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Matching Sequences fromTamiflu Resistance Patients in Seattle
Recombinomics Commentary 11:11
August 24, 2009

Of the four oseltamivir resistant 2009 influenza A (H1N1) viruses, two were original clinical samples detected by the neuraminidase inhibition assay, and two were viral isolates detected by sequence analysis of a neuraminidase gene.

The above comments from the latest CDC update describe the four reported examples of pandemic H1N1 oseltamivir resistance in the United States.  The four isolates are from two clusters.  One cluster involves two immuno-suppressed patients in Seattle who were not epidemiologically linked, as well as two summer campers in North Carolina who were taking prophylactic Tamiflu because of a pandemic H1N1 outbreak in the camp.  These two sets of clusters suggest the resistance is not due to independent spontaneous events.

The CDC has released the HA and NA sequences from the two immune-suppressed patients.  Both NA sequences have a defining polymorphism (A1230G), in addition to H274Y (encoded by C823T), which also supports the presence of a minor species circulating with this sub-clade, and raises concerns that the resistance associated with this sub-clone is widespread.

The public sequences are from the 18M patient with a recurrence (A/Washington/28/2009) and 47F (A/Washington/29/2009), who remains hospitalized after treatment with Tamiflu, Relenza, and Ribaviron.  Although initial samples collected from both patients were Tamiflu sensitive, the isolates collected significantly after the start of Tamiflu treatment had H274Y.  Although both had clean signals for C823T (which encodes for H274Y), both sequences had mixed signals at other positions.  Both sequences also had addition changes that were not in common, indicating those changes were acquired after the acquisition of A1230G.  However, the linkage of A1230G and C823T may have been established in a minor population at an earlier date, raising concerns that H274Y is widespread.  A1230G is present in multiple isolates from Washington state (see list here), but is also present in multiple isolates from Mexico and Nova Scotia. as well as sequences from Oregon, Florida, China (Jiangsu and Guangdong), New Zealand, and Singapore.

The concept silent circulation of minor populations with H274Y is also supported by the two cases from the summer camp in North Carolina. Although sequences from the two campers haven't been released, the clustering of two cases in campers at the same location at the same time further supports a minor species.  Two independent events are unlikely since both patients were attendees of the same camp.  Moreover, the two cases in July were followed by rapidly spreading outbreak in schools in August in adjacent regions (see map), raising concerns that H274Y is also widespread in the area and contributing to the rapid spread among students in the area.

Sequence data from the campers, as well as students in the area would be useful.

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