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Human to Human H5N1 Transmission During Tamiflu Prophylaxis

Recombinomics Commentary

October 15, 2005

An H5N1 influenza virus, A/Hanoi/30408/2005, was isolated on 27 February 2005 from a 14-year-old Vietnamese girl (patient 1) who had received a prophylactic dose (75mg once a day) of oseltamivir from 24 to 27 February and was given a therapeutic dose (75mg twice daily) for 7 days starting on 28 February.  No virus was isolated from specimens after the administration of increased doses of oseltamivir. The patient recovered and was discharged from hospital on 14 March 2005.

The timing of infection in these two patients, together with the lack of known interaction of the girl with poultry, raises the possibility that the virus could have been transmitted from brother to sister.

The above comments from a pre-released Nature paper raise serious questions about the prophalactic use of Tamiflu and human-to-human (H2H) of H5N1.  The sister, Nguyen Thi Ngoan, of the index case, Nguyen Si Tuan, was taking the FDA approved prophylactic dose of Tamiflu, 1 pill per day. However, even while on Tamiflu, she developed H5N1 bird flu symptoms.  Genetic analysis of the virus suggested that she was infected by her brother, even though she was taking Tamiflu.

The above paper focuses on resistance markers in isolated clones from the sister.  However, the brother and sister were part of a large case cluster of H5N1 infections.  The grandfather of the two patients also tested positive for H5N1 antibodies.  Although H5N1 was not isolated, it is not clear if the grandfather was taking Tamiflu when his grandson was in the hospital.

Similarly, the index case's nurse developed avian influenza.  He maintained that he had no exposure to poultry, yet developed laboratory confirmed H5N1.  It is not clear if the nurse was taking Tamiflu at the time of his infection.

There was a second nurse who developed bird flu symptoms.  She tested negative for H5N1 by PCR.  Results from serum tests were not disclosed.

The effectiveness of Tamiflu against H5N1 was also raised in in vivo mice experiments.  Mice were given the equivalent of 20 pills of Tamiflu per day.  This high level was justified by observations on species specific differences in metabolism.  However, even after correcting for species differences, the mice were treated with an equivalent of two pills per day.  However, the dose was based on treatment, even though the mice were give the drug four hours before infection.  However, even with these favorable conditions, 50% of the mice died if treated for 5 days.  If treated for 8 days, the percentage dead fell to 20%..These mice studies raised dosing questions for oseltamivir against H5N1.  Use at the FDA approved level, priced less than ideal results.

Similarly, the cluster of human cases described above raises dosing question.  The H5N1 appeared to be susceptible to a doubled dose of Tamiflu and the isolated H5n1 was sensitive to Relenza.  However, nations are stockpiling Tamiflu, and the above results suggest that the FDA approved dose for prophylaxis may be inadequate.

Similarly, Tamiflu resistance is another concern.  The number of H5N1 cases in Vietnam is still relatively small.  It is unclear how many people in Vietnam are on Tamiflu.  The identification of a Tamiflu resistant variant in the small number of people being treated is cause for concern. Similarly, prophylactic treatment in health care workers and family members may not have been sufficiently high to prevent H5N1 infections.

Thus the proper dose of Tamiflu and the frequency of resistance in Vietnam remains unclear.  Similarly, the impact of wider use of Tamiflu in Indonesia is another area of concern.

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