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S246N and H274Y Tamiflu Resistance In Fatal Australian Case
Recombinomics Commentary 19:30
June 12, 2011

In Perth, Western Australia, an immunocompromised patient was found on 1 March 2011 to be infected with an influenza virus that contained the S247N NA mutation (A/Perth/30/2011) (Table). Oseltamivir treatment was commenced two days after detecting the initial S247N variant (3 March). A sputum specimen collected five days later (8 March) contained an influenza virus with both the S247N and H275Y NA mutations (A/Perth/29/2011) (Table). Despite commencement of intravenous zanamivir the patient died on 16 March from multiple organ failure. The isolate with the dual S247N and H275Y mutations had an oseltamivir IC50 nearly 6,000-fold higher than sensitive viruses and 10-fold higher than seen for influenza A(H1N1)2009 viruses with the H275Y mutation alone (Table).

The above comments from the recent Eurosurveillance rapid communication on “moderate” oseltamivir (Tamiflu) resistance due to S246N describe detection of H274Y in a sample collected five days after the start of oseltamivir treatment.  The rapid appearance of H274Y strongly suggests that the polymorphism was circulating in the patient prior to treatment (although it was not present in the published sequence, A/Perth/30/2011, collected prior to treatment), and the moderate resistance (six fold), linked to S246N significantly facilitated the increase in H274Y (present in the later collection, A/Perth/29/2011), which was reported in the absence of a wild type signal at position 274.

The appearance of H274Y in patients treated sub-optimally was not unexpected.  Treatment of children in Japan with sub-optimal dosing of oseltamivir was linked to the appearance of resistance at multiple positions, and clusters of H274Y have been reported in immunocompromised patients treated with Tamiflu.

Increased monitoring of immunocompromised patients is common and the increase in resistance can have clinical consequences, including death, as seen in the above patient.

The level of H274Y in circulation is under-reported because WHO collaborating groups have agreed not to publicly report H274Y levels below 50%.  The resistance is reported to physicians, because as seen above, the frequency increases quickly and significantly after the start of treatment, and as indicated by the IC50 value reported above, the treatment is useless.

The recent report of efficient transmission of S246N in Singapore and Australia raises concerns that associated increases in the levels of H274Y will become increasingly common.

Release of data on H1N1 samples with H274Y levels below 50% would be useful. 

The WHO agreement to withhold this data continues to be hazardous to the world’s health.

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