Antiviral compound blocks SARS-CoV-2 from entering cells
medicine.wustl.edu
medicine.wustl.edu
There's a caveat, most treatments that look promising don't pan out, but there are a lot in the pipeline and it seems likely that some will. What I think will happen is a cocktail of antivirals, and together these will significantly reduce the mortality. We need that, because it looks like the virus will probably be circulating endemically. The other great thing about a cocktail (as opposed to a single antiviral) is that the virus developing resistance is both less likely and less of a problem if it does happen.
Having said that, we have a good demographic understanding of who tends to get severe Covid-19, and a large testing capacity, so a cheap anti-viral treatment with few side effects could still be effectively deployed.
Sure, there will always be sceptics, but for large parts of people, organisations and governments having less perverse incentives might improve things a lot.
The vaccine-hesitant aren't going to go for treatment until the outlook is dire.
Additionally, in my experience, physicians aren't terribly concerned about infections in vaccinated individuals. When I was last tested, the physician essentially just assured me that vaccinations have been shown to drastically reduce the likelihood of complications, and not to really worry about it. Granted, I could have had a less rigorous physician, or it could that I'm totally healthy.
Many of them seem quite willing to get ivermectin (whether it works or not is another issue). This is a tribal thing: one tribe has determined that the vaccine isn't something their tribe gets, but many of them seem willing to try other treatments that are acceptable to the tribe. (and yes, that's not rational, but humans are often irrational)
The JJ mechanism of action is better understood and less risky, in my view at least it is more acceptable for emergency approval.
As for J&J, yes it’s generally the fact that it’s one and done so it feels less risky to people that didn’t want to get vaccinated. Then there’s the whole mRNA thing as well.
That made zir not fit in, and accelerated zir dropping out of CS and discovering the LGBT community, and non-binary identity.
I don't buy the first model year of a car, very rarely take an on patent drug, and I won't inject myself with a medical device before the long term studies have been completed.
There is no substitute for time. Very few people have had the vaccine for more that 1 year. None have had it more than 5.
Not trolling here, I'm genuinely interested and thank you for sharing.
The vaccine doesn't even need to be "safe" for it to be worthwhile. A person with a short enough expected lifespan (elderly or comorbid) may derive a great benefit from a drug with real long-term risks.
For long term risks, nothing can substitute for time. I'm relatively young. I have an expected lifespan of 40+ more years. Ideally, I would want 40+ years worth of long term data. Realistically, I will settle for 5 years of good data. That should give good enough information to make an informed decision.
The biggest hurdle to overcome is censorship. A large portion of the media and big tech is censoring "misinformation". Its not just social media like Facebook, Reddit, Twitter, etc. nor main stream media like CNN, Fox, MSNBC, etc. Companies like Google are removing advertisement from pages if it says something they disagree with. With this heavy handed skew, can you really trust the information that comes out?
It's not surprising people are far more willing to try out sprays and tablets than injections, even if there wasn't any misinformation and tribal politics
I have personally heard of a number of pretty bad breakthrough cases where a person has had a fever for almost a month, another was extremely sick and there are still people who are afraid of covid for this very reason(and they are vaccinated). Having an effective anti-viral solution will bring down the fear about these scenarios and get people back to work and bring normalcy to society again.
Also, Isreal is no longer vaccine heavy. They were an early leader, but many other countries exceed their vaccine rates these days.
SARS-CoV-2 is clearly not a death sentence, because more than 99% survive if they contract it. And there is a factor of natural immunity, which the US government is oddly trying to smokescreen/astroturf into "get vaccinated anyway".
I am not "anti-vaccination". I had my shots. I am simply against government coercion to push not the best, but the most profitable solutions.
And saying it isn't a death sentence is ignorant, we've lost over 700k Americans alone to it, no idea how many people globally. I dare you to go to someone who's lost a loved one and say that its not a death sentence, because to so many it is.
And bad faith argument? There's no astroturfing. Its a good idea and way more than 50% of the US population supports it. You been drinking the kool aide.
You have a huge important point about all this that I almost missed reading your response, because its mired in 'I'm not an anti vaxer' mixed with hints of conspiracy theories. Big pharma is getting fat off this. Its a problem. It needs to be fixed for the sake of the american people.
We need intelligent people like you to fight for that.
Don’t you think that cocktails of novel antiviral drugs are a higher profit margin solution then the vaccines that are already available? A remdesivir course costs almost two orders of magnitude more than an mRNA vaccine (in the US). Can’t really imagine these novel antiviral drugs will be much more affordable. To be clear, I do think both are important tools that we should use.
