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In Vivo Data and Tamiflu Pandemic Containment Myth
July 18, 2005
Of 80 mice infected with H5N1 virus, 20 received a placebo, 30 were given oseltamivir at one of three dosage levels for five days, and 30 received the drug at one of three dosage levels for eight days. None of the mice receiving a placebo survived. Only five of 10 mice given the highest daily dose of oseltamivir for five days survived. Although oseltamivir suppressed the virus in the mice, the virus continued to grow if the drug was stopped after five days.
Mice given the drug for eight days fared better. Survivors included one of 10 mice given the lowest daily dose, six of 10 given the middle-range daily dose, and eight of 10 given the highest daily dose. The eight-day dose of oseltamivir allowed more time for virus levels to fall and less chance for avian flu to rebound after the drug was stopped.
The above description of the in vivo test of oseltamivir (Tamiflu) is consistent with prior in vitro studies which strongly suggest that use of Tamiflu at the recommended dosage will produce little benefit. Many countries have stockpiled Tamiflu and more have placed orders. However, the amount of Tamiflu ordered was based on the assumption that a course of 10 pills would be effective for 10 days of prevention or 5 days of treatment. However, this assumption was not supported by in vitro data and now is also not supported by in vivo data.
Tamflu targets the NA gene product neuraminidase. Influenza A codes for nine NA serotypes and Tamiflu had been previously tested against all nine, using two representative viruses for each. Although Tamiflu could inhibit spread of the virus, it was far more effective against N2 (as in human H3N2) than N1 (as in human H1N1 or avian H5N1). All of the human H5N1 isolates since 2004 have had a 20 amino acid deletion in N. Recent studies using the more recent isolates which have the deletion again showed that Tamiflu worked, but was even less effective than N1 without the deletion.
The latest in vivo results again show that Tamiflu works against H5N1 but when used at the recommended dose (2 pills a day for 5 days). Its benefit was marginal (50% of the treated mice died). However, in the latest test the Tamiflu was not administer after symptoms appeared, which in humans is 2-4 after infection), but instead was initially administered 4 hours before infection. Since 50% of the mice died when treated for 5 days, beginning before infection, treatments that begun after symptoms would probably produce little, if any benefit, even in the absence of Tamiflu resistance
The resposnse was dose dependent and suggests improvement may be obtained if a higher dose is used or if treatment is for a longer period of time, but the FDA approved treatment regime would probably not be effective.
These marginal results under ideal experimental conditions do not suggest Tamiflu would be effective under pandemic conditions if used at the recommended dose for the recommended time. Indeed, Tamiflu was used on tigers exposed to H5N1 at the Sri Rahka zoo in Thailand last year. Control of the outbreak with culling and aggressive Tamiflu use failed to save many, if any, of the exposed tigers, which may have been limited to the 147 that died or were euthanized.
The H5N1 isolate, A/Vietnam/1203/2004, used in the mouse experiments is a more aggressive version of the 2004 isolates and it is neurotropic, causing hind leg paralysis in infect ferrets. It has the G1906A polymorphism that produces the E627K change in the PB2 protein, which was also found in most of the tiger isolates as well as all isolates from Qinghai Lake. Thus, it might be useful to determine the effects of Tamiflu treatment on the ability of the H5N1 to reach the brain of infected mice if they survive the bird flu infections.
Clearly more work is required to determine the effective dose of Tamiflu. The boxun reports indicate that there are at least 10 distinct strains of H5N1 in China, and 8 can infect humans. Therefore information the effect of Tamiflu on a range of H5N1 variants might be useful.
However, at this time it seems that usefulness of Tamiflu at FDA recommended doses remains questionable for control of an H5N1 flu pandemic.