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Migrating Tamiflu Resistance in Qinghai H5N1
Recombinomics Commentary
January 31, 2007

The recent report of Tamiflu resistance polymorphisms in the Gharbiya cluster has raised concerns about resistance circulating in Qinghai H5N1.  Initial reports described the NA polymorphism, N294S, in samples from two cluster members.  The samples were collected two days after the start of Tamiflu treatment and had no evidence of wild type H5N1, which would have been expected if resistance developed in response to Tamiflu treatment.  N294S had been detected in a patient in Vietnam, but detection was several days after the start of treatment and three versions of NA were detected.  One was wild type, another had N294S, and a third version had H274Y.  H274Y was subsequently detected in additional patients that developed Tamiflu resistance during treatment.

Recently, sequences from samples collected prior to treatment of the Gharbiya werer released, and these sequences also had N294S, indicating the polymorphism did not develop during treatment.  N294S had been reported previously in ducks in China and Hong Kong.  However, those isolates had NA sequences that did not have the 20 amino acid deletion, that is characteristic of the Z genotype and present in a recent human H5N1 cases, including those involving the Qinghai strain (Clade 2.2).  Acquisition of H5N1 polymorphism via recombination is common, and provides a mechanism of placing N294S on a Qinghai background such as the H5N1 in the Gharbiya cluster, which also had a number of additional regional markers that identified the sequences are coming from isolates in Egypt.

Egypt, is one of a limited number of countries with WHO confirmed human cases involving the Qinghai strain.  The other countries were close to Egypt (Turkey, Azerbaijan, Iraq, Djibouti), but each country had regional polymorphisms that distinguished the H5N1 from other countries that reported Qinghai H5N1 in birds, but not in patients.

Therefore, the acquisition of N294S on an Egyptian Qinghai background was cause for concern because the strain could link to other countries with Qinghai infections, and recombination could transfer additional polymorphisms, including those associated with human infections and Tamiflu resistance.

Similarly, the report of Qinghai H5N1 sequences with the other Tamiflu resistance marker, H274Y in isolates from swan(s) in Astrakhan raises the possibility of further recombination that would put this polymorphism on a genetic background associated with human cases.

The confirmation of Qinghai H5N1 in a familial cluster in Lagos, Nigeria is cause for additional concern.  Qinghai H5N1 has been reported throughout Nigeria, as well as neighboring countries (Niger, Ivory Coast, Burkino Faso, Cameroon).  This season H5N1 has been isolated from turkeys in the Ivory Coast, and more reports of H5N1 in the region are expected. 

In addition to the Tamiflu resistance in the Gharbiya cluster, the HA sequence contained M230I, which is a polymorphisms adjacent to the receptor binding domain and found in all human influenza strains in circulation (H1N1, H3N2, influenza B).  This polymorphism has converged in bird sequences in Egypt recently, and may also be migrating to locations connect by flyways that pass over Egypt.

More sequences in Egypt, as well as western Africa, including sequences from patients, would be useful.

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