Mouse Studies of Oseltamivir Show
Promise Against H5N1 Influenza Virus
Experiments in mice show that an antiviral drug currently
used against annual influenza strains also can suppress
the deadly influenza virus that has spread from birds
to humans, killing dozens of people in Vietnam, Cambodia
and Thailand since early 2004. This study, the first
published report conducted on oseltamivir against the
H5N1 influenza strain circulating in Vietnam, found
that the drug, sold commercially as Tamiflu, dramatically
boosted the survival rate of infected mice.
The National Institute of Allergy and Infectious Diseases
(NIAID), part of the National Institutes of Health (NIH),
funded this research at St. Jude Children’s Research
Hospital in Memphis, TN. Results of the study are now
available online in the Journal of Infectious Diseases.
Public health experts fear that the avian flu virus
could develop the ability to spread easily from person
to person and kill millions in a deadly flu pandemic. “We
need to know whether antiviral drugs can prevent and
treat avian flu, because in the early stages of a global
outbreak, most people would be unvaccinated,” says NIAID
Director Anthony S. Fauci, M.D. “If a pandemic occurs,
it will take months to manufacture and distribute a
vaccine to all who need it.”
In its study, the St. Jude research team gave one of
three possible daily dosage levels of oseltamivir or
a placebo to mice infected with H5N1 influenza virus.
The highest dosage level, adjusted for weight, was equivalent
to the dose currently recommended for humans sick with
the flu. Although the recommended human dose of oseltamivir
is taken for five days, the researchers also tested
an extended eight-day course in half of the mice. Oseltamivir
decreases the ability of influenza virus to spread from
infected cells to uninfected cells by inhibiting neuraminidase,
which is an influenza protein required for the virus
to exit infected cells.
Of 80 mice infected with H5N1 virus, 20 received a
placebo, 30 were given oseltamivir at one of three dosage
levels for five days, and 30 received the drug at one
of three dosage levels for eight days. None of the mice
receiving a placebo survived. Only five of 10 mice given
the highest daily dose of oseltamivir for five days
survived. Although oseltamivir suppressed the virus
in the mice, the virus continued to grow if the drug
was stopped after five days.
Mice given the drug for eight days fared better. Survivors
included one of 10 mice given the lowest daily dose,
six of 10 given the middle-range daily dose, and eight
of 10 given the highest daily dose. The eight-day dose
of oseltamivir allowed more time for virus levels to
fall and less chance for avian flu to rebound after
the drug was stopped.
In addition to testing the efficacy of oseltamivir
against H5N1 virus in mice, the St. Jude researchers
compared the virulence of the new Vietnam virus with
a 1997 variant of H5N1 that killed six people in Hong
Kong. Researchers found that the 2004 H5N1virus, currently
circulating in Vietnam, is much more virulent than its
1997 predecessor. A longer course of antiviral treatment
may be required to conquer the aggressiveness of the
new antigenic variant of H5N1 virus, the researchers
suggest.
“The H5N1 avian flu viruses are in a process of rapid
evolution. We were surprised at the tenacity of this
new variant,” says St. Jude researcher Elena A. Govorkova,
Ph.D. “Our results provide baseline information that
will be needed for further studies on preventing and
treating avian flu with antiviral drugs.” Co-authors
include Hui-Ling Yen, M.S., and renowned flu researchers
Robert G. Webster, Ph.D., also of St. Jude, and Arnold
S. Monto, M.D., of the University of Michigan.
British researchers reported finding H5N1 flu virus
in the spinal fluid of a young boy who died of influenza
in Vietnam earlier this year, an indication that H5N1
is able to infect the human brain. The St. Jude researchers
say that further study is needed to see if using higher
doses of oseltamivir for a longer period of time can
prevent the H5N1 virus in the lungs from gaining a foothold
and then spreading to the brain. The researchers are
planning additional studies in small animal models in
which avian flu infection closely resembles the disease
in humans.
NIAID is a component of the National Institutes of
Health, an agency of the U.S. Department of Health and
Human Services. NIAID supports basic and applied research
to prevent, diagnose and treat infectious diseases such
as HIV/AIDS and other sexually transmitted infections,
influenza, tuberculosis, malaria and illness from potential
agents of bioterrorism. NIAID also supports research
on transplantation and immune-related illnesses, including
autoimmune disorders, asthma and allergies.
The National Institutes of Health (NIH) — The
Nation's Medical Research Agency — is comprised
of 27 Institutes and Centers and is a component of the
U. S. Department of Health and Human Services. It is the
primary Federal agency for conducting and supporting basic,
clinical, and translational medical research, and investigates
the causes, treatments, and cures for both common and
rare diseases. For more information about NIH and its
programs, visit www.nih.gov. |