The public may not have bird flu on the front burner but there is action elsewhere. New vaccine technologies are being worked on and so are antivirals. One ready to be used clinically is peramivir, made by BioCryst. Peramivir is another neuraminidase inhibitor like oseltamivir (Tamiflu) and zanamivir (Relenza) although it has to be given intravenously or by intramuscular injection.
Tamiflu and Relenza are chemically similar, looking like the natural cell surface receptor (sialic acid) the virus latches on to to initiate infection and which it needs to be released from when the replicated virus is budding off from the hijacked cell so it can find new host cells to infect. The neuraminidase inhibitors work by preventing this release. Peramivir looks chemically different than the other drugs, although it also works by occupying the same spot in the neuraminidase enzyme, blocking its action. It remains to be seen whether this will produce a different pattern of resistance mutations which would allow the drug to be used even on a virus resistant to one or both of the other drugs and whether it works better than those drugs for treatment.
There are differences as well as similarities. Tamiflu is taken orally and then converted by the liver into the active form of the drug. Relenza begins in the active form but it cannot be absorbed, so it must be inhaled and thus is more difficult to administer if there is breathing difficulty, the patient is asthmatic or can't follow directions. While Relenza cannot be absorbed, it could be administered by direct injection into the blood stream and its maker, GlaxoSmithKline is working on an intravenous version. Now we have i.v. or i.m. peramivir.
One feature of the newest antiviral is that injecting it can produce much higher levels than oral Tamiflu and tests on volunteers suggest people can tolerate these higher levels for up to ten days. However the safety profile is not yet well established. Its use would be limited to treating those already hospitalized. Last month BioCryst received a contract from the US Department of Health and Human services for additional work.
Peramivir is not the only new antiviral. Lauerman's Bloomberg story also mentions a new oral drug from toyama Chemical and a "topical treatment" (presumably inhaled) by Nexbio, Inc. We have no further information on these drugs which presumably are also neuraminidase inhibitors.
All this is to the good, although it is pretty late in the game. Whether any of these developments will reach the level where they are useful and available in sufficient quantities will depend on events outside of our control, the behavior of the virus as it invades ever new ecological niches in the natural world.
Meanwhile, we must agree with the dean of flu virologists, Dr. Robert Webster: we are losing the battle against H5N1.
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Revere
That same Bloomberg article mentions Daiichi Sankyo Co.'s CS8958 in the same light as the ''oral drug from toyama Chemical and a "topical treatment" (presumably inhaled) by Nexbio, Inc''. But you left CS8958 out of your story.
Is it because it is Relenza in another form. Studies have shown it has the potential to be 1000 times more effective than the inhaled form.
Or is it that i'm getting paranoid in my old age.
An injectable, intramuscular of intravenous treatment?
I'm sure this will be great news for that five percent of the population that due to financial resources or social standing, will have the avaliability of in hospital treatment.
How long is going to take to finally get the message that antivirals won't work with a pandemic virus?
Tom: This discussion has many dimensions. You are fixated on one of them. Therapy is another one. And the use of antivirals in this is not so cut and dried. Several good analyses show that there could be benefit from using antivirals on only a small proportion of the population. I'll try to lay out these arguments from the literature and we can talk about it again. But it is more complicated than I previously assumed and we should remain open to this. This has been shown by all sorts of different models with various assumptions using many different datasets. So it should remain on the table.
I do not believe I am "fixated"...but on that particular point, I am in a conflict of interest. /:0)
"Several good analyses show that there could be benefit from using antivirals on only a small proportion of the population."...Who paid for these studies?
I'll make a deal with you. You can have the vaccines and antivirals...
...I will take the broadspectrum antibiotics (erythromycin) and the prednisolone..and the oral electrolyte powders...and the anti-fever medications...and the morphine...and the telephone or online advice from healthcare professionals, either nurses or doctors.
Every move that has been made in the past nine years, has played into the hand of H5N1...there are some very unwise persons running the show and it is a little late to change things now...
...a monkey could have done a better job.
Tom: I'll take that deal (easy to say since neither of us will have much choice when it comes down to it). I disagree about the decisions that have been made. Many may turn out wrong but they were made for themost part in good faith and with the information at hand. Other decisions could also have been made and I fault them on not taking care of the system as a whole, but things look very diferent from their vantage and I don't think you are being fair. It is easy to be critical (or hypercritical) when you don't have the responsibility or the constraints. Whatever, we still need to try to be constructive and helpful.
