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Paradigm Shift Intervention Monitoring
The recent examples of spread of
Tamiflu resistance markers H274Y and S246N have raised concerns that
resistance levels overall will increase, creating a genetic environment
for the fixing of H274Y, as seen in seasonal H1N1 in the 2008/2009
season. These concerns were increased by the release of 2011
sequences from Japan.
These sequences also demonstrated the spread of H274Y by clonal expansion, and like the spread in Maryland and Delaware, the S188T sub-clade was involved. Although the geographical distinct expansions could also be distinguished by regional markers, both examples of expansion involved the dominant sub-clade in the northern hemisphere, confirming that the acquisition of H274Y did not impose a fitness penalty.
Similar results for S246N were seen in Singapore and Australia on a distinct but rapidly expanding sub-clade with R208K and I219V. The co-circulation of distinct sub-clades with H274Y or S246N raises concerns that recombination will put the same markers on the same gene as was seen in the fatal case in Australia, where the resistance synergized to reduce Tamiflu efficacy by 6000 fold.
The reported levels of H274Y are well below actual amounts. WHO consultants have agreed not to report mixtures with H274Y levels below 50%. However, such mixtures are widespread and quickly rise to levels above 50% as seen in the Perth case, A/Perth/29/2011, who was reported as H274Y positive 5 days after the start of Tamiflu treatment (initially the isolate, A/Perth/30/2010, had S246N, but was reported as wild type for position 274).
Although there were examples of H274Y and S246N clonal expansion 2009 and 2010, the number of transmissions was limited because of little immunity in the populations under 65, so there was little selection for individual sub-clades.
In 2011 the immunity levels are higher, leading to a small number of rapidly spreading sub-clones, like S188T, which is dominant. H274Y is now transmitting in multiple versions of the S188T sub-clade, including Delaware isolates which also have A189T or those in Japan with A200T. The acquisition of these additional receptor binding domain changes parallels the seasonal H1N1 evolution associated with the fixing of H274Y.
Thus, the fixing of H274Y in pandemic H1N1 is increasingly likely in the near term.