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H5N1 Outside of Vietnam and Thailand is Amantadine Sensitive

Recombinomics Commentary
June 19, 2005

>> China's use of the drug amantadine, which violated international livestock guidelines, was widespread years before China acknowledged any infection of its poultry, according to pharmaceutical company executives and veterinarians.

Since January 2004, avian influenza has spread across nine East Asian countries, devastating poultry flocks and killing at least 54 people in Cambodia, Thailand and Vietnam, but none in China. <<

The media reports on China's widespread use of amantadine has received quite a bit of attention, but the link between amantadine use in China and the H5N1 in Vietnam, Thailand and presumably Cambodia is weak.

There are no 2005 H5N1 sequences available at GenBank, so there are no isolates from Cambodia.  However, there are a large number of M2 (the protein targeted by amantadine) sequences from Vietnam and Thailand, as well as other countries affected by the H5N1 spread in Asia in 2004.  The resistance markers are almost exclusively in Vietnam and Thailand.

The first H5N1 amantadine resistance markers appeared in Hong Kong in 2002, but these genes were more like those found in H9N2 avian or H3N2 swine sequences.  Moreover, these isolates only had the S31N change.  There were only four isolates that were more closely related to the 2004 isolates from Vietnam and Thailand.  There was one each from Shantou Province in China (A/Dk/ST/4003/2003), Hong Kong (A/Ck/HK/WF157/2003) and Indonesia (A/Ck/Indonesia/2A/2003) in 2003 and one from Guangdong Province (A/chicken/Guangdong/178/04) in 2004. 

There were several additional isolates from each region and none of the M2 sequences had the amantadine resistance markers.  Similarly, none of the isolates from other provinces in China as well as Japan and South Korea had the markers.  In contrast, all M2 sequences from Vietnam and Thailand had the marker.  These isolates also had a second marker, L26I, which was not detected in any of the H5N1 isolates (or any other isolates).

Thus, although all isolates from Vietnam and Thailand had two amantadine resistant changes, no other isolate had both, and a very small number had one.  Moreover, the isolates that had one and were most closely related to the isolates in Vietnam and Thailand were from 2003 or 2004, even though amantadine had been used in China since the late 1990's.

Thus, amantadine is not useful for treating H5N1 infections in Vietnam and Thailand, but it is effective against the vast majority of H5N1 isolates outside of Vietnam and Thailand (and probably Cambodia).

Third party reports on H5N1 outbreaks in western China have indicated that there have been human infections and media reports indicated the H5N1 isolated from bar headed geese in Qinghai Lake were similar to isolates in southeastern China.  Thus, it remains to be see if this version of H5N1 has the amantadine resistant markers.  Media reports on human cases in western China, suggest these isolates have the most dangerous combination of efficient human-to-human transmissibility and lethality.

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