Tamiflu Resistance in H5N1 and H1N1
Recombinomics Commentary 16:34
March 4, 2008
It is important to note that these increased levels of resistance have only been reported spontaneously in this year's H1N1 (Solomon Islands) seasonal strain, and not an avian strain such as H5N1, and not in patients who have been administered TAMIFLU.(12)
The above comment from the recent Roche press release on the utility of Tamiflu (oseltamivir) in the treatment of H5N1 patients is in error.
Although the data presented did show a benefit in the treatment of H5N1 patients, the main concern with regard to Tamiflu use is the development of resistance, which has been seen at two positions in N1. One change, N294S, as been detected in patients in Egypt who had the resistance prior to treatment with Tamiflu. These data suggest that N294S is evolutionarily fit, which is further supported by the detection of N294S in ducks. The other change, H274Y, has been detected in H5N1 patients during treatment, but it has also been reported in H5N1 in birds, indicating this change is also evolutionarily fit.
However, the sudden appearance of H274Y in H1N1 seasonal flu has “startled” experts because it had been report to not be fit and the detection was highest in countries where Tamiflu treatment is not widespread and the patients with H274Y had not received Tamiflu.
This change began to appear in the United States in 2006 and the change was not in Solomon Island variant (or more common Brisbane/59 strain), but was initially seen in the older New Caledonia strain.
The sudden appearance of H274Y on two different H1N1 genetic backgrounds is not easily explained by adaptive mutation but supports movement of H274Y from H5N1 to H1N1 via recombination in area where Tamiflu blankets are applied.
The use of Tamiflu blankets has increased dramatically in recent years, and this usage could contribute to the spread of H274Y from H5N1 to H1N1. The prophylactic dose of Tamiflu is half the treatment dose, and Tamiflu doses for H5N1 are marginal. Although the data presented demonstrates a benefit at this dose, the lower dose has been linked to the development of Tamiflu resistance in the sister of an H5N1 index case.
Since H5N1 is not efficiently transmitted to humans, H274Y in H5N1 is not likely to spread at this time. However, a co-infection with H1N1 would allow for transfer of H274Y on H5N1 to H1N1, which could then be transmitted to others leading to the sudden increase in H274Y in the absence of Tamiflu treatment if the H1N1 was evolutionarily fit, which is supported by the widespread appearance worldwide.
Thus, it is important to not that the sudden appearance of H274Y on seasonal H1N1 is not limited to one seasonal flu variant, and the identical change in H5N1 and H1N1 may not be a coincidence.
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