If there's an influenza pandemic in the near future all bets are off when it comes to unplanned for consequences. Well, maybe not all bets. Right now the only oral antiviral likely to have any effectiveness in a pandemic is oseltamivir (Tamiflu), although how effective and how long it would retain any effectiveness is in question. But there's a lot of it out there and it will be taken in high volume and, either in its capsule form [oseltamivir ethylester-phosphate (OE-P)] or its active form [oseltamivir carboxylate (OC)], excreted into the sewer system in massive quantities (discussed here and here in previous posts). The UK has already stockpiled almost 15 million courses of treatment (10 capsules), amounting to 11 metric tons of OE-P. In a pandemic almost all of this could be used in a 9 to 12 week period. There is little biotransformation of either OE-P or OC in sewage treatment plants and it doesn't cling to sewage sludge, where it could be segregated. Instead both are highly soluble in water. Hence they will make their way readily into the aquatic environment, even after sewage treatment. Could the presence of Tamiflu in coastal or riverine waters contribute to antiviral resistance in aquatic waterfowl who are reservoirs of various influenza virus subtypes, including those like H5N1 that are potential pandemic viruses?
Andrew Singer at the Centre for Ecology and Hydrology in the Oxford raised the issue in 2006 and now he and 39 other scientists have reported on a workshop they held in October 2007 on "Tamiflu and the Environment: Implications of Use under Pandemic Conditions." Not unexpectedly there were more questions than answers. In particular the ecotolicologic data were sparse, although based on what was known, there were no obvious alarm bells. The possible promotion of antiviral resistance is a bigger question mark. My reading of the somewhat optimistic judgment of the attending virologists was that it expressed more wishful thinking that scientific evidence. The thinking seemed to be that resistance will develop in patients, not birds. Maybe. Maybe not. Can OE-P or OC affect the bugs that make a sewage treatment plant work and lead to its failure? There seems to be a plausible argument this could happen but at the moment, no one knows for sure.
Here's their provisional judgment:
Based on the identification and risk-ranking of knowledge gaps, the consensus was that oseltamivir ethylester-phosphate (OE-P) and oseltamivir carboxylate (OC) were unlikely to pose an ecotoxicologic hazard to freshwater organisms. OC in river water might hasten the generation of OC-resistance in wildfowl, but this possibility seems less likely than the potential disruption that could be posed by OC and other pharmaceuticals to the operation of sewage treatment plants. The workgroup members agreed on the following research priorities: a) available data on the ecotoxicology of OE-P and OC should be published ; b) risk should be assessed for OC-contaminated river water generating OC-resistant viruses in wildfowl ; c) sewage treatment plant functioning due to microbial inhibition by neuraminidase inhibitors and other antimicrobials used during a pandemic should be investigated ; and d) realistic worst-case exposure scenarios should be developed. Additional modeling would be useful to identify localized areas within river catchments that might be prone to high pharmaceutical concentrations in sewage treatment plant effluent. Ongoing seasonal use of Tamiflu in Japan offers opportunities for researchers to assess how much OC enters and persists in the aquatic environment. (Singer et al., Environmental Health Perspectives)
This is not just a Tamiflu problem. Pharmaceuticals in abundance are finding their way into wastewater and even drinking water. But the sheer volume and condensed time frame of a pandemic wave makes this problem of particular interest.
Just one more vexing piece of the dauntingly complicated pandemic preparedness puzzle.
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"Ongoing seasonal use of Tamiflu in Japan offers opportunities for researchers to assess how much OC enters and persists in the aquatic environment."
For how much longer? The at the rate resistance is building in seasonal flu it is no longer much use for H1N1 and we will have to see if the same occurs in H3N2. The lack of any apparent fitness penalty does not augur well for the usefulness of the UK and other pandemic stockpiles.
There are other problems with Tamiflu including being linked to potentially dangerous side effects including suicide. It's not a wonder drug.
http://drvitelli.typepad.com/providentia/2007/11/does-tamiflu-ca.html
Romeo: We've written quite a lot about Tamiflu here and the old site. Click on "antivirals" in the Categories list on the sidebar.
