Now there appears to be another frontline flu antiviral on the horizon, a neuraminidase inhibitor like Tamiflu and Relenza. It's generic name is peramivir, being developed by Alabama-based BioCryst Pharmaceuticals. Tamiflu can be taken orally. Relenza must be inhaled. So far, peramivir has to be given intravenously or via injection. Much of the optimistic information that has come out in the last two days is from BioCryst, so we don't know how much is real and how much is hype. Information from researchers said to be independent of the company (what this means exactly we don't know) were presented at a meeting in San Francisco of the American Society for Microbiology:
They gave more than 60 healthy volunteers intravenous peramivir each day for up to 10 days in doses ranging from about 30 mg to 600 mg.All doses were well tolerated with no serious adverse effects . . .
The U.S. Food and Drug Administration gave peramivir "fast-track status" in January to allow speedy review for approval. The company has said peramivir has shown broad spectrum activity against various strains of flu, including the H5N1 virus that causes bird flu, in animal trials. (Reuters via SciAm
Doctors are anxious to have several antivirals. In the event resistance to one develops, they hope others will work (unless there is cross-resistance). The BioCryst solution to resistance is to use high doses:
"We demonstrated that you can go to very high levels of peramivir in humans," Dr. Charles Bugg, Chairman and Chief Executive Officer of BioCryst, said in a telephone interview.
"We did escalating doses -- starting at a low dose and showing it's safe and going until we have a dose way, way above what we think it takes to inhibit the virus. We can go to very high levels," Bugg added.
[snip]
He said mutation of the viruses is the reason for testing very high doses of drugs. "You hit them with a drug and they eventually will figure out how to get around the drug. The way you get around this is to go in with huge amounts," Bugg said.
Bugg said peramivir is easier to make than Tamiflu, which requires rare ingredients. [although researchers at Harvard and in Japan have found alternative paths that don't require these ingredients. See post here).
"We can manufacture large amounts of peramivir," he said.
He said one Swiss manufacturer can make one metric ton of peramivir a month, and the company had identified a U.S. facility that can be up and running in seven months.
He estimates that one ton of peramivir would treat 8 million flu patients."It is not enough to treat everybody but we have got enough to treat millions and millions per month," Bugg said.
In a second paper given at the same meeting, peramivir was reported to have protected mice and ferrets against the lethal effects of H5N1. It was not clear what the timing of the drug infusion was relative to infection:
A single injection allowed 70 percent of the mice to survive, and five days of injections boosted survival to 80 percent. Only 36 percent of untreated mice survived, the researchers told the meeting.
Among the ferrets, 86 percent survived when injected for five days, versus 43 percent of untreated animals.
"They found at blood levels that we can achieve very easily in humans, the drug is very effective at protecting animals from death," Dr. Charles Bugg, chairman and chief executive officer of BioCryst, said in a telephone interview. (Maggie Fox, Reuters)
So we have a possible new antiviral. It is not a cure. It may help. Neither a vaccine nor the new antiviral will be available in any appreciable quantities for a year or more, and then only enough for a small fraction of the world's population. Too bad we didn't start this earlier. Tell your governments.
Life is about timing.
- Log in to post comments
Please note this: The vector for human H5N1 infections is unknown. Anyone who tells you they have evidence the vector is domestic poultry is full of shit. Domestic poultry is a reservoir for H5N1. That does not mean it is a vector. If you have scientific evidence to contradict this postion, post it here now. The vector may be some animal, such as a dog or a cat; but the brilliant scientists involved in bird flu research refuse to make this a high priority. And the cultural barrier to the consideration of dogs or cats being the vector is almost total in the US. American had rather die of bird flu than kill their pet dogs and cats. Since the vector is unknown, there is no way in hell a pandemic can be slowed down. So the almost expontential increase in human bird flu clusters cannot be slowed down or controlled.
Science has shit to offer you to stop this pandemic. There is no vaccine, and it would take 5 years to develop one. And now let us talk about anti-viral drugs.
http://www.telegraph.co.uk/news/main.jhtml?xml=/news/2006/10/01/nflu01…
Please read this article. It is important.
