Tamiflu side effects have been much in the news and we have concurrently been posting our mega-series on modeling antiviral resistance in influenza control. The two subjects are related in two ways, one obvious (Tamiflu is the main antiviral being stockpiled for influenza control) and one not so obvious: both topics are related to the fact that million, tens of millions or hundreds of millions of doses are contemplated. For antiviral resistance this means even very rare mutations producing a fully transmission-competent resistant virus can spread widely through the population (you will see that shortly in the modeling series). For drug side effects it means that even very rare side effects will occur almost certainly. The same will be true for vaccine use, and for drugs or vaccines used prophylactically (to prevent disease) it is made more difficult in that the victims will be healthy people.
What do we know about the Tamiflu problem? The data come from the country where the drug is used much more than elsewhere, Japan. The widespread use of Tamiflu there -- 9 million prescriptions compared to 3 million in all other countries combined -- provides the millions of possible exposures that could also produce detectable numbers of rare side effects. Last month two teenagers, both 14 years old, jumped to their deaths while on the drug. This month two more teenagers were injured after jumping from buildings. Fifteen children 10 to 19 have died jumping from buildings while taking the drug.
A news article in Nature by Ichiko Fuyuno (subscription firewall, alas) summarizes some of the other pertinent information:
Tokyo-based Chugai Pharmaceuticals, which distributes the drug in Japan, says that it has reported 289 cases of psychoneurotic effects, including three suspicious deaths, to the Japanese health ministry since the drug was launched there in 2001. Chugai now lists the possibility of severe neurological side effects on the drug's labelling and has distributed a warning note to hospitals. The Japanese health ministry insists that there is no clear evidence of a link, however, and points out that flu itself can cause symptoms such as abnormal behaviour. Roche agrees, adding that the number of suspicious deaths is tiny compared to the number of people who have been prescribed the drug.
Tamiflu was cleared initially when seven paediatricians and a statistician looked at the side effects of it and other influenza drugs, as well as at the symptoms of flu itself. The study, which ended in February 2006, followed up 2,846 children aged mostly ten or younger who had been diagnosed with flu. The frequency of abnormal behaviour in children who took Tamiflu was 11.9%, compared with 10.6% in those who didn't take it, which the researchers concluded was not a significant difference.
Shunpei Yokota, head of the study group and a paediatrician at Yokohama City University's Graduate School of Medicine, admits that the study had shortcomings, including a poor definition for the term 'abnormal behaviour'. So in February, at the government's request, Yokota's team launched a larger study, which will trace 10,000 people aged 0-18 years. The team aims to release the results by this autumn. (Nature, subscription)
Unfortunately there are more complications to the study than just "shortcomings." There is a whiff of conflict of interest, as well. Yokota and two other members of the study team received fees from the distributor, although not in relation to the study. Meanwhile, the Japanese are advising against use in anyone ages of 10 and 19 unless they are "high risk." The US and Canada have also asked that warnings be placed on the drug label.
This is part of a generic problem of how to detect and cope with rare adverse reactions to drugs and biologics like vaccines. If there is a one in a million risk of death and you give the drug or vaccine to 100 million people, well, you do the arithmetic. If it happens in a short space of time, say 2 months because of a mass vaccination or antiviral prophylaxis and it happens to otherwise health people, well, you predict the public reaction. The paradoxical result could be that more people would die because of a failure to convince the public the risk benefit equation of dying from a vaccine reaction versus dying of the flu heavily favors the vaccine.
So it's a problem even if you know it's going to happen. It's even bigger if you are caught unawares, as with Vioxx and possibly Tamiflu. The FDA and most other national systems for detecting adverse drug reactions are passive, depending on the voluntary filing of reports by physicians. Most doctors who see adverse reactions don't bother to report them and aren't required to. So now there are suggestions that existing repositories of health information be actively "data mined" for adverse drug events.
Last week, Mark McClellan, a former FDA commissioner, told a Senate committee considering new drug-safety legislation that the system "needs to do better than just seeing the tip of the iceberg of a safety problem after it has already hit us". Health-information technology for drug safety is "an idea whose time has come", he added.
