Study: Oseltamivir helps mice survive H5N1 infection

Jul 18, 2005 (CIDRAP News) – Researchers report that the antiviral drug oseltamivir helped mice survive infection with the H5N1 avian influenza virus, boosting hopes that the drug could be an effective weapon if the virus sparked a human flu pandemic.

Up to 80% of mice treated with oseltamivir survived the infection, whereas all mice treated with a placebo died, according to a report by a team of leading influenza virus researchers in the Journal of Infectious Diseases.

The team also determined that the current strain of the H5N1 virus, which has killed at least 54 people in Southeast Asia in the past 19 months, is much more virulent than the H5N1 strain that killed 6 of 18 people infected in Hong Kong in 1997.

The H5N1 virus is regarded as likely to trigger a flu pandemic if it evolves into a form that could pass easily from person to person. If that happens, it will take months to produce a vaccine specific to the virus. In the meantime, oseltamivir (Tamiflu) and similar drugs, called neuraminidase inhibitors, might be the only effective medications for preventing and treating the illness, according to disease experts. Neuraminidase inhibitors block a protein that enables flu viruses to leave host cells.

"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," said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Disease (NIAID), which sponsored the study. Fauci was quoted in an NIAID news release.

The NIAID said the study is the first published research on the use of oseltamivir against the H5N1 strain now circulating in Vietnam. It was conducted at St. Jude's Children's Research Hospital in Memphis and authored by Hui-Ling Yen, Arnold S. Monto, Robert G. Webster, and Elena A. Govorkova.

The investigators used an H5N1 strain derived from a Vietnamese patient who died. They inoculated 80 mice with the virus and treated them with one of three possible dosages of oseltamivir (0.1, 1, or 10 mg/kg of body weight per day) or a placebo. The highest dosage was proportional to the dosage humans receive when treated for the flu. Thirty mice received oseltamivir for 5 days—the same regimen as is recommended for humans—while 30 received the drug for 8 days.

Survival rates for the mice depended on their daily dose and regimen length. Five of 10 mice that received 10 mg/kg/day for 5 days survived, but all the mice that received lower doses for 5 days died. Among mice on the 8-day regimen, the survival rates were 1 of 10 on the lowest dose, 6 of 10 on the middle dose, and 8 of 10 on the highest 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," the NIAID said. In mice on the 5-day regimen, analysis of the lungs showed that the virus survived and grew again after the treatment ended. Most of the mice that died had severe neurologic symptoms.

The researchers found that oseltamivir was less potent against the 2004 Vietnam strain of H5N1 than it had been against the 1997 Hong Kong strain in a previous mouse experiment at St. Jude's. Therefore the investigators compared the virulence of the two strains by assessing their growth and infectivity in chicken eggs, canine kidney cells, and mice. They found significantly higher yields for the 2004 strain than the 1997 strain.

"The higher brain and blood titers in mice infected with the VN1203/04 [Vietnam 2004] virus indicated a greater propensity toward systemic spread," the report states. It adds that the higher virulence of the 2004 virus may help explain why oseltamivir didn't work as well against it.

"The H5N1 avian flu viruses are in a process of rapid evolution," author Govorkova said in the NIAID release. "We were surprised at the tenacity of this new variant."

The researchers also did a genetic analysis to look for any emerging mutations that could make the virus more drug-resistant. They sequenced the neuraminidase and hemagglutinin genes from several viruses isolated from the mice and found no amino-acid changes.

The NIAID noted that H5N1 virus was found in the spinal fluid of a Vietnamese boy who died last year, suggesting that the virus is able to infect the human brain. The authors say more research is needed to determine if a higher dosage or longer regimen of oseltamivir might stop the virus from growing in the lungs and spreading to the brain.

They conclude that it is "encouraging" that the 2004 virus was sensitive to oseltamivir in mice, even though a longer treatment regimen and higher dosage were required.

Yen H, Monto AS, Webster RG, et al. Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 influenza virus in mice. J Infect Dis 2005 Aug 15;192(4):665-72 [Abstract]

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