Tom: I'll take that deal (easy to say since neither of us will have much choice when it comes down to it). I disagree about the decisions that have been made. Many may turn out wrong but they were made for themost part in good faith and with the information at hand. Other decisions could also have been made and I fault them on not taking care of the system as a whole, but things look very diferent from their vantage and I don't think you are being fair. It is easy to be critical (or hypercritical) when you don't have the responsibility or the constraints. Whatever, we still need to try to be constructive and helpful.
"It is easy to be critical (or hypercritical) when you don't have the responsibility or the constraints."
There are a lot of people who have a great deal of responsibility in this world: in fact way more front line responsibility than this bunch who leave there Ivory Towers only when forced to interact with the 'little people'...
...This agency is amazingly water tight, don't you think.
Sorry, if they can't find the will to stand up and be counted, then they are complicit by their silence.
If the errors of 2003 were dealt with rather than swept under the carpet...then things might be very different today...
...but hey, it's only my opinion and thanks again for letting me express it. /:0)
The Toyama product is referred to as T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide). The company announced the launch of phase I clinical trials last month. You can read more about it here: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedi… and here: http://aac.asm.org/cgi/content/abstract/AAC.01051-06v1
Slightly off topic, but I just asked a question about vaccines over on Crof's blog, and it occurs to me that I should go where the experts are to ask this question. Pardon me while I c&p.
Various companies are working on vaccines using current strains of the virus, either for possible use as pre-pandemic vaccines, or to work out some of the kinks of an H5N1 vaccine now.
What if one of those vaccines were given in a targeted way to people in those affected areas? Residents of Lagos and Jarkata, for example. Or just health care workers in Jakarta, and families and neighbors of known or seriously suspect cases.
The use of a "Tamiflu blanket" around a cluster has happened already, and is an optimistic plan for trying to squelch more efficient H2H clusters. Why not try using a "vaccination blanket" in high risk places before the start of a pandemic? The vaccine would presumably more closely match the current viruses than it would a pandemic virus, and administering it would give H5N1 fewer opportunities/hosts to develop efficient H2H.
AND, while you'd still require a significant amount of vaccine, it would be in the thousands or tens of thousands of doses, rather than the millions/billions of doses.
On top of that, it might well encourage countries to admit outbreaks (*cough*China*cough*) or beef up surveillance, knowing that prompt reporting could get them the vaccine, and potentially stop a pandemic from emerging in their country.
Once a given vaccine has been tested for safety and efficacy, why can't this be tried? I understand the cost would be significant, but it's the kind of plan I think donors could get behind, if it were pitched as "our best hope for stopping H5N1 from becoming a human pandemic." And a promised purchase order from WHO of n thousand doses of a vaccine meeting certain criteria would be an extra incentive for the vaccine-making companies.
P.S. I misspoke about the number of doses required; vaccinating all residents of Jakarta would require almost nine million doses, and they're not the only place that could use it. Still, that's a more doable number than 300 million (U.S.) or 6 billion worldwide. And an order for, say, 50 million doses that didn't depend on a pandemic occuring could help ramp up production.
And obviously I wasn't suggesting Tamiflu blankets not be used; by the time a family member is sick, it'd be too late to vaccinate. But vaccinating around bird outbreaks might be in time. And if I were a poor farmer, the prospect of receiving a vaccine that could save me and my family would be a serious incentive for reporting suspicious bird deaths, even without compensation for those culled.
caia: If you are talking about doing it ahead of time so that it would be available if it looked like there was an outbreak then you couldn't test it for efficacy so you would be taking a chance. But hoping for cross reactivity is a sensible thing to do if you have nothing else. But this is still beyond our abilities at the moment. We don't have the vaccine or the production capacity to do as you suggest yet.
So this is where the serious science is discussed? Sure! More like where the PR spin is absorbed. Peramivir is as suceptable to H274Y mutation resistance as Tamiflu. But that shouldn't stop Biocryst from sucking governments into buying millions of doses, glossy advertising trumps hard science, just ask Roche.
When I said test for efficacy, I meant for antigens, or whatever it is they test people's blood for after a vaccination in a clinical trial. Obviously that's not a definite test for efficacy against live virus, but it's a good clue, right?
And I was proposing using vaccine even sooner not when there's a large H2H cluster when it looks like it's going pandemic, but when and where there are bird outbreaks and individual human cases and small clusters. As in Jakarta, right now (or as soon as there was an appropriate vaccine available).
After all, if the vaccine were made with a relatively recent isolate from the same region/clade, it would protect pretty well against the H5N1 that's circulating now, right? Better than it would against a pandemic virus. And assuming the virus is "trying" to mutate/reassort/recombine to an efficient human virus in humans (as opposed to pigs or other animals), preventing people from getting what's out there now would greatly cut the risk of it going pandemic... right?