Is there some other pragmatic solution you have in mind?
This statement should always come with information about the relative rate at which it occurs.
One "can still" get pregnant despite using contraception. This is not an argument against using it, because the relative rate is far lower than if one did not use it at all.
Does every discussion of about post-exposure prophylaxis have to have comments about vaccination?
> And it works great without the constant need for testing.
A primary reason for testing has been to help stop the spread of the virus (test positive = isolate), not necessarily to let people with mild symptoms or no symptoms know that they're infected.
Vaccinated individuals can still spread the virus and some people are at higher risk even when vaccinated, so testing is still of value.
> I have to imagine that anyone willing to undergo treatment at the very start of getting covid, would have also been willing to be vaccinated.
That's quite an assumption. Without passing judgment about his decision not to get vaccinated and to throw the kitchen sink at COVID once he was infected, Joe Rogan is an example of a person who is willing to treat an infection but not get vaccinated. I doubt he's the only one.
> Additionally, in my experience, physicians aren't terribly concerned about infections in vaccinated individuals.
Vaccination certainly reduces the incidence of hospitalization and death, and the data to date suggests that vaccinated individuals are less likely to develop "long COVID" symptoms. But there's still a lot we don't know. Research indicates that individuals with breakthrough infections can have viral loads that are as high as unvaccinated individuals, and some percentage report courses of illness that are virtually identical to a typical course of illness in unvaccinated individuals (respiratory symptoms, extreme fatigue, etc.) so I think it's premature to make too many assumptions. Especially since in immunologically naive people, some with "mild" or even largely asymptomatic infections also report lasting issues too.
I think results like vaccinated individuals “can” have viral loads as high as unvaccinated individuals are next to useless. I need to know how likely I am to have high viral loads and my understanding of the science there is that vaccines still do a decent job of lowering the odds. I know you aren’t really arguing against vaccination here, but it seems like it needed to be said and I think the “vaccinated individuals can have high viral loads” line is particularly bad
https://www.medrxiv.org/content/10.1101/2021.09.28.21264262v...
https://www.ucdavis.edu/health/covid-19/news/viral-loads-sim...
How is a statement about what some researchers are finding "particularly bad"? If vaccinated individuals routinely have viral loads as high as those seen in unvaccinated individuals, it warrants more research into how the virus affects their bodies and what, if any, risks they might face both short term and long term.
According to one study[1], vaccination reduces the risk of long COVID by 49%. Given that some studies have found the incidence of long COVID is in the double digit percentages[2], exploring this issue is not purely academic. It is pertinent to the hundreds of millions of vaccinated individuals who are still at risk of infection, even if their risk of hospitalization and death has been significantly reduced.
Science works when we ask and investigate important questions. It doesn't work when we ignore these questions because we're afraid of the optics and how they might be misconstrued by some people.
In fact, when it comes to COVID generally, it seems evident to me that shying away from difficult questions has had the opposite of the intended effect. It has probably caused more people to adopt anti-science views and reject beneficial measures like vaccination.
[1] https://www.usnews.com/news/health-news/articles/2021-09-02/...
[2] https://www.medicalnewstoday.com/articles/more-than-one-thir...
That's why the CDC website says Covid (leaky, non-sterilizing) vaccines only provide protection (in blood) against serious illness, not infection (in nose). A future nasal vaccine may provide sterilizing immunity (what most people assume they are getting from a "vaccine", like their personal experience with the MMR vaccine).
What? No, there isn't. The Covid vaccines we have today are not sterilizing. Period. This isn't a conspiracy theory or anything like that, it's just a simple fact.
BBC article on immunity, https://www.bbc.com/news/health-58270098
> There is a whole different suite of antibodies (known as immunoglobulin As) in the nose and lungs, compared with those (immunoglobulin Gs) that we measure in the blood. The former is more important as a barrier to infection. Natural infection, because it is in the nose rather than a jab in the arm, may be a better route to those antibodies, and nasal vaccines are being investigated too.
Intramuscular (arm injection) vs intranasal (inhaled) vaccines: https://news.ycombinator.com/item?id=28165287
Nasal vaccine trials: https://news.ycombinator.com/item?id=28284504
This is conjecture. It's a hypothetical effect to take into consideration, but it's certainly not borne out in data that the vaccines increase asymptomatic transmission, much less for this reason.
> Based on evolving evidence, CDC recommends fully vaccinated people get tested 5-7 days after close contact with a person with suspected or confirmed COVID-19.
