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Transmission Linked To Rapid Appearance of Tamiflu Resistance

Recombinomics Commentary 15:36
March 27, 2010

We describe rapid selection for the H275Y resistance mutation during therapy in 2 immunocompromised individuals at 9 and 14 days of therapy, as well as the first described case of clinically significant resistance to peramivir.

The above comments are from the abstract of the paper “Rapid Selection of Oseltamivir‐ and Peramivir‐Resistant Pandemic H1N1 Virus during Therapy in 2 Immunocompromised Hosts” and provide additional data supporting the selection of minor species carrying H274Y, and are not due to de novo copy errors.  Table one of the paper defines the time space for detection of H274Y.  In patient A the detection is between days 4-9.  In patient B, the detection time is between days 0 and 14.  These times are similar to those reported previously in immune-compromised patients in Seattle.  The time frame was between day 4-11 in one patient and day 1-18 in another.  In the latter patient, samples were collected at earlier dates post the start of Tamiflu treatment, but results from those patients were not released. However, the sequences from the two patients were released, and both H1N1's were from the same sub-clade, further supporting the prior acquistion of H274Y in a sub-population.

Moreover, patients who were not immune-compromised, but prophylatically treated with Tamiflu developed symptoms 5 or 6 days post the start of treatment, further highlighting the selection of pre-existing H1N1 with H274Y.  The presence of H274Y at low levels in these patients is a concern, because the patients initially test negative for H274Y, but the levels quickly rise after the start of treatment, leading to symptoms in patients who are not immune-compromised, or complications in immune-suppressed patients.  In a treated patient in Singapore, H274Y was detected within 2-3 days.

Although some recent data has been presented showing mixtures of H274Y with wild type, many still maintain that the H274Y is due to de novo synthesis and random mutation.  However, the detection of H274Y is not due rapid for de novo synthesis.  Instead, the H274Y is transmitting below detection limits and is not reported unless samples are collected and tested post treatment, which is rare.  However, as the level of H274Y increases, it is reported more frequently.

NIID in Japan recently release 15 NA sequences at GISAID.  Five of the fifteen were from 2010, and all 15 had H274Y.

H274Y in pH1N1 is following the same path as H274Y in seasonal H1N1, which led to fixing H274Y an almost all seasonal H1N1 isolates in the 2008/2009 season.

Ignoring the transmitting H274Y in pH1N1 and reliance on a random mutation model for influenza evolution continue to be hazardous to the world’s health.

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