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"Antiviral Effects of Ivermectin in COVID-19- Clinically Plausible?"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225296/

"In a study demonstrating the in vitro antiviral activity of ivermectin, upon incubation of infected Vero/hSLAM cells with 5 μM ivermectin, there was an approximately 5000-fold reduction of viral RNA by 48 hours in ivermectin treated samples as compared with control. The IC50 of ivermectin was found to be approximately 2.5 μM. Ivermectin seems to act on IMPα/β1 and inhibits the nuclear translocation of SARS-CoV-2 (Caly L et al., 2020). Further in-silico studies are required to confirm this target of ivermectin in SARS-CoV-2. The concentrations of 2.5 and 5 μM correspond to plasma concentrations of 2190 and 4370 ng/mL, respectively. These concentrations are 50–100 times the peak plasma concentration achieved with the 200 μg/kg of ivermectin (the US Food and Drug Administration recommended dose for treatment of onchocerciasis) (Chaccour C et al., 2017). Even with a dose 10 times greater than this dose (i.e., 2000 μg/kg), a peak plasma concentration of only ~250 ng/mL has been achieved (Guzzo CA et al., 2017)."

"On the basis of the rationale above, any significant antiviral activity could not have been achieved with the dose used in the study and the resultant plasma concentration of the administered ivermectin. Thus, although ivermectin, in vitro, is a potent inhibitor of SARS-CoV-2 replication, in vivo, the plasma concentration required to achieve the antiviral effect far exceeds the therapeutically applicable dose."

This thread discusses why the example of Uttar Pradesh's program isn't good evidence.

https://twitter.com/GidMK/status/1440131176665006088

Later studies have also shown that Vero cells are probably not a good choice for in vitro Covid tests, due to differences in how the virus infects those cells vs. human lung cells.

This appears to be an innocent mistake; vero cells are very popular with virologists because they’re easy to work with and familiar. But unfortunately they are a very poor proxy for testing Covid cures on, given that they’re actually monkey kidney cells. But it’s a shame we’re still headed down this wrong path publicly.

https://www.qps.com/2020/08/17/vero-cell-studies-misleading-...

Consider dexamethasone.

> There is, no, no large-scale RCT for IVM. However, it is inherently obvious that none will happen, none that give it a fair shake.

Well, the gold standard RCT Recovery (https://www.recoverytrial.net/) had a look.

> The entire public health apparatus in the West has a huge desire to treat all illness with only on-patent, new medications.

Dexamethasone is a cheap steroid. (For that matter, vaccines are incredibly cheap and yet nobody seems to have stopped them in favour of, say, monoclonal antibodies.)

> Do you not thin that this incentive influences what gets into the news?

Evidently not terribly much, given that dexamethasone was at least in all the British newspapers.

> Do you think the public health authorities in Uttar Pradesh are lying?

Quite plausibly. UP is perhaps the worst governed state in India and has been under all political parties. The case of Kafeel Khan is rather illustrative.

More to the point, I don’t care whether they’re lying. The whole article is full of vague statements that are hardly a good basis to believe anything about ivermectin.

> The vast majority of the studies about Ivermectin have been observational, run by front-line clinicians.

OK, so weak evidence.

> Prior to 2020, basically everyone on earth agreed (including the WHO, who STILL agrees) that front-line clinicians and observational studies are excellent signals that can lead to scientific investigations that can lead to medical breakthroughs.

Sure-- weak/crappy evidence and practitioner intuition can definitely point at worthwhile things to study rigorously, even if most of what they generate is trash.

> The evidence for IVM as a treatment for covid (and many other viruses) is quite strong.

??? Quite a leap you made there.

Calling the investigatory and experiential evidence of thousands of highly-trained doctors (some of whom pioneered the standard of care for covid) as "weak evidence" is something that only somebody carrying water for large pharmaceutical companies would say.

Doctors in my area are prescribing IVM to treat covid because in their experience and that of their peers IT WORKS. They have fewer deaths, fewer complications.

But it's "weak" evidence just because Pfizer didn't sponsor a gigantic RCT to "prove" it.

"The only science is real is expensive science done by large corporations!"

Agreed, retract all the meta-analyses you want, but never dismiss actual front line results by physicians. If you have a regimen with zero deaths for a disease, I don't think we should be suppressing their clinical data. What a world...

“Zero deaths” should have set off your alarm bells. That’s way too neat of a number for the real world; you only get that kind of result with small sample sizes or fraud.

Even the vaccines, which are very effective, do not have a 0% death rate from infection.

