There have been three reported oseltamivir (Tamiflu) resistant isolates of H1N1 swine flu (added: and now a fourth in Canada) but with those exceptions all others have been sensitive to this oral antiviral. This is in marked contrast to the other H1N1 strain, the seasonal variety which is almost entirely resistant. The spread of Tamiflu resistance in the seasonal strain happened with dramatic suddenness in the winter of 2007 - 2008 and came as an unhappy surprise. People assume that a rapidly mutating virus would inevitably become resistant, but based on several laboratory studies there were reasons to believe the mutation or mutations conferring resistance also made the virus less fit to replicate, infect host cells or cause disease. Moreover the resistance developed and spread very rapidly in areas where the virus was under little antiviral pressure. But the resultant H1N1 seasonal viruses transmitted readily and caused a typical influenza illness. It was a public health problem, but also in interesting scientific one. Now a clue may be emerging in findings just published in a Letter in Emerging Infectious Diseases from scientists in Luxembourg.
Several mutations in the neuraminidase (NA) gene can cause Tamiflu to lose its effectiveness at blocking the virus's ability to detach its replicated progeny after infecting a host cell (and thus preventing further infection of other cells), but by far the most common is one designated H274Y. The 274 part is the amino acid location along the protein, while the H and Y say that Y has been substituted for H at that location. H is an abbreviation for the amino acid histidine, while Y is the abbreviation for tyrosine. In other words, in a resistant H1N1 virus, there is a change at a single place along the long string of amino acid beads that make up the N1 protein and it occurs 274 places down the line, substituting a tyrosine from a histidine building block. That's a pretty small change but it's enough to interfere with the docking of the Tamiflu to the neuriminidase enzyme on the virus's surface and allow it to perform its detaching function. But is this change all that's involved? Apparently not.
NA is not the only protein made by the virus. Also on its surface is hemagglutinin (HA, one version of which, H1, gives H1N1 part of its name), which is involved in viral attachment to the host cell (and other functions) and 6 other gene segments, most internal to the virus and involved in replication and other functions. Could it be that the virus with mutant NA had other less visible mutations that somehow "mde up for" or corrected the lack of fitness found in resistant viruses with only H274Y? The scientists in Luxembourg compared sequences in all 8 gene segments in Tamiflu resistant versus sensitive H1N1s to see if there was another consistent change. They looked at 140 different isolates collected by Luxembourg's National Influenza Sentinel Surveillance System over the period when resistance emerged (December 2007 - March 2008). About a quarter of these isolates were Tamiflu resistant. They then searched for another genetic marker that accompanied H274Y but wasn't in H274 (the sensitive virus). No difference in most of the other genes -- PB1, polymerase A, hemagglutinin, nucleoprotein, matrix, nonstructural (NS) -- seemed to differentiate resistant from non-resistant. The exception was the PB2 gene, where a serine for proline change at position 453 (Pro453Ser) seemed to fit the bill. They looked at all published PB2 sequences to see if this was a common mutation and were able to find only three instances collected since 1918: one each in 1933, 1976 and 1988. The bottom line here is that these two genetic changes -- H274Y in NA and Pro453Ser -- are associated and seem to be related to the unexpected fitness of Tamiflu resistant seasonal H1N1.
Science is a slow process and fitting all the pieces together takes even more time. There are false starts and backtracks and sometimes things that seem significant are only side tracks or misinterpretations. Whether this finding is indeed true, and if true, how it works mechanistically we don't know. But it's a clue that might tell us something important about viral fitness and Tamiflu resistance. Could it affect the pandemic? Possibly, if the existence of Pro453Ser could be used as a marker or early warning of developing Tamiflu resistance. Another possibility, that it might provide information about a new therapeutic target, is probably too distant to have any application in the next year or two.
Science marches to its own rhythm.
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Love your blog -- I have linked to it from mine. Would you consider reciprocating?
Thanks
Marya
http://evimedgroup.blogspot.com
This is a familiar pattern BTW. Drug resistance mutations sometimes result in a loss of fitness. If one keeps the selection pressure on, eventuallly a compensatory mutation somewhere else restores the lost fitness.
