Tamiflu could boost drug-resistant flu in wild birds 10:49 18 October 2006 NewScientist.com news service Debora MacKenzie
antiviral drug Tamiflu, but new research shows that ultimately much of the drug will pass through the people taking it and end up in waterways. Chances are it will then linger long enough to promote Tamiflu-resistant flu viruses in wild birds.
As a vaccine tailored to the particular pandemic flu strain is unlikely to be widely available in the early days of an outbreak, emergency plans specify that sick people and, in some cases, people who have been exposed to the virus should be treated with Tamiflu.
A dozen countries have stockpiled more than three billion capsules of the drug. Andrew Singer and colleagues at the Centre for Ecology and Hydrology in Oxford, UK, estimated how much of this could potentially be flushed into lakes and rivers.
The team used detailed sewage runoff models of 16 river catchment areas in the US and UK, and also a model of the expected number of cases of flu per day in a pandemic (see Only drugs and vaccines will deflect bird flu pandemic).
Breaking down Previous studies have shown that Tamiflu is unusually resistant to being broken down in the body – about 80% of it is excreted in its active form. The drug also dissolves readily in water, and is not broken down in sewage sludge or by common chemical reactions in nature.
Putting all this together, the researchers found that all the UK catchments, and most in the US, developed high enough concentrations of the drug to stop a flu virus from replicating, for weeks or months.
Avian flu viruses normally live in the guts of birds. In ducks that drink Tamiflu-contaminated water, the drug concentration that the team predicted would prevent susceptible viruses from replicating, giving drug-resistant viruses a selective advantage.
Such viruses may not make much difference to ducks. But flu viruses regularly swap genes, so Tamiflu resistance could end up spreading to human strains of flu, they warn.
“We recommend more research to study how Tamiflu behaves in water, and to determine cheap and easy ways to break it down before it reaches the river,” says Singer, who led the research. The team suggests that perhaps some chemical that destroys Tamiflu might be put down the toilet by people taking the drug.
Journal reference: [[http://www.ehponline.org/members/2006/9574/9574.pdf | Potential Risks Associated with the Proposed Widespread Use of Tamiflu]] full article 26 page pdf (only front matter included below) Environmental Health Perspectives (DOI: 10.1289/ehp.9574)
Abstract Background: The threat of pandemic influenza has focused attention and resources on virus surveillance, prevention, and containment. The World Health Organization has strongly recommended the use of the antiviral Tamiflu both to treat and prevent pandemic influenza infection. A major concern for the long-term efficacy of this strategy is to limit the development of Tamiflu-resistant influenza strains. However, in the event of a pandemic, hundreds of millions of courses of Tamiflu, stockpiled globally, will be rapidly deployed. Given its apparent resistance to biodegradation and hydrophilicity, oseltamivir carboxylate (OC), the active antiviral and metabolite of Tamiflu, is predicted to enter receiving riverwater, from sewage treatment works, in its active form. Objective: To determine the likely concentrations of oseltamivir carboxylate released into USA and UK river catchments using hydrological modeling and current assumptions about the course and management of an influenza pandemic. Discussion: We predict that high concentrations of OC (ìg/L) capable of inhibiting influenza virus replication (ìg/L) would be sustained for periods of several weeks, presenting an increased risk for the generation of antiviral resistance and genetic exchange between influenza viruses in wildfowl. Owing to the apparent recalcitrance of oseltamivir carboxylate in sewage treatment works, widespread use of Tamiflu during an influenza pandemic also poses a potentially significant, uncharacterized, ecotoxicological risk in the affected nation’s waterways.
Conclusion: To gauge the hazard presented by Tamiflu use during a pandemic we recommend: (1) direct measurement of Tamiflu persistence, biodegradation and transformation in the environment; (2) further modeling of likely drug concentrations in the catchments of countries where humans and waterfowl come into frequent close contact, and where significant Tamiflu deployment is envisaged; and (3) further characterization of the risks to generating Tamiflu-resistant viruses in oseltamivir carboxylate-exposed wildfowl.
Tamiflu down the drain Effect Measure Category: Bird flu Posted on: October 18, 2006 7:15 AM, by revere
A paper has just been published that is a real wake up call. I am stunned more of us didn’t think about this sooner.
We all remember the Tamiflu frenzy that ensued in 2004 when people first realized the bird flu train might be coming down the tracks. There was a great deal of talk about how Tamiflu (oseltamivir) was the only antiviral capable of saving someone from the virus and it was in short supply. So many people started to stock up:
Fears of an outbreak of bird flu led Americans to hoard the anti-viral medicine Tamiflu in 2005, with prescriptions spiking most sharply when media coverage rose, a study released on Tuesday said. Filled prescriptions for Tamiflu rose nearly five-fold between September and October of 2004 and the same period in 2005, according to the analysis by the U.S. Centers for Disease Control and Prevention (CDC) and pharmacy benefits manager Medco Health Solutions Inc..
Because there was little or no influenza activity reported during these periods, researchers said the data suggest patients were stockpiling the drug over fears of an epidemic.
The study adds weight to anecdotal reports of patient hoarding a year ago, when governments around the world were scrambling to build up supplies of Roche Holding AG’s and Gilead Sciences Inc.’s Tamiflu, one of only two drugs that can treat avian, or bird flu.