Miso you're welcome to your opinion of the worth of antivirals, of course. But if you really believe the Reveres are uncritical observers, or PR shills for anybody, you clearly haven't been paying very close attention to this blog.
Caia,
I'm sorry I upset you to the point you needed to make a pointless off-topic post. Did you read the bit where I critisised Peramivir, and Tamiflu, (not all antivirals)?
Dispite Relenza being constantly derided for being administered with an inhaler, zanamivir is still the best influenza A antiviral we have, GSK should never have stopped development of the injectable.
Miso: Not sure how you know this about peramivir. We (myself and a bioinformatics colleague I got interested in it) just started doing structural modeling of the NIs and this is not obvious to us (at this moment) from looking at the contact points within the wildtype and mutated binding pocket. Do you have a cite? I gather from your comment you are a solid believer in Relenza. Reason? I don't work for a drug company, have stock in a drug company or care about drug companies except in a negative sense. But I am interested in the science, so if you have science please tell me about it. It would be helpful to what we are doing.
Characterization of drug-resistant recombinant influenza A/H1N1 viruses selected in vitro with peramivir and zanamivir
Mariana Baza, Yacine Abeda and Guy Boivin
Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, Québec City, Que., Canada
Antiviral Res. 2006 Nov 20
Abstract
There is a limited information with regard to the neuraminidase (NA) mutations conferring resistance to peramivir and zanamivir in the influenza N1 background. In this study, an influenza A/WSN/33 (H1N1) recombinant virus was passaged under peramivir or zanamivir pressure. The peramivir-selected variant had a H274Y mutation in the neuraminidase (NA) gene conferring resistance to peramivir and oseltamivir but susceptibility to zanamivir. The zanamivir-selected variant had a massive deletion in the region encoding the NA active center and an A200T hemagglutinin mutation. This variant exhibited reduced susceptibility to zanamivir with a drug-dependent phenotype.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&li…
This may not be a definitive study, but if the H278Y variant of H5N1 is likely to confer resistance shouldn't this be disproved before we are fooled into relying on peramivir, as we have been in Tamiflu?
Oh, I wasn't upset. But thank you for the apology, I will apply it to your pointlessly confrontational tone. Apology accepted.
As for off-topic, did this:
Not imply that the Reveres were parroting/swallowing PR spin? My mistake. I can't imagine where I got that impression.
While waiting for my post to be reveiwed by the moderator (does anyone review the jibberish posted by caia?) here is some more scientific evidence that peramivir is not all that.
"High-level antiviral resistance to oseltamivir results from the substitution of a single amino acid in N1 neuraminidase (His274Tyr). Such variants have been detected in up to 16 percent of children with human influenza A (H1N1) who have received oseltamivir. Not surprisingly, this resistant variant has been detected recently in several patients with influenza A (H5N1) who were treated with oseltamivir. Although less infectious in cell culture and in animals than susceptible parental virus, oseltamivir-resistant H1N1 variants are transmissible in ferrets. Such variants retain full susceptibility to zanamivir and partial susceptibility to the investigational neuraminidase inhibitor peramivir in vitro."
http://content.nejm.org/cgi/content/full/353/13/1374
"Gubareva et al. showed that resistance to peramivir is also associated with the R292K (influenza A virus N2 subtype) and H274Y (influenza A virus N1 subtype) mutations, as this drug also contains a bulky hydrophobic group that requires reorientation of the NA active site. Baum et al. recently reported the generation of a peramivir-resistant influenza B virus which harboured an H274Y change in NA and additional changes in HA. This mutant showed cross-resistance to oseltamivir, but retained sensitivity to zanamivir similar to the A N2 R292K and A N1 H274Y mutants."
http://jac.oxfordjournals.org/cgi/content/full/55/2/162
Miso: Thanks for the cite. Haven't had a chance to read the paper yet so I'm not sure what to think of it but it is a data point. The abstract implies that resistance to zanamivir also exists, which is to be expected. Most, if not all, resistant mutants so far are thought to have reduced viral fitness, so the appearance of resistance is not the end of the story for any o fthe drugs. Modeling studies of resistance and Tamiflu all suggest that it is still beneficial (see Lipsitch et al., PLoS Medicine two weeks ago) even when completely resistant strains emerge, so the implication Tamiflu would be useless is so far not valid given what we know. I am struck by your fierce promotion of Relenza. I think it's a good drug to use but not the only one to use. Peramivir looks like it has some advantages, too. We will need all the arrows in our quiver to deal with a pandemic, which was the point of the post, more or less. I am not shilling for Tamiflu or peramivir. The question is, are you shilling for Relenza? BTW, what did I say about peramivir that is PR spin? Just curious.