Dr. William Stewart, chairman of the Health Protection Agency in the UK, has warned the drive to fight a flu pandemic with special anti-viral drugs risks creating an untreatable superflu virus.
The widespread use of anti-viral drugs to treat illnesses, including bird flu and seasonal flu, is causing viruses to mutate into drug resistant forms.
Tamiflu is marginal at best in the treatment of H5N1 infections. If it were more than marginal, you would not see the incredible lethality rate among bird flu patients in Indonesia. What is the death rate? There are different estimates. But it could be as high as 68%. If you have a different number, please post it here.
I am not saying the development of new anti-virals is bad. Of course it is good. But these anti-virals will only have a marginal impact at best.
And then there is the question of timing. H5N1 has already been discovered in wild birds in the US. The winter flu season will soon appear. The human H5N1 infections in Indonesia are expanding much faster than in the past, and we are probably only seeing the tip of the iceberg.
And virologists has warned that H5N1 is capable of mutating at incredibly fast rate, meaning any attempt to use anti-virals will be rapidly negated by this fast mutation rate, and the speed of this development of resistance to anti-virals will explode as soon as those with money start trying to swallow tamiflu pills, even though they do not have the flu, as a preventive measure.
Sorry,
post should say: the virologists have warned
William: I'm a retired RN who's been closely reading this blog for a very long time. I've only commented once--so long ago that I can't remember how I signed. I've never completely lost patience with anyone before, but you take the cake. Could you run your comments through a diatribe filter before posting, please? Today, as usual, I recognized you before your second sentence. I had to force myself to read the rest. Too bad, because you often have good questions, or important things to say. But I won't force myself much longer to read your posts.
Reveres: My great thanks to you for your hard work and genuine caring, past and present. This blog, aside from everything else you do, really matters and is deeply appreciated.
william(s),
I am beginning to suspect your pseudonym points to more than one person, just like Revere's. Either that, or you are one person who exhibits wild fluctuations in anxiety, reflected by the changes in your rhetoric. While you are typically on point in theme, sometimes you are apologetic and moderately equivocal, and other times you are fanatically absolute.
Your theme--that you are (rightly) concerned over bird flu, government encroachment, footdragging--is generally justifiable. But your rhetoric indicates your emotions are interfering with your ability to distiguish potential things from absolute things. Your outbursts of name-calling and subsequent apologies additionally hint at roller-coaster emotions.
Maybe your apparent mood fluctuations are the product of mind and mood altering chemicals, perhaps psychiatric medicines, the doses of which could maybe be adjusted to produce a smoother effect. Maybe they are instead an indication that you might benefit from some kind of prescription treatment. I truly don't know, and it's most certainly not my call anyway. The anonymous nature of all this means you might just be a blog troll.
But seriously, I suggest finding some way to chill out. You write irrational things. Yes, be concerned. Be skeptical. Just don't jump to conclusions. Stop thinking that the whole world is wrong and you are one of the select enlightened few who knows the truth. You should be familiar with the vast number of people on this planet after thinking about how many might die in various scenarios. Consider how unlikely it is that you and a handful of others possess the ultimate knowledge and everyone else is just foolishly and gullibly trapped by their ignorance and futile actions.
It's in almost nobody's best interest for a pandemic to occur, and although the footdragging has its origins in inability to perceive a threat, very few doubt the existence of this threat now. Maybe it's too late, hopefully it's not. Realize this. Realize the uncertainty everyone maintains. Go back and look at the way you have commented here, and observe the fluctuations in the way you write. What do you think about this?
And you need not apologize to me. You have not offended me, and if you happen to, I can easily ignore your comments if necessary.
William,
I was just getting ready to say almost the same thing as Nurse BDineen said above. So, I will anyway. I know you think you are being forceful and adamant when you write in the style you have chosen, but it unfortunately comes across as hysteria. This takes away from your message, sometimes almost entirely. The first paragraph is just absolutely useless for discussion. You essentially are telling everyone to give up, that we are all idiots. That is pretty presumptuous of you to say the least. From what I've observed, most of the time you simply pick up information from other blogs like Niman's, and parrot it back as if you are saying something new. We all read the same stuff before you ever post it, so all you end up doing is looking sort of foolish.
