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S246N and H274Y Tamiflu Resistance Clinical Concerns
Recombinomics Commentary 16:00
June 13, 2011

Pharmacokinetic data would suggest that the maximum drug levels achieved via the recommended dose easily exceed the observed IC50 values of the S247N mutant [11], and therefore the variant is unlikely to be clinically resistant.

The above comments in the recent report on the rapid clonal expansion of S246N (S247N in N1 numbering) is widely disseminated in media reports and refers Tamiflu data from a 1999 publication.  However, clinical data data on actual patients treated with Tamiflu raises serious concerns about the effects of a six fold reduction in the effective dose of Tamiflu (or a corresponding 3 fold reduction in the effectiveness of Relenza).

Most of the clinical data has been on patients treated with Tamiflu, since it has been approved for a longer time period and has been used in the treatment of prevention of H5N1 as well as season and pandemic influenza. 

Tamiflu is most frequently used in Japan, and earlier use of lower doses in children led to widespread resistance in seasonal H3N2 linked to genetic changes at multiple positions.  Earlier in vitro studies using all nine neuraminidase serotypes indicated Tamiflu was less effective against N1, which would help explain clinical issues with H5N1, seasonal H1N1, or pandemic H1N1 associated with H274Y (H275Y in N1 numbering).

Resistance in H5N1 was initially associated with the appearance of H274Y and S296N in a contact treated prophylactically with Oseltamivir (and prophylactic treatment is used at 50% the treatment dose).  This two-fold difference led to the use of Tamiflu at double the recommended dosage as well as clinical trials using Tamiflu at a double dose for H5N1.

However, data on Tamiflu treatment for seasonal and pandemic H1N1 is more extensive and clinical results again raise concerns that H1N1 (pandemic and seasonal) can effectively evade the effects of Tamiflu).  For seasonal H1N1, H274Y began to appear in patients not receiving Tamiflu signaling fitness of H1N1 with H274Y.  Low levels were seen for clade 1 (New Caledonia), and clade 2C (Hong Kong), but dramatic increases were seen in clade 2B (Brisbane/59) in the 2007/2008 season.  High levels (above 50% were reported in northern Europe) and then the level of H274Y rose to 100% in the southern hemisphere in 2008, followed by 100% of H1N1 in the northern hemisphere in the 2008/2009.

The 2009 H1N1 pandemic displaced / replaced seasonal H1N1, but H274Y continued to be a concern.  Initial cases again involved H1N1 treated prophylactically, again signaling concerns that a two difference in dosing could lead to infections.  Similarly H274Y was identified in patients who had not been treated with Tamiflu, and increasing community transmission has been noted, most recently in Delaware and Maryland.

The spread of S246N, which reduces the efficacy of Tamiflu six fold, would likely accelerated the spread of H274Y, which lowers the efficacy of Tamiflu 600 fold and is additive with S246N.

Moreover, H274Y is circulating as a mixture (and levelss below 50% are not being reported), leading to rapid detection after the start of treatments as seen in the H1N1 fatal infection (40M) in Perth.  The sample collected prior to treatment, A/Perth/30/2011, had S246N, while sample collected 5 days after the start of treatment, A/Perth/29/2011, has S246N and H274Y.

Thus, the 6 or 3 fold reductions in effectiveness for Tamiflu and Relenza respectively cased by S246N, can have profound and far reaching clinical effects, which cause considerable concern due to the rapid spread of S246N in Singapore and Australia.

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