoka, suggests that oseltamivir-resistant viruses arise frequently in children treated with the drug.

"We don't know how virulent these viruses are, but they can be a source of another infection, possibly by resistant viruses," he says.

Oseltamivir is a well-known drug and is widely used in Japan. Its use in the United States is restricted, primarily because of cost.

Kawaoka emphasized that while the emergence of resistant flu virus was worrisome, the compound oseltamivir is still a valuable therapeutic drug.

"This is still a good compound," he says. "As with any antiviral compound, the therapeutic value of these agents can be compromised by the emergence of drug-resistant mutants."
In addition to Kawaoka, co-authors of The Lancet paper include Maki Kiso, Keiko Mitamura, Yuko Sakai-Tagawa, Kyoko Shiraishi, Chiharu Kawakami, Kazuhiro Kimura, Frederick G. Hayden and Norio Sugaya.

The research was support by the U.S. National Institutes of Health, the Japan Science and Technology Corp., the Japanese Ministry of Education, Culture, Sports, Science and Technology, and the Japanese Ministry of Health.

Note: Kawaoka is traveling in Japan. He will respond to queries made via e-mail.

Terry Devitt, (608) 262-8282,

University of Wisconsin-Madison

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