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WHO Failure to See Spread of Tamiflu Resistant Pandemic H1N1
Recombinomics Commentary 15:19
August 16, 2009

China and Singapore have found Tamiflu-resistant pandemic viruses, Charles Penn, a scientist with the Geneva-based agency, said in an interview with The Canadian Press.

He revealed that the WHO has also been alerted informally to the discovery of a small number of other Tamiflu-resistant viruses. He would not say where they were found or how many there were in total.

"It's a small number. It certainly doesn't change the scale of what we're seeing," Penn said.

The above comments were issued in response to queries about osletamivir resistance in Singapore and Hunan, China, as indicated by sequences made public at GISAID and Genbank.  Those two instances were acknowledged, but the rationale behind the withholding of additional cases remains unclear.  At the time Thailand had already acknowledged at least one case, and additional reports from Hong Kong and an MMWR Dispatch describing two immuno-compromised patients in Washington State were made public on Friday.  Cases in Texas along the border with Mexico area till being denied, although the initial report included detail on two of the cases, suggesting the denials were largely based on semantics.

The cases in Texas would change the inferred scale, because the cases were at opposite ends of the border and had much in common with the initial H1N1 described in southern California.  Those cases were unlinked to each other or swine, yet the sequences were virtually identical, indicating the virus was widespread.  The same conclusion could be made from the cases in Texas, which may be related to the withholding of the information associated with these cases.

However, the detail that has come out in the past few days has left little doubt that the WHO's "scale of what we are seeing" is false.  The failure to see the true scale of the H274Y spread is due to the limited testing, which is largely focused on samples collected prior to Tamiflu treatment, which can be "seen" in results from patients on prophylactic Tamiflu treatment or in samples collected a few days after the start of Tamiflu treatment in symptomatic patients.

The Hong Kong case described Friday was another patient who became symptomatic while on prophylactic Tamiflu.  Earlier detail on patients in Denmark and Japan indicated they became symptomatic on day 5 of prophylactic treatment.  Since the incubation period of influenza is in the range of 2-4 days, the slightly longer time period indicated the H274Y was already present when Tamiflu treatment began, but because it was a minor component, disease onset was delayed by 1-2 days.  The recent patient in Hong Kong developed symptoms on day 6.

However, the confirmatory data on silent spread of H274Y came from Singapore, where additional data on first confirmed case was disclosed.  The sequence was from a May 30 sample from a 28F, but the detailed reports at the MOH indicated the patient (American working in Singapore who arrived late on May 26 after becoming symptomatic during flight, but passed fever scans, but was hospitalized on May 27 and confirmed on May 28.  The recent comments indicated the patient was initially Tamiflu sensitive (May 28 test), and resistance was discovered after patient improved (she was discharged May 31).  Thus, the resistance in the May 30 sample was present only a few days after the start of treatment and the sequences (on HA, NA. MP) had no evidence of a mixture, indicating the resistant sequence quickly replaced the wild type sequence, signaling silently spread of H274Y.

Thus, the WHO failure to see the resistance was linked to limited and delayed testing of samples collected a few days after the start of treatment, and the standard testing / sequencing failed to detect the H274Y transmitting as a minor population.  The HA Singapore sequence has a polymorphism that was found in isolates in the US, Sweden, China, and Argentina, raising concerns that the H274Y was creating additional problems in Tamiflu treated patients as seen in the two immune-compromised patients in Washington State as well as rising fatalities being reported worldwide.

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