Scott McPherson's Web Presence

My first read every morning when I sit in front of the computer is www.recombinomics.com, the Website run by Dr. Henry Niman.  Dr. Niman has some very interesting information regarding the H274Y Tamiflu-resistant mutation that is the subject of an increasing number of media reports over the past few days.  Even the New York Times and AP have picked up on the Helen Branswell/Canadian Press story of this week.

Here's what is peculiar:  Normally, you would expect Tamiflu-resistant H1N1 influenza to show up in areas where Tamiflu is prescribed.  But that is not the case here!  There are no known cases of H1N1 with the H274Y mutation in Japan, where Tamiflu is habitually overprescribed; and 70% of H1N1 is showing Tamiflu resistance in distant Norway, where Tamiflu is rarely, if ever, prescribed.  Quite a conundrum.

Dr. Niman believes that Tamiflu-resistant H1N1 with the H274Y mutation has already been detected in these US isolates:

ISDN282211  A/Hawaii/21/2007  H1N1  
ISDN282224  A/Hawaii/28/2007  H1N1  
ISDN282222  A/Hawaii/28/2007  H1N1  
CY027037      A/Kansas/UR06-0104/2007  H1N1  
ISDN282240  A/Minnesota/23/2007  H1N1  
ISDN263890  A/Texas/31/2007  H1N1 

According to Dr. Niman,

The above comments describe the appearance of the oseltamivir resistance marker, H274Y, in recent H1N1 isolates in Europe. 

However, a search of public sequences identifies H274Y suddenly appearing in 2007 H1N1 isolates from the United States (see list below.  The number of complete human influenza sequences has grown steadily, largely because of the NIAID influenza sequencing project.  At the Los Alamos sequence database, there are 1030 N1 sequences from H1N1 human isolates.  340 are from 2007 and all of the sequences below are from 2007.  Thus, although the percentage of samples was low, all were from 2007 and all were Solomon Island-like.

In the United States the change was in the Solomon Islands variant, which links back to Asia, where the identical change has been seen in H5N1 from patients treated with Tamiflu, as well as birds, including wild birds in Astrakhan in 2005.

These Solomon-Island lake sequences trace back to Asia, where Tamiflu blankets are frequently applied in the treatment of H5N1.  The N1 in H5N1 has donor sequences for human N1 in the region adjacent to the acquisition which generates H274Y, which is the precise change found in the most common form of oseltamivir resistance in H5N1 patients, primarily in Vietnam.

The two complete commentaries from Dr. Niman can be found at:

http://www.recombinomics.com/News/01290802/H1N1_Tamiflu_US.html

http://www.recombinomics.com/News/01300804/H1N1_H274Y_H5N1.html

Remember that the "A" refers to Influenza A, next comes the location where the virus was first typed, then the lab number, then the year, and then the subtype. 

Now, over at FluTrackers, the forum is as lively as ever.  And speculation centers around the actual inner workings of Tamiflu itself.  I am treading dangerously close to incompetence if I speculate any further, having reached the edge of my envelope on the surface properties of N1 vs. N2 subtypes of neuranimidase and their susceptibility to Tamiflu versus Relenza.  So I will simply give you the link and let you follow the bouncing ball:

http://www.flutrackers.com/forum/showthread.php?t=51648

So what does this mean?  It means that Tamiflu is still the #1 arrow in the quiver against pandemic flu.  It also means the people who make Relenza can rejoice somewhat, because it ups the ante for buying their product. 

But the deeper meaning is this: After years and years of use, the sudden appearance of this genetic marker in seasonal H1N1 has to be the result of a relatively recent series of developments.   Tamiflu resistance had to be acquired by H1N1.  The most likely place for it to have done so is in Asia, or Egypt.  Or both: There are compelling arguments for both, as we see geographically distinct Hawaii, Kansas and Minnesota isolates showing the mutation.  And talk about geographically distinct!  Again, from Branswell's story:

Eight of 81 H1N1 viruses tested carry the H274Y mutation - one each from British Columbia and Newfoundland and Labrador, and six from Ontario. Plummer said that total includes one virus (from British Columbia) recovered from a child who is believed to have been infected in Sudan.

That means this mutation is all over the place!  It could have come from anywhere.  But it is appropriate to zero in on the areas where Tamiflu resistance is most likely to be manufactured:  Wherever a Tamiflu blanket has been applied to try and quell an H5N1 outbreak.  Dr. Niman makes a compelling argument that these Tamiflu blankets may have spawned this mutation.