Evolution is powerful force over longer time frames and predictive. It was predicted that a new flu pandemic would occur sooner or later. Here we are. It was predicted that Tamiflu resistance would occur. It is happening now.
OT but related.
We can get an idea of what will happen this winter by seeing what happens in the southern hemisphere which is now in their winter. The ICUs are full in New Zealand. Swine flu is off the radar for most Americans right now. That will change in a few months.
Hard to imagine what will happen in Third world countries like China , India, and Africa.
New Zealand has more than 26 Intensive Care UNITS (so even if the ICUs are small 26 people cannot be that high of a percentage). If 26 H1N1 ICU cases causes them to be full then there is a bigger story than H1N1.
Isn't the bigger story just that ICUs don't have much spare capacity, at any time?
I'm copyandpaste not Bloomberg. It says:
Intensive care units in some New Zealand hospitals are full
Some ICUs are full. You have to realize New Zealand is a big spread out island nation of 4.2 million people, not a point in space. Given the patchiness of the pandemic, some could be full while others are almost empty.
Not sure what stage of the pandemic they are in either. If it is just starting like their winter, it could be early.
Wait until it hits China with 1.3 billion people or third world countries that don't have ICUs in our sense of the word.
:) Thanks for the perspective Revere.
So... Relenza then, eh?
Raven: we're not at the start of our season. Southern Hemisphere spring starts in about 6 weeks. Dunno why this is such a common misunderstanding.
Complicating matters, though (and this is from my utterly non-expert observations) is that the out-of-season fitness of this particular loogie has been especially high. So we might get what is effectively a second-go-round, with strong out of season strength compounded by the much larger "crossover" effect with travel to/from the bigger reservoir that will exist in the north during your season. More flu up there may well translate to a summer "season" down here that is as bad as our regular winter one was. Which is pretty crazy. Maybe that's what you meant - if so, apologies.
On a slightly different issue, regarding how we handled it / are handling it (I'm in Australia): I should note that reports of surgery being cancelled are somewhat misinterpreted. It doesn't mean hospitals were full, but that beds were being freed up in case the pandemic got worse. We seem to be doing alright so far: no-one (AFAIK) died due to lack of hospital capacity. Sure, it reflects poor resorting (just like everywhere), but it's a smart use of the resources we do have.
So we're doing ok. If everything remains similar for the north this year, any country with a health system of similar strength to Australia should do ok.
The issues, then, are 1. northern countries with big populations who have worse healthcare than Australia (like China, India and - bafflingly, gobsmackingly - the US), and 2. changes in the virus (giving widespread Tamiflu resistance / generally higher rates of serious complications). We relied pretty heavily on Tamiflu to keep hospitals free for high-riskers, so if you lose even that then there's going to be trouble (even given the basically-placebo effect of Tamiflu given as late as a lot of ours was, it still keeps low-risk people at home). All the instances of resistance so far have occurred in the North - even out of season it's a bigger reservoir, and if we see serious upgrades to this little bugger, it's going to happen up there.
So, I guess 3. the inevitable Big Bastard that has to happen eventually (next year being a reasonable candidate), for which we are still woefully unprepared. We're doing ok this time, but only barely. The Reveres' position on public health is one I wholeheartedly agree with, and the situation gives me nightmares.
This is a joke right?
I'm sick of posting about H274Y and Tamiflu and you treat it like a recent "eureka" moment in science as if the flaws haven't been published in journals for a decade.
It might have seemed like a no-brainer to pick the Tamiflu pill over the Relenza puffer, and that's what it was, because further manufacture, and research and development, in resistance proofed zanamivir was dumped.
So "just in time" public health thinking has left us scrabbling for the "second best" treatment rescued from the waste bin.
