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Silent Spread of Tamiflu Resistant Pandemic H1N1 Confirmed
Recombinomics Commentary 14:26
August 15, 2009

A Health Ministry spokesperson said that the isolated case involved a patient who fell sick towards the end of May and was admitted to hospital for isolation and treatment.

The patient was infected by a Tamiflu-susceptible strain of the virus and treated with Tamiflu. The resistant strain emerged during treatment and was detected through laboratory testing but by then the patient had already improved clinically.

The above comments provide additional detail on the first confirmed case of Tamiflu resistance in a swine pandemic H1N1 case.  The H274Y was identified in an NA sequence, A/Singapore/57/2009, which was recently deposited by the CDC, along with the HA and MP sequences.  All three were clearly from the swine H1N1 pandemic strain, but the presence of H274Y in NA signaled oseltamivir resistance.  The sample was from a 28F and was collected May 30, consistent with the description of the above Health Ministry spokesperson.

The MOH website provided a great deal of detail on the initial confirmed cases and contacts.  The first confirmed case was May 27, and the third confirmed case matched the description associated with Singapore/57.  The only 28F confirned patient ib Singapore in late May / early June was an American who was working in Singapore,  She arrived from Honolulu via Tokyo on a flight that arrive just before midnight (23:53) on the night of May 26.  Although she did not feel well during the flight, she was not detected by the fever scanners at the airport.  However, the next she was transported by ambulance and arrive at the hospital in the afternoon of the 27th, and tested H1N1 positive on the afternoon (16:10) of the 28th. 

The NA sequence from the 28th has not been made public, but the comments above indicate the sample was Tamiflu sensitive,  It is not clear if treatment began the 27th (upon admission to the hospital), or the 28th, following confirmation of H1N1, because the MOH website does not mention Tamiflu treatment.  The patient was described as having a mild case, and was discharged May 31st.

However, the sample collected on May 30th had H274Y, which was 3 days after admission or 2 days after confirmation, indicating the H274Y was silently spreading since it was not detected in the May 28th sample.  Detection in the May 30th sample indicates that the H274Y was already present in May 28, but not detected, based on the comments by the spokesperson above, supporting silent spread which is detected in samples collected after Tamiflu treatment.

Although the May 28th sample was Tamiflu sensitive, the May 30th sample had H274Y in the NA sequence, as well as a polymorphism in the HA sequence that was subsequently detected in California and New York in the US, as well as Guangdong Province in China, Mexico City, Stockholm, and the first fatal case in Sao Paulo, Brazil (see list here), raising concerns of silent spread of H274Y worldwide.

The presence of H274Y in a minor species would explain the failure to find H274Y in the above locations, but its presence just below the detection level in untreated patient may explain the recent increases in fatalities.  Agencies have repeatedly cited the lack of H274Y detection, leading to the widespread use of Tamiflu in H1N1 in positive cases, including the two immuno-suppressed patents in the state of Washington, where H274Y was detected for the first time in the United States.  In those two patients H274Y was not detected until the patients either had a reoccurrence of symptoms or a failure to respond to treatment.  The resistance was found in August, even though both patients developed resistance weeks or months earlier.  These detection delays and recent reports of patients, who were resistant in May and June, raise concern that the number of samples with H274Y is significantly higher that the 11 confirmed cases thus far.  Media reports have described in at least one patient in Thailand, and earlier media reports described multiple cases in Texas along the Mexican border.

However, the detection of H274Y in the sample collected a few days after the start of treatment in the patient in Singapore suggests the actual incidence is much higher than the reported or withheld cases described by WHO, and a more intense screening program is critical, especially of samples collected after the start of osletamivir treatment and the increasingly common fatal cases.

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