Paradigm Shift Intervention Monitoring
Commentary
Rising
Death Toll Linked to
Tamiflu Resistant Pandemic H1N1?
Recombinomics Commentary 18:24
August 10, 2009
The above translation describing the patient in Thailand with Tamiflu resistant pandemic H1N1 indicates the resistance was not linked to Tamiflu usage by the patient. Other reports indicated the patient has recovered and the resistance was discovered through routine surveillance of collected samples.
These results are similar to the San Francisco patient who was tested in Hong Kong. Sequencing of her sample, A/Hong Kong/2369/2009 had H274Y, even though the patient recovered without Tamiflu treatment.
Those results were similar to a patient in Singapore, who developed symptoms while en route from Honolulu, with a stopover in Tokyo. She was the third confirmed case in Singapore, and her case was also mild. She arrived on May 26, tested positive on May 28, and was discharged on May 31. The detailed report at the MOH website did not indicate she was treated with Tamiflu. Her sample, A/Singapore/57/2009 also had H274Y, but was distinct from the Hong Kong sequence.
Thus, the above examples from Thailand, Hong Kong ex-San Francisco, and Singapore ex-Honolulu, appear to involve distinct evolutionarily fit pandemic H1N1 with H274Y.
This is also likely to be true for another patient (63F) from Hunan China. Her sample, was collected on June 13, and the sequence, A/Hunan/SWL3/2009 also had H274Y. The delay between the release of the sequence and the collection date also suggests this sequence was created during routine surveillance and the patient (who was likely to have been a traveler and one of the first confirmed cases in Hunan) was also not taking Tamiflu. This sequence was also distinct, indicating an independent introduction.
Some have suggested that the identification of H274Y is due to expected random mutation selected by the Tamiflu treatment. However, the development of resistance during treatment is rare. There are examples of cases in children in Japan involving sub-optimal dosing, but in those case resistance was linked to changes at a variety of positions and the resistance was limited to the patients being treated.
However, there is no indication that the above cases were treated with Tamiflu. Moreover, there have no reports of resistance in a patient undergoing treatment for a pandemic H1N1 infection. All other examples of resistance involved patients who developed symptoms while on prophylactic Tamiflu. Thus, these patients were asymptomatic when prophylactic treatment began, and when they developed symptoms, samples were collected and the sequence with H274Y was identified. Although such H274Y positive sequences from Quebec and Tokushima have not been released, each of the other sequences (A/Denmark/528/2009, A/Yamaguchi/22/2009, A/Osaka/180/2009) have H274Y and also signaled independent introductions.
Thus, the H274Y in pandemic H1N1 is similar to H274Y in seasonal H1N1, which involved multiple introductions due to recombination and genetic hitchhiking, raising concerns that the level of H274Y is markedly higher than reported. Evolutionarily fit H274Y is circulating in mild cases were are being sequenced on a delayed basis at best, or it is circulating at a mixture, and detected in prophylactic patients when they develop symptoms.
These data raise concerns that at risk patients with H274Y are being treated with Tamiflu, leading to an increase in hospitalizations and deaths, which have been on the rise worldwide in recent weeks .
Thus, more aggressive and timely testing of mild cases as well as samples collected after patients fail to respond to Tamiflu treatment would be useful.
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