Miso: Just to be clear, I don't purposely hold any comments for moderation. The system arbitrarily does it for reasons none of us at ScienceBlogs understands. I have to check to make sure there are no unpublished comments to see they get posted and I am not always able to do this immediaately as I have a busy day job. It would be appreciated if you could be a bit less personally aggressive toward other commenters. I expect some passionate feelings here and overlook it most of the time, but it just isn't very helpful in our common interest of figuring out what to do. Your citations are useful and I am glad to have them.
Miso
I understand your frustrations. Given what we know today. GSK has been negligent in its promotion / development / supply of both IV Relenza and Relenza (Zanamivir).
The facts will come out.
Revere
Don't forget Daiichi Sankyo Co.'s CS8958 topical (LANI).
( Formed by two molecules of Zanamivir )
You wonder why the fierce promotion. Two reasons:
1.I believe it will save my life in the event of a pandemic vs a vaccine that may take months to develop.
2.GlaxoSmithKline have done everything possible to limit the success of this product.see link
http://www.biota.com.au/uploaded/154/1021127_55biotaprovidesmarketupda…
Why?? Most probably so they can make more money out of Vaccines.
I'm not focused here on whether GSK marketed sufficiently or whether Relenza is better than Tamiflu. That's an empirical and inferential question I'll address soon (I hope). The point of the post (read it again) is that there is movement on the antiviral front and that's a good thing. I didn't leave out Sankyo for any reason except it was late at night. Vaccines will likely not be available (this could be modified if we don't have a pandemic for 10 years; we should be so lucky but it's possible). So this was about antivirals.
"(does anyone review the jibberish posted by caia?)"
Yes, I review all of the "jibberish" posted by caia...
...because I learn every time I read it.
Thanks caia
One thing that always bugs me a little is the tendency to completely ignore the "other" class of antivirals, the M2 inhibitors. Apparently, this is due to the fact that resistance to these drugs, which develops more easily than it does to the neuraminidase inhibitors, was observed in a high percentage of isolates tested during the 2005-2006 season -- as well as the fact that the genetic markers have been found in some (but not all) of the H5N1 isolates. I know that the July 2006 CDC recommendation against the use of Amantadine/Rimantadine for seasonal flu still stands, but I haven't been able to find anything on how the isolates from this season are actually testing out as far as resistance.
Clade 2.2 is resistant to the M2 inhibitors. Clade 2.1 (Indonesian strain) is susceptible. Remember it is Clade 2.1 that has caused the most human fatalities.
No one knows exactly what will happen here.
In any case, the focus on Tamiflu is silly. Tamiflu has low affinity for N1 neuraminidase subtype. It's expensive and difficult to make. If you have taken Tamiflu, you may have experienced firsthand the sudden urge to return the half digested pills back to the box.
Tamiflu is basically useless on N1 virulent strains in vivo, regardless of the mutation flavor of the week. Tamiflu might work great at 50 ug/mL in MDCK cells, but H5N1 infected mice are still going to drown in neutrophils. People need to stop drawing parallels between seasonal flu and pandemic flu, they are very different, and there are different selection pressures operating on these strains. The pathologies are distinct.
We should be focusing on vaccines and drug therapies, but not the damn neuraminidase inhibitors. They are useless, okay? The emporer has no clothes here. Tamiflu has minimal outcome on survival. You are better off using that money to provide oxygen, corticosteroids, NAC, and IM interferon.
T-705 from Toyama is promising. But if you extrapolate the data, you are looking at treatment in grams. Yes, grams. We are talking 1g - 50g a day to treat pandemic influenza in humans. Luckily it looks pretty easy to make. But it's patented.
The best drug type of influenza therapy will be similar to HAART for HIV (multidrug cocktail). However, this will be prohibitively expensive, and we don't have enough tested influenza drugs yet. Our real goal here should be not necessarily antivirals, but the instead the reduction of mortality.
As for "containment". Once the basic reproductive ratio is greater than one, OR there is saturated viral infectivity and in the presence of coinfection with R0 less than 1, there will be an explosion of cases. There is no "containment" without a vaccine, and there is no vaccine without a pandemic strain. Anyone who believes that the governments of the world can contain a serious outbreak with Tamiflu is delusional.
Luckily we probably have some time.
Alexander Jones
Durian Biology