There's been a bit of a buzz about a paper by Australian researcher Jennifer McKimm-Breschkin at the Toronto flu meetings last week. McKimm-Breschkin told the gathering of 1500 flu obsessed scientists just what they didn't want to hear: that she and her colleagues had evidence from the laboratory that clade 2 H5N1 avian influenza virus isolated from birds in Indonesia were becoming resistant to the only oral antiviral effective against the virus, oseltamivir (Tamiflu). In comparison to clade 1 (southeast asian) virus from a few years back, the sensitivity was 20 to 30 times less.
We'll have to await more details of the study, but there are a number of caveats worth keeping in mind. Susceptibility as tested in the laboratory is not the same as clinical effectiveness or lack of effectiveness because the virus may be either less fit genetically, less virulent or less transmissible. These are matters of whole animal biology, not activity in a cell culture. As usual, Helen Branswell's reporting has the relevant cautions as well as the news of the report:
"With a disease like H5N1, there are a lot of factors that impact on whether treatment will control replication and give benefit to the patient," said Dr. Frederick Hayden, an antiviral expert working with the World Health Organization.
For instance, Hayden noted that if a virus with reduced susceptibility replicates less well in an infected person, it might be easier to treat than a virus that replicates rapidly and with ease.
"One can't only look at the susceptibility. One also has to look at the fitness of the virus, the pathogenicity (virulence) of the virus," said Dr. David Reddy, pandemic task force leader for Hoffman-La Roche, the maker of Tamiflu. (Helen Branswell, Canadian Press)
It's not surprising Roche, the maker of Tamiflu, would urge caution. After all, government orders to stockpile Tamiflu have been profitable for them. But Reddy's remarks are also correct. So we'll have to see. Here's some more of Branswell's excellent story for readers wanting more background:
The Eurasian H5N1 viruses are broken down into three groups or clades, each with its own molecular characteristics. They can be thought of like a large extended family with several branches. Some characteristics are shared across all branches, others are specific to a branch.
The clade 2 viruses are further divided into three subgroups. Indonesian viruses are classified as clade 2.1.
Scientists have wondered if the molecular variations between the clades and sub-clades translate into differences in attack rates or disease severity in people who become infected, looking for ways to explain why, for example, 80 of 100 cases in Indonesia have died while in Egypt only 15 of 36 cases have died. (Viruses in Egypt belong to a different subgrouping of clade 2 than those in Indonesia).
A lot is packed into six sentences. That's just good science reporting and it's not easy to do.
Back to Tamiflu resistant virus. I can't tell from the news reports it there is any information on how widespread these resistance mutations are. That would provide some indication of how fit the resistant viruses are. But the set of posts I did on modeling antiaviral resistance by Lipsitch et al. indicated that even extremely rare but genetically fit resistance mutants would eventually predominate, although in every scenario use of antivirals for prophylaxis and treatment wins over not using them:
Important predictions that we believe to be robust to model structure are that (1) antiviral use will favor the spread of resistance even if such use rarely generates de novo [spontaneously arising] resistant strains; (2) despite the spread of resistance, prophylaxis and treatment can both delay and reduce the size of the epidemic; (3) nondrug interventions (if effective) and antiviral use - which will likely be used together in the response to a pandemic - generally have synergistic benefits, despite the fact that nondrug interventions may promote resistance; and (4) relatively minor differences in fitness cost may make large differences in outcomes, even when emergence probabilities are low.
[snip]
Optimism about the benefits of antivirals in an influenza pandemic should be tempered by the knowledge that transmissible, pathogenic resistant strains are a real possibility and could reduce the benefits of antiviral use in pandemic control. Successful implementation of nondrug interventions to control resistance will, in most circumstances, amplify the benefits of antiviral use in controlling the pandemic, although such interventions may increase the proportion of resistant cases. Because the impact of resistance is relatively insensitive to the rate at which resistant strains emerge de novo in antiviral recipients, efforts to control influenza transmission overall may be of greater benefit than efforts to reduce the de novo rate of emergence of resistance. Despite these caveats, we do not believe that concerns about resistance should preclude the widespread deployment of antivirals as part of the response to a pandemic. If these drugs, used prophylactically or for treatment, are effective in reducing transmission of the next pandemic strain, they should provide benefits by reducing the number of infected patients and delaying transmission, even if resistant strains ultimately become widespread.(Lipsitch et al., Antiviral Resistance and the Control of Pandemic Influenza)
The results and conclusion of Lipsitch et al. are not specific to Tamiflu. They are equally valid for any antiviral that can be used for prophylaxis and treatment, such as GlaxoSmithKline's Relenza (zanamivir). Virus that is resistant to one of these neuraminidase inhibitors is not necessarily resistant to the other, although it could be resistant to both. So stockpiling more than one might be a partial hedge against resistance. But Relenza has to be administered with a special inhalor while Tamiflu is a tablet, so there are important differences in the logistics of mass prophylaxis. Moreover there is far less Relenza available than Tamiflu.