Revere- thanks for discussing the paper. Your interpretation of the results is spot on. There are as many questions raised as answers being provided. And I agree that some interpretations were a tad on the rosy side, but it was all we had to work with at the time. There will be a paper dealing with some aspects of the ecotoxicology of Tamiflu coming out shortly, which should be worth a look.
There is certainly a problem with having widespread Tamiflu resistance in H1N1, however, it doesn't necessarily inform us of the characteristics of a pandemic virus. A more diverse national antiviral stockpile might be prudent, in this light.
Andrew thanks for commenting.
What I suppose is really underlying my concern with the resistance in H1's N1 is the importance of homologous recombination as a mechanism for redistributing polymorphisms. If it plays anything more than the most minor role and the Tamiflu stockpile is deployed against an H5N1 pandemic strain then dual infection will quickly render this tools fairly useless. All it will achieve is the pollution of the water course. If recombination is a negligible mechanism it is more difficult to account for the timing and geographical spread of H274Y. Found in 9 of the 10 sequences recently released here in the UK.
Another problem occurs to me regarding this issue. Consider the ongoing problems in Indonesia, most recently the suspicious village group of 17 suspected H5N1 cases, whether or not such clusters are in fact avian flu infections: very likely, "Tamiflu blanket" sorts of local treatments are given to those local areas, possibly to hundreds of residents in a village or neighborhood area. So, what is the local ecology of these various settings? If these folks excrete into systems (including privies that drain into surface moisture flow as "systems") that very quickly reach fairly large waterways, likely no harm would be done. But, what if some localized outbreak area has a configuration allowing drainage into some smallish pond or swamp or estuary? Like an ecologically productive wetland inhabited by waterfowl, ducks especially? You could, im(non-expert)o, get endemic H5N1 strains directly exposed to Tamiflu-resistance selection pressures well in advance of any fully H2H adaptation emerging. Just another unhappy thought.
Great article, and a very interesting take on how the virus could develop resistance to the only amunition we have against it - if you can call it that.
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I'm not aware of anyone who is looking at the recent outbreak regions for impact of Tamiflu on the abundance of tamiflu-resistant viruses in the waterfowl population. But you raise a good point and this should be looked at. No one is prepared to say they know for sure what would happen. If there is an effect on the abundance of tamiflu resistance in waterfowl, then you need to ask, "so what?"...will it ever make its way into humans..what's the probability. It's a very difficult topic to discuss without hard numbers at hand.
In previous discussions, and idea I've often found it hard to wrap my head around is that antiviral resistance is not necessarily driven by the selective pressure that would be expected with increased use of the drugs. That's always seemed counterintuitive to me; I mean, if the antiviral drug actually works, and limits the proliferation of the virus, how could that NOT constitute a strong selective pressure? I don't get that.
My conversation with a seasoned virologist on the issue you raise, Racter, is that the mutation(s) that confer Tamiflu resistance have increased in the past year by sheer luck. In previous years there was evidence to suggest that a resistant virus was less able to infect. It turns out that was wrong, as the virus has figured out a way to do that. However, there is no evidence that the resistance has been generated due to Tamiflu use, but simply as a result of chance. Really bad luck, is the going theory.
Based on not a lot beyond the studies that have been performed in the past on fitness (that lead to this perceived wisdom) and resistance (like the H1N1 & H3N2 studies in Japanese school children, how quickly the first H5N1 cases occurred etc) I would argue the most plausible hypothesis is that selection pressure of Tamiflu usage has always produced a stream of resistant strains in both H3N2 & H1N1 but they have been short lived due to their fitness penalty. Eventual one of these H274Y changes occurred in an N1 that left the resultant protein biologically unimpaired. I don't know if this is just bad luck or a reasonably predictable outcome of providing a selective advantage to resistance mutations on an otherwise randomly varying genetic background. I am sure the virologist Andrew discussed this with knows far more than I but I would be interested in understanding his/her thinking.
Under these circumstances it seems using Tamiflu as a 'blanket' in infected and endemic areas seems counter-productive to me.
The unintended consequence maybe the role that antivirals are currently playing, directly and indirectly, in the continued evolution and adaption of particularly H5N1.
JJackson, you've summed it up well. I think the debate about whether it was luck or selection is not a terribly productive one, as you can never rule out selection as a mechanism when Tamiflu is in widespread use and you can never have selection without a bit of luck.