Officially the FDA and CDC say there have been 0 deaths from adverse events. I agree, that's way too neat of a number for the real world.

https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-...

3 deaths from TTS following J&J as of May 7th where there were 8.73 million doses of J&J administered.

You're saying re: vaccines? There's been several deaths believed to be caused by the vaccines and attributed as such by the FDA/CDC.

And, you know, a few hundred thousand lives saved.

Not a troll: how do you know that number? Pfizer’s own RCT showed no difference in all cause mortality after six months

That was the trial that only had 40k participants. Adverse effects are so rare, it had to be administered to tens of millions of people to the public at large before just a few showed up.

Which number? The few hundred thousand saved?

There's possible confounds, but none can explain vaccinated people being fewer than 6% of deaths (my MLE: about 2% of deaths) and more than 50% of the population. Especially since the vaccinated are, overall, a sicker and older population than the country at large.

The vaccine RCTs were not powered sufficiently to show a reduction in COVID death, given that they had no or basically no COVID death in either group. They did show a huge reduction in illness and severe illness, and now we're observing a commensurate reduction in death in the population.

https://www.cdc.gov/mmwr/volumes/70/wr/mm7037e1.htm?s_cid=mm...

population normalized death incidence is down by 10x in vaccinated over unvaccinated (which includes recovered individuals in with the unvaccinated, so the number compared to susceptible is probably 20x). with a bit over half the population vaccinated that suggests that at least the 100,000 deaths since june would have been twice as bad without vaccinations. not including any effects of vaccination on reducing infection/transmission (and for all the hype about "waning" the protection against infection is still substantial).

Nitpick: there were plenty of deaths reported as adverse events. It was just found that they were mostly expected in a normal population.

I know in Germany we did have over 20 dead from AZ thrombosis.

Was that 20 more dead from thrombosis than would normally be seen in a similar population of that size? Or 20 total? Because my understanding is that it was only a few more than usual.

I can't seem to find the information and think I probably confused this with the UK reporting:

https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vacc...

It's weak evidence because COVID-19 observational studies are riddled with confounders due to COVID patients generally throwing everything at it they can to try and stay alive.

The exact same pattern occurred with hydroxychloroquine. Lots of small observational studies showed promise. Then it repeatedly failed large RCTs. It turns out that the people with the resources to use HCQ also had the resources to use other things, things that were actually effective.

So what were those other things, then?

Dexamethasone, Remdesivir, and monoclonal antibodies are part of the go to treatments for severe Covid cases. They’re the major exotic bits of what they gave trump when he got sick, along with a bunch of over the counter stuff (zinc, vitamin D, melatonin, etc.) My understanding is that the monoclonal antibodies are the really expensive treatments.

The Dexamethasone one is an interesting story. It started out as a more controversial “throw everything at the wall and see what sticks” solution by a specialist who knew steroids well. Later studies have shown a strong effect on survival, so it’s become a fairly uncontroversial part of the tool kit for severe Covid.

Of course, what made Dexamethasone such a breakthrough wasn't really the drug itself; I think there's some evidence now that other steroids might actually work better. The big breakthrough was that some UK researchers managed to use the fact that the country got hit hard early on in the pandemic to immediately run a bunch of large randomized controlled trials on all the most promising throw-things-at-the-wall treatments to get evidence on which actually worked as soon as possible.

> "The only science is real is expensive science done by large corporations!"

The only science that's real when it comes to public health is the science done across large enough populations and with enough methodology to rule out many confounding issues.

That tends to cost money, indeed.

> Calling the investigatory and experiential evidence of thousands of highly-trained doctors (some of whom pioneered the standard of care for covid) as "weak evidence" is something that only somebody carrying water for large pharmaceutical companies would say.

Keep in mind that bleeding with leeches was once the standard of care-- based on clinical intuition and observational evidence.

People-- even very smart, well-educated people-- are easily fooled. There is a reason why the RCT is the gold standard.

The RCT is the gold standard, but observational studies can be sufficient to establish causality when the effect size is large enough with a clear dose response curve. No one has ever conducted an RCT to prove that cigarette smoking causes lung cancer, but we're pretty sure that it does.

> to establish causality when the effect size is large enough with a clear dose response curve.

And when there's some plausible underlying mechanism that can be studied by more rigorous means. Otherwise, observational studies can find correlation, not causation-- and they're not even very robust at that.

No the dose response curve alone can be sufficient. Remember that the FDA has approved multiple SSRI drugs for treating clinical depression despite a lack of understanding on the actual mechanism of action. There are several plausible hypotheses but we really don't know why they work.