McClellan and others are pushing the idea of data mining of existing health-record databases as an active surveillance system to pick up early warnings of adverse side effects. By pooling existing databases run by private insurance plans, government agencies and industry, information on well over 100 million people could be studied in something much closer to real time, he says. The FDA could then identify priority questions and the mechanisms for answering them. If such a system had been in place when Vioxx came on the market in 1999, that drug's dangers could have been detected in months rather than years, McClellan contends.
The same thinking is gaining currency in Europe. "There is great potential in the use of these healthcare databases," says Panos Tsintis, who oversees the safety of marketed drugs for the European Medicines Agency (EMEA) in London. (Meredith Wadman, Nature [subscription])
Maybe this will work, although my knowledge of data mining technology tells me there are substantial obstacles. Meanwhile, we will have to resign ourselves to the rare adverse event when hundreds of millions are being dosed. It's a bit like buying a lottery ticket with each capsule, where the prize is death. Even if the risk is small, you at least want to be sure that the pay-off is likely and worth it. I'm not sure we can say that for many of the drugs now taken in high volume that have much more frequent adverse reactions than Tamiflu or a vaccine.
Just one of the many paradoxes of public health practice.
- Log in to post comments
There is an additional problem with mass inoculations: maximizing profits on a one-time massive-scale mass production means cutting all conceivable corners. There won't be a second chance to make the money, so it all has to be made on the first and only go.
If 100 million doses are made up, and then all are distributed in a mass inoculation, bad batches won't be correctly detected until a lot of people get hurt.
It would be wise to keep in mind that these operations are strictly for-profit.
I do not believe it is a rare side-effect and this situation is very reminiscent of the discussion in respect to the 'rare' side-effect of anti-depressants. The long history of anti-depressant regulatory inaction and the reasons for it are well known...it seems history repeats itself again...with one difference. Tamiflu at standard treatments are causing the side-effect while authorities are contemplating double or triple dosages and prophylactic treatments, also with increased dosages, for possibly months at a time.
By the way, I believe the person in charge of the review panel was under the employ of the pharmaceutical company at the time.
Tom: You don't "believe" the side effect is rare. That's OK with me and it doesn't affect the argument I'm making, but I'm curious, Why? The dosage it happens is a different issue from rarity. People get allergic reactions at standard doses, too. Regarding the "review" panel. Which one? I noted in the post (and the link has more details) that the study director had received fees from the distributor. Is that what you are referring to or something different? Which country?
Revere. What data do you have to say that this is a rare reaction? Secondly, how do you know that each case is reported? Thirdly, all usage of Tamiflu with respect to prophylaxis and treatment of H5N1 is now off-label and far exceeds the dosages already causing problems.
I read in passing that the person in charge of the review in Japan was in a undeclared conflict of interest. You don't have a problem with that?
I have asked Tan06 to send us a link regarding Tamiflu that she has gleaned from the Europapers about the plan to DOUBLE the recommended dosages for H5N1. This would as you say be way over the study numbers that gave approval for this wouldnt it Revere. A Kiwi girl day before yesterday went off the reservation after taking it for ordinary flu.
My reaction to the Tamiflu thing though is simple. Can ANYONE point and say that someone recovered from H5N1 as a result of taking Tamiflu? Its been in just about everyone who has contracted the bug and its fairly apparent to me that this has to be in you before you become symptomatic.
Even then, looking at the straw poll numbers I have been able to get from the limited information only three out of 137 at the time survived. It aint science though and it sure isnt a study. Might not have time to do a study as indicated.
Hmmmm. Psychosis is the least of my worries about T-Flu. A good swack of sedative can fix that as they drool and sleep. I just hope to Hell that we havent just put all of our eggs into a Tamiflu basket. In fact, we all have around the world apparently.
"Hmmmm. Psychosis is the least of my worries about T-Flu. A good swack of sedative can fix that as they drool and sleep. I just hope to Hell that we havent just put all of our eggs into a Tamiflu basket. In fact, we all have around the world apparently."
Randolph.
One of my problems is that they are going to take 'the bravest of the brave' healthcare workers and put them in an unbelievably stressful situation for an extended period of time while at the same time treating them daily with off-label, experimental, untested dosages of Tamiflu. This is a recipe for disaster and it is obvious that there will be a variety of consequences...
...and as you said, this is without any assurance whatsoever that it works other than in a lab with laboratory animals under unnatural conditions.