For many people, this description could apply to daily activity, e.g. riding on public transit. So the CDC is recommended regular testing of vaccinated people. Since the vaccine can suppress symptoms, testing can be used to detect infection earlier, enabling isolation and/or treatments which only work early in the progression of Covid.
In a July 2021 paper from academics advising UK SAGE, https://www.gov.uk/government/publications/long-term-evoluti...
> Whilst we feel that current vaccines are excellent for reducing the risk of hospital admission and disease, we propose that research be focused on vaccines that also induce high and durable levels of mucosal immunity in order to reduce infection of and transmission from vaccinated individuals. This could also reduce the possibility of variant selection in vaccinated individuals.
Note the reference to transmission from vaccinated individuals. There was also a study of Vietnamese healthcare workers, showing that 70% of infections were pre-symptomatic, https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3897733
> 69 healthcare workers were tested positive for SARS-CoV-2. 62 participated in the clinical study. 49 were (pre)symptomatic ... Breakthrough Delta variant infections are associated with high viral loads, prolonged PCR positivity, and low levels of vaccine-induced neutralizing antibodies, explaining the transmission between the vaccinated people. Physical distancing measures remain critical to reduce SARS-CoV-2 Delta variant transmission.
If 2021 consumer media is offering variable definitions, Cui Bono?
Trying to avoid the sort of bias that comes from trying to reinforce rather than question existing views, but I do still think the statement "No Significant Difference in Viral Load Between Vaccinated and Unvaccinated, Asymptomatic and Symptomatic Groups Infected with SARS-CoV-2 Delta Variant" despite being much more precise is still a bit unintuitive in it's implication. Because essentially what this means right is that they sampled people's viral loads, and then cut out everyone below a value they choose to mean "infected". It's still true that even if I had symptoms because I'm vaccinated my odds of having a high viral load are much lower. Presumably if you didn't remove all the samples with less than some concentration you'd see significant differences.
I think that something the scientists got wrong consistently with covid was not unflinchingly communicating what was likely to be true mostly out of a fear that the public would take interventions that only moderately improved their safety like wearing a mask, and start doing riskier things or because of a bias towards doing nothing when clear evidence didn't exist. It can feel like similar things are happening with vaccination where it does seem pretty clear that getting vaccinated reduces your risk of passing on covid both because you're less likely to ever get a colony of the virus sufficient to count as "infected" and because you're likely to have a shorter infection.
Huh? Please cite the part of the study you're referring to to argue that the title of the study means the exact opposite of what it says.
Every manufacturer of a PCR test specifies a Ct cutoff above which the result is considered false.
> It's still true that even if I had symptoms because I'm vaccinated my odds of having a high viral load are much lower. Presumably if you didn't remove all the samples with less than some concentration you'd see significant differences.
The study says the exact opposite:
> There were no statistically significant differences in mean Ct-values of vaccinated (UeS: 23.1; HYT: 25.5) vs. unvaccinated (UeS: 23.4; HYT: 25.4) samples. In both vaccinated and unvaccinated, there was great variation among individuals, with Ct-values of <15 to >30 in both UeS and HYT data (Fig. 1A, 1B). Similarly, no statistically significant differences were found in the mean Ct-values of asymptomatic (UeS: 24.3; HYT: 25.4) vs. symptomatic (UeS: 22.7) samples, overall or stratified by vaccine status (Fig. 1B). Similar Ct-values were also found among different age groups, between genders, and vaccine types (Supplemental Figure 1).
Maybe I'm misinterpreting the study. I interpreted that as being among the fraction of people who are infected both because that's what the title says, and because they say later that "75% of the positive samples were from unvaccinated individuals" which would seem to be inconsistent with the groups having similar viral loads.
I thought we were dealing with a random variable composed something like this
VIRAL_LOAD = INFECTED ? LOAD_FOR_INFECTED : LOAD_FOR_UNINFECTED
And the study is saying that the random variable `LOAD_FOR_INFECTED` isn't correlated with vaccination status. That's indeed an interesting fact, but since `INFECTED` still was correlated (I think) overall for some random person `VIRAL_LOAD` would be too. Honestly a table would make all of this more clear.
With no offense intended, I think you're misunderstanding the whole concept of "viral load". If you are not infected with SARS-CoV-2, you don't have a SARS-CoV-2 "viral load".
I neither stated nor implied any such thing and these sorts of PSAs are really not constructive. HN I believe has a generally well-educated and technical audience that is capable of having intelligent, nuanced conversation about scientific research.