Now, as for the rest of your post below the link, that was actually something new and interesting and important. And I appreciate the information. But like the nurse above, I almost didn't get that far I was so put off by the tone of your starting rant.
If you are seriously that concerned about the pandemic, are you writing to US legislators, the CDC, WHO, your local officials, the Department of Health etc? If so, great. But if all you are doing is ranting at the handful of us, you are preaching to the choir and not very effectively either. As a matter of fact, I am going to put my money where my mouth is and spend the rest of the afternoon writing letters to all my congressional representatives and any relevant official I can think of, to express my concerns with the general lack of preparation for a pandemic, and ask them to make emergency preparedness supplies available NOW for all those who cannot afford to stockpile things themselves. Sure, some poor people may eat up all their stuff ahead of time, but we can try at least. Maybe you could do the same. The more letters they get, the more likely they are to act.
Well said! Here's a thread which started on a new antiviral and I'm not even sure "William" read it before commenting. He appears to have his own agenda!
Like so many, he's made ups his mind. We know. And you apparently believe strongly in Niman's theories. We are aware of them as well.
Take a breath and consider other points of view, for you own mental health, if nothing else.
Thanks for participating.
We need everything available to fight this threat. To just point to an article that was concerned about oseltamivir resistance and to make that the cornerstone of an argument that "science has shit" to fight this is defeatist and plain wrong.
Revere, other studies have been done with oseltamivir, peramivir and zanamivir on the A/Hong Kong/156/97 variant of H5N1 and they usually administer the antiviral 4 hours or so before inoculation with virus, and then continue antiviral treatment for a number of days afterwards. All three antivirals at sufficient dosage and sufficient length of follow up treatment conferred 100% survival of mice against A/Hong Kong/156/97 H5N1. Indeed oseltamivir was the most effective in a mg/kg comparison.
http://tinyurl.co.uk/19qc
A study on oseltamivir (again given pre inoculation) against the more pathogenic A/Vietnam/1203/04 variant conferred similar survival rates (80%) to this peramivir study (given a high dose and extended treatment).
http://tinyurl.co.uk/isqw
These are the only two studies AFAIK to study antivirals on the A/Vietnam/1203/04 variant. I assume they gave peramivir some hours before inoculation (as all the other studies have) to increase the positive news to their study.
The biggest question to my mind is whether or not treatment is possible with antivirals after infection. We need studies with intravenous antivirals given at varying intervals after infection to test this (not really studies on IV antivirals before infection). We need to study not only IV Peramivir, but also IV zanamivir, which also has been given without side effects at high doses (600 mg bd) to healthy human volunteers. Interestingly IV Zanamivir is the only antiviral so far proven to completely prevent influenza cytokine and chemokine response and reduce viral shedding to zero. Given that the massive cytokine responses are so implicated in the fearsome mortality rates with this infection, this warrants further study. Crucially, this was done on humans, not mice, and done 7 years ago!
http://tinyurl.co.uk/uly8 ( IV zanamivir study)
Strangely, no further work on intravenous zanamivir has been done since 1999!
Both peramivir and zanamivir appear more "resistance proof" than oseltamivir. Zanamivir resistance in particular has been recently studied to demonstrate that resistant mutants developed in the lab are very unfit and unlikely to cause transmissable disease. http://tinyurl.co.uk/gmqw The biggest problem with zanamivir is that it has poor systemic bioavailablility and so is best suited to be used as prophylaxis.
Oseltamivir resistant mutants are usually less fit too but seemingly (and particularly in the case of H5N1) not to the same extent. The oseltamivir resistant H5N1 variants in Vietnam certainly maintained their lethality and tranmissable resistant mutants have been found in ferrets and perhaps in tigers.
There are also some monoclonal antibodies under development, but my understanding is that they are frightfully expensive and thus impractical.