Tom: The data on rarity come from Japan, where it is has been used extensively. How accurate the data are is something to consider, but the point of my post was different. In any event, those are the data we have. You are free to conjure up reasons why you don't believe them, but I note that the outcome -- self-inury in teenagers -- is not as likely to go unnoticed as other outcomes. However, that's the information we have and you seem to have none to indicate otherwise except your prejudice (meaning prejudgment). I'm not sure what you mean by use of Tamiflu for prophylaxis and treatment is off label. Please explain.
The conflict of interest issue was in the post and explained there. I also indicated I thought it was a problem. It sounds as if you didn't read the whole post.
Randy: Tamiflu works for influenza A, that is quite clear. There are no controlled studies for H5N1. How would you do such a study? But we know it inhibits neuraminidase activity in that virus just as in other subtypes. What kind of evidence would you accept and how would you get it? I'd say it was a lot better than evidence for masks, handwashing, social distancing and much else. This is not meant to denigrate those measures, only to point out that there is similar lack of evidence for them.
Revere. I believe an off-label use of a pharmaceutical is defined as using it in a way that is not described on the label. I do not believe that longterm prophylactic usage is on the label. I don't think that shortterm prophylactic usage is on the label...and I don't think that the dosages-concentrations being given to patients is on the label either.
"There is a whiff of conflict of interest, as well. Yokota and two other members of the study team received fees from the distributor, although not in relation to the study."
I may have misconstrued your comment. It didn't seem that you had a serious concern on the matter with the 'although not in relation to the study'...if someone is on the payroll what would it matter whether they are specifically being funded for this study or not, if it was an undeclared conflict?
"The frequency of abnormal behaviour in children who took Tamiflu was 11.9%, compared with 10.6% in those who didn't take it, which the researchers concluded was not a significant difference."
In addition, if the above statement is true, there may be 10 % of healthcare workers in a highly stressful situation with a significant neurological deficit.
This on one hand wouldn't be good for the patients and the healthcare system...we already have enough patients dying needlessly...
...and secondly, I don't want to hear about healthcare workers flying from tall buildings when they stayed to fight.
When it is your child or your spouse or your parent who has the reaction, the odds for your family are 100% (I speak from a personal life-threatening vaccine reaction experience).
I think you and I would agree that no one is expendable and the situation needs to be closely monitored given the drug may not work at all.
Tom: There is plenty of evidence it works in people for influenza A, and the mechanism is such (inhibition of neuraminidase) it should also work in H5N1/A as well as all other subtypes where it inhibits neuraminidase. If you have some Tamiflu, Tom, please donate it to the community. I don't have any and if I wind up as a care giver (and I hope to have the courage) I will surely take any that is offerred to me.
Revere. I don't want the vaccine or the antiviral because neither works. When you have a couple of hundred cases and already three or more have demonstrated resistance...the likelyhood that this treatment will make a difference in a pandemic is zero...and the fact that they squandered limited funds on Tamiflu before it was fully examined is not my problem.
Secondly, the retiring regional director of the Asian office of the WHO said a few years ago that H5N1 had 'made a liar out of every scientist who had made a prediction'.
It wasn't very long ago that I read a comment from an expert who said that Tamiflu would work because if the virus became resistant to it, it would lose its virulence...maybe he was on the payroll too.
There has been one technological advancement that works since 1918...and that is the development of hepa filters and filters with the ability to filter out viruses and bacteria...that and disenfectants.
Tom: LOL. Hepa filters to stop a pandemic? That's rich. Any evidence? Nevermind. Anyway, you might want to read the antiviral modeling series (since you engage in informal modeling with every scenario you spin, so you obviously aren't opposed to doing it more explicitly) to reconsider whether there will be zero effect if resistance emerges. Logic and models and commonsense suggest otherwise, but most of us will be glad to have your share of the antivirals and vaccine while you sweat away, 24/7, in your space suit. Hve you ever worn a full face respirator? I guess you aren't expecting to drive (right, no gas, no electricity) because you can't do so easily in a full face respirator. Or if you do, I hope I'm not on the same road with you. Drinking and eating might be a bit difficult, too, but I understand there won't be any food or water so no big deal.
