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Emergence of H7N9  R292K Tamiflu Resistance
Recombinomics Commentary 18:30
May 28, 2013

We found the Arg292Lys mutation in two of three patients in the ECMO group; in one of these patients this mutation was only noted when the sample was taken 9 days after antiviral treatment started, a time that coincided with a rebound in viral load in that patient, suggesting that resistance emerged de novo, probably as a result of the oseltamivir therapy.

The above comments from a Lancet paper on H7N9 bird flu cases in Shanghai describe the emergence of Tamiflu (oseltamivir) resistance in two severe H7N9 patients.  The R292K change (N2 numbering) was seen in N9 sequences released at GISAID by Institute Pasteur (A/Shanghai/Patient2/2013 - 88M and A/Shanghai/Patient3/2013 - 56M).  This emergence was also seen in the recent case in Taiwan.  Although position 294 was wild type in an egg isolate from this patient, A/Taiwan/1/2013 - 53M), R292K was present in two subsequent sequences (A/Taiwan/T02081/2013 and A/Taiwan/S02076/2013).  Similarly, this change was also seen in the first H7N9 sequence, A/Shanghai/1/2013 - 87M.

An in vitro test of the clinical sample from the initial case showed a low level of resistance.  However, as noted above, the ratio of resistant to sensitive sequences increases over time, so even a low initial level of resistant sequences can become dominant and produce an unfavorable outcome. 

Although the patient in Taiwan recovered, two of the patients from Shanghai died, while the third remains on an ECMO machine.

Since the resistance was detected after the start of treatment, sequences from sample collected prior to, or shortly after the start of, treatment may have undetectable levels of R292K.  In vitro testing of cloned sequences with R292K reduced the effectiveness of Tamiflu by 100 fold and Zanamivir by 30 fold, raising serious resistance concerns.

More information on collection dates relative to Tamiflu treatment for other H7N9 sequences would be useful.

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