The theory is that H5N1 segments recombined with H1N1 seasonal flu to produce a new, Tamiflu-resistant substrain of H1N1.  Also keep in mind that the Southeast Asian strain of H5N1 is of a different clade (Fujian) than the Egyptian strain (Qinghai), so Tamiflu resistance would either have been conferred before the subtype split into two distinct clades (sometime in early 2005?), or they independently mutated with simultaneous Tamiflu resistance.  This "parallel development" theory is entirely plausible. 

But what if H1N1 was not the only virus that changed?  If H1N1 and H5N1 can get together this way, have they already gotten together before and spawned a mild H5N1 that is easily passed off as seasonal flu?  Again, Niman postulates that in Southeast Asia and in Egypt, there may be a mild form of H5N1 that is beginning to spread.  Now before we rejoice at the thought of a mild, nonlethal reassortant/recombinant H5N1, recall that in 1918, the second pandemic wave -- not the first wave -- was the murderer.  The first wave was passed off as normal, seasonal influenza.  Experts said, "No biggie; nothing to see here, folks." 

Of course, today's typing and surveillance is so much better, right?

If you say "Yes," then you didn't read my blog of yesterday.  Go get it: http://www.scottmcpherson.net/journal/2008/1/30/no-magic-bullets-to-fight-panflu.html

From today's AP story:

Drug-Resistant Flu Is Found in Europe

By MARIA CHENG

LONDON (AP) — A small number of flu viruses resistant to Tamiflu, a top antiviral drug, have been detected in Europe, health authorities said this week.

Data from more than a dozen European countries show that Tamiflu doesn't work in about 13 percent of H1N1 viruses, the main flu strain causing illness this year. Normally, resistance levels are well below 1 percent.

"It's an unexpected finding and a signal worth watching," said Fred Hayden, a flu expert at the World Health Organization. The resistant strains most likely emerged elsewhere, but were first identified in Europe.

The strain is resistant because of a single mutation. It doesn't cause more serious disease than regular strains, and can be treated with other antivirals. But experts are worried that if the resistance becomes widespread, Tamiflu, one of the best tools for fighting flu, might become useless.

"If I had only a single drug to choose for influenza, oseltamivir (Tamiflu) is the one I would go for," said Dr. Angus Nicoll, influenza coordinator for the European Centre for Disease Prevention and Control. Tamiflu, made by Roche Holding AG, has been stockpiled by WHO and by countries around the world for possible use in a flu pandemic.

But the resistant H1N1 strains do not mean that H5N1, the bird flu many experts fear could spark a flu pandemic, will develop similar resistance.

"The chance of this happening in an H5N1 virus is not zero, but probably very rare," said Dr. Joseph Bresee, chief of epidemiology and prevention at the United States' Centers for Disease Control and Prevention. At least two Tamiflu-resistant H5N1 strains have been found in Asia in the last few years.

Experts said that relying exclusively on Tamiflu is unwise. "This is a very good reminder that we don't know what the next pandemic strain will be sensitive to," Nicoll said. "Perhaps we should have more mixed antiviral stockpiles."

At the moment, health authorities are scrambling to find out how prevalent the resistant strain is worldwide. The highest levels have been found in Norway, where nearly 70 percent of tested strains have been resistant.

Resistance varies across Europe, with Italy reporting no resistant strains, and Britain, France and Denmark all reporting low but significant percentages.

In the United States, nearly 3 percent of tested flu samples have been resistant. "We don't know right now if this is a trend on the upswing or just a small blip," Bresee said.

Laboratories worldwide are also sequencing the mutated virus to try to determine where it came from and how it developed. Usually, resistant strains arise in people who have been treated with the drug. But that's not the case here.

In Norway, none of the viruses were from people who had been treated with Tamiflu. And in Japan, where Tamiflu use is the highest in the world, no resistant viruses have been reported this year. Investigations are ongoing in other countries.

Until now, experts had also believed that if viruses developed resistance, they would be less transmissible. "That assumption appears to have been incorrect," Hayden said.

As the flu season has only just started in Europe and North America, experts will be anxiously monitoring any further spread of the resistant H1N1 strains.

None of the other circulating human flu strains have so far been found to be resistant. Public health agencies say their recommendations on Tamiflu use remain unchanged.

It's still too early to know for sure what this means," Nicoll said. "But watch this space." (bold all mine)