A dose response curve in an observational study is irrelevant for establishing causation.

There is a dose-response relationship between umbrellas outside and rainfall., but umbrellas do not cause rainfall.

And the SSRI point is tangential: they were approved based on RCT evidence. Observing umbrella use and concluding it causes rainfall, even though we don't know of a reason why umbrella use would cause rainfall, is quite different.

> is something that only somebody carrying water for large pharmaceutical companies would say

This is directly against the HN guidelines.

I'd consider it weak because covid mostly has non-severe symptoms.

A sugar pill could also get the same observational results because the number of severe cases is very low.

Given the recent fall from grace of prestigious journals like the Lancet on the Coronavirus evidence, I think it is useful for all of us to remain skeptical and purely science-based.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6...

Your assertion of the financial incentives of on patent vs off patent doesn't make sense for ivermectin.

For one, the company that sells ivermectin in the US (Bayer) does not currently have an alternative covid treatment. They have publicly stayed that they do not believe ivermectin helps against covid. Secondly, an RX of ivermectin (for humans) appears to cost more ($35) than the vaccine ($20). Additionally, the vaccine is already paid for, whether or not people use it, many countries (especially the US) pre-purchased hundreds of millions of vaccine doses.

Given that vaccines are already sold and adding ivermectin is pretty safe and is being added to the cocktail of treatments, already being used, I see no financial incentives for drug companies to discourage it.

> I see no financial incentives for drug companies to discourage it.

Then you’re not looking hard enough. You don’t think endless booster shots are an incentive to dismiss Ivermectin? Discouraging Ivermectin means, not billions, but trillions in revenue.

And that’s not even considering the fact that the vaccines could never be legally approved for emergency use if Ivermectin works.

False. The existence of a therapeutic does not block approval of other treatments or vaccines. In fact, there were multiple emergency authorized therapeutics for c19 when the made the eua for the vaccine.

And no one is talking about endless vaccines. We now have a 3rd booster for at-risk populations. It's possibly/likely that if they extend that recommendation to the rest of the population that 3 doses may be all that is needed for long term, strong immunity. Just like there are 3 doses for hep B and several other vaccines.

If the FDA approves a therapeutics for covid19, then the emergency approval for experimental vaccines is gone. Not only do they lose vaccine mandates with that, but they also lose liability shield. There is a financial incentive to suppress covid19 therapeutics from pharma (and their stockholders).

This is a myth that keeps getting passed around. The FDA actually had more than one therapeutic with eua for covid19 when they created the eua for the vaccine. There is no rule forbidding an EUA for a vaccine if a therapeutic exists.

> Do you think the public health authorities in Uttar Pradesh (https://indianexpress.com/article/cities/lucknow/uttar-prade...) are lying?

It's possible, the number of excess deaths in the region over a period (1 July 2020 and 31 March 2021) was measured at 197k compared to other years, but they only reported 4500 covid deaths.

Feel free to actually read the article, it covers this.

> The entire public health apparatus in the West has a huge desire to treat all illness with only on-patent, new medications.

This and

> The vast majority of the studies about Ivermectin have been observational, run by front-line clinicians.

> Prior to 2020, basically everyone on earth agreed (including the WHO, who STILL agrees) that front-line clinicians and observational studies are excellent signals that can lead to scientific investigations that can lead to medical breakthroughs.

and

> Doctors in my area are prescribing IVM to treat covid because in their experience and that of their peers IT WORKS. They have fewer deaths, fewer complications.

Don't really add up. Best case interpretation of your argument is that you think doctors are split in half - not wholly aligned behind novel treatments - the "throw shit at the wall and see what sticks" group and the "only throw new custom expensive stuff at it" group, but even that doesn't really match what I'm seeing.

A large number of doctors are out there throwing all sorts of things at a new disease because nobody knows what works yet. The data is going to be incredibly messy. One thing that has looked effective in many cases is steroids, very much not new. Other things that looked potentially effective haven't continued to look effective as more studies have been done.

Where's the massive pushback against steroid treatment if this is an institutional greed thing?

It looks to me much more like some people get married to their early hunches and dig in hard when the evidence doesn't pan out.

Throw enough shit at the wall in enough places and all sorts of false leads are going to appear. Some of them getting shot down isn't a conspiracy. It's how we learn.

> Do you think the public health authorities in Uttar Pradesh are lying?

Yes.

Heh, nobody is ever ready for that response.