Study Of Flu Patients
Reveals Virus Outsmarting Key Drug
September 13, 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.