In fact, with all due respect, given that you've repeatedly misconstrued and misunderstood the research presented, and by your own admission abused terms, all in an effort to argue something that was totally unrelated to what was being discussed, I'd suggest your efforts are actually counterproductive.
But that's totally expected (depending of course on how you define "some"). If the vaccine had 100% efficacy, it would be shocking. The fact that it doesn't is not a surprise.
I'm assuming the point you're trying to make is vaccines aren't as good as expected. If the point is just that there is still value in developing treatments even with vaccines, than yes i agree with you.
No, I was responding to "Additionally, in my experience, physicians aren't terribly concerned about infections in vaccinated individuals" and pointing out that there's still a lot we don't know about the risks associated with infection after vaccination and arguing that these things deserve additional scientific study.
It’s about ‘the vaccine does not protect against getting infected and being infectious in over 50% of cases’.
I'm a teacher and vaccinated. If I found out that I was exposed, and then tested positive... post-exposure prophylaxis sounds great.
Also there's my dad, who has an immune condition due to old age. He's vaccinated, but who knows how effective the vaccine was for him. The existence of PEP could make it possible for him to do more at a similar level of safety... vs. the current option of staying in a small bubble for the rest of his life despite being otherwise able-bodied and capable.
https://www.covid19treatmentguidelines.nih.gov/therapies/ant...
https://www.medicalnewstoday.com/articles/molnupiravir-vs-co...
Vaccines are a 10x or 20x improvement in death and hospitalization rates. That's just a fact. All these antivirals won't have that kind of impact and are closing the barn doors after the horse has escaped. Which is not to say we don't research both, but vaccination is the simple easy and effective answer. There's a considerable technological fetish with antivirals while boring vaccines are now treated with skepticism, which is backwards. Antivirals should be used after vaccines have failed in vulnerable populations, the major weapon against viruses is vaccines, and they work.
I know basically nothing about virology, but I remember hearing a podcast a million years ago talking about mRNA vaccines, and I remember after it was over thinking "if this is even half as cool as it sounds to a lay person, the implications of this are huge". It appears that it's substantially more than half as cool as it sounded, and the fact that we are even having discussions about being able to wipe out malaria is mind-boggling to me (in a good way).
I too am very hopeful for mRNA vaccines, although I don't know how much I should temper my expectations. The idea of curing certain cancers, not just preventing them, is wild.
I think I'm going to temper my expectations to "faster and more vaccines increasingly exotic diseases" for now. I would absolutely love to be proven wrong though.
...
In CAR T-cell therapies, T cells are taken from the patient's blood and are changed in the lab by adding a gene for a man-made receptor (called a chimeric antigen receptor or CAR). This helps them better identify specific cancer cell antigens. The CAR T cells are then given back to the patient.
https://www.cancer.org/treatment/treatments-and-side-effects...
Right now this is done in a very personalized and labor intensive way. I think the thought is mRNA is potentially a gigafactory compared to artisanal methods.
Fantastic podcast covering topic by interviewing the father of these therapies:
Podcast available on Apple podcasts etc. The Drive episode 177.
can't recommend enough.
Traditionally a vaccine has to keep efficacy for a year. We haven’t got a year of data but the efficacy has dropped significantly
https://twitter.com/rishirajgoel/status/1448711946010710023
By basically all measures, these vaccines work better than the flu vaccine, which for some reason doesn't attract the same sort of criticism.
Then Twitter surfaces a recent breakthrough infection study among 620k US veterans in the "More Tweets" section: https://twitter.com/EricTopol/status/1448815262522773520 After six months from initial vaccination (Mar-Aug) the J&J vaccine appears to have zero (!) VE against infection. Pfizer is holding at a modest 53% against infection. Worse, the curve has the same shape as J&J, merely 2 months delayed.
In spite of very promising cellular and molecular studies, I am left scratching my head: are the vaccines any good at preventing infection in the long term, where we define long term as a few years down the road? The question is somewhat rhetorical, as we don't have epi studies from 2025 yet.
PS. I am more than happy to make a distinction between infection and severe infection. The main reason I pay attention to VE against infection are vaccine mandates and the whole stigma buildup against unvaccinated people.
PS2. > the flu vaccine, which for some reason doesn't attract the same sort of criticism.
People are free to get or not get a flu vaccine. Not getting a covid vaccine means loss of livelihood, loss of basic liberties and social ostracism.
https://www.nature.com/articles/d41586-021-02689-y
https://www.businessinsider.com/delta-variant-made-herd-immu...
