Researchers: Pandemic readiness demands mix of antivirals

May 15, 2008 (CIDRAP News) – Certain mutations that make the H5N1 influenza virus resistant to the antiviral drug oseltamivir (Tamiflu) leave it susceptible to zanamivir (Relenza), a finding that suggests nations should not rely on oseltamivir alone in preparing for a flu pandemic, according to a report published by British scientists this week.

Writing in the journal Nature, the scientists describe the properties and molecular structures of the neuraminidase proteins from two H5N1 variants that have been found in some humans who were treated with oseltamivir. Their findings show that these mutant forms are resistant to oseltamivir but still susceptible to zanamivir and have structural peculiarities that explain this difference.

In combination with other recent findings about oseltamivir-resistant forms of H5N1 and the seasonal flu virus H1N1, "our results indicate that it would be prudent for pandemic stockpiles of oseltamivir to be augmented by additional antiviral drugs, including zanamivir," says the report by Patrick J. Collins, of the National Institute for Medical Research in London, and colleagues.

Oseltamivir makes up 80% to 85% of the US stockpile of antiviral drugs for flu, with zanamivir constituting the rest, according to a recent report by the congressionally chartered Institute of Medicine. The report recommended increasing the stockpile, which contained about 71 million treatment courses as of last month.

Neuraminidase, which corresponds to the "N" in virus labels such as H5N1, is a viral surface protein that gives new copies of the virus within infected cells the ability to slip through the cell membrane and find other cells to infect. The British scientists studied the neuraminidase found in wild-type H5N1 viruses and N1 forms of neuraminidase that contained three different mutations:

  • His274Tyr, which has been linked to oseltamivir resistance in some fatal human H5N1 cases and was also found in a number of H1N1 viruses from seasonal flu cases this past winter
  • Asn294Ser, which has been found in more than one subtype of flu virus from patients treated with oseltamivir
  • Tyr252His, which has been found in one clade of H5N1 virus and has not been linked with drug treatment

The researchers analyzed the ability of both antivirals to bind to and inhibit these neuraminidases. They found that, compared with the wild-type neuraminidase, the His274Tyr and Asn294Ser variants showed strong resistance to oseltamivir, while the Tyr252His form was actually more susceptible to the drug. None of the mutant forms showed much increase in resistance to zanamivir.

The scientists used x-ray crystallography to examine the structure of the neuraminidases in the hope of finding a physical explanation for the oseltamivir resistance. They detected and diagrammed specific structural characteristics of the oseltamivir-neuraminidase and zanamivir-neuraminidase complexes that appear to account for the differences in resistance.

The structural basis for the differences has to do with "an altered hydrophobic pocket in the active site of the enzyme required for oseltamivir binding," the report says.

The researchers note that the His274Tyr mutant was found recently in many oseltamivir-resistant H1N1 viruses isolated from flu patients in Europe, even though the patients had no known exposure to the drug. Like the neuraminidase variants used in the study, the H1N1 isolates remained susceptible to zanamivir.

"Evidently, if the His274Tyr mutation also becomes common in avian H5N1, the effectiveness of oseltamivir would be limited and the value of stockpiles compromised," the scientists write. "Considered together with the success of HAART (highly active antiretroviral therapy) against HIV, it would be prudent to reassess the suitability of single-drug, pre-pandemic stockpiles and to develop effective drug combination treatments."

Bill Hall, a spokesman for the US Department of Health and Human Services (HHS) in Washington, DC, called the Nature report interesting but said it would not prompt a change in the agency's antiviral stockpiling strategy.

"We have known about selected instances of resistance to oseltamivir for some time, but so far, the number of reported instances of such resistance has been extremely limited," Hall told CIDRAP News by e-mail. "The instances of Tamiflu-resistant viruses are not correlated strongly with intensity of Tamiflu use in a given population or environment. It's also important to remember that any Tamiflu resistance that may exist in currently circulating viruses is in no way predictive of potential resistance in a yet-to-emerge virus with pandemic potential.

"So, this article is interesting from a scientific perspective, but given the limited instances in which resistance has been documented, our public health approach to our stockpiling strategy remains unchanged."

Collins PJ, Haire LF, Lin YP, et al. Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. Nature 2008 (online publication May 14) [Abstract]
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature06956.html

See also:

Apr 25 CIDRAP News story "IOM: US likely to need bigger antiviral stockpile"

Mar 19 CIDRAP News story "Researchers warn of resistant flu, foodborne microbes"

Jan 29 CIDRAP News story "Europeans find Tamiflu resistance in seasonal flu virus"

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