I didn't say hepa filters would stop a pandemic. Nothing will stop a pandemic including vaccine 18 months after it starts...maybe and antivirals where significant resistance has already been demonstrated and in fact, was demonstrated several years ago with seasonal influenza which might have been an indicator if they weren't so happy to jump on their 'magic pills'.
I am not giving you spin. I have no conflict of interest. I am giving you my honest opinion from twenty years of working with farm animal disease...hopefully respectfully...and I supppose I will continue to give you my honest opinion "explicitly".
I actually have worn hepa filters for several for extended periods over many years and have also used full face masks for several hours at a time that I agree with you, is more difficult to manage. I would ask you the same question?
I have learned not to put stock in models. We can't model something (nature) that we don't understand, in my opinion...and I think part of the problem is that human practioners think they understand animal disease which they don't, again in my opinion. If they did they would have never downplayed the risk in the first place...and we would be more prepared today as a result.
You can treat your patients with antivirals and vaccine as a back-up. I will treat patients with proper filtration systems, proper gowns disenfectants and gloves...and we will see.
Thanks as always.
Sorry, I meant to say that you can treat your patients with antivirals and vaccine as personal protection...
...and I will treat my patients with masks, gowns, gloves and effective disenfectants..
...and we will see.
There is nothing worse then healthcare workers walking around with a blind and unfortunately false sense of security.
Notably, the actual reaction here in Japan is very sensible: avoid Tamiflu for juveniles, but not for adults (where there is no data supporting behavioral change) or small children (that are in constant overwatch anyway). And do use Tamiflu if warranted but make sure you have obseration in place just in case.
revere and TomDVM: You both make for interesting reading. Too bad you can't get past your differences. Passion for one's beliefs is intriguing.
Full moon coming too, normally there's a great deal of action and misunderstandings during it.
revere: Personally taking Tamiflu is not an option for me, call it a gut feeling to not put any trust in it. I do agree with TomDVM who said, "We can't model something (nature) that we don't understand".
There's a great deal of truth to that statement and it brings up the potential topic of the unknown and how frustrated Flublogians are living in that unknown. That's just it though, we won't know the full story until during and after the pandemic. And a sidenote, it'll probably be one of the best recorded events in medical history.
Just my two cents, don't get your knickers in an uproar.
Lea, Tom: I think there is a basic misunderstanding. We use models to understand Nature. Almost all of our understanding is in a model. We use them formally and informally all the time. So I think Tom's statement is nonsensical.
I think..."We use models to understand Nature"...is nonsensical.
/:0)
Tom: Hmmm. The Rutherford model of the atom? (solar system) The double helix model of DNA? The "Standard Model" in particle physics? Newtonian mechanics? Relativity? God? Animism? Freud? Lewis structures in chemistry? Chomskyan linguistics (formal grammars)? Resonance in benzene? Etc., etc., All models and all used to understand Nature or the world. That's my partial list of how we use models to understand the world. That's the sense I'm using it.
I'd be interested to hear what you think we use models for if not to understand the world or at least as one of the ways we understand the world. Models can be used for other things, too, of course, but according to your formulation cannot ever be used to understand the world. Isn't that what you said, in essence? In what different sense are you using it?
I have an IDEA! The Indons were so fired up to get the vaccine. Lets give them the option of testing it out on their people first then we can draw conclusions from that and then give them the right of first refusal on the first million doses or so.
As for the testing of Tamiflu Revere it might take some guy like the one that did Malaria testing with nets and proved that it was mosquito borne. Again, its not anywhere near H5N1 and yep, I wouldnt have a clue in all seriousness as to how to even find a volunteer. Monkeys, mice, ferrets and pigs are all going to take a serious hit as we get closer to the vaccine across the next few years.
I wish we had more time and more resources but its just really more time. This vaccine that Webster has is as hot as a firecracker as I understand it and the scuttlebutt is that its a weapon of last resort and took a lot of eggs to make. How many doses? Dont know, probably not enough to even do the city. I keep hearing molecular level vaccines but no one has anything to show for it yet. Problem is that this if the bug comes, then there wont ever be any because the HCW's all work in and around hospital type environments... the big hit. Jeez, spend all of your young life to become a doc, just to get whacked helping some schmo die of H5N1. Oughta be a law that if it comes and they get the numbers on whats happening that they hold back the young docs because I think med school is going to be closed for a while afterwards. There's something those models will be able to generate fast. The number by percentage that HCW's take the hit. After it gets to a certain point they need to pull back and just let what happens go on. Be rough enough to survive post flu, but without the care for the other things in life afterwards its going to be even worse. Vets become human doctors post flu environment?