Gee, I wonder if something happened recently that made stopping Covid more pressing than making everyone get a flu shot? Sure seems like there’s some reason, maybe a few hundred thousand reasons, why as a society we’re taking Covid and vaccination against it more seriously than the flu.
Vaccine protection isn’t binary. Even if you end up infected your disease will be less severe AND you will be less contagious.
Yes, there are lasting changes from the vaccine, no that doesn’t indicate much about level of protection.
I definitely would never get a flu shot with its ridiculous efficacy numbers. If you forced me to get it to remain a part of society it would require my resistance by any means.
If you didn’t respond like an asshole id give you a couple sources. But, bullshit and all.
Even if it's only effective for 6 months, that's still 6 months of slowing the spread, and conceivably we can extend the efficacy by administering booster shots.
But the protection against hospitalization and death is still very robust even after almost a year.
Triggering the immune system does a lot more than produce a single wave of antibodies.
At first glance this sound like a really bad idea, given that the #1 concern is future covid mutations.
There's a lot of detailed discussion about different types of cells. Vero cells don't have TMPRSS2, but Calu-3 (human lung epithelial) cells do. To dramatically oversimplify, this compound works on the latter type but not the former.
They also did a little safety testing in a mouse model. This is early stage, as you point out there are a lot of things that work well in the lab and not so much in real humans, but still I find it promising.
> We analyzed pseudotype entry driven by the spike protein of SARS-CoV-2 (SARS-2-S) or the glycoprotein of vesicular stomatitis virus (VSV-G) into the TMPRSS2-positive human lung cell line Calu-3 (7, 29). VSV-G was used as a control, as it does not depend on TMPRSS2 for host cell entry. Besides Calu-3 cells, we further used Vero cells (African green monkey, kidney) as a control, as these cells do not express TMPRSS2, and therefore any reduction in SARS-2-Sdriven entry would be related to either unspecific side effects or cytotoxicity.
I'm curious how was this published October 26, 2021? (Currently Oct 15)
PNAS recently moved to a continuous publication process so the paper comes out in the planned issue whenever ready rather than effectively coming out twice: once ahead-of-print and once in the issue.
https://www.pnas.org/page/updates#pnas-continuous-publicatio...
Note that TMPRSS2 has been a potential target for treating covid basically since the beginning, so some one lying and claiming it as a mechanism of action isn’t surprising
[1] https://pubmed.ncbi.nlm.nih.gov/32251768/ [2] https://pubmed.ncbi.nlm.nih.gov/32983936/
https://twitter.com/__ice9/status/1368634545717788677
If it works, the OTC nature is important. Hard for any drug to be very effective if the get-an-appointment-see-a-doctor-get-a-prescription-get-it-filled system takes you well past peak viral load before you even start using it.
you mean they only studied it in a computer simulation?
However, this:
> It also just isn’t the sort of thing there would be incentive to lie about
is not true.
There are two incentives to lie about this, if you are in any way associated with drug or vaccine manufacturers.
1.) Ivermectin is out of patent and dirt cheap; basically not profitable at all
2.) Emergency use authorization for the vaccines relied on there being no available alternative treatment
Again, I have no opinion regarding whether or not ivermectin is remotely useful for COVID. But there are plenty of incentives aimed against any older generic being repurposed.
Again, my argument against you was that you said that there was no motivation against it, and I said that wasn't true.
That's simply so factually wrong it's tough to take it as serious. having a treatment that might lessen the severity of some percentage of the people that get covid has absolutely nothing to do with a prophylactic EUA for a vaccine that is wildly efficacious against mild and severe covid cases and stop you from getting it in the first place. Let's do a thought experiment even if that were true... that would mean the other vaccines that are under an EUA would have been revoked the moment Pfizer got their full approval which didn't happen. This is "there are naval insignias on the flags therefore we are not a constitutional democracy" level of conspiratorial thinking.
> 1.) Ivermectin is out of patent and dirt cheap; basically not profitable at all
that's the reason they threw it at the virus in the first place. They were looking for anything that might help.
Sure, ivermectin is dirt cheap, but that doesn't mean somebody couldn't make a buck off of it. Not to mention that any doctor who actually proved something like that to be effective would be quickly hailed as a hero.
This is the problem with the "Covid Conspiracists"--magically everything is 100% worldwide unified action with perfect lockstep and no deviations--in spite of the fact that many of these countries have primal hatred for one another.
So yes, there are more countries, and many ARE accepting ivermectin for treating COVID. And again, I don't know or care if it works, I'm vaccinated and wouldn't take it, nor am I a conspiracy theorist, your point is just not correct.
