Migrating Tamiflu Resistance in Egypt Raises Pandemic Concerns
Recombinomics Commentary
January 25, 2007
Sequence information made public on GenBank on 23 January by the U.S. Naval Medical Research Unit 3 (NAMRU-3) in Cairo shows that both were infected with a virus strain that is moderately resistant to the antiviral drug Tamiflu.
That's why Boynton says the evidence suggests "a more disturbing" theory: that both were infected by a sick bird that already harbored the mutated virus. If more such birds exist, doctors may see more H5N1 patients who don't respond well to Tamiflu. And if such a resistant strain were to spawn a pandemic, the world's vast Tamiflu stockpiles might be less helpful. Tests are currently under way to determine whether the patients had the resistant strain before they took the drug and whether virus from a third suspected H5N1 patient in the household, who also died, has the same mutation, Boynton says. Veterinary virologists are also checking to see whether the mutated virus can be found in birds in Egypt.
The above comments on the NA polymorphism, N294S raise questions regarding the origin of the Tamiflu resistance polymorphism. Not only was the polymorphism found a short time after Tamiflu treatment, but the sequences had no evidence of wild type H5N1. If the patients had developed resistance, evidence of the wild type sequence would have been seen in the sequence encoding N294S since the sequences were from RNA extracted directly from the clinical sample.
This issue will be conclusively settled with the data from samples collected prior to treatment. The presence of N294S would indicate that the H5N1 that infected the patients already had the polymorphism.
The potential for such an acquisition by recombination remains high. Both of the sequences had several “new” polymorphisms on an Egyptian Qinghai genetic background. These polymorphism are acquire via recombination. Two of the “new” polymorphisms, HA V223I and NA M31I have been previously found in H5N1 from geese in Shantou. The presence of these changes in two genes in H5N1 in the two cluster members supports acquisitions via recombination.
Sequencing of poultry isolates will help identify more proximal parental strains that provided the Tamiflu resistance polymorphisms. The distribution of these polymorphism in birds in Egypt will be important in the likelihood of such additional cases in Egypt, as well as spread to downstream locations such as western Africa, where new poultry outbreaks have been described in Nigeria and a suspect human cluster has been described in Lagos.
The sequences in Egypt also link upstream to Qinghai H5N1 in Europe and the Middle East, as well as downstream to Djibouti, Sudan, Nigeria, and Niger. As more isolates are sequenced, more linking polymorphisms will be identified, because the Qinghai sequences are transported and transmitted by migratory birds.
The frequency of N294S in birds will be of interest. The existing data clearly indicate that the N294S did not arise in the Gharbiya cluster.
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