Revere. With all due respect, you and I both know that there is a big difference between the examples you chose in your post and disease emergence or Tamiflu whatever etc. etc.
This may be unimportant to human practioners but I saw a disease that had not been seen at all (not one case) for fifty years, in three weeks emerge simulataneously on almost every farm in a several square mile district.
H5N1 emerges on an 88 year schedule...not a heck of a lot of difference.
There are a multitude of examples in animal exotic desease emergence...humans control the variables...humans don't understand the variables...humans will never understand the variables...our technologies don't work...we have no power over the issue...hard to accept.
nature is 'regularly irregular'...it never does the same thing twice in a row...if you don't learn from history, you will repeat it...and in respect to pandemics, this is perfectly applicable.
I don't know how anyone could say that a novel pandemic virus that hits the earth regularly three times per century is a 'high impact-low probability' threat.
Tom, explain 88 yrs please. Is that the average between pandemic, moderate pandemic and then superpandemic?
Back to the end of days section at the UN. Their number shows a superpandemic every 384 years if thats what you are saying. If not 'splain pls.
The side-effects thus reported for Tamiflu are a far lot better than those we know about for amantadine, which it is essentially replacing.
Randolph.
I have learned from twenty-years experience that nature (specifically with respect to animal disease emergence and re-emergence) is regularly-irregular.
Disease emergence is intricately connected to environmental factors including weather changes. For instance, Anthrax outbreaks are triggered by rain storms at the end of droughts. Leptospirosis abortion storms in cattle vary with deer populations (deer urinate in ponds from which the cattle drinkthe bacteria then circulates within the cattle herd for months, until again weather conditions initiate abortion storm in the herd but more often geographically distinct herds). As I said earlier, I had not seen a case of blackleg and no one had in our area for approx. fifty years. The disease then showed up on a number of geographically distinct farms within a three week period. So just because we humans cant identify the pattern, nature when it comes to disease is synchronous or harmonic or rhythmic.
The idea that weather patterns influence a wide variety of farm animal diseases is not news to farm animal veterinarians. Anyone who works with cattle knows that calving difficulties and particularly the rate of uterine torsions and uterine prolapses increases with certain but not all full moons
so my natural tendency is to look for overlapping patterns.
The first thing to note is that an unknown pressure has been pushing the mutation of a wide variety of bugs: parasite, bacteria and viruses. In relation to avian influenza, something happened before 1997 to bring out human cases of H5, H7, H9, H11 and H3N8 that jumped from horses to dogs. And it is not just avian influenza viruses. We have had significant mutations in Dengue Fever, West Nile and a wide variety of othersand in addition, a unique exotic disease has been emerging every year for some time. The observable difference with animal influenza viruses is that a series of influenzas emerged simultaneously indicating an unobserved environmental-evolutionary pressure.
Without knowing the precise triggers or series of triggers it should not be expected that we can accurately predict an exact time but rather a time period say 2-10 yearsso even though I picked that specific time period for a reason which I will get into in a minute, the triggering of events happen at some point before the event happens and the time before the disease emerges can also take an indeterminate amount of time, influenced by other environmental factors.
If an earthquake occurs on the west coast of North America every 500 years or even better, if an asteroid hits the earth every 500,000 years, then I can understand the term high impact low probability but not in the case of influenza pandemics. Even though the historical record for pandemics has gaps in it and we did not even know that a virus was the cause of the outbreak in 1918 until decades later, there is a lot of patterning to be mined
We have had ten pandemics in the past three hundred years. In each century we seem to get a couple bunched together (maybe ten years apart) (1729-30, 1732-33, 1781-821830, 1833-34, 1889-901918, 1957, 1968 and one other). The longest inter-pandemic period in history is forty-two yearswe are presently at 39 years from the last pandemic
The statement has been made that 1918 was an outlier and that pandemics normally, more closely resemble the 1957 and 1968 pandemics which were much milder. In fact that is not true. Of the last six pandemics, 1830, 1890 and 1918 were of approximate virulenceand the pandemic in 1580 was described as some cities were nearly entirely depopulated. For that reason, I believe that the outlier was actually the 1968 pandemic and that more virulent pandemics are the norm rather than the exception. I think part of the problem with assessing pandemics is that in different geographical areas you might have different resultsvirulent strains in some places and less virulent strains in othersso pandemics can be described as mild when they are in fact more virulent. The above predictions of virulence are based on peer-reviewed journal articles so I think we can assume that they are correct.
