Not enough studies have yet been done to determine the most effective way of using the antiviral drug oseltamivir (Tamiflu) and other antivirals against the H5N1 strain of avian influenza, a leading expert has warned. “In terms of dose, time, or strategy, all the studies have so far been done on H3N1 and H1N1 flu,” said Professor Robert Webster, of the division of virology at St Jude Children's Research Hospital, Memphis, Tennessee, and visiting professor at the University of Hong Kong's department of virology. “It is inevitable that we will get resistance, but we also need to learn how best to use these drugs against H5N1 avian flu. So far, animal studies suggest that they are useful, but we are still on a learning curve.”
Roche, the manufacturer of oseltamivir, says that the drug may need to be used in combination with other antivirals and in larger doses than first thought to combat H5N1 avian influenza. “Roche agrees that other treatment regimens for the H5N1 virus need to be explored, including higher dose and/or longer duration of treatment with Tamiflu, or a combination of antiviral agents,” a statement from the company said.
The statement was in response to a paper published in the New England Journal of Medicine on 22 December that described resistance to oseltamivir in two fatal cases of H5N1 avian flu in Vietnam (2005;353: 2667-72)16371632. In the first case, a 13 year old girl began treatment with oseltamivir and remained stable for three days, but, on the fourth day, she became increasingly dependent on oxygen, white cell and platelet counts fell, and she developed hepatitis. “At the time of her death, the viral load in her throat had increased. These observations suggest that the development of drug resistance contributed to the failure of therapy and, ultimately, the death of this patient,” the authors wrote.
In the second patient, the viral load declined during treatment but was still detectable. “Although a direct relationship between the emergence of resistance and this patient's death was less clear, the presence of replicating virus after 14 days of illness suggests an effect on outcome,” the paper's authors wrote.
Tamiflu remains the best available treatment for H5N1 avian influenza, however, and signs of resistance are not necessarily cause for alarm, said the World Health Organization. “Whenever you use any kind of drugs, antivirals or antibiotics, you expect to see resistance develop in organisms. Finding some resistance of itself is not surprising and is not necessarily alarming,” said Keiji Fukuda, an expert in WHO's global influenza programme, in an interview with Reuters. “It just points out the need for more information... what is really critical in understanding whether the way we are using the drugs contributes to that (resistance),” he said.