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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 sequences for most countries outside of North America allows for a repeat of silent spread of Tamiflu resistant 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. 

Moreover, rapid release of associated sequences would be useful.

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