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Commentary
Hidden Transmission of
H1N1Tamiflu Resistance
Recombinomics
Commentary 16:39
December 10, 2009
The above comment from the WHO Oct 30 Weekly Epidemiology Record appears to be missing the cluster of seven patients who were infected with pandemic H1N1 with H274Y during a train trip in Vietnam. The train trip was in July and the first three cases were confirmed on Sept 9, yet there has been no mention of this large cluster until publication in the current New England Journal of Medicine. However, the WER compilation has no category for cases who were treated with Tamiflu, but had H274Y in samples collected prior to treatment. It is common for samples to be collected prior to treatment, although the resistance is frequently detected long after the patients have been treated and recovered, yet the only grouping of such cases would be in the patients "associated" with Tamiflu treatment.
As seen in the cluster from Vietnam, the "association" of Tamiflu treatment has no relevance because the patients were resistant prior to treatment. However, the reporting by WHO leaves the impression that the association with treatment was relevant, when the vast majority of the time it is not (because the patients are resistant prior to treatment).
This clear slanting of the data is not limited to WHO reports. Weekly reports from the CDC also do not distinguish between patients treated with Tamiflu even though they are already Tamiflu resistant, and those patients who present with resistance during treatment.
In cases where H274Y is detected after treatment has begun, the relationship between the treatment and the generation of resistance is likely to be more related to detection of resistance than creation of resistance. In the first cases in Singapore, the patient initially tested as wild type, but was H274Y positive two days later, suggesting H274Y was already circulating as a minor species.
The presence of H274Y as a minor species also explains the rapid appearance of H274Y on patients being treated prophylactically with Tamiflu (5 or 6 days after the start of treatment).
Moreover, WHO and the CDC have yet to show a single case supporting H274Y emergence via a spontaneous mutation. In the cases of two immune-suppressed patients in Washington, no data was present to exclude detection as early as 5 days after the start of treatment. One patient had wild type at day 4, and had H274Y at day 11, but could have had detectable levels as early as day 5. Similarly a second case had wild type at day 1 and H274Y at day 18, but results from samples collected at day 3 and 6 were not disclosed. Thus, there was no data presented that would exclude the presence of H274Y as a minor species, and since the two Washington patients were infected with the same sub-clade, it is likely that these patients also did not develop H274Y via spontaneous mutation.
Thus, neither WHO, CDC, nor Roche have presented data supporting a spontaneous mutation in seasonal H1N1 or pandemic H1N1, although all frequently cite random mutation as the underlying basis of antigenic drift.
However, all cases of Tamiflu resistance in H1N1 involve H274Y and there are no recent examples of Tamiflu resistance in H3N2, indicating early reports of resistance in Japanese children treated with sub-optimal dosages of Taniflu were an anomaly which has been eliminated by proper dosing.
Thus, the report of seven passengers in Vietnam in July strongly suggest that reports by WHO and the CDC seriously underestimate the frequency of H274Y transmission by combining hospital cases with H274Y prior to treatment with cases where H274Y is detected during treatment.
This slanted reporting and poor surveillance continue to be hazardous to the world's health.
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