In a similar phase of development to peramivir (phase I/II) is dimeric zanamivir, (LANI/Flunet) with a potency 100 times that of monomeric zanamivir and much extended residence times in lung tissue that may allow once weekly dosing. If it is shown that treatment, even with intravenous antivirals, is futile, then this is perhaps our best antiviral prospect for prophylaxis. Mainly because it will be so cheap! Given you need a hundred times less of it, and 14 times less often, we should be able to make over a thousand times more than we can make of ordinary zanamivir in the same time. If we can make millions of courses a year of zanamivir now, we should be able to make billions of courses per year of dimeric zanamivir! It should be ideal for pandemic preparedness stockpiling as it should work against any influenza pandemic threat. Again, it is only suitable for prophylaxis against systemic influenza disease.
Given that they have to fiddle the studies and give IV antivirals pre inoculation we may find that prophylaxis (as one of several protections, just as we do with malaria) to essential workers to keep essential services going is the main practical use of antivirals in a pandemic anyway. But I for one would like to know there are IV antivirals available in case a less severe form of influenza emerges as pandemic influenza which is feasable to treat.
For those who say that a H5N1 may be transmitted through the orofecal route, I say that pandemic influenza must be respiratorily transmitted to become a pandemic. We don't have cholera pandemics anymore.
Revere already knows I am crazy, but he is kind enough to let me post here anyway. And I apologize for using the word shit, and all the other nonsense. You need to develop a sense of black humour, and then people like me will not bother you at all, since H5N1 is a deadly serious problem. Please ignore my posts if they bother you. I will attempt to give an appearance of sanity, even though I am probably insane. But what about the issue of the H5N1 vector? What do you think? Is domestic poultry the vector, and if so, why?
Just to show I can sometimes be optimistic, please read the information shown below.
Tamiflu significantly reduces flu death risk:
The drug Tamiflu is effective in reducing the risk of death associated with seasonal flu in severely ill patients, according to a new study released on Saturday.
Tamiflu, also known as oseltamivir phosphate, has been widely acknowledged as a specific antiviral drug against flu viruses. Latest studies have proven its effectiveness in treating people infected with the H5N1 highly pathogenic avian flu.
According to a research team from the Mount Sinai Hospital, Toronto, Canada, the drug could reduce the mortality by 71 percent while treating adults infected with seasonal flu. The researchers reported their findings at the InterScience Conference on Antimicrobial Agents and Chemotherapy in San Francisco.
"This new analysis contributes to the accumulating evidence that oseltamivir also has a significant impact in preventing serious complications including death in older at-risk individuals, " said Allison McGeer, lead investigator of the study.
The study was conducted during two consecutive influenza seasons on 512 patients who were admitted to hospital for illness associated with a positive test for flu. More than half of patients, mainly those with underlying illness, had been previously vaccinated.
Eighty four percent of the patients were treated with antibacterial agents, while 32 percent with oseltamivir at time of admission, the researchers reported. Of those patients, 67 percent were diagnosed with influenza, 13 percent with respiratory infection and 62 percent with fever.
Of all adult patients, 6.4 percent died and these deaths were attributed to influenza, and treatment with oseltamivir was linked with more than a two third reduction in death from influenza, the researchers said.
They concluded that despite prior vaccination, influenza remains a major cause of mortality in patients with underlying illness.
In addition, they suggested that hospitalization may be better avoided by antiviral rather than anti-bacterial therapy in patients with influenza-like illness.
Just to pick up on one point here not discussed: "A single injection allowed 70 percent of the mice to survive, and five days of injections boosted survival to 80 percent. Only 36 percent of untreated mice survived, the researchers told the meeting.
Among the ferrets, 86 percent survived when injected for five days, versus 43 percent of untreated animals."
Good news/bad news. Those of us who don't get any treatments - which no matter what will probably still be the vast majority of humans on this earth - are facing a lethality of 36 to 43% (if humans have comparable immune responses to ferrets and mice).That's the bad news. Good news is this isn't 80% like in indonesia? Does this mean there are contributing factors there which make this already highly pathogenic virus even more lethal to the Indonesians than to the rest of us ferrets and mice?