I got the chance to try Relenza for myself recently. I'm a GP treating lots of "walk ins", acutely unwell people, and I've had dozens of patients with confirmed H1N1. It was only a matter of time. I started getting a sore throat, runny nose, then aches and pains, nausea, mild confusion and a sweaty fever, increasing VERY quickly over a few hours. 6 hours after symptoms started, when I knew that this was it, I started Relenza. I'm a mild asthmatic, but knowing that this caution over Relenza is probably anecdotal and against the evidence it didn't worry me. (In one treatment study involving 525 patients with asthma or chronic obstructive pulmonary disease, zanamivir recipients had a small but significantly increased mean morning peak expiratory flow rate (PEFR))
from http://tinyurl.com/kqeeut
Indeed, all symptoms abated very rapidly (within hours) including the systemic effects. It's unlikely that most people will get access to treatment within hours, but if you catch it early, antiviral treatment is marvellous. No nausea either with Relenza. I could have spent a week in bed, instead I was fine.
Hey Dank
Interesting post. Do you still post at HC.!! I miss your input.
Miso: If you read the post you will see it is about the molecular biology of this mutation. Try not to get your Tamiflu obsession in the way of your reading comprehension. I've given you plenty of space to talk about promoting Relenza and your claims about how the marketing has been mismanagement or is the result of a conspiracy. You may be correct about that; I'm not saying they aren't. But we write here about what we want to write about and at some point it may be about what you want us to write about. Yesterday wasn't that day.
Revere
I can't wait for that day. We have a great story to tell. ''The greed of big business vs public health''
CPG
Revere et al: Question: In H5N1 high doses of Tamiflu seemed to be effective even in presence of resistence. Will higher doses of Tamiflu or combining it with other antiviral agents that are completely useless by themselves work or be of any utility?
The entire western world has based their respective pandemic response plans on having tamiflu. Modeling shows that NPIs such as school closure layered with isolation and home quarantine and social distancing will drop the Ro by 15-20% but you need an effective antiviral added to drop the Ro close to one.
BostonDoc: I haven't seen data about H5N1 resistant strains beins susceptible to higher doeses (not sahying it isn't true, but haven't seen the data, that's all; anecdotally, perhaps). Regarding the right dose of Tamiflu in general, I think that's an ongoing question and some trials are going on I think using double doses. Then there's Relenza which still seems effective even for Tamiflu resistant strains, and many places are also stockpiling that drug. In the bigger picture, this is therapy, not prevention. I have doubts as to whether antivirals will make much difference in the epidemic curve but they are likely useful for treatment once you are a point on the curve.
revere,
I saw the "new" slant you used, on the "old" news, to cover your decade long blind spot.
"Tamiflu obsession" that's rich considering the reveres have insisted that all NIs were identical except Relenza would asphyxiate you "because it's a lung dust" and all antivirals develop resistance anyway. Or more recently, Tamiflu is a cash cow and researches everything, Relenza has no research funding,.... so Tamiflu is best for a baby in the womb. No-brainer.
Health professionals followed YOU to this place, not me, I had a logical science background, reading comprehension of science journals, and a conviction that I should nag in my considerable free time (when I used to think there was hope ).
How could I comprehend your stuff, half way down your posts I'm distracted by the dyslexia, Z-A-N-A=M-I-V-I-R, once you can spell it you might even look it up yourself.
I hear vaccines are the next Tamiflu, I'm sure my new obsession will be at odds with yours, unless you agree with me that Aesope's Fable was make believe, and the virus rarely falls asleep waiting for a vaccine to catch up and beat it.
P.S. I.V. peramivir is trying to overcome H274Y resistance by using higher concentration during trials. First 100mg, then steps up to 600mg. Biocryst still hasn't announced a trial with results that confirm peramivir beats H274Y, just "we are as good as Tamiflu".
http://www.learningmarkets.com/index.php/200907223214/News-Feed/News-Fe…
Tamiflu is loosing market share so they are bumping concentrate of Tamiflu( do they need trials to assess adverse reactions to higher concentrations?....I think not. We're Tamiflu. We Rule. (sing along revere). Lets market to fat people and little babies, and tell them two packets are better than one.
