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Roche Comments on Tamiflu Resistant H1N1 Raise Concerns
Recombinomics Commentary 16:11
June 29, 2009

While receiving the drug, the patient appeared to develop resistance to it," David Reddy, Roche's pandemic taskforce leader, told reporters on a conference call on the Danish case. "This is the first report we have of it in H1N1."

The Danish patient, who has since recovered, was taking the drug as a prevention to avoid the contraction of swine flu, Reddy said. He was probably already infected with the virus, and resistance to the drug emerged because he was given the lower prevention dose

The above comments in media reports following the Roche conference call raise serious doubts about the claim that the osletamivir (Tamiflu) resistance arose in the Danish female patient because if prophylactic treatment.  The patient had been exposed to an H1N1 positive contact outside of Denmark and was given a prophylactic dose of Tamiflu as a precaution.  She subsequently developed symptoms and recovered when treated with Relenza.

However, there has been no data presented to show that wild type H1N1 infected the Danish patient or the patient who infected the Danish patient.  Moreover, the use of the qualifiers "appear" and "probably" suggests that no such data exists.

Patients have been know to develop resistance in response to treatment.  In Vietnam, a contact (sister) of a patient developed resistance at two NA positions (H274Y and N294S), which are two changes known to confer resistance and which were not detected in H5N1 from her brother, supporting development of resistance in response to treatment of his sister.

However, in the Danish case, no such evidence was presented.  If resistance was present in the contact that infected the Danish case, the result would have been as described,  The prophylactic treatment would have had little effect, and the resistant H1N1 would still have been sensitive to Relenza.

Therefore, the report of Tamiflu resistance (which was probably H274Y) raises concerns that resistance will spread via recombination, as happened fro H274Y in seasonal flu.  Initially, the polymorphism was rare.  It was first in clade 2C in China, followed by clade 1 in the US and UK, followed by clade 2B.  In each sub-clade the polymorphism appeared on multiple genetic backgrounds in the absence of Tamiflu treatment.

The hitch hiking led to an expansion of H274Y, and when it paired up with HA A193T, the subclade expanded and both acquistions became fixed.

The large reservoir of H274Y in seasonal flu provides donor sequences for H274Y acquisition in swine H1N1.  The report of resistance in the Danish patient raises concerns that the resistance can rapidly spread under the section pressure of Tamiflu treatment.

Information on the contact location for the Danish patient, as well as sequence data on samples collected before and after treatment would be useful.  However, since some media reports suggest she was on prophylactic Tamiflu for five days prior to symptoms, there probably is no isolate collected prior to treatment.  However, H1N1 from her contact would be useful, although the existence of such material is doubtful, based on the qualifiers in the Roche statements, as well as the failure to provide any hard data supporting the contention that the resistance developed in response to treatment in Denmark.

Absent such evidence, the resistance is likely to have developed prior to treatment, and represents an evolutionarily fit H1N1. 

Sequence data from the patient will help trace this sub-clade to provide additional evidence on the likelihood that the resistance emerged in Denmark, which, at this point, appears to be doubtful.

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