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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 <a rel="nofollow" href="http://www.recombinomics.com/News/08120901/H274Y_More.html">comments</a> were issued in response to queries about osletamivir resistance in <a rel="nofollow" href="http://www.recombinomics.com/News/08090903/H274Y_Singapore_Hawaii.html">Singapore</a> 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 <a rel="nofollow" href="http://www.recombinomics.com/News/08090901/H274Y_Thailand.html">Thailand</a> had already acknowledged at least one case, and additional reports from <a rel="nofollow" href="http://www.recombinomics.com/News/08140901/H274Y_HK_More.html">Hong Kong</a> and an MMWR Dispatch describing two immuno-compromised patients in Washington State were made public on Friday. Cases in <a rel="nofollow" href="http://www.recombinomics.com/News/08040901/H274Y_TX_Cases.html">Texas</a> along the border with Mexico are still 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 <a rel="nofollow" href="http://www.recombinomics.com/News/08150902/H274Y_SS_Confirmed.html">additional data</a> 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 <a rel="nofollow" href="http://www.recombinomics.com/News/08091001/H274Y_Toll.html">rising fatalities</a>being reported worldwide.
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"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
WHO Withholding Tamiflu Resistant Pandemic H1N1 Locations
Recombinomics Commentary 13:55
August 17, 2009
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 by WHO are curious. WHO is funded by member nations and has a mandate to protect citizens of member nations. The withholding of important information such as the number and location of Tamiflu resistant pandemic H1N1 virus is not consistent with that mission. Tamiflu is widely used and recommended by WHO, so the withholding of information on resistance leads to inappropriate use of the antiviral, and places patient care and health care systems at risk.
This type of risk was easily seen in the two immuno-suppressed patients detailed in the recent MMWR dispatch. WHO has maintained that resistance is rare and due to spontaneous mutations selected in Tamiflu treated patients. However, recent data, including that from the <a rel="nofollow" href="http://www.recombinomics.com/News/08170901/H274Y_Fit_US.html">patients in Washington state</a> suggested that the limited number of reports is related to limited and <a rel="nofollow" href="http://www.recombinomics.com/News/08150901/H274Y_WA.html">delayed</a> testing, which is compounded by the <a rel="nofollow" href="http://www.recombinomics.com/News/08160901/H274Y_WHO_See_NOT.html">withholding</a> of information on identified isolated.
The MMWR describe patients who were H1N1 infected in June. The patients were treated with Tamiflu and detectable resistance developed quickly. However, treatment was increased and resistance was not confirmed until August, after one patient developed a Tamiflu resistant recurrence and the other patient continues to be hospitalized in spite of treatment with Tamiflu, Relenza, and ribavirin. The ability of Tamiflu resistant pandemic H1N1 to persistence in such aggressively treated patients increases concerns that the recent worldwide rise in <a rel="nofollow" href="http://www.recombinomics.com/News/08091001/H274Y_Toll.html">patient deaths and hospitalizations</a> is linked in part to such resistance.
When WHO stated it was withholding the information on resistance, there had already been 8 examples in patients which were supported by sequence data. Another example (in <a rel="nofollow" href="http://www.recombinomics.com/News/08090901/H274Y_Thailand.html">Thailand</a>) had already been described in media reports and shortly after the proclamation by WHO, <a rel="nofollow" href="http://www.recombinomics.com/News/08140901/H274Y_HK_More.html">Hong Kong</a> reported another cases of resistance in a patient being treated prophylatically and the two patients in Washington State were detailed. Moreover, <a rel="nofollow" href="http://www.recombinomics.com/News/08150902/H274Y_SS_Confirmed.html">additional information</a> on the American patient in <a rel="nofollow" href="http://www.recombinomics.com/News/08090903/H274Y_Singapore_Hawaii.html">Singapore</a> provided compelling data that H274Y was silently circulating because the vast majority by WHO and consultants involved samples collected prior to Tamiflu treatment, which were failing to detect the H274Y present as a mixture in the H1N1 samples being sequenced.
The WHO should be encouraging countries to promptly report resistance and expand testing to patients who have been briefly treated with Tamiflu. A true accounting of H274Y in pandemic H1N1 is long overdue.
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"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
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