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Amantadine and Rimantadine Treatments for Migratory Bird H5N1
August 12, 2005
A vaccine for H5N1 will not be available in the foreseeable months. Even if pharmaceutical manufacturing begins soon after an outbreak, there would not be a sufficient supply for the countries most in need-ie, the Asian nations. Antiviral drugs are consequently the only specific treatment, pending availability of effective vaccines. These include M2 inhibitors (amantadine and rimantadine), which are ineffective against H5N1 in vitro, and the neuraminidase inhibitors (oseltamivir and zanamivir).3 The neuraminidase inhibitors reduce the severity and duration of symptoms, and prevent clinical influenza as post-exposure and seasonal prophylaxis.4 Influenza contingency plans by the WHO and most governments generally advocate detection, isolation, staff protection, and the start of antiviral treatment for patients, and their contacts.5 Many governments, including those of Hong Kong, Thailand, Singapore, Malaysia, and Korea, have already stockpiled, at a very substantial expense, vast quantities of oseltamivir to prepare for an outbreak.5
The above paragraph from today's Lancet article comparing the labeling on oseltamivir and zanamivir, incorrectly states that that amantadine and rimantadine are ineffective against H5N1 in vitro. As noted above, these two drugs are M2 inhibitors, so their ability to inhibit M2 is dependent on the structure of the M2 gene product, which is not dependent on the serotype of the H or N genes.
Most of the recent H5N1 isolates from Asia are classified as the Z genotype, which is a loosely defined category based on the constellation of the 8 influenza genes. Consequently, within the Z genotype group are many differences in the individual genes, which include regional differences. Although isolates from Vietnam and Thailand have polymorphisms that are unique for each country, there are a number of polymorphisms that are both in both Vietnam and Thailand isolates.
Included in these polymorphisms are two that are located in the ion chanel of M2, and alterations generate amantadine and rimantadine resistance. One change takes the normal Leucine (L) at position 26 and changes it to Isoleucine (I). This change, L26I, has not been reported for any other H5N1 isolate, but it is present in all recent (2004 and 2005) isolates from Vietnam and Thailand. Therefore, these isolates are resistant to amantadine or rimantandine. However, there isolates also have a second mutation which changes Serine (S) to Aspargine (N) at position 31. This change, S31N, is also in all Vietnam and Thailand isolates that have the L26I change. S31N is also found in a few H5N1 isolates in Asia, including China and Indonesia. However, the vast majority of H5N1 isolates outside of Vietnam and Thailand are sensitive to Amantadine and rimantadine. The ion channel sequences is wild type, with L at position 26 and S at position 31.
Included in these isolates that have a wild type ion channel are the H5N1 isolates from Qinghai Lake. Thus, like the H5N1 isolates from 1997 in Hong Kong, these H5N1 isolates are sensitive to amantadine and rimantadine. In 1997 Hong Kong stockpiled amantadine because of the H5N1 outbreak. The stockpiling was relatively inexpensive, because generic versions of both drugs are available at a modest cost.
The initial data on sequences from Novosbirsk indicates that they are closely related to the Qinghai sequences. The NA gene is virtually identical, the HA gene has the same cleavage site, and the PB2 gene has the same E627K virulence change. Thus, it is likely that the M2 in Novosibisk will have the same wild type ion channel in M2 and will also be sensitive to amantadine and rimantadine.
The H5N1 from Qinghai Lake and Chany lake are being spread by migratory birds. Thus, for the first time HPAI H5N1 was reported in Russia, Kazakhstan, and Mongolia. This version of H5N1 is expected to spread throughout Asia and Europe in the coming weeks and should be sensitive to amantadine and rimantadine.
The Qinghai/Chany Lake strains are very virulent and although not confirmed in people, the have E627K and are probably neurotropic, raising questions about their role in the meningitis cases in northern India, where bar headed geese winter, and the cases in Tomsk, adjacent to Novosibirsk (see map).
In additional there have been three sets of suspect cases in Kazakhstan and a journalist has been hospitalized in Novosibirsk with bird flu symptoms.
In summary, H5N1 susceptibility to neuramindase inhibitors is dependent on the structure of neuramindase, and susceptibility to M2 ion channel blocks is dependent on the structure of the M2 ion channel. Although resistance markers are found in all recent isolates from Vietnam and Thailand, there have been no reports of such markers in isolates from Qinghai Lake or Chany Lake in Novosibirsk.