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H5N1 Tamiflu Blankets and Resistance in European H1N1

Recombinomics Commentary 16:58
January 29, 2008

Influenza experts admitted today that they have been startled by the discovery this season of an unexpectedly high number of human flu viruses that appear to be naturally resistant to Tamiflu, the drug that countries around the world are stockpiling for use in the next flu pandemic.

The viruses have been isolated from people infected with influenza A viruses of the H1N1 subtype in a number of European countries.

The World Health Organization is convening a virtual meeting of experts tomorrow to try to get a handle on how far afield the resistant virus has been found, how common it is and what the findings signify.

"I think this is a very concerning change in influenza virus resistance patterns," Dr. Frederick Hayden, a leading antiviral expert and a member of the WHO's Global Influenza Program, said from Geneva.

The above comments express surprise and concern regarding the sudden appearance of oseltamivir (Tamiflu) resistance in H1N1 seasonal flu, and fail to draw the connection between this dramatic change and the widespread use of Tamiflu blankets to treat H5N1.  The change in the human N1 in H1N1 is identical to the avian/human N1 change in H5N1.  Both N1’s have created H274Y via the identical nucleotide change, C763T.  Although this change has been found in H5N1 patients in Vietnam and Indonesia treated with Tamiflu, it has also been found avian isolates, including mute swans in Astrakhan in 2005 (A/swan/Astrakhan/Russia/Nov-2/2005(H5N1) and A/swan/Astrakhan/1/2005(H5N1)) .

Question of fitness have been raised previously, but the presence of H294Y in wild birds flying around Europe as early as 2005 indicates the chnage does not carry a significant fitness penalty.  Moreover, H274Y was found as early as 2002 in a chicken in Hong Kong, A/chicken/Hong Kong/3123.1/2002(H5N1).

H294Y can move from the N1 in H5N1 to the N1 in H1N1 via recombination.  The opportunity for co-infections involving seasonal and pandemic influenza can be found in patients with mild H5N1 infections.

Such infections were suspect in 2005 in northern Vietnam.  In contrast to outbreaks in 2004, the case fatality rates of H5N1 in northern and southern Vietnam were dramatically different in early 2005.  In the north the clusters were larger and the infections were milder, suggesting H5N1 in humans was becoming more common, and transmitting more efficiently.  Almost 1000 samples were collected for analysis.  H5N1 was detected locally, so samples were sent to the CDC in Atlanta for confirmation.  Positives were also seen in Atlanta, so samples were repeatedly tested until they turned negative.  However, the lab results had little effect of the H5N1 in circulation, which was commonly treated with Tamiflu.

This treatment would select for human H1N1 or avian H5N1 with H274Y.  This change began to appear in the United States in 2007. The isolates with H294Y were Solomon Island-like, which link back to Asia.  Similarly, H5N1 outbreaks in the Middle East were also treated with Tamiflu.  In Egypt, a scenario similarly to Vietnam developed in 2007.  Early cases in the north were largely fatal, but outbreaks in southern Egypt were mild, again allowing for more efficient spread and co-infections with H1N1 seasonal flu.  These co-infections would again create conditions for the movement of H294Y from H5N1 to H1N1 in areas where Tamiflu was used excessively.

Thus, the appearance of H294Y began in 2007 and now is becoming increasingly common in human H1N1 in 2008.

This increasing frequency of Tamiflu resistance in seasonal H1N1 is cause for concern, as is the potential for additional expansion in H5N1.

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