Recombinomics Commentary 19:43
March 23, 2009

During this period, a total of 30 countries from all WHO regions reported oseltamivir resistance for 1291 of 1362 A(H1N1) viruses analysed. The prevalence of oseltamivir resistance was very high in the following countries/territory: Canada (52 of 52 tested), Hong Kong SAR (72 of 80), Japan (420 of 422), the Republic of Korea (268 of 269) and the United States of America (237 of 241).

The resistance prevalence was relatively low in China (6 of 44 tested). In Europe, H1N1 circulation was low during this period while the resistance prevalence was high: France (12 of 12tested), Germany (66 of 67), Ireland (9 of 10), Italy (16 of 16), Sweden (11 of 12) and the United Kingdom (61 of 62).


The above comments from the latest WHO update on Tamiflu resistance confirm that H274Y has become fixed in clade 2B (Brisbane/59) in the northern hemisphere, and similar levels will be expected in the upcoming flu season in the southern hemisphere. The only northern hemisphere country with lower levels is China, which is due to high levels of clade 2C. However, clade 2C has been largely replaced by 2B in all northern hemisphere countries, and many, especially those in Asia, previously had relatively high levels of clade 2C last year. Levels in the US were approximately 10% of H1N1, while this year levels are below 1%.

The dominance of clade 2B with H274Y not only creates treatment problems for patients with seasonal flu, but also raises concerns regarding the acquisition of H274Y by H5N1 via reassortment or recombination. Examples of exchanges between H1N1 clade 2B and clade 2C have been documented. One isolate from Hong Kong had a clade 2C HA and a clade 2B NA (with H274Y). Moreover, recombination has led to hitch-hiking of H274Y across multiple sub-clades (2C, 1, and 2B) as well as within each of the above sub-clades. Moreover, the H1N1 that led to the fixing of H274Y acquired additional clade 2C polymorphsms, including A193T, which is now present in all clade 2B isolates with H274Y.

This acquisition has been accompanied by additional changes in HA and NA, especially those that are adjacent to A193T. Multiple changes have been reported at positions 187, 189, and 196, an isolates with these changes have spread widely and rapidly, and are likely for vaccine resistance in Japan, Taiwan, and Italy.

The acquisition of these changes via recombination between H1N1 sub-clades raises concerns of H274Y acquisition in hosts co-infected with H1N1 and H5N1. These concerns have been increased by reports of mild H5N1 infections in Egypt. All eight H5N1 cases in 2009 have survived H5N1 infections, and the course of disease in several patients is short and mild, raising concerns of a significant number of unreported cases due to recovery with or without Tamiflu treatment for seasonal flu.
Acquisition of H274Y by H5N1 would create serious concerns, especially in countries like Indonesia, where the high case fatality rate suggests many milder cases are unreported.