Reporting Delays of Tamiflu Resistant Pandemic H1N1Recombinomics...

Reporting Delays of Tamiflu Resistant Pandemic H1N1
Recombinomics Commentary 10:55
August 9, 2009


The quite release of Tamiflu resistant pandemic H1N1 sequences from Singapore and China this week has raised concern. The releases were not associated with news story describing the circumstance surrounding the resistance, but the collection dates of May 30 and June 13, respectively, strongly suggests the resistance was identified through routine sequencing.

Most of the prior isolates were associated with patient contacts who had been placed on prophylactic Tamiflu, so when they developed symptoms, samples were collected and the H274Y was rapidly identified. The first two patients identified were described weeks ago even though the collection dates were also in mid-June. The delays linked to the sequences released this week were likely due to a backlog in sequencing samples collected weeks or months ago. Similarly the recent report of resistance in a recovered patient in Thailand is also likely linked to routine sequencing and this resistance may not be linked to Tamiflu treatment.

The sequence from Hong Kong was from a traveler from San Francisco who had a mild case and was not taking Tamiflu when diagnosed, and the patient declined antiviral treatment. Thus, the evolutionarily fit H1N1 was in a mild case that recovered without treatment. These characteristics raised concerns that such cases are wide spread but not detected because many countries, including the United States, are no longer testing mild cases. Moreover, cases detected because of prophylactic Tamiflu treatment might represent mixture of virus, with lower levels of the H274Y positive strains circulating below detection levels.

Many had expected H274Y in pandemic H1N1 because of the high levels in Brisbane H1N1 seasonal flu. The jump of H274Y from seasonal flu could happen via reassortment, which would be due to the acquisition of the human N1 gene, or ressortment, which would be due to the acquisition of the portion of the human N1 gene that encoded the H274Y. Both mechanisms require a dual infection involving seasonal and pandemic H1N1, and recently released seasonal flu sequences from June isolates from central America and South America have H274Y, but the jump via reassortment or recombination would be easily distinguished from a jump via recombination. None of the reported cases have acquired H274Y via reassortment involving a human N1 gene. Moreover, no pandemic H1N1 sequence has acquired any human flu genes. However, acquisition of human N1 by pandemic H1N1 would probably not pose a health risk, because swine isolates that acquire a human N1 almost always also acquire a human H1. Indeed, recent reports from Saskatchewan, Canada described 2 or 3 farm workers infected with a swine H1N1 that had acquired Brisbane H1 and N1 and although the reassortant had H274Y, the human immune response is largely directed against the H and N genes and most people have immunity to Brisbane H1N1 because of vaccination or prior H1N1 infections.

However, acquisition of H274Y would produce data that matched the reported sequence data. Each example of Tamiflu resistance would involve the same genetic change, H274Y, and the polymorphism would jump from one pandemic genetic background to another. This mechanism of recombination and genetic hitchhiking as been described for seasonal H1N1, and linked to the evolution and spread which resulted in levels if H274Y in the Brisbane/59 strain of H1N1 which became dominant in most regions of the world, and H274Y resistance levels in H1N1 approached 100%. The increase to 100% was also linked to one particular sub-clade with A193T in HA becoming dominant.

In pandemic H1N1, one sub-clade has not become dominant. There are currently multiple sub-clades, and several have been linked to the acquisition of H274Y. Each of the public sequences represent H274Y on a different pandemic H1N1 background, raising concerns that H274Y jumps are frequent and will lead to a association with an emerging sub-clade.

The widespread use of Tamiflu for the treatment and prevention of pandemic H1N1 increases the examples of emergence from minor populations, and the release of sequences from Denmark, Singapore, and China, coupled with a report of resistance in Thailand raise concerns that the frequent detection is due to Tamiflu treatment, as well as H274Y emergence on evolutionarily fit pandemic H1N1.