Commentary
Mismatched
Flu Antiviral Recommendations in the United States
Recombinomics Commentary
12:41
December 8, 2008
Based on the level of oseltamivir resistance observed in only one influenza subtype, H1N1, and the persisting high levels of resistance to the adamantanes in H3N2 viruses, CDC continues to recommend the use of oseltamivir and zanamivir for the treatment or prevention of influenza in the United States.
The above comments are from recent CDC weekly reports on influenza. The statement on uncertainty is from the latest (week 48) update, while the statement on antiviral recommendations was in the week 46 report.
However, the antiviral situation in the United States is quite straight forward, and unlikely to change with additional near term data. Resistance to the adamantines is at or near 100% for H3N2, while resistance to oseltamivir (Tamiflu) is at or near 100% for H1N1. Since the vast majority of influenza A in the United States is H1N1 at this time, the current recommendations discourage use of adamantines, when most influenza A is sensitive, and encourage oseltamivir, when most influenza A is resistant, creating a significant mismatch in antiviral recommendations for the United States.
The basis for a prediction of near term stasis is base on results for this season for North America and Europe, where oseltamivir resistance is approximately 100% for H1N1 and adamantine resistance is approximately 100% for H3N2. Although resistance levels in H3N2 has been largely unchanged in recent seasons, the level of oseltamivir resistance (H274Y) has evolved significantly over the past few seasons, but the levels of 100% began to appear in the 2008 season in the southern hemisphere, and now is confirmed in the northern hemisphere for this season.
Initially, H274Y appeared on a number of H1N1 genetic backgrounds in patients not receiving oseltamivir. H274Y was reported in clade 2C (Hong Kong) in the 2005/2006 season in China. It then appeared in clade 1 (New Caledonia) in the United States and England in 2006/2007. Last season it was in clade 2B in the United States and England, but did not initially dominate. A second change, D3548G, which had been in clade 2C and clade 2A (Solomon Island) previously, was acquired by clade 2B via recombination, and this sub-clade, which both H274Y and D354G began to dominate.
In south countries in Europe (Norway, France, Russia) and North America (Canada) levels increased to more than 40% of H1N1 isolates. In the United States the level was closer to 10% because clade 2B and 2C were co-circulating and there was no reported H274Y in clade 2C in the United States. Moreover, most of clade 2B also did not have H274Y.
However, the following flu season in the summer hemisphere, the sub-clade with H274Y and D354G seed the season, and resistance levels rose to 100%, raising concerns that the new 2008/2009 season in the northern hemisphere would also be seeded by the same sub-clade and resistance would also increase to 100%. H1N1 resistance testing Europe and North America have confirmed the increase to 100%.
In the United States this season H274Y levels rose to close to 100% in clade 2B, and initial testing failed to identify clade 2C (which was at 100% adamantine resistance in the US last season). Thus, the levels of antiviral resistance in influenza A are related to the relative levels of H1N1 and H3N2, and at this time H1N1 levels are widespread and account for 80% or more of influenza A isolates in multiple regions.
As a result, the current antiviral recommendations in the United States are mismatched with the levels in co-circulation. The vast majority of influenza A is H1N1 which is oseltamivir resistance and adamantine sensitive, yet use of adamantines are discouraged and oseltamivir is encouraged in current CDC recommendations.
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