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H5N1 Bird Flu Sensitivity to Antivirals Amantadine and Tamiflu

Recombinomics Commentary

August 9, 2005

Indeed, Dr. Chan faced such complaints after the first cases of A(H5N1) avian influenza appeared in Hong Kong in 1997. No vaccine was effective against the strain. But the virus was susceptible to a drug, amantadine, and Dr. Chan authorized the equivalent of $1.3 million to buy a large supply of it in case a large outbreak occurred.

"The cost was peanuts, and it was an insurance policy for which I was happy not to have to make a claim," Dr. Chan said she told the auditor, who, she added, "never said anything more."

Since 1997, the A(H5N1) strain has become resistant to amantadine. But it remains susceptible to a more costly antiviral drug, Tamiflu. Influenza experts theorize that if A(H5N1) mutates to spread easily among people before a licensed vaccine becomes available, the immediate use of Tamiflu might slow the spread of the virus, if not stopping it from becoming a pandemic.

So Dr. Chan's department is discussing with countries how much Tamiflu to order. The United States has bought enough Tamiflu to treat influenza in 2.3 million Americans. It is not known how much Tamiflu manufacturers could make.

The above comments on amantadine and Tamiflu clearly indicate that an update of these two drugs in relationship to H5N1 circulating in Asia and soon to be circulating in Europe requires clarification once again.  This confusion is of an even greater concern, because it has become quite clear that the pandemic vaccine being developed worldwide has some serious issues regarding production capacity as well as utility against evolving H5N1, especially the version being transported and transmitted by migratory birds.

Amantadine resistance is found in all reported isolates of H5N1 in Vietnam and Thailand.  Thirty eight M2 sequences from Thailand in 2004 have just been released and all 38 have the same two amantadine resistance mutations seen in all other 2004 isolates from Vietnam and Thailand.  One of these changes has not been reported in any H5N1 isolate. The other is in a small number of H5N1 isolates inside and outside of China.  Thus, the vast majority of H5N1 isolates are not amantadine resistance and like the 1997 isolates described above, would be sensitive to amantadine or rimantadine.  Although these drugs have side effects, they are available in quantity and are far less expensive than Tamiflu.

All 16 of the M2 sequences from Qinghai Lake have wild type M2.  Thus, they can be treated with amantadine and rimantadine.  The H5N1 being spread by migratory birds is probably from Qinghai Lake, and those versions of H5N1 would also be susceptible to both anti-viral drugs.  This sensitivity is important, because it is unlikely that the current pandemic vaccine will be effective against these versions of H5N1 because of the large number of changes relative to the pandemic strain used to make the pandemic vaccine.

All of these H5N1s are susceptible to Tamiflu, but recent animal studies have raised serious questions about the utility of Tamiflu for preventing or treating H5N1.  In vitro data had shown that Tamiflu could inhibit the spread of H5N1, but the dose requirement for N1 was considerably higher than N2.  Moreover, H5N1 required more Tamiflu than H1N1.

The requirements for larger amount of drug became clear from the recent mouse experiments.  Although the NIH press release associated with the publication announcement of the study indicated that Tamiflu was used at the FDA approved dose, that statement appears to be in error.  The doses commonly used for Tamiflu treatment or prevention are 2 mg/kg/day or 1 mg/kg/day respectively.  The most effective dose in the mouse studies was 10 mg/kg/day, which is 5 to 10 times the FDA recommended dose.  Thus, prevention would involve 10 capsules per day, or an entire treatment course per day.  The long term effects of taking 10 Tamiflu capsules per day could be significant.  However, the short supply of the drug would probably limit use at that level.

Thus, although H5N1 does not have identified specific mutations that make the H5N1 resistant to Tamiflu, the N1 in H5N1 is generally resistant to Tamiflu.

Therefore, Tamiflu's role in treating or preventing H5N1 spread may be limited.

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