MiH: I'd say it's "I'm not sure what kind of news" and "No informative news". Case fatality in ferrets and mice is not the same as case fatality in humans. We are trying to make the mice and ferrets sick and we aren't doing anything to get them well and of course, they are ferrets and mice living in cages, not humans. Regarding efficacy, we don't know when this stuff was given. If given before symptoms, then these data are pretty worthless for anything because you aren't going to use iv administration for prophylaxis. So this is real scientific data but the information released is more hype than informative. This might indeed be a very important and useful drug and I'm guessing it is and will be. But we know very little from the informaation we have.
Now everyone is convinced they need Tamiflu in their medicine cabinet, there is only one problem. You need a prescription. And you have to take it immediately upon becomming ill, to be most effective.
http://crofsblogs.typepad.com/h5n1/
Please see the article at the above site entitled: Civil Unrest in a Pandemic
It says there could be civil unrest in a bird flu pandemic in the UK, because there is only enough Tamiflu for 25% of the population. The delivery system in the UK is uncertain, and risks producing violence and resentment. Obviously some patients ill with bird flu will not receive Tamiflu. How do you decide who is to receive it and who is not?
I also wanted to mention my dogmatic position regarding domestic poultry as a vector has crashed. I hope I am intelligent to learn a good leason from this.
The most recent information states the evidence indicates an unknown reservoir exists in Java, Indonesia; but there is every reason to believe in other parts of Indonesia human infection was probably transmitted by domestic poultry.
Life is not kind to those like myself that take dogmatic positions.
Do we know whether any poultry producers are still using antivirals? If they have stopped using them then it seems to me that antiviral resistance will be selected against, and existing antivirals should be more likely to work.
One problem with both the old and new antivirals is how people can be expected to know when to use them. Prophylaxis is one thing, but how many doses would we need to treat everyone who feels that they're about to come down with the 'flu?
Joe, I would also hope that lack of antiviral use in animals would select against resistance, but the speed that it emerged with oseltamivir in Vietnam and the fitness of that resistant H5N1 is terrifying. While resistance to ordinary flu occurs relatively rarely, and seldom is of clinical significance, there seems to be something in H5N1 that makes antiviral resistance, in particular clinically significant oseltamivir resistance more likely.
I would think that prophylaxis would of necessity be limited to essental workers (probably more important to be utility and food supply workers than health care workers) while everyone else bunkers down. Simply because we don't have enough antivirals. The advantage of using antivirals mainly for prophylaxis is that we immediately have 2 current antivirals for use rather than just one, and Relenza is inherently more resistance proof than Tamiflu, and the Vietnam H5N1 retained full sensitivity to Relenza. (Zanamivir is probably unsuitable for treatment of systemic influenza, but might be useful for respiratorily limited influenza). But we clearly don't have enough of either. But it might make the difference between taking us back to the Stone Age or the Iron Age!
just got this info from the CIDRAP website
http://tinyurl.com/lgbfg
"Bugg said treatment (with Peramivir) was started an hour after the animals were infected with the virus. He said additional studies will involve longer time lapses between exposure and the start of treatment."
They also mention plans to try and use it on humans in bird flu affected areas.
gp from oz: The reports I remember about Tamiflu resistance in a Vietnamese case were one doctor's anecdotal evidence. Is there more solid evidence with multiple cases and reporters?
There is analytic work by Dr. Anna Moscona showing that Tamiflu is possibly easier to guard against: when it blocks the "N" receptor, it forces the receptor to bend. Relenza does not have this problem. Her speculation was that the virus could evolve a stiffer receptor that would fend off the Tamiflu molecule.
GZB: There is a Nature article from August on the crystal structure of N1 that shows the issue is much more complex. Drug design for Tamiflu and Relenza were based on the N2 structure, which is somewhat different at the receptor site but by a fortunate circumstance binding of the drug ligand on N1 makes it look like the N2 site. From that paper it is not clear that there is a difference. There is another target revealed at N1 that might be exploited by a drug, however. Much work on this is continuing.