We need more antivirals with different targets and this is an active area of research and development. Whether any of it will pan out in time to make a meaningful contribution to treatment in a pandemic is unknown. But one important aspect of Lipsitch et al.'s work needs to be emphasized: there is a synergy between antiviral use and the non-pharmaceutical interventions made possible by an effective and functioning public health and social service infrastructure.
It's not just pills. Even when the pills work.
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"Susceptibility as tested in the laboratory is not the same as clinical effectiveness or lack of effectiveness..."
'They' decided to put all of their eggs...and I mean all...in two baskets in 2005, when public attention demanded a response of some kind...and expedient is always bes, at least in the short term.
...and since then, there has been an awful lot of 'dancing on the head of a pin'...to rationalize significant shortcomings of both technologies in field applications....and of course, 'they' are not good at changing direction or admitting mistakes.
If the Indonesian clade is in fact considerably more resistant than the other clades, that seems surprising. We haven't been using Tamiflu widely -particularly in birds, so we aren't directly creating evolutionary pressure. So it seems like Tamiflu resistance may vary widely, as a side effect of other changes in the virus.
bigTom: It's a subclade, apparently, but we need to see the paper and the methods. It isn't at all clear how widespread this is. Presumably this is a spontaneous mutation, not one that has persisted because of antiviral pressure.
Revere,
THANKS for all the explaining you do.
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gilmore: My pleasure. Thank you for the comment. One of the few rewards of an anonymous blog is positive feedback. I don't always have time to acknowledge it but it is always appreciated.
If I had an expensive bird and I was given tanmiflu would I be tempted to give the bird some of it ? Just a little bit say 1/20th of a tablet?
Or maybe one tablet in the feed of 100 chickens each day.
NO. I wouldnt do that even to save my family's only source of income.
Darwin: Yes, but remember antivirals don't cause the mutations. They only play a part in selecting for them. Resistance to adamantanes has spread very fast and quickly in seasonal flu in the US despite the fact these drugs are rarely used here. It is likely the mutations are hitchhiking or co-riding with other genetic changes that confer a selective advantage. So it isn't at all necessary to invoke oseltamivir use in birds as an explanation.
Revere:
Very true but adamantanes are / were used in other countries in large quantities.
But the bigger question is do virus's pick up just bits of other virus's? I thought they only swapped one (or more) of the eight genes and not bits and peaces. If what you are saying is true, I should worry a lot more about H5N1 than I have been.
Damn. Now I have to get my preps up to 6 months instead of two weeks. Glad I bought those statins though.
By the way I really like your writing stile. Its clear, concise, and amusing.
PS. I also have a green 1992 Volvo 960. Only 129,000 miles. Brand new compressor. Great price for a wonderful car.
REVERE WROTE: "My pleasure. Thank you for the comment. One of the few rewards of an anonymous blog is positive feedback. I don't always have time to acknowledge it but it is always appreciated."
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You may not always have time to acknowledge it, but know more importantly that we your faithful readers don't always take the time to say it. You are teachers of the highest caliber, taking precious time to enlighten.
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That is all
Darwin: There are three potential driving mechanisms for genetic variation: mutations at specific spots on the RNA from improper copying or other replication error; exchange of "internal" pieces of one segment with another (non homologous recombination) either of the same virus or a co-infecting one or the same "parallel" segment of a co-infecting virus (homologous recombination); or swapping of a whole segment of one virus with a co-infecting segment from another (flu) virus (reassortment). There is some contentious disagreement about recombination, which some say doesn't happen with negative sense RNA viruses like this and others say is the main mechanism in flu virus. I don't want to get into that argument. But the first mechanism, a change in the sequence that occurs when the virus replicates, is the presumed way that resistance mutations occur. I'll let others argue about how they are spread.
It is unlikely that adamantane resistance in US seasonal flu virus is due to selective pressure from the use of these drugs. But we don't need selective pressure to account for it, either.
