H1N1 : Tamiflu Resistant Pandemic H1N1 Spread to Canada and Japan

Tamiflu Resistant Pandemic H1N1 Spread to Canada and Japan

"We know the exact, specific mutation, and this is a mutation that has been reported before in human viruses that were resistant to Tamiflu, so it's not totally unexpected," said Boivin.

Boivin said he suspects the Quebec father was already infected when he was given a low preventive dose of the antiviral drug Tamiflu.

The above comments describe another case of oseltamivir resistance in pandemic H1N1 swine flu.  The description indicates the resistance is due to H274Y because all reported oseltamivir resistance since 2007 has been H274Y in H1N1.  Earlier this month there were three cases described, and two of the three were also on prophylactic oseltamivir. However, since all cases have involved H274Y, the treatment may simply be aiding in the detection of H274Y, rather than selecting for de novo mutations.  Sequence data reports consensus sequences, so a low level of H274Y would not be seen unless multiple clones were sequenced or levels increased due to the elimination of wild type H1N1 by oseltamivir treatment.

In addition to the H274Y in Quebec, a sequence released today from Yamaguchi Province in Japan also had H274Y.  The characterization sheet provides little detail on the patient, but Yamaguchi Province gives detailed reports on each H1N1 confirmed case, and the reports give no support for the development of H1N1 in contacts under prophylactic treatment.  Therefore, it is likely that the Yamguchi isolate is from a sample collected prior to Tamiflu treatment.

The sequence of A/Yamaguchi/22/2009 is distinct for the other two published sequences with H274Y.  However, like A/Hong Kong/2369/2009, there are several NA sequences which are exact matches, other than position H274Y.  These precursors are widespread, and the earliest isolate is from the United States (Sullivan county in New York), and all subsequent isolates are from other countries (Japan, China, Brazil) once again raising questions about surveillance of mild H1N1 cases in the United States.  In Japan there have been no reported pandemic H1N1 deaths and most of the cases in in Yamaguchi province have been mild and patients have recovered without hospitalization.

These two cases of resistance raises the total to five and all involve H274Y, the same polymorphism reported in seasonal H1N1, where the level quickly rose to 100% last season and is reported at 100% in the southern hemisphere this season.  The presence of H274Y on seasonal H1N1, which is co-circulating with pandemic H1N1, offers the opportunity of recombination between seasonal and pandemic H1n1 to allow the H274Y to jump from seasonal H1N1 to pandemic H1N1.

The reports of H274Y in five patients this month raises concerns that the frequency will rise in the near term, with recombination and genetic hitchhiking driving the levels to 100%, due in part to widespread use of oseltamivir and in part to the large reservoir of H274Y in seasonal flu. Source : Recombinomics

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