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Systematic Under-reporting Of H1N1 Tamiflu Resistance
Recombinomics Commentary 19:00
March 30, 2011

Clinically and epidemiologically relevant resistance (>50% of viral quasi-species in the original clinical material harbour the H275Y mutation) are reported weekly in HPA weekly influenza reports, to the European Centre for Disease Prevention and Control (ECDC) via the European Surveillance System (TESSy) and to the World Health Organization (WHO) headquarters and the WHO Regional Office for Europe. Clinical specimens with quasi-species harbouring <50% resistant virus are reported back to clinicians as resistant for patient management but not internationally, according to the agreed WHO strategy (Technical consultation meeting (8 September 2010) proceedings paper under preparation by the WHO).

Only cases with >50% resistant viruses in the sample will be designated resistant and reported publicly, nationally and internationally, by the HPA.
Presumptive (screening) diagnosis of oseltamivir resistance will be reported within HPA and the devolved administrations, but not disseminated further. This will enable the reference laboratory to be aware of all viruses they should be testing for confirmation. Such data will not be used to form the numerator of resistant cases nationally. Treatment outcome in cases with low proportions of resistant virus (<50% H275Y viruses in the sample) may be affected and will be reported to the clinician involved, but will not be reported nationally, in accordance with suggested protocols for reporting to WHO (WHO technical discussion Hong Kong 2010).

The above comments from a Eurosuveillance article or the HPA website describe the failure to report clinical samples with Tamiflu resistance (H274Y) levels below 50%.  This high cut-off is little more than a political decision to hide the true levels of H274Y in H1N1 detected in clinical samples.  Clinicians are told of the resistance, because a level of 49%, 30%, or even 10% would be little different than a level of 100% because H274Y would jump to 100% in a matter of minutes or hours after the start of Tamiflu treatment.  Similarly, high levels of resistance would silently spread from patient to patient because the H1N1 would be considered as Tamiflu sensitive, when sequence data clearly demonstrated the resistance (as a mixture or quasi-species).

Moreover, WHO and consultants would maintain that the appearance of H274Y was “spontaneous” and due to random “copy errors”.  This claim was also put forward by Roche, the Tamiflu manufacturer.  The “spontaneous” mutation claim did not match the rapid appearance of the resistance.  In Singapore a patient switch from Tamiflu sensitive to Tamiflu resistant in two days.  Similarly, contacts of confirmed patients would be given prophylactic Tamiflu and develop symptoms 5-6 days later, which was an incubation period that is only slightly longer than wild type.  Rapid appearance of resistance in immuno-compromised patients has also been frequently described.
However, in the above instances, the rapid appearance of the resistance was inconsistent with a “spontaneous” mutation or “copy error” which would produced a fully resistant sequences in a much longer time frame (weeks or months).

Unfortunately, these misrepresentations are not limited to H274Y.  Other important changes, such as G158E associated with immunological escape, or D225G, associated with a more virulent infection are frequently found as mixtures and grow more efficiently in cells with gal 2,3 receptors such as chicken embryos or human lung.  Thus, mixtures can be under-reported in “consensus” sequences or viruses isolated in mammalian cells and selected against these clinically important changes.

The technical considerations can be used to deny transmission of these important changes, and grossly under-represent the levels of these changes in target populations.

Although lab to lab variations, as well as the rapid appearance of Tamiflu resistance made it clear that many of the reported sequences were subjected to heavy bias, the above descriptions indicate this bias was mandated by the WHO and consultants, leading to surveillance reports that hijack science to generate and distribute thinly veiled propaganda pieces.

These propaganda pieces and authors continue to be hazardous to the world’s health.

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