Moderate Reduction of N294S Tamiflu Susceptibility In Egypt
Recombinomics Commentary
January 22, 2007
Current laboratory testing suggests that the level of reduced susceptibility is moderate. This mutation has previously been identified in Viet Nam in one case in 2005.
The above comments from the WHO update on H5N1 oseltamivir resistance in Egypt describe a moderate reduction in susceptibility associate with N294S. As noted in the update, this genetic change in H5N1 was noted previously in a 2005 case in Vietnam. That case was the first reported example of H5N1 Tamiflu resistance. The patient (14F) had been receiving the prevention dose of 75 mg Tamiflu per day because her brother was hospitalized with confirmed H5N1. When her clinical condition began to decline, the dosage of Tamiflu was increased to the treatment level of 2 X 75 mg. H5N1 from the patient was plaque purified, and clones were tested for Tamiflu resistance. The clones fell into three categories, low, moderate, and high susceptibility to Tamiflu. Ten clones were selected for sequencing. One clone with high susceptibility matched the wild type sequence of the index case. The three clones with moderate susceptibility had N294S and the six clones with low susceptibility had H274Y.
The detection of resistance in Vietnam led to a use of a higher level of Tamiflu for the treatment of H5N1 infect patients, and NIAID initiated a clinical trial to test the use of a doubled dosage of the FDA approved treatment level of 2 X 75 mg / day.
The above WHO comments indicate that the level of susceptibility of N294S in H5N1 from the two related patients in Gharbiya is similar to the susceptibility of the H5N1 in the first reported case. However, unlike previous reported cases of Tamiflu resistance in H5N1 patients, which have H274Y, the isolates from Gharbiya had no detectable wild type or H274Y in sequences generated directly from the clinical samples, strongly indicating that N294S was present in the two patients prior to Tamiflu treatment, which began two days prior to collection of samples.
Collection of additional bird samples for testing has begun, to determine the frequency of N294S in animals. Previously, N294S has been detected in H5N1 infected ducks in Hong Kong and Zheijiang, but was not detected in any previously reported Qinghai sequences, including those generated by samples collected last season in Egypt or the other confirmed human cases in Egypt this season, including A/Egypt/0636-NAMRU3/2007.
Widespread detection of N294S in birds would raise serious questions about the use of Tamiflu in the treatment of associated patients
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