Um, exactly? We have millions of scrips issued and still nobody can produce data.
Now, what we can posit is that there is a worldwide conspiracy to suppress the fact that ivermectin is effective OR we can posit that ivermectin doesn't actually work very well for Covid.
The problem with anecdotal medical treatments is that the human organism is highly variable. Just about any disease "treatment" will work for somebody, somewhere. But that's not enough to proclaim that something works. This is going to be especially true in countries where parasitic infestation (which ivermectin does treat) is more common. If a significant fraction of your population got their parasitic infestation cured, their Covid numbers are going to look quite a bit better, too.
If we're trading on anecdotes, then I'll say that ivermectin doesn't work. We had lots of people taking ivermectin at various level in US Red State land. Their hospitals still got overrun. If anything, ivermectin use is correlated with more hospitalization. This is, in fact, a tautology--but not because ivermectin makes Covid worse (or better) but because people were getting poisoned by ivermectin and most ivermectin users were in red state areas which had lower vaccination rates.
This is why you don't believe claims without data.
> And again, I don't know or care if it works, I'm vaccinated and wouldn't take it, nor am I a conspiracy theorist, your point is just not correct.
The problem is that your "I'm just a skeptic" ignores the fact that nobody can cough up any data. Continuing to promulgate things in the absence of data articulates your position quite clearly.
My original argument was against the poster who said that there was no reason to lie about the utility of ivermectin. I said that there was.
In arguing against points that I didn't make, though, you keep making points that I still disagree with. Such as this false dichotomy you keep laying out:
> Now, what we can posit is that there is a worldwide conspiracy to suppress the fact that ivermectin is effective OR we can posit that ivermectin doesn't actually work very well for Covid.
Those aren't the only two options. A third option is that ivermectin does actually have some mechanism of action that has some utility in treating COVID, and that the informal clinical data which continues its usage is because of that. You're acting as if there are formal studies which indicate that it has no utility, but all of the data debunking the utility of ivermectin instead suggests that there is simply not a rigorous study formally demonstrating the utility.
For the third or fourth time, I'm not even saying that I believe that it does have utility. I actually don't care about ivermectin.
> If we're trading on anecdotes, then I'll say that ivermectin doesn't work
I don't remember laying out an anecdote saying that ivermectin does work. An argument was put forth saying that if ivermectin did work, there would be scientists and doctors all over the world studying and using it. I said that there were scientists and doctors all over the world studying and using it. I think it's entirely possible it does nothing and those things could still be true. You're the only one between us who is actually making a claim about the utility of the drug.
> This is why you don't believe claims without data.
I don't know what claim I'm purported to be believing.
I guess you could see what their business plan is?
Also, what happened to hydroxychloroquine? That was the big thing in 2020. guess 2021 is ivermectin.
The vaccines were authorized under emergency use with trial participants comparable to samples conducted with Ivermectin.
How is it not worth considering for a drug that's already known to be safe to administer and cheap?
Beyond that, there are practicing doctors advocating that they've had good results. This should be more than enough to consider it's use, and not dismiss it as some 'thing of the year to dismiss'.
Wow so there was an ivermectin study with 44k people? Where is it?
I agree that it should be able to be studied and probably used. But what's going on is that people are looking for an ALTERNATIVE to the vaccine... which is detrimental when the vaccine is proven to be our best tactic against death/serious illness.
Perhaps I should have spoken more precisely, but I don't get the impression you're trying to seriously consider whether ivermectin is useful.
Preemptively, if you're interested in picking apart why one RCT can't be compared in any way to a collection of studies, only some of which are RCTs, I'm not.
> But what's going on is that people are looking for an ALTERNATIVE to the vaccine
*some people
You're effectively strawmanning, and choosing not to engage with the actual doctors who don't advocate this. Which is practically all of the ones I can find. But by all means, please link me all of the doctors stating we should use ivermectin as an alternative. I'll bet I can link a lot more that aren't.
The website I linked above even explicitly states this in bold, on the front page.
>which is detrimental when the vaccine is proven to be our best tactic against death/serious illness.
The trial you're citing seems to indicate there was no observed effect on mortality.
There wasn't. Once you eliminate the studies that made up their data it is clear ivermectin doesn't work in the few studies that are left so nobody would bother doing a big study.
https://www.medrxiv.org/content/10.1101/2021.07.28.21261159v...
