Tuesday, November 25, 2008

The Emergence and Dominance of N1 Tamiflu Resistance


The Emergence and Dominance of N1 Tamiflu Resistance
Recombinomics Commentary 21:08
November 24, 2008

Recently released H1N1 seasonal flu sequences from England provided additional insight into the emergence and dominance of H274Y, which confers Tamiflu resistance on N1. Resistance to antivirals is on the rise. S31N on M2, which confers resistance to amantadines has become fixed in both influenza A human serotypes, although the levels in H1N1 have been almost exclusively in clade 2C (Hong Kong). These levels were achieved several years ago.

However, the fixing of H274Y in H1N1 clade 2B (Brisbane/59) is ongoing, and recently released H1N1 sequences allows for tracing of key events. The emergence of H274Y began in patients in China in clade 2C in the 2005/2006 season. The positive patients were not taking Tamiflu, indicating the acquisition of H274Y did not produce a fitness penalty. However, although H274Y was viable in patients not taking Tamiflu, it did not have a selective advantage over wild type H5N1 and the levels remained low.

In the 2006/2007 season, H274Y began to appear on clade 1 (New Caledonia) H1N1 in the United States and United Kingdom. Once again most of the patients were not taking Tamiflu, but once again the levels of H274Y remained low.

In the 2007/2008 season H274Y began to appear on clade 2B in the United States and United Kingdom, but initially was still at a low level. However, in 2007 an additional acquisition, D354G, created a selective advantage, which appeared throughout northern Europe, and was most prevalent in Norway, where it and H274Y was found in 65% of the H1N1 cases.

In the middle of 2008 it appeared in countries in the southern hemisphere and approached 100% of H1N1 isolates. The most reported cases were in South Africa where all of the first 215 isolates tested had H274Y (and presumably D354G which was in all public sequences representing the dominant clade 2B sub-clade.

Initial reports from the northern hemisphere this season suggest the high frequency in clade 2B will emerge this season, and presumably these isolates will also have D354G. Initial reports on H1N1 clade 2B suggests that the levels are 12/13 in England, 2/2 in Scotland, 1/1 in Norway, 1/1 in Canada, and 1/1 in the United States.

Thus, the fixing of H274Y required one additional change in the NA sequence which was a polymorphism found in all recent clade 2C and clade 2A (Solomon Island) isolates, indicating the change also produced dominant sub-clades in those earlier examples.

The level of this sub-clade rose to 100% when it emerged in the southern hemisphere, and then maintained that level in the following season in the northern hemisphere.

The movement of H274Y from one H1N1 sub-clade to another, followed by the movement of D354G was facilitated by homologous recombination, which mixes and matches polymorphisms to produce dominant genotypes.

The high levels of H274Y in clade 2B, with possible increases appearing this year in clade 2C, raise concerns that H274Y can move to H5N1 when levels increase in humans.

The recent reports of H5N1 in a large cluster in Indonesia increases concerns that an increase in oseltamivir resistance in evolutionarily fit H5N1 may appear in the upcoming season.

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