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Fit Tamiflu Resistant Cluster in Hong Kong
Recombinomics Commentary 19:09
September 9, 2009

The virus was isolated from the specimen taken from a 38-year-old man who had no history of taking Tamiflu.

The patient developed flu-like symptoms on July 26 and his respiratory specimen taken at a Designated Flu Clinic was tested positive to HSI on July 30.

Investigation revealed that four other family members also suffered from laboratory confirmed HSI including his wife, son, and two younger brothers sequentially at end of July. One of his younger brothers, aged 32, who had onset of flu like symptoms on July 23 had received a full course of Tamiflu treatment.

Except for this patient, all available isolates from other members of the family, including the specimen taken from the younger brother before he received Tamiflu treatment, were tested to be sensitive to Tamiflu.

The patient and all other affected members had mild illnesses and recovered.

The spokesman said that there was no evidence of further transmission of Tamiflu-resistant HSI from the patient.

The spokesman said that PHLSB conducted routine sensitivity tests on specimens taken from confirmed HSI patients.

The above comments describe pandemic H1N1 with H274Y that is evolutionarily fit enough to transmit.  This is the second such case identified in Hong Kong.  The earlier case was a traveler form San Francisco who also had no history of Tamiflu use, but was infected with a mild strain of H1N1 with H274Y.  The appearance of Tamiflu resistance in patients not taking Tamiflu was recently described in seasonal H1N1.  The resistance was due to the same genetic change, H274Y, and prior to becoming fixed in the seasonal H1N1 flu population (clade 2B), it jumped from one genetic background to another via recombination.  The H274Y was not only present in multiple clade 2B genetic backgrounds, but had been detected earlier in clade 2C and clade 1 in patients who had not taken Tamiflu.

The two examples in Hong Kong raise concerns that the same scenario is developing in pandemic H1N1 (swine flu), except at this time, most transmission is via a minor population that quickly appears after Tamiflu treatment.  This minor population transmits silently, because it is below the detection limits of sequencing or sensitivity assays.  It is most frequently detected in patients who have been treated with Tamiflu.

The results cited above support that interpretation.  The cluster of cases is likely linked to the index case for the familial cluster.  Initially, his sample was Tamiflu sensitive.  However, the treatment quickly led to a mixture, including sequences with H274Y which infected the older brother (38M), while other family members were infected with the sensitive strain.  The three day time frame between symptoms in the two brothers supports H274Y in a significant percentage of sequences, and after the short treatment, the mixtures produced a resistant infection in one family member and Tamiflu sensitive infections in others.

Although there is no evidence of further spread in this cluster, the ability of H1N1 with H274Y to infect the older brother indicates it was evolutionarily fit, and under circumstances that did not include close monitoring, further spread would be likely.

The detection of both fit H1N1 isolates in Hong Kong is likely linked to their testing program, which routinely tests H1N1 positive samples.  It is likely that similar transmissions are happening worldwide, but are not detected because of testing limitations.

Thus far, the public sequences with H274Y have been heterogeneous'  However, parental sequences lacking H274Y are widespread, leading to concerns that such sequences with H274Y will be detected at increasingly high frequencies.

The release of the sequences from the latest case of evolutionariiy fit pandemic H1N1 would be useful.  Nineteen other cases have been described, but sequences from cases in Canada, Japan, Thailand, and multiple sequences from North Carolina, California, and Texas have not been released.  Release of these sequences would be useful.

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