Also, the 1918 pandemic was cause by a low pathogenic avian influenza virus (H1N1) which differentiates it from H5N1 and from the pandemic virus in 1890. In 1878, a disease causing high mortality in poultry emerged and became known as Fowl Plagueso we can assume that large die-offs of bird populations occurred before the 1890 pandemic. We are currently ten years from the emergence of H5N1. Also, it was found that those who had experience the 1890 pandemic were immune to the 1968 virus strain and that may have been part of the reason for the milder pandemic.
Okay, to get back to that 88 yr. time framefirst of all, it is not unusual with animal viruses for them to cycle in 50 or 100 or 150 year cycles for that matter. If you look at 1830-1918-2006 time period, there is a gap of eighty-eight years. If you follow that pattern back in history, you will find pandemics and other events in the same approx. time period and you will also see abnormal and unusual weather patterns causing droughts etc. at the same approx. periods. The question becomes what is driving the weather patterns and what role do sunspots and other astronomical arrangements play because it is known that sunspots and viral mutations seem intricately related for unknown reasonsbut you dont have to know the exact causation to see the patterns. Study the patterns, come up with time frames and then examine them in historical context on the internetit is kind of fun!!
The conclusion I have come to after a thorough examination of the imperfect historical record is that H5N1 is a freak of nature, a one in two thousand year virusand that a pandemic rather than being a high impact-low probability event is imminentthe problem being that nature takes its own sweet time in these things and we still could be days or years from it happening. My bet based on my examination of the evidence is that it will occur sooner rather than later. The fact that there is no other cause that can cause s an equivalent devastating correction, I would hope the spinners and risk managers would take an objective look at the data and make their decisions on science and not expediency as has been the case for the last five years, in my opinion. The public can handle the truth, the whole truth and nothing but the scientific truthand where you get in trouble is when the truth is bent for political reasons. No one has acted in a more expedient fashion then the UN subordinate, the World Health Organizationand it is their poor leadership in the matter that has left us in the position we are in today. Sovereign Governments and Regulators have continually used the WHOs flawed and deliberately misleading science as an excuse for inaction, in my opinion. They are only now starting to realize the truth in my opinionafter a decade of lost opportunities to prepare.
Tom DVM wrote
In addition, if the above statement is true, there may be 10 % of healthcare workers in a highly stressful situation with a significant neurological deficit.
You misunderstand the figures Tom. Look at the figures again. If there is a real effect of Tamiflu on juveniles, then it is around 1.3% (the difference between the control rate, 10.6% and the rate in juveniles taking Tamiflu, 11.9%). If adults reacted the same as juveniles, then at most you would expect around 1% to get some degree of neurological deficit. Again, that assumes the 1.3% difference is real. No measures of variablity was given, but the researchres stated it was statistically insignificant (which accords with my experience of variability in this kind of data). So on the basis of the current data any real difference is much lower or non-existent. This is consistent with the data on adults from Japan suggests the real rate of adult neurological reactions is around 0.03%.
Taking more precautions with adolescents is good, but at the moment the data do not suggest that young people are excessively at risk from adverse events compared to adults. The current concern is due to an apparent "cluster" of suicides by jumping, but Japan has a juvenile suicide rate of between 2-5 / 100,000 (depending on age cohort and sex), and jumping is the second most common form of suicide, so serious statistics is required to determine if there is an excess of suicide deaths in juveniles.
Ian.
As Marissa stated, I don't think there is a debate about whether antivirals can and do produce serious neurological side-effects.
Having convinced myself that we will soon be in the midst of a pandemic, it is my sense that time will tell whether off label, untested and unlicensed use of Tamiflu at elevated dosage rates for prolonged periods of time will produce unintended consequences...
...It will be a shame if healthcare workers suffer needlessly.