Recombination and Hitch Hiking Drive H1N1 Tamiflu Resistance

Recombination and Hitch Hiking Drive H1N1 Tamiflu Resistance

January 11, 2009


Last winter, about 11 percent of the throat swabs from patients with the most common type of flu that were sent to the Centers for Disease Control and Prevention for genetic typing showed a Tamiflu-resistant strain. This season, 99 percent do.

"It's quite shocking," said Dr. Kent A. Sepkowitz, director of infection control at Memorial Sloan-Kettering Cancer Center in New York. "We've never lost an antimicrobial this fast. It blew me away."

The above comments from the Donald McNeil NY Times article that brought the Tamiflu resistance issue to light, apply to the United States. However, the spread of H274Y is worldwide and for some Asia countries, like South Korea or Japan, the switch is even more dramatic. Resistance in South Korea last season was 0% (in 99 isolates tested) and 3% in Japan (largely concnetrated to a single prefecture). That was largely because another clade of H1N1 (Hong Kong/2562 or 2C) was circulating, largely due to the acquisition of HA A193T which drove adamantine resistance to 100% in H1N1 2C..

In some locations, like Hong Kong or Hawaii, both sub-clades were co-circulating, which allowed A193T to jump from 2C to 2B via homologous recombination. The acquisition of A193T by 2B drove H274Y to 100% worldwide, including South Korea and Japan.

The increase in South Korea and Japan is cause for concern because both countries frequently report H5N1 infections in poultry, and last spring a culler in South Korea was PCR H5 positive. Moreover, H274Y in Japan and South Korea at levels close to 100% of H1N1 strongly suggest the same sub-clade is in China and Russia, where H1N1 is common. In Beijing, a recent H5N1 case was confirmed, and a health care worker also developed symptoms, raising H2H transmission concerns.

In addition to the transmission of H5N1, there also is the concern that H5N1 infected patients could be dually infected with H1N1 also, allowing H274Y to jump from the H1N1 background to H5N1 and lead to widespread H274Y on H5N1. This concern will increase as H5N1 transmissions in humans becomes more efficient.

H274Y already has a history of jumping from one H1N1 genetic background to another. In the 2006/2007 it was present at low levels on clade 2C in China. It then jumped to clade 1 (New Caledonia) in isolates in the US and UK in the 2007/2008 season. However, levels remained low until the 2008/2009 season, when H274Y jumped to clade 2B (Brisbane/59) in Hawaii. Additional acquisitions, including D354G on NA (which was acquired from earlier H1N1) lead to the spread of H274Y to many countries in Europe and North America.

However, the acquisition of A193T in the US and UK in late 2007 led to its spread into the southern hemisphere over the summer, when H274Y levels rose to 100% in South Africa. That rise was followed by levels approaching 100% in the northern hemisphere. In addition to North America and Europe, the clade 2B with H274Y on NA and A193T on HA has emerged in Japan, where H1N1 matched the major sub-clade in the United States. The additional HA changes (G189V and H196R) have forced school closings in Japan and are they likely cause for the explosion of Tamiflu resistant H1N1 in South Korea.

Since influenza in China and Russia is dominated by H1N1 and the spread in Asia of H274Y in seasonal flu would increase the likelihood of a jump from H1N1 seasonal flu to H5N1 pandemic flu.