This is where I "obsess" and mention GSK's I.V. zanamivir has no resistance but GSK decided not to compete with GSK vaccines, so GSK i.v.Relenza trials stopped, GSK/ S.E.Asian Research Network trials had no IND or zanamivir, and finally S.E.Asian Research Network trials might get some zanamivir/Relenza soon and have the first results in a year, after five years pumping out Tamiflu trials, of getting WHO to do it for a nudge and a wink.
And i.v. peramivir is advertising what they haven't got yet, and i.v. zanamivir has it all except it hasn't attracted GSK's attention from vaccines to complete trials (or fail) so peramivir will be our next injectable version of Tamiflu. And I'm still waiting for trial results of individual titre volume reduction and not just average figure success against H274Y sprinkled influenza A trials.Wouldn't it be the first thing you'd announce?
Miso, once you start gleefully leaping atop typies, you've lost the argument. Give it up.
We're all well aware of Tamilfu resistance. Now (s)he is discussing the science behind it. Not: ZOMG Tamiflu resistance!!@!. Rather: look at this interesting stuff behind a well know effect.
Read. Comprehend. Chill.
So I read it, and made notes until I realised the point of this post is all about saving Tamiflu (and peramivir) and less about saving lives. Instead of moving on to a H274Y indifferent antiviral, the name of which is on the tip of my tongue, this post discusses a way of fixing H274Y .i.e. rebuild Tamiflu and reveres dignity.
"People assume that a rapidly mutating virus would inevitably become resistant"
revere has said this. It's based on the theory that it's the waters fault if it escapes a hole in the bucket. An excuse for hanging on to Tamiflu sales which sucks the marrow out of better alternative antivirals research funds.
"based on several laboratory studies there were reasons to believe the mutation or mutations conferring resistance also made the virus less fit to replicate, infect host cells or cause disease."
This fingers-crossed science method in the U.S.saved Tamiflu at least three years of resistance research so they could be fast tracked through FDA and in the shops with Relenza at the same time. Conveniently for Gilead, Relenza resistance research results must have been assumed to be general for all NI antivirals. If the proper research had been done Gilead would have lost millions and look for something better than Tamiflu, assuming they weren't bankrupted (the way Biota was for not locking up their pioneering research. The only smart thing Biota did was good science, taking their pick of the most salicylic acid like molecule to use against influenza A , Gilead got second best but didn't care as long as it would work as a pill.
I forget, was it snakeoil or carpetbaggers that were born in the U.S.of A?
I'll just keep posting and if I'm forced to repeat myself (see all the discussion above) you can find most of the original sources I've wasted my time posting here over the years, but I appreciate effectmeasure has not deleted it.
Jeez, miso. If that's how you read it, I can't help you. I don't give a rat's ass about Tamiflu other than it's something related to flu and people are interested in it and so am I. I don't delete your comments as long as they provide something and are more or less civil. There is a tradition of strong argument here and often I don't mince words and I allow others more or less the same leeway. But it's not about my dignity (I lost that long ago). I'm worried about doing the best I can and I can make mistakes and when I do I try to correct them. Meanwhile we write about what we want to write about, not necessarily about what you wish we'd write about. But you are free to start your own down-with-Tamiflu blog where your time won't be wasted. It's easy. Go to blogger.com and follow the directions. We reveres have our own blog, here. It's a big internet. There's room for you in it, too.
revere,
I think I'm going to have to branch my research to include the effects of sibutramine combined with late night posting and influenza associated stress(but I won't be posting further on the subject here).
26 Luxembourg sequences are available at genbank now.
Counting amino acids at 453(segment 1) and 275(segment 6)
for all human genbank H1N1 since 2007
gives:
HH:300 (2007)
HY:1 ()
PH:70 (Managua(24),Luxembourg(14),Boston(5),Japan,2007)
PY:6 (England(1),Managua(2),Naypyitaw(3))
SY:25 (Luxembourg(14),Managua(4),
Shanghai,Yangoon,Boston,Denmark,England)
SH:494 (mexflu)
SY:3 (mexflu)
it could be normal evolution, that the 2 changes
first happened together and then were maintained
together - just coincidence, no connection
of the two induced virus-properties ?!