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 Childrens Research Hospital in Memphis. 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, MD. 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, PhD. Our results provide baseline information that will be needed for further studies on preventing and treating avian flu with antiviral drugs.

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.

Reference: H. Yen et al. Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 (H5N1) influenza virus in mice. Journal of Infectious Diseases DOI: 10.1086/432008 (2005).

Source: National Institutes of Health