My 1995 dk grn Volvo 940 has 90K on it. It is a piece of crap but I can't afford another car at the moment so I'll keep driving that shit box until it won't go any more. At least those are my plans. Mrs. R. is urging me to get another car but I am resisting. All I want is something to get me from point A to point B and so far it is doing that. But it looks like hell. YMMV.
If this is a spontaneous mutation towards antiviral resistance, could it swing back. . . or once the cat is out of the bag (adamantanes) the resistance will always stay???
gilmore: In theory it could go in any direction, but in reality it depends on the interaction of that genetic change with others, the environment and the host. We don't know the main elements of that interaction at the moment or whether the resistance mutation has its won or is linked to some other selective advantage or increase in genetic fitness. One of the reasons providing sequence data isn't enough and we need the viral isolates is that there is still a large gap between the sequence information and the biology.
"So it isn't at all necessary to invoke oseltamivir use in birds as an explanation"
The Tamiflu Blanket in third world countries always an inherent flaw built in...who controlled the Tamiflu and how freely it was dispensed.
Some farmers and pet owners value their prized animals above all else...I fully expect that Tamiflu has been fed to prized poultry ever since the blanket was imposed several months ago...
...and that is the problem with the Tamiflu Blanket...short term gain...medium term pain.
Also, I guess another issue would be what happens to the tamiflu if it is excreted unaffected in populated areas with concurrent populations of mice and rats and cats etc.
Can you have resistance as a result of random mutations...yes...but I don't think that is the case here or in North America...it goes down as one more unknown in relation to influenza.
There is no better way to get resistance to Tamiflu then by feeding Tamiflu directly to poultry...and I have absolutely no doubt that this has been happening in Indonesia and China.
In my opinion, the Tamiflu Blanket was always going to hasten the onset of pandemic potential viruses...several at once.
The best way to get mutations to a treatment is to use a non-therapeutic (low) dose or to use a treatment that is only partially effective...I think Tamiflu clearly falls into the 'partially effective' group ensuring resistance as soon as it is used to treat H5N1.
McKimm-Breschkin was careful to say that these mutations were spontaneous and not the result of selective pressure from inappropriate drug use. Intriguingly and defying a commonly observed pattern, the resistance gain appears to be "low cost" - it does not make the virus any less fit. FWIW a second paper detailed mutations in Philippine H1N1s that would potentially decrease the effectiveness of zanamivir and peramivir. Those very clearly make the case that mutation can be spontaneous and not driven by drug pressure, since zanamivir isn't sold in the Philippines and peramivir is still in trials.
maryn.
If resistance can occur that easily spontaneously, things do not look good for the effectiveness of Tamiflu...of course resistance in Japan indicated that things didn't look good for Tamiflu before the WHO directed everyone to stockpile it.
If these are spontaneous mutations then there has to be an evolutionary advantage that has maintained them instead of strains that are not resistant...
...doesn't quite make sense...but then alot about influenza doesn't quite make sense.
Who is to say that the mutation did occur do to pressure elsewhere and travel to the third country...that seems more likely to me...there are lots of potential vectors for this...and if this is the case, influenza travels alot easier then we had previously considered.
Re: point 3: why would nondrug interventions promote resistance? I would think they'd be rather neutral, neither promoting nor discouraging resistance.
And, thank you for explaining that the resistance doesn't indicate a particular virus subclade has been exposed to Tamiflu... my first thought was that birds had caught viruses from humans, and I figured that couldn't be good.
caia: The NPI promoting resistance appeared in the modeling but it makes sense. What is necessary for resistance to develop and spread is time and that is what NPI does, spreads out the epidemic curve. There are more details buried somewhere in the 16 posts I did on the Lipsitch et al. paper.
Ah! I see, thanks. :)
maryn.
If resistance can occur that easily spontaneously, things do not look good for the effectiveness of Tamiflu...of course resistance in Japan indicated that things didn't look good for Tamiflu before the WHO directed everyone to stockpile it.
If these are spontaneous mutations then there has to be an evolutionary advantage that has maintained them instead of strains that are not resistant...
...doesn't quite make sense...but then alot about influenza doesn't quite make sense.
Who is to say that the mutation did occur do to pressure elsewhere and travel to the third country...that seems more likely to me...there are lots of potential vectors for this...and if this is the case, influenza travels alot easier then we had previously considered.