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Japan H274Y Tamiflu Resistance Clonal Expansion Concerns

Recombinomics Commentary 14:00
June 20, 2011

Based on available data, among Japanese oseltamivir resistant viruses, the vast majority were from cases treated or prophylaxed with oseltamivir.

The recently released H1N1 sequences from Japan clearly demonstrate the spread of oseltamivir resistance (H274Y) via clonal expansion.  10 of the 13 sequences with H274Y were closely related and mapped to a branch that had no isolates without H274Y.  Moreover one additional sequence, A/Kagawa/2/2011, was closely related and was on an adjacent branch with one isolate, A/Shiga/35/2011, that did not have H274Y.  One of the other isolates with H274Y, A/Iwate/1008/2011, was related to other sequences from Japan, while the other H274Y positive sequence, A/Hiroshima/45/2011, was related to US S188T sequences. 

Thus, 12 of the 13 sequences were from 2011 (representing 38.7% of the 2011 sequences released by NIID) and the vast majority were spreading via clonal expansion, contracting the above quote in the most recent WHO update on H247Y in pandemic H1N1.

This pattern, which included a dominant sub-clade with H274Y, as well as additional examples of H274Y in the same sub-clade but on a distinct background, faithfully matches the pattern of H274Y in seasonal H1N1 in early 2008, which led to the fixing of H274Y in late 2008.  In seasonal flu the pattern was independent of Tamiflu usage.  H274Y was in patients who were not taking Tamiflu as well as countries where Tamiflu usage for treatment of seasonal H1n1 was minimal.

Thus, although the sequence data clearly demonstrates a pattern of clonal expansion of H274Y in pandemic H1N1 in Japan in 2011, the latest WHO report claims that such samples are from patients linked to Tamiflu usage.  Since the expansion pattern covers the entire country and is clonal in nature, and the clone does not contain H274Y sensitive isolates, the WHO comments represent a glaring inconsistency.

The inconstancy is another example of WHO comments which are not supported by the sequence data generated by WHO affiliated labs, and like labs worldwide, describe the rapid appearance of H274Y in parients treated with Tamiflu,  The short time frame between the start of treatment and the detection of H274Y signals spread via an H274Y mixture.  The level of H274Y has now increased so the clonal expansion is clear, as is the lack of a requirement of Tamiflu treatement for the detection of this spread.

The remarkable parallels of the pattern in H274Y spread in seasonal H1N1 in 2008, and pandemic H1N1 in Japan in 2011 strongly predicts the fixing of H274Y in pandemic H1N1 in the near term.

Moreover, the WHO statement on the linkage to Tamiflu use represents a profound failure to communicate this clear clonal pattern that is not linked to Tamiflu usage, and raises significant competency concerns regarding the analysis of the evolution of pandemic H1N1 by WHO consultants and communicators.

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