> During the blinded, controlled period, 15 BNT162b2 and 14 placebo recipients died; during the open-label period, 3 BNT162b2 and 2 original placebo recipients who received BNT162b2 after unblinding died. None of these deaths were considered related to BNT162b2 by investigators.
There was actually one more death in the experimental group, albeit that's not significantly significant.
So some combination of the following must be true:
(1) The vaccination is effective at reducing COVID mortality, but COVID mortality for people in the trial was such a joke that eliminating 95% of COVID mortality doesn't actually change one's risk of dying in a non-negligible manner
(2) The vaccination is effective at reducing COVID mortality, which does spare lives, but it ends up killing just as many from adverse events / side effects
(3) The vaccine isn't effective and they doctored the numbers.
My money is mostly on (1) with a sprinkling of (2), personally.
---
And since people like to be binary thinkers, this is where I mention that I'm not an Ivermectin shill and as a medical nihilist I'm strongly skeptical of treatments in general. And while I haven't looked at the IVM data very much at all, what I have seen is incredibly weak evidence at best, as well as a bunch of really crappy associative arguments from the IVM crowd ("Africa uses IVM and Africa has less COVID mortality than the US!" as if that proves anything)
To quote (slightly paraphrased) the great Jacob Stegenga:
> If we consider the ubiquity of small effect sizes in medicine, the extent of misleading evidence in medical research, the thin theoretical basis of many interventions, and the malleability of empirical methods, then our confidence in medical interventions ought to be low.
Is the implication that we should have expected it to? The study endpoints are clearly "vaccine efficacy (VE) against laboratory-confirmed COVID-19 and safety data".
It's a general principle of medicine (or at least, it used to be) that the important outcomes are the actually clinically relevant outcomes. Did people die less? Did they achieve a better quality of life? When you get into proxy metrics you get to this weird place where you can show that something is insanely effective for proxy metric X, and yet it makes no difference (or is even deleterious) in thing-you-actually-care-about Y.
Did we need RCTs demonstrating a reduction in all-cause mortality for polio or measles vaccines before it became blindingly obvious that they were a good idea?
For skeptical readers - The linked paper is a medrxiv preprint, with authors from several locations. Many of the authors list affiliations with Pfizer, and the last author is an MD at Pfizer. This seems to be a required report from the ~6-month point of a clinical trial. There really are 14 and 15 all-cause deaths reported in the placebo and treatment groups, respectively. The causes of death for each group are in table S4 [2]. The incidence of COVID in the treatment group is much lower than in the placebo group.
I'm surprised by these results because I would have expected to see significantly lower mortality in the vaccine group.
One possible reason for this surprising result is that only a small fraction of people - even in the placebo group - caught COVID at all. I'm not sure how to account for possible missed infections but Figure 2 of the main text indicates that 0.08% of the placebo group became CASES (which I think means something like "person felt bad enough to see a medical professional, who then diagnosed them with COVID"), and the table in Figure 2 indicates that there were 1034 "occurrences" out of ~22,000 people in the placebo group (which I read as "~5% confirmed infections").
So, it's possible that the beneficial effect of the vaccine is still hidden in the statistical noise since there have been so few infections in the placebo group. It's also possible that some people _were_ harmed by receiving the vaccine (see table S4 [2]), so there's a fixed harm upfront to the vaccine group, which may eventually be surpassed once more of the placebo group gets infected.
Thanks for posting this!
[1] I really do appreciate you making this post, and it helped me learn something. I would have been more willing to read it initially if it had excluded the phrases "such a joke", "since people like to be binary thinkers", "crappy associative arguments", "to quote the great...". It seems like there's a silent majority of HN lurkers that are interested in all perspectives, and really are open to quality arguments like this, but might dismiss this post before reading it because of the choice of phrases.
[2] Link to supp material PDF is on this page: https://www.medrxiv.org/content/10.1101/2021.07.28.21261159v...
Glad you got some value out of my comment!
Thanks for the feedback on my tone. In particular the references to specific examples was very helpful to me. I’ll [try to] be mindful of its effect in the future.
Not that it's necessary but just because it's kind of interesting to psychoanalyze, I think some of the tone comes as a [maladaptive] response to past times on HN where I'd go really deep into analyzing certain studies, etc and then would get downvoted or even flagged because the conclusion was that lockdowns were deleterious or that mandates are a bad idea, etc.