[snip]
The report found that Tamiflu prescriptions filled rose to about 134 claims per 100,000 enrollees in 2005, from about 27 prescriptions per 100,000 enrollees in 2004. ( Reuters )
This week a report fulltext.pdf in the prestigious journal, Environmental Health Perspectives, added a new wrinkle to the Tamiflu question, illustrating once again the complexities of an influenza pandemic. Andrew Singer and his colleagues at the Centre for Ecology and Hydology at Oxford asked a logical question most of us had overlooked: What if everyone who had Tamiflu started taking it all at once?
Lead researcher Dr Andrew Singer, said “An antiviral drug has never been widely used before, so we need to determine what might happen. During a flu pandemic, millions of people will all take Tamiflu at the same time. Over just 8 or 9 weeks, massive amounts of the drug will be expelled in sewage and find its way into the rivers. It could have huge effects on the fish and other wildlife.” ( NERC ) There is a shitload of Tamiflu already out there. Singer et al. list 3 million treatment courses (10 tablets per course) in the Belgian stockpile; 14 million in France; 16 million in German; 200,000 in Greece; 30 million in Italy; 5 million in The Netherlands; 840,000 in New Zealand;150 million in russia; 10 million in Spain; 14.6 million in the UK; and 81 millioin in the US. Another 5 to 6 million are in a stockpile in case they are needed in a blanket containment attempt somewhere in the world. Each course of treatment is 3/4 of a gram.
What happens when someone takes a Tamiflu tablet? The molecule in the tablet isn’t the active form of the drug. It is a prodrug, one able to be absorbed and then converted into the active form by the body’s own metabolism. The form in the tablet, oseltamivir phosphate (OP) is absorbed in the gastrointestinal tract and converted to the active neuraminidase inhibitor, oseltamivir carboxylate (OC) by liver enzymes. It is OC that grabs onto the active site of the viral neuraminidase, preventing it from detaching itself after budding through the host cell’s membrane after replication.
That’s the good part. The bad part is that most of the OC appears to remain intact and is excreted into the environment through the kidneys and feces, after which it appears to be resistant to degradation in the environment.
In other words, in a short amount of time most of those pills will go from us to toilets and then into waterways via sewage discharges. Or so Singer and colleagues believe. It turns out there is little direct information on the fate of environmental Tamiflu. The very fact we don’t know more is a damning indictment of our shortsightedness. As often as I’ve written about it here, this never occurred to me, despite the fact I am well acquainted with the problem of pharmaceuticals showing up in waterways after passing through millions of human pill takers.
What are the possible adverse consequences? Mutations or reassortments and/or recombinations during avian co-infections in a low level Tamiflu environment could produce new drug strains with Tamiflu-resistant neuraminidase genes. Rough calculations of the range of Tamiflu concentrations in wastewater that might result from plausible pandemic scenarios show the estimated levels to be of potential pharmacologic significance. We also have not investigated whether the drug might have serious effects on particular species in the environment. Nobody has looked.
It’s urgent to investigate this, now that it has been called to our attention. Failure to do so is negligence of the worst kind. Unfortunately, that is the kind of negligence we are most familiar with.
The horse has left the barn folks. I haven’t stockpiled Tamiflu, but if I had, would the expectation be that I wouldn’t use it for PF because it might cause resistance in wild birds? Most people don’t even recycle paper or compost…whatever any science study finds the back end effect to be—it won’t change what the majority of people do. This is part of the grasping at any straws mentality in the face of possible mortality. I don’t think Roche will fund this clinical study or the US gov. The investigation will have to be done on charity. Sorry, to be so cynical, lets hope the first study is flawed.
We talked about the reuse of tamiflu several months ago on fluwikie and it was the consensus and I believe even Roach was contacted at the time; that tamiflu is destroyed by first pass liver degradation hence the pro-drug design. So even if the rivers are full of it and the animals are ingesting it, its not actually getting into their system. So by my understanding this is a non issue. I would be more concerned with all the humans taking it incorrectly and causing increased resistance that way.
Revere is right. This is a known hazard with other chemicals that are excreted eg birth control pills. Well, at least someone has thought of it now.
I hope it wakes the UK government up. Cos they are waving tamiflu as the magic wand to justify not doing anything else.
No, on second thought, this piece of science (nor indeed any other logic) is not going to wake the government up. What will wake them up is a lot of people making noises. Shouting the emporer has no clothes.
Like patient support groups.
what will wake them up is the prices of mortality bonds rising, the price of Tamiflu and vaccines rising, the economical experts taking this serious, life-insurance shares going down many people asking for panflu-insurance and Tamiflu-prescriptions, people abandonning their health-care-jobs, people asking for home-jobs- possibilities during panflu, people emigrating to countries with better panflu preparation etc.
I still 100% disagree, if you can understand the biochemistry behind how tamiflu works you would be able to understand that this is not going to be an issue. Its not like birth control pills or other substances at all, its a completely different compound that works in a very specific way. Just because flu virus is in contact with a small amount of it in a birds gut does not make for drug resistance viruses overnight, if ever. Its just not how drug resistance works. If you want me to go into details I will, but I respectfully disagree with the Reveres on this one.
Plus lets not forget that when it jumps H2H its likely not going to involve birds anymore, it will be a purely human disease. I stand by my statement that we have an infinitely greater problem with people not taking the drug correctly and causing resistance that way.
Links to an article describing the poor oral absorbence of the active tamiflu drug.