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WHO Comment On H274Y Tamiflu Resistance Raises Concerns

Recombinomics Commentary 12:00
June 21, 2011

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

The recently release sequences by the US CDC and Japan’s NIID provided clear examples of H274Y (oseltamivir / Tamiflu resistance) clonal expansion in the United States and Japan.  The US isolates were geographically clustered in Delaware and Maryland, with four isolates each.  These isolates formed small clusters of clonally expanding H274Y.  Seven of the eight were in the S188T sub-clade.  The first three isolates from Delaware had A189T appended onto this background.  A189T is the receptor binding domain change in the Chihuahua sub-clade and the only public Chihuahua sequence with H274Y is also in Maryland.  Thus, the US sequences demonstrated the movement of H274Y onto geographically clustered genetic backgrounds due to recombination driven by a high concentration of H274Y.

The sequences from Japan represented the converse situation, where the same sub-clade, which was also S188T, had spread throughout the country.  This sub-clade had A200T appended onto the S188T background and 10 fo the 13 sequences for a branch which was exclusively populated by sequences with H274Y.  This expansion and distribution closely mirrored the spread of H274Y in seasonal H1N1, where H274Y was in clade 2B (represented by Brisbane/59/2007) and most isolates were closely related and matched the initial sequences from northern Europe, but H274Y was also present in smaller clusters which were clade 2B, but slightly different than the larger cluster, reflecting additional recombination leading the spread of H274Y in closely related sub-clades.

The striking parallels between H274Y spread in seasonal H1N1 in 2008 and pandemic H1N1 in 2011 strongly suggests that H274Y will soon become fixed in pandemic H1N1.  Like 2008, the spread is driven by clonal expansion and not selection through Tamiflu treatment, which is why the latest comment by WHO on sequences in Japan is cause for concern.  The clear clonal expansion is ignored in the WHO update, and instead reference is made to a linkage between the detection of H274Y and use of Tamiflu by the corresponding patients.  This disconnect between the sequence data and the WHO announcement raises serious competency concerns regarding those responsible for this conclusion / announcement.

The lessons learned from the fixing of H274Y in seasonal H1N1 were clear and the failure to relate this pattern to pandemic H1N1 is alarming.

An explanation by WHO of the data and rationale behind their bizarre announcement (stated above) is needed, along with an independent scientific investigation of  the underlying data and personnel responsible for this gross misinterpretation or misleading comment linked to very clear cut sequence data.

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