That didn't take long. I wonder if the patient survived.
first mutation of tamiflu resistance in Denmark
Dansker den første med H1N1-mutation
http://www.bt.dk/danmark/dansker-den-foerste-med-h1n1-mutation
http://www.recombinomics.com/News/06290903/H274Y_Swine_Roche.html
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.
http://www.recombinomics.com/News/06290903/H274Y_Swine_Roche.html
Thanks for the update.
Commentary
Silent Spread of Tamiflu Resistant Pandemic H1N1
Recombinomics Commentary 13:05
June 30, 2009
He had to start with no ill. That was in the preventive treatment with Tamiflu, because he had been in close contact with a swine influenza hit abroad. Since there had been five days of Tamiflu, the person suddenly ill with H1N1, but it not appear that the medicine worked. It appeared as through the samples here and in England that the person had been resistance, “says Nils Strandberg.
The above translation provides additional information on the patient who developed a pandemic H1N1 infection while taking a prophylactic dose of oseltamivir (Tamiflu). The five days suggests the patient was infected after her contact, who was infected overseas, returned. The patient was given Tamiflu because of her infected contact and developed flu-like symptoms while taking Tamiflu, which led to the isolation of the virus and sequence data (generated in Denmark and England) showing resistance (which was almost certainly H274Y).
The above description made no mention of an isolate from the patient who traveled overseas and no indication that an isolate was collected. Therefore, it is highly unlikely that a wild type sequence from the overseas traveler or the patient with resistant H1N1 exist. This absence was also signaled by statements from Roche and other agencies who used the qualifiers of “appears” and “probably” when describing the develop of resistance, because there is no evidence that resistance developed in the patient in Denmark.
A more likely scenario involves the silent spread of oseltamivir resistant H1N1. Denmark, like most countries in Europe, has focused on detection of H1N1 in travelers and contacts. Consequently, the number of H1N1 positive cases has been low. Although countries have been making sequences public shortly have collection of isolates, the number of public pandemic H1N1 sequences from Denmark at Genbank or GISAID remains at one. The NA sequence has been released and it is wild type. However, the isolate was collected from a patient in April, so there are no recent public sequences from Denmark.
Similarly, sequences from other countries are also limited and in many cases the public sequences do not include NA, so even if H274Y was in the isolate, it would not be in the database. The publicity associated with the Danish case will likely lead to more isolates and more sequences, and the explosion of cases in England, may lead to a more serious approach toward testing for community spread in European countries like Denmark, which are focused on airport travelers and contacts.
Airport screening will only detect a small subset of infected patients, because those infected shortly prior to travel will not yet have symptoms and about 30% of infected patients don’t develop a high fever. Moreover, others take medication for flu-like symptoms, which lowers fevers. Thus, infected patients have been flying into these countries undetected for months, and community spread is significant, but not reported because of a lack of testing.
The detection of H274Y in pandemic H1N1 has parallels with H274Y in seasonal H1N1. The resistance was widely reported in early 2008 in Norway, but subsequent testing demonstrated that the resistance was widespread in the fall of 2007 and had silently circulated for months prior to detection. The limited number of NA sequence for most countries outside of North America allows for a repeat of silent spread of Tamiflu resistantant pandemic H1N1 at this time.
More detail on the current case and contact who was infected overseas would be useful, as would serious testing and for community spread in countries reporting low levels of infections, which includes most countries in Europe, and rapid release of associated sequences.
http://www.recombinomics.com/News/06300901/H274Y_Swine_Silent.html