Commentary
Recombinomics Commentary 18:26
July 3, 2009
The patient, who was admitted to Queen Mary Hospital for isolation, tested positive for the new H1N1 flu strain and opted not to take Tamiflu, Hong Kong's health department said. She had mild symptoms and was discharged upon recovery on June 18.
"The key point is whether the strains will become dominant and then we will have a problem," he said. "At this moment, I don't think there is cause for alarm. There is certainly cause for heightened surveillance."
"Constant, random mutation is the survival mechanism of the microbial world," WHO Director-General Margaret Chan said in an address to a meeting on the flu pandemic in Cancun, Mexico, yesterday. "Like all influenza viruses, H1N1 has the advantage of surprise on its side."
Studies have shown that Tamiflu-resistant bugs develop in 0.4 percent to 4 percent of adults and children treated for seasonal influenza, Claudia Schmitt, a spokeswoman at Roche, said by phone from Basel today.
The above comments on the emergence of H274Y and associated oseltamivir (Tamiflu) resistance clearly show that lessons were not learned from the spread of H274Y in seasonal flu (limited to H1N1). The spread of H274Y in seasonal flu destroyed the old paradigm of influenza evolution by selection of "random mutations", but as seen above, WHO is still citing that mechanism to try to explain the emergence of H274Y in pandemic H1N1 in Denmark, Japan, Hong Kong, and San Francisco.
Roche is still citing old data on the emergence of resistance in Japan years ago, when children were treated with sub-optical doses. That data provided a classical example of resistance, which was linked to the sub-optimal dosing, as well as mutations in H1N1 and H3N2 at multiple locations within each sero-type. However, those changes were only viable in the presence of Tamiflu, which killed off the competing wild type strains.
I
n 2005 when resistance developed in treated patients or contacts infected with H5N1 the same assurances on lack of fitness and failure to spread were offered. The first example was a patient on a prophylactic dose because her brother was a confirmed case. She developed an infection, but responded to a therapeutic dose, even though H5N1 with H274Y as well as N296S was identified in sub-clones from the patient.
Although the spread of resistant H5N1 in patients was not reported, the appearance of H274Y in H1N1 in wild birds later that year was cause for concern. The wild birds in Russia were not given oseltamivir, yet H5N1 was isolated from dead birds indicating H5N1 with H274Y was evolutionarily fit, leading to transmission between birds and fatal infections.
Concerns of H274Y were increased the following year when it was reported in seasonal flu in China. The clade 2C (Hong Kong strain) with H274Y was found in patients who were not taking Tamiflu, again showing that evolutionarily fit could transmit to humans who were not taking Tamiflu.
The following season (2006/2007), H274Y jumped to another H1N1 sub-clade (clade 1 - New Caledonia strain) in the United States and United Kingdom. The multiple sub-clades within clade 1 signaled multiple introductions into patients not taking Tamiflu.
The following season (2007/2008), H274Y jumped again. Initial cases in the United States were in Hawaii were clade 2B (Brisbane strain), but did not spread. However, the H274Y jumped onto another clade 2B sub-clade which did spread in the United States and Europe. This sub-clade was initially reported in Norway in early 2008, but had been silently spreading throughout the fall.
In the summer of 2008 the H274Y in combination with HA A193T emerged, which then led to the fixing of H274Y at levels approaching 100% of H1N1. The A193T, as well as several additional polymorphisms had been co-circulating on clade 2C. The acquisition of these polymorphisms, including three consecutive polymorphisms in NA signaled recombination, because the NA polymorphisms were not only consecutive, but included a synonymous change, which offered no obvious selection pressure.
Thus, the data was inconsistent with a "random mutation" mechanism. The key changes were co-circulating on a related sub-clade, and were appended onto a clade 2B backbone. The H274Y jumped from background to background in patients who were not taking Tamiflu. This spread of H274Y via recombination and genetic hitchhiking did not require de novo mutations. The key polymorphisms were already circulating in clade 2C, and had earlier been found in other H1N1 or H1N2 isolates.
The mechanism of evolution raised serious concerns when swine H1N1 acquire efficient transmission in humans. This transmission offered the opportunity of genetic exchanges between human seasonal H1N1 and swine H1N1 which was now also in humans. Dual infections would allow for H274Y jumping form seasonal flu to pandemic flu in patients infected with both viruses.
Thus, the detection of H274Y in Denmark this week was not a surprised. However, since the patient had been on a prophylactic dose of oseltamivir, the random mutation paradigm was used to explain the data and offer assurances that the resistance wouldn't spread. However, the appearance of H274Y in the treated patient raised concerns that H274Y was lurking in a minor sub-population that was missing in sequencing of untreated patients, and was detected only in treated patients.
The data from Denmark was repeated in Japan this week, when another patient being treated with a prophylactic dose of oseltamivir also gave rise to the detection of H274Y. However, the appearance of H274Y in the absence of other resistance changes raised concerns that H274Y had already been acquired via recombination and was silently spreading in association with wild type H1N1.
The concerns were increased by the announcement in Hong Kong at a traveler from San Francisco, who was not taking Tamiflu was harboring a resisitant sequence, which was almost certainly H274Y. The presence of resistance in a patient not taking Tamiflu indicated the pandemic H1N1 with H274Y was evolutionarily fit and not only was in Hong Kong, but was also in San Francisco, the origin of the traveler.
However, H274Y has not been reported in the United States, raising serious surveillance concerns. Most efforts are directed to hospitalized serious cases, and state across the country announced that they were no longer testing mild cases. However, the Hong Kong, ex-San Francisco case was mild, which may explain the lack of detection.
However, of greater concern is the ability of H274Y to jump from one background to another in the absence of oseltamivir selection.
However, statements above indicate the lesson from seasonal flu was not learned, and the old discredited random mutation explain is once again offered, along with assurances that the H274Y will not spread (even after it has been found or implied on three continents).
Increased surveillance will demonstrate not only that H274Y can spread, but that it has already spread, under the radar of the current surveillance system. Moreover, the reliance of the old "random mutation" paradigm will lead to more "surprises" but those who adhere to an paradigm which is inconsistent with the sequence data.
An increase in surveillance and sequencing will allow for more accurate products of future acquisitions, which are due to recombination and not due to de novo mutations, as repeated again and again by those who ignore the data, or quote those who ignore the data.
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