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Commentary
Fatal Tamiflu
Resistant H1N1 Cases In the Netherlands
Recombinomics
Commentary 13:55
December 8, 2009
A spokesman for the Public Health Service Heart Brabant reports that in one hospital in the region a woman who is already ill with the deceased Mexican flu. The other two deceased patients with the resistant variant had been seriously ill before they received the Mexican flu. In four others were also resistant forms of the Mexican flu found.
The above translation describes three H274Y fatalities, as well as four additional cases in the Netherlands. These data extend numbers released last week which indicated a Tamiflu resistance tipping point had been crossed. In the past three weeks the rate of reported H274Y cases in the US increased almost 10 fold, and human to human transmission had been reported at Duke University hospital as well as a hospital in Wales. Other geographic clusters had been reported in the Washington, DC area as well as eastern Pennsylvania in the US, and Edinburgh in Scotland. This explosion in Tamiflu/Peramivir resistance led to concerns of H274Y pairing up with receptor binding domain changes at position 225.
This type of pairings had been seen in seasonal flu. H274Y had jumped from one H1N1 background to another (Clade 2C, Clade 1, Clade 2B) in the absence of Tamiflu treatment. Although H274Y had jumped from background to background within each sub-clade, the movement in Clade 2B was most extensive and when compared with a receptor binding domain change, A193T, the resistance was fixed in H1N1 season flu.
Similar events were seen in H3N2 seasonal flu and the fixing of S31N, Those events centered on two receptor binding domain changes, S193F and D225N.
Consequently, when the first pandemic H1N1 with H274Y and no linkage to Tamiflu treatment was on an HA with D225E there was concerned that the receptor binding domain change would be linked to a more fit swine H1N1 that would transmit in the absence of Tamiflu. These concerns were increased when another isolate in Tennessee had H274Y and D225E.
However, of even greater concern was the linkage of H274Y with D225G because of the associated receptor binding domain change that drove virus to the lower lung and showed resistance to the swine flu vaccine, as seen for one of the Ukraine isolates with H225G.
These concerns were realized with reports out of France which described two fatalities with D225G and one also had H274Y. H274Y in fatal cases is a significant concern, and three of the four cases at Duke died.
The current case in the Netherlands extends the number of fatal cases with H274Y and raises more concerns on linkage between H274Y and D225G.
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