Efficient Transmission of Tamiflu Resistant Pandemic...

Efficient Transmission of Tamiflu Resistant Pandemic H1N1
Recombinomics Commentary 14:19
September 16, 2009


Almost two dozen people have developed swine flu infections that don't respond to Tamiflu, a mainstay of therapy for the outbreak that began in April. The genetic mutation that helps the virus evade the drug also thwarts its transmission, so the infection isn't passed on to other patients, said David Mercer, acting head of the communicable diseases unit of the WHO's European region.

The above comments on the transmissibility of pandemic H1N1 with H274Y are similar to claims made years ago by scientists at Roche. However, H274Y on seasonal H1N1 transmitted quite efficiently and was the dominant serotype in seasonal flu in North America and many countries in Asia, and H274Y became fixed in the clade 2B (Brisbane//59).

The spread of H1N1 with H274Y in patients not taking Tamiflu was not limited to clade 2B. In 2006 it was in clade 2C in China, followed by clade 1 in the US and UK in the 2006/2007. Although these other sub-clades with H274Y were transmitting, the expansion of H274Y began in the 2007/2008 season, and was driven by a series of additional changes, the established one dominant sub-clade. That dominant sub-clade then acquired HA A193T and then spread globally. Thus, the establishment of H274Y in seasonal flu involved movement of the polymorphism from one genetic background to another via recombination, until it was acquired by a dominant sub-clade. Consequently, the Tamiflu resistance was limited to H1N1 with H274Y, which was efficiently transmitted.

The fixing of H274Y in seasonal flu raised concerns that a similar scenario would develop in pandemic H1N1 since Tamiflu was widely used, and the H274Y in seasonal H1N1 provided a large reservoir of donor sequences fro a jump to pandemic H1N1. Initial concerns suggested two different mechanisms for the jump, involving the exchange of genetic information via reassortment or recombination. Both mechanisms required a dual infection, but the reassortment would replace the swine N1 with human N1. To date there have been no reports of a recent acquisition of human N1 or any other gene segment into pandemic H1N1. However, there have been two dozen reports of H274Y appearing in pandemic H1N1 via recombination.

Many different backgrounds of pandemic H1N1 with H274Y have been reported, as was seen in seasonal H1N1. Moreover, the detection of H274Y has been in samples collected shortly after the start of Tamiflu treatment. In prophylactic cases, H274Y has been detected 5 or 6 six after the start if treatment, which is just 1-2 days longer than the 2-4 day incubation period for wild type H1N1. Similar, resistant H274Y has been found in patients infected with sensitive H1N1 after just two days of treatment.

The detections shortly after the start of treatment strongly suggest pandemic H1N1 with H274Y is transmitting, but as a minor species which is not detected in samples collected prior to treatment.
However, there is additional data supporting transmission of H274Y as the dominant species. One example was a traveler to Hong Kong from San Francisco. She had no Tamiflu treatment, but had H1N1 with H274Y, indicating the H1N1 was evolutionarily fit and transmiting.

Similarly, H1N1 with H274Y was transmitted for one family member who was treated with Tamiflu, to another family member who had no Tamiflu exposure. This cluster was also in Hong Kong, and the two cases are likely linked to an aggressive screening program in Hong Kong.

However, another example of transmission was seen in cabin mates in North Carolina. Although both were on prophylactic Tamiflu, the two patients developed symptoms four days apart and both isolates had the same rare polymorphism, in addition to H274Y, indicating one camper infected the other. Thus, examples of H274Y transmission are beginning to appear, as the reservoir of H274Y in pandemic H1N1 grows.

These increases are being reported daily. In the past week new cases were reported in Alberta, Canada, Australia, and Israel. These are in addition to recent cases in Hong Kong, Thailand, China, and Singapore. As these reservoirs grow there will be more examples of transmission as the dominant species, as happened in H1N1 seasonal flu.