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N294S in Gharbya H5N1 Cluster Prior to Tamiflu Treatment
Recombinomics Commentary
January 30, 2007

The NAMRU-3 detection of Tamiflu resistance polymorphism, N294S, in the NA sequences from the Gharbiya cluster, has caused concern.  The sequences, A/Egypt/14724-NAMRU3/2006 and A/Egypt/14724-NAMRU3/2006, were confirmed by the CDC in Atlanta.  In vitro testing indicated the two sequences have a 10X-15X reduction in sensitivity to Tamiflu.  The samples were collected two days after the start of Tamiflu treatment, and wild type H5N1 was not detected in the sequences, which came directly from the clinical samples.  These data strongly suggested that the N294S was not generated by treatment of the two cluster members, but was present in the H5N1 which infected the patients.

Sequence data from samples collected prior to the start of Tamiflu treatment show that both cluster members were infected with H5N1 that contained N294S.  The detection of N294S in the pre-treatment samples raises concern about the distribution of the Tamiflu resistance marker.  This polymorphism has been detected previously in H5N1 from ducks in Asia and therefore is evolutionarily fit, but this is the first report of N294S in the Qinghai strain (Clade 2.2) of H5N1.  Moreover, it is the first report of N294S in H5N1 infected patients, in the absence H274Y.

The detection of N294S in the two pre-treatment samples raises concern on the distribution of this polymorphism in bird or mammalian reservoirs.  Last season Qinghai H5N1 migrated through Europe, the Middle East, and Africa.  Since N294S was not in prior Qinghai sequences in Egypt, it appears to be a relatively new acquisition via recombination.  Initial sequences of H5N1 from birds in Egypt has not yet detected N294S, but a more extensive survey is required to accurately assess the distribution of this polymorphism in Egypt, as well as countries upstream and downstream in migration pathways.

The emergence of Tamiflu resistance markers in Vietnam led to an increase in Tamiflu treatment doses of 1.5X – 2.0X.  Moreover NIAID is conducting a clinical trial using Tamiflu at double the FDA approved  dose.  However, widespread distribution of N294S would raise serious questions about the use of Tamiflu in the treatment of H5N1. Similarly, prophylactic use of Tamiflu over a wide area, as has been done previously in Indonesia and Turkey would be problematic.  Indonesia H5N1 is Clade 2.1 and N294S has not been reported in that sub-clade.  However, H5N1 in Turkey, like all countries west of China, involve the Qinghai strain (Clade 2.2).  The Qinghai strain has also spread to South Korea and Japan, where it has caused multiple poultry outbreaks in both countries, although human cases have not been reported there.  Similarly, recent poultry outbreaks of Qinghai H5N1 in Hungary, Krasnodar, Nigeria, and Ivory Coast have been reported.  Suspect human cases in Azerbaijan and Nigeria are under investigation.

More testing of domestic and wild bird Qinghai isolates will be required to determine the distribution of N294S worldwide and rationale for treatment or prevention of H5N1 avian influenza with oseltamivir.

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