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Flaws Drive Silent Spread of Tamiflu
The virus was isolated from the specimen taken from a 16-year-old girl coming from San Francisco. She was intercepted by Port Health Office at the Hong Kong International Airport on June 11 upon arrival. The girl was then admitted to Queen Mary Hospital for isolation. She was tested positive to HSI but opted not to take tamiflu. She had mild symptoms and was eventually discharged upon recovery on June 18.
The above comments from a Hong Kong DOH press release on Tamiflu resistance in pandemic H1N1 highlight severe limitations in worldwide surveillance. Although this case was identified by routine surveillance of H1N1 positive patients in Hong Kong, it is an effort largely focused on travelers. Like countries outside of the Americas, most efforts have focused on travelers and largely ignored local community spread. The recent explosion in cases in the UK has led to a focus on the community spread there, but many other counties in Europe are reporting low numbers of confirmed pandemic H1N1 because of limited testing in the community.
In the US, efforts are focused on the community, but severe cases are targetted. Most states have stopped reporting and testing mild cases, so real monitoring of this group is minimal. However, the case in Hong Kong originated in San Francisco and was mild. The United States has not reported any Tamiflu resistance. The CDC has tested over 200 isolates and failed to identify H274Y.
This may be due in part to virus mixtures. In Denmark and Japan the H274Y was discovered in patients undergoing Tamiflu prophylactic treatment. The Tamiflu treatment would reduce wild type H1N1 and allow a minor population with H274Y to expand and be detected. Therefore, it is likely that the H274Y is spreading silently and under the radar of the sequencing efforts, which are focused on the dominant (consensus) sequence.
The acquisition of H274Y by pandemic H1N1 was not unexpected. H274Y has a history of jumping from one sub-clade to another, as well as jumping to multiple different backgrounds within a subclade via recombination and genetic hitchhiking. This has produced resistance that is limited to H1N1 and H274Y within H1N1. The co-circulation of human H1N1 seasonal flu with swine H1N1 in humans, has created a favorable environment for the jump of H274Y from seasonal flu to pandemic flu. Moreover, the widespread use of Tamiflu in patients infected with pandemic H1N1 will drive the rate of spread in pandemic H1N1.
Although countries have been placing sequences on deposit in a timely manner, there are still major deficiencies in the surveillance program, as described above. Moreover, the recent reports of Tamiflu resistance in isolates in Denmark, Japan, and Hong Kong have not lead to the release of these sequences.
An increase in surveillance and release of full sequences is still necessary. The pandemic H1N1 is now rapidly spreading in the southern hemisphere, which is just beginning its flu season. Sequences from fatal and mild cases are required to determine important changes in pandemic H1N1 associated with increased virulence as well as increased spread.
A serious comprehensive surveillance program is long overdue.