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Human H5N1 in China and Indonesia Are Amantadine Sensitive

Recombinomics Commentary
December 13, 2005

All of the samples of the virus that have been isolated from patients in China would be sensitive to amantadine, Dr. Shu said. Those findings dovetail with research on virus samples that have been taken from patients in Indonesia and also show sensitivity to the drug, according to Hariadi Wibisono, director of vector-borne disease control for the Indonesian Ministry of Health in Jakarta.

Those early results have prompted officials in Beijing and Jakarta, as well as WHO officials, to consider whether amantadine eventually may play a role in fighting the disease. Right now, however, there are too few samples to draw any firm conclusions.

"If we tested a hundred isolates, and most of them were sensitive, we might recommend amantadine and oseltamivir to treat human cases of avian influenza," Dr. Shu says.

The above comments confirm the amantadine sensitivity of human H5N1 case in China and Indonesia.  This sensitivity is not surprising since none of the H5N1 wild bird flu sequences reported to date have the amantadine resistant mutations found in isolates from southeast Asia.

All 2004 H5N1 isolates from Vietnam, Thailand, Cambodia. Laos, and Mayanmar had two amantadine resistant markers, including isolates from humans.  These mutations precluded use of the amantadines for treating H5N1 infected patients.

However, these two mutations were only found in isolates from the countries listed above.  One of the resistance mutations was found in a few of the isolates from China and the frequency was somewhat higher for Indonesia, but none of the isolates outside of southeast Asia had both mutations.

Infections that involved the H5N1 wild bird M2 sequences would not be expected to be amantadine resistant and the recent outbreaks in China have clearly been linked to the transport and transmission of H5N1 by migratory birds.  Therefore, it is not surprising that none of human H5N1 cases are resistant to amantadine.

In Indonesia there was also speculation that the recent outbreaks, including the infections at the zoo in Jakarta were linked to wild birds.  The lack of amantadine resistance in human cases in Indonesia would therefore also not be surprising if wild birds were contributing M2 sequences in the human H5N1 infections.

If the sequences of the human cases are closely related to the wild bird sequences, then the comments by WHO would be surprising because there would be little reason to suspect the wild bird linked outbreaks would be sensitive.

Another polymorphisms linked to the H5N1 wild bird sequences was PB2 E627K, which was not found in H5N1 bird sequences until the Qinghai Lake outbreak this year.  E627K is associated with virulence in mammals and a poor outcome in humans.  It would be of interest to know if bird or humans isolates from China or Indonesia have E627K.

Thus far Indonesia has not released any 2005 H5N1 sequences, and sequences from China stopped after the Qinghai Lake sequences were published.  Release of bird and human sequences post Qinghai Lake would be useful. 

Migratory birds are spreading HPAI H5N1 across a wide global expanse, and the relationship between the wild bird flu sequences and those isolated from humans and birds in Indonesia and China would be useful.  Similarly, Vietnam and Thailand have not released any recent H5N1 sequences, including those from recent infections in humans.


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