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S246N and H274Y Tamiflu Resistance Combination Concerns
Recombinomics Commentary 14:30
June 30, 2011

But researchers from the WHO Collaborating Centre for Reference and Research on Influenza found that 30 per cent of H1N1 samples collected in Darwin and 10 per cent in Singapore, had the mutation S247N. This variant has lower resistance to current drugs, Tamiflu and Relenza.

Deputy director of the WHO Centre and senior author of the study, Dr Ian Barr, said the mutation was worrying.

"We'd prefer our viruses be completely susceptible to all our medications, so, it's always a concern when we see even low-level resistance to them in these viruses," he said.

Dr Barr said treatments generally would work against the new flu strain, but the greatest problem would be treating patients with more than one type of mutated virus.

A sample from a Perth patient who died in March revealed he had the new S247N mutation, but also another variant, H275Y, a combination 6000 times more resistant than the 2009 pandemic strain.

The above comments raise concerns that additional evidence of S246N in associate with H274Y (Tamiflu resistance) or I222R (Relenza resistance) has been identified following the Eurosurveillance report detailing the clonal expansion of S246N in Singapore and Australia as noted above, as well as the detection of S246N and H274Y in a sample, A/Perth/29/2011, collected five days after the start of Tamiflu resistance.

The rapid appearance of H274Y raises concerns that the H274Y was present prior to treatment.  The report does not mention collections of samples at earlier time points, leaving open the possibility that H274Y was readily detected hours after the start of treatment.  This possibility could be addressed by aggressively cloning the sample collected prior to treatment.  Sequence analysis of several hundred clones from the original sample would address the level of H274Y in the sample prior to treatment.

The evidence for H274Y in the area comes from multiple reports.  One of the first isolates from Singapore was initially wild type and was H274Y positive two days after the start of Tamiflu treatment, again signaling the presence of H274Y as a mixture prior to treatment (and as the dominant species shortly after the start of treatment).  Similarly, reports from Vietnam described the clonal expansion of H274Y in train passengers, and H274Y has been reported in routine surveillance of samples from patients in Thailand.  Moreover, the only other reported sample with S246N and H274Y was from another Australian patient treated with Tamiflu, A/Victoria/2139/2009.

The true level of H274Y in the region is under-reported because most samples are collected prior to Tamiflu treatment and WHO collaborating labs have “agreed” to not report H274Y in samples where the level is less than 50%.  Thus, even when H274Y is detected as a minor species, the sample is reported as wild type (Tamiflu sensitive).

Thus, the latest comments may reflect additional data linking S246N and H274Y to samples collected prior to Tamiflu treatment.  Similarly, the Eurosurveillance paper did not discuss sequences on samples collected at autopsy.  The fatal case with S246N and H274Y was also treated with intravenous Zinamivir (Relenza) raising the possibility that detectable I222R was present at autopsy.

An update on the current situation (the Eurosurveillance report did not cover samples collected after March, 2011) regarding the detection of H274Y and/or I222R in association with the clonally expanding sub-clade with S246N is overdue.

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