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Tamiflu Resistant Pandemic H1N1 - Singapore ex-Hawaii
She returned to Singapore on flight United Airlines 803 from Honolulu via Tokyo on 26 May 2353 hrs. She became unwell while on board and passed through the thermal scanner at the airport as she did not have a fever then. She was referred by her company doctor to TTSH for assessment on 27 May afternoon via a 993 ambulance. Laboratory results confirmed her infection at 1610 hours on 28 May.
For the above cases, they have been discharged from CDC today as they have been cleared of H1N1 virus. They are now on medical leave.
The above descriptions match the patient linked to the recently released NA sequence, A/Singapore/57/2009, by the CDC at GISAID. Although the sequence represents the earliest reported case of H274Y in pandemic H1N1, it was released without fanfare on Thursday. Media reports (see Singapore map) contained the information in the first paragraph above. This information, and the additional information described in Singapore MOH press releases, indicate the case was mild and made no mention of Tamiflu treatment, consistent with the short course and discharge on May 31.
The characterization sheet indicates isolation was on May 30 from a 28 year old female, which is consistent with the above information. The first confirmed case in Singapore was on May 26, and above patient was the third confirmed case. It is the only patient matching age and gender, indicating she is the source of A/Singapore/57/2009. Since she developed symptoms while in flight, the infection was likely from a contact in Honolulu, which is similar to the history of the American traveler from San Francisco. She also had a mild case and refused Tamiflu, but recovered quickly. Although media reports indicated she had a fever when she landed, Hong Kong reports suggested she was asymptomatic at landing, but tested positive shortly thereafter. Thus, infections in both passengers were confirmed in countries in Asia, but infections were in the United States, where there have been no reported cases of Tamiflu resistance.
The export of Tamiflu resistance in the absence of detection in the United States sends a strong signal of a flawed surveillance system. Since both of these cases were mild, yet involved a fit H1N1 with H274Y, the failure to detect similar cases in California or Hawaii may be due to an emphasis on testing more severe cases. The decision to ignore and not report mild cases creates an environment for silent spread of the H1N1 as well as the associated Tamiflu resistance.
Moreover, the release of the sequence in August from a patient infected in May, raises concerns of more such examples in samples collected, but not sequenced, analyzed, or reported. These concerns have been heightened by the frequent detection of H274Y in patients receiving prophylactic Tamiflu, which would be among those most easily identified, as well as additional reports of resistance in China and Thailand, which lack information on the Tamiflu treatment status of the patients or in the case of Thailand, the sample collection date. The sample in China was collected on June 13, again signaling a long delay between sample collection and release of the associated sequences, suggesting that these patients were also not taking Tamiflu, and sequencing of these milder cases has a low priority or a large backlog.
The resistance in patients in Singapore, China, and Thailand released this week adds to concerns associated with the prior Tamiflu resistance cases in Denmark, Japan, Canada and Hong Kong (ex San Francisco), which support silent spread of Tamiflu resistance worldwide.
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