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09 March 2010Journal of Health Geographics
Pandemic flu shows signs of resisting Tamiflu
If the behavior of the seasonal form of the H1N1 influenza virus is any indication, scientists say that chances are good that most strains of the pandemic H1N1 flu virus will become resistant to Tamiflu, the main drug stockpiled for use against it.
Researchers at Ohio State University have traced the evolutionary history of the seasonal H1N1 influenza virus, which first infected humans during the 1918 pandemic. Within H1N1, two strains of virus circulate in humans: a seasonal form and the pandemic form of influenza known as swine flu, which has sickened millions and killed thousands of people since it first emerged in North America last spring.
Over time, the H1N1 strain of seasonal influenza surviving around the world has developed mutations that have caused it to become resistant to oseltamivir-based agents. Tamiflu is the brand name for oseltamivir phosphate. “Something happened in 2008, when drug resistance took hold,” said Daniel Janies, associate professor of biomedical informatics at Ohio State and primary author of the study. “The drug-resistant isolates became the ones that survived all over the world. This is just static now. The seasonal H1N1 influenza virus is fixed at resistant.”
Janies and colleagues have traced the history of the same mutation in the pandemic H1N1 strain of the virus as well, with data from its emergence last spring until December 2009. And they are starting to see the same kinds of mutation in this virus – changes to an amino acid that allow the virus to resist the effects of oseltamivir – that they saw in the seasonal H1N1 flu. The research appears online in the International Journal of Health Geographics.
So far, most pandemic H1N1 strains that have been isolated from humans are susceptible to Tamiflu. As of Feb. 3, 2010, 225 cases of pandemic H1N1 were reported to be resistant to the drug out of the predicted millions of cases of illnesses with swine flu across the United States and elsewhere in the world. But those resistant cases, as well as the way mutations have led to Tamiflu resistance in seasonal H1N1, offer clues about how the virus changes itself to survive against the popular drug.
Janies and colleagues analyzed mutations in neuraminidase proteins from 1,210 seasonal H1N1 viruses isolated around the world between September 2004 and December 2009. For pandemic H1N1, the researchers examined mutations in specific points on neuraminidase proteins of 1,824 viruses collected between March 2009 and December 2009.
Once they selected the isolates for study, the researchers used powerful supercomputers to analyze the evolution of these proteins and their various mutations. The computational power allows them to match similar regions on the proteins and put the mutation data into context in time and geography. “With the rapid availability of public sequence data on pandemic influenza, we are able to essentially watch evolution in real time,” Janies said.
In tracing the history of neuraminidase in pandemic and seasonal H1N1, the group found that mutations in the same amino acid position in both seasonal and pandemic H1N1 drove the viruses toward resistance to antivirals.
The researchers also used a technique in which they compared different types of mutations – those that do cause antiviral resistance and others that don’t have that effect – to see which type of mutation is more common. “We look at the ratio of mutations that do confer resistance vs. those that don’t, and if the ratio is higher than 1, it means that change is being promoted by natural selection rather than chance. Something is driving the evolution of drug resistance,” Janies said. “We could see that happening in seasonal influenza and in the data we have so far for pandemic influenza, as well.
The group also examined mutations that alter these two strains of H1N1 viruses’ responses to Relenza. Resistance to that drug is relatively rare, Janies said, which could be attributed to less frequent use of the drug or to the possibility that mutations leading to resistance to Relenza aren’t tolerated by the virus itself, so those strains die off.
Free full text of the study
D.A Janies, I. O Voronkin, J. Studer, J. Hardman, B. B Alexandrov, T. W Treseder, C. Valson: Selection for resistance to oseltamivir in seasonal and pandemic H1N1 influenza and widespread co-circulation of the lineages. International Journal of Health Geographics 2010, 9:13, doi:10.1186/1476-072X-9-13