The binary thinkers comment specifically (you're right that it will tend to put people off btw) was because in general (not just on HN) it happens all the time that if I point out, say, how we don't even have an RCT that shows a reduction in all-cause mortality from getting COVID-vaccinated, very often I'll get a response to the tune of "Ivermectin doesn't even work you dummy" because most people seem to only have two boxes to put people in (you're either team trump or team biden, team vaccine or team ivermectin, etc). But obviously even if I had done it in a more diplomatic way, making reference to people being binary thinkers is only going to distract from the actual points being made.
I am curious of your mentioning of being offput by "to quote the great...". Did it sound like I was being sarcastic, or was it something else about it? Because I intended it in the literal sense, i.e. indicating my respect for Stegenga and his work.
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Back to the actual study:
> One possible reason for this surprising result is that only a small fraction of people - even in the placebo group - caught COVID at all. I'm not sure how to account for possible missed infections but Figure 2 of the main text indicates that 0.08% of the placebo group became CASES (which I think means something like "person felt bad enough to see a medical professional, who then diagnosed them with COVID"), and the table in Figure 2 indicates that there were 1034 "occurrences" out of ~22,000 people in the placebo group (which I read as "~5% confirmed infections").
Yes. I suspect that this is partially due to the fact that they actually take some steps to confirm that it really is COVID, whereas in the real world (at least in 2020, but probably still now) they'd run a PCR test with an absurdly high cycle threshold cutoff and then call that COVID even if you were completely asymptomatic (which as an aside is an oxymoron because COVID is supposed to stand for "Coronavirus Infectious Disease", and yet an asymptomatic individual is not diseased (nor are they very infectious btw)). So one interpretation is that when care is taken to actually be somewhat careful about calling something a COVID case, that the prevalence of COVID infection ends up being quite low. Whereas when that care is not taken (whether due to negligence or institutional incentives to drum up case counts / fear in general) you end up with much higher apparent case counts.
This is quite speculative, I know. I'd really like to look at a chart of reported COVID cases in the US versus the rate of cases in this trial. I'd be curious if they are similar shape / relative magnitude, or if there's dramatically more cases in the US in general than the laboratory-confirmed cases in the trial.
I couldn't actually find an actual case definition (maybe it's in the supplement?) but I found this under the Efficacy subheading in the main text:
> BNT162b2 efficacy against laboratory-confirmed COVID-19 with onset ≥7 days post-dose 2 was assessed descriptively in participants without serological or virological evidence of SARS- CoV-2 infection ≤7 days post-dose 2, and in participants with and without evidence of prior infection. Efficacy against severe COVID-19 was also assessed.
So I think that means when calculating their overall VE number, they don't "start counting" lab-confirmed COVID-19 until it's been at least a week post second dose. I do know in general in these trials they like to play that game (ignoring infections before the "fully vaccinated" cutoff to get a better-looking VE number). Although Figure 2 seems to provide numbers starting immediately after dose #1 so I suppose those numbers tell us that while VE is quite bad immediately after the first dose, its expected value doesn't seem to be negative (at least in this cohort)
As an aside, I'd note that they blew up the control arm after 6 months, so this is basically the only clean data we're ever going to get. Which should be very concerning to people considering the enormous push to mandate vaccination for an intervention that has never been shown to reduce all-cause mortality in the studied populations.
> So, it's possible that the beneficial effect of the vaccine is still hidden in the statistical noise since there have been so few infections in the placebo group. It's also possible that some people _were_ harmed by receiving the vaccine (see table S4 [2]), so there's a fixed harm upfront to the vaccine group, which may eventually be surpassed once more of the placebo group gets infected.
Unless the data is doctored or has some flaw that I'm not seeing, I agree that a much higher base rate of COVID infection would probably have shown a positive effect on mortality. Which brings us back to #1 of the 3 possible explanations I gave in my original comment. I find it very interesting that actual COVID mortality (or even bad outcomes) were so rare in this cohort of >44,000 people, that a well-over-90-percent-effective-in-reducing-COVID-mortality intervention literally did not make a detectable effect on net mortality. I think from a societal perspective it's quite interesting because during the time this trial was running, people were (and still are btw) getting bombarded by fearmongering, giant red eternally-incrementing "live" death tickers, etc.
It doesn't take some grand conspiracy to see why that might be, but I think it's something interesting to reflect on. It's a large part of why COVID took me from kind of libertarian leaning to full-blown anarchocapitalist, because I am personally so disgusted by what the media, the public health "authorities", and "polite society" at large did in terms of catalyzing such tremendous suffering on a worldwide scale (via the hysteria, global supply chain disruption, missed medical appointments, cancelled elective surgeries, and outright authoritarian/totalitarian public policy), for something that for most people, they would literally never notice if not bombarded about its existence.