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N294S Tamiflu Resistance Marker In H5N1 Ducks
Recombinomics Commentary
January 18, 2007

The drug-resistant strains found in Egypt likely developed after the patients were hospitalized and treated with Tamiflu, with the virus responding directly to the drug, Hayden said. It was not proven, however, that that was the case, and a more worrying scenario would be if drug-resistant strains were already circulating among birds.

Though Tamiflu remains the drug of choice to treat H5N1, experts may have to consider other options if they find more resistant viruses.

"What the resistance tests look for are markers associated with antiviral resistance," though finding the markers did not necessarily mean Tamiflu would not work, said Dr. Angus Nicoll, flu director at the European Centre for Disease Prevention and Control.

Hayden said the mutations found in Egypt were different from Tamiflu-resistant H5N1 viruses found two years ago in Vietnam. The Vietnamese strains were definitely resistant to Tamiflu, whereas the Egyptian viruses have only proven they are not as susceptible to the drug, he said.

The above comments provide additional detail on the isolates from the Gharbiya cluster, but fail to note that samples were collected within 48 hours of Tamiflu treatment, suggesting the changes did not develop in the patients.  Although recent sequences from Qinghai isolates from birds in Egypt have not been reported, sequences in H5N1 infected ducks in China have been reported.

Thus, the N294S change has already been found in the wild, indicating the change did not create a fitness penalty that prevented the altered H5N1 from competing with wild type H5N1.

The N294S was found in all four sequences from the two Gharbiya cluster patients, which also suggests the changes were not linked to treatment of these patients.  Additional sequences from Qinghai infected birds and patients in Egypt will help resolve these questions, but the available data points toward a circulating H5N1 with N294S.

The level of resistance can be influenced by the genetic background surrounding the change.  The H5N1 in ducks in China provide donor sequences for the Qinghai sequences found in Egypt.  Data on Tamiflu resistance levels on the duck isolates have not been reported.  However, the H5N1 from the patients in Egypt has been tested and as indicated above, the H5N1 from Egypt were not as susceptible to the drug.

However, this is a major concern if the N294S is widespread because there have already been reported problems with H5N1 resistance to Tamiflu. H274Y has already developed in patients treated sub-optimally with Tamiflu, and many countries have increased the H5N1 treatment dosage.  The newly reported change would raise serious questions about the use of Tamiflu for both treatment and prevention of H5N1 containing N294S.

Tamiflu blankets have been applied in prior outbreaks, including Turkey and Indonesia, and suboptimal treatment may lead to additional isolates with N294S or a combination of resistance markers if N294S is already present.

More information on N294S frequencies of H5N1, including Qinghai H5N1 in Egypt, would be useful.

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