It's important to interpret these results carefully: "no evidence of efficacy" does not imply evidence of no efficacy, and in fact the uncertainty in this study is quite large. The sample size is small enough that it would be very hard for this study to detect the effect of hydroxychloroquine unless that effect is very, very large.
From the abstract:
> In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13-2.89), and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days (24 vs 23 events, RR 1.14, 95% CI 0.65-2.00).
The relative risks and confidence intervals are the important numbers here. For example, the relative risk for death is 0.61, meaning the observed risk of death was lower for patients treated with hydroxychloroquine -- but the confidence interval is 0.13 to 2.89, meaning the data is consistent with anything from the risk being much smaller to the risk being much larger. Since there were only 3 deaths in the treatment group and 4 deaths in the control group, it's very hard to draw precise conclusions about death rates.
I think we can interpret this result to mean that hydroxychloroquine doesn't have a miraculously large effect, but the evidence is weak. Other commenters are correct that large randomized trials will be more definitive.
This is not the bar that's typically applied for drug trials. The goal of a drug trial is not to prove beyond a shadow of a doubt that it DOESN'T work. The goal is to prove to a high level of confidence that it DOES work.
For example, it's highly unlikely (roughly less than 2.5%) that HCQ reduces the onset of ARDS by half.
If it ultimately turns out that HCQ reduces the rate of death by 5%, we'd have to do a tremendously large trial to distinguish that effect from the control with any confidence that it's not actually killing 2% more people. Additionally, you'd have to consider that vs. the fact that it will kill some fraction of people who take it from its cardiac side effects, even if doctors are vigilant about discontinuing therapy when arhythmias are detected.
Typical trials are designed to have a large enough sample size that they will be able to detect any effect big enough to be clinically important.
Here, they just went with the sample size they had available (understandably), which was so small that only a very large effect could be clearly established. It is completely wrong to interpret the lack of a statistically significant effect with this small sample size as showing that the drug doesn't work.
Consider the result regarding transfer to ICU or death:
20.2% patients in the HCQ group were transferred to the ICU
or died within 7 days vs 22.1% in the no-HCQ group (16 vs 21
events, relative risk [RR] 0.91, 95% CI 0.47-1.80)
The best estimate is for 9% less risk from using the drug, with the possibility of the drug cutting the risk by more than half not being excluded in the 95% confidence interval. Of course, the possibility that the drug actually makes things worse is also not excluded, but this can certainly not be characterized as proving that the drug doesn't work.
I have no problems with the way this test was set up. It was a quick study that would have told us quickly if there was a huge benefit from HCQ. That wasn't the outcome. Larger tests with better statistical power will tell us if there is a smaller positive effect. My point is, the smaller the beneficial effect, the larger the test will have to be to find it, but also the lower the overall benefit to patients.
Again, note also that more patients on HCQ were diagnosed with ARDS, so if you pick a different measure, you get the opposite result.
My immediate reaction was that I would not expect to see an effect if you are giving HCQ to patients after they have been hospitalized by the virus. You are now into the inflamation/cytokine storm phase of COVID-19. The best chance of HCQ working is very early, ideally before or directly after exposure. The jury is still out if you take HCQ after the onset of sympthoms if that is also too late.
Based on this in-vitro study - https://www.nature.com/articles/s41421-020-0156-0 - if I hypothetically had both Chloroquine (CQ) and Hydroxychloroquine (HCQ), I would prefer HCQ for prophylaxis/pre-sympthoms, but if I was sympthomatic, I would choose CQ. The loading time or HCQ is longer and it appears less effective at higher MOIs "the data suggest that the anti-SARS-CoV-2 activity of HCQ seems to be less potent compared to CQ, at least at certain MOIs."
> The best chance of HCQ working is very early, ideally before or directly after exposure.
Adding to this, there are at least two reasonably sized ongoing trials of HCQ with appropriate randomization and blinding in North America alone (I believe there are a number of others elsewhere). I would encourage everyone to withhold judgement until either they post results, or a similarly reliable alternative data source appears.
Yeah I was wondering about that myself. There are 5 participating locations listed, but even then it's a large sample size and an aggressive time frame. On the other hand, just about any healthy adult who recently came into contact with a confirmed positive case is eligible to enroll so maybe it won't be so difficult under the circumstances?
For pre-symptomatic C19 patients, we're already doing a large-scale natural experiment, because HCQ is part of widespread protocols for common ailments like RA, and the dosages those patients get are comparable. As I understand it: we're admitting lots of RA patients with C19; there doesn't seem to be a huge effect with early dosages either?
Yeah, it's pretty clear there isn't a huge effect. But there may still be a big enough effect to move the needle. I have no knowledge of the RA/Lupus subgroup, so any anecdotes to share are welcome!
I'll track down the source I read this from, but my claim was specifically that we are hospitalizing people with RA on HCQ already. So that doesn't really respond to what I said.
> For example, it's highly unlikely (roughly less than 2.5%) that HCQ reduces the onset of ARDS by half.
is not one that can be justified by frequentist statistics such as those used in the article. We can't make probabilistic claims like that unless we go Bayesian.
Well-designed drug trials typically plan in advance to have the sample size necessary to detect an effect of clinical significance. If, say, a 20% reduction in ARDS would be valuable, you would work out what sample size you'd need to reliably detect such a reduction. In this case, we simply don't have the sample size to conclude much of anything, because the confidence intervals include what I (as a non-physician, admittedly) see as a pretty wide range of clinically meaningful effect sizes, and we can't distinguish between them.
Actually, I CAN make that claim based upon the data in the article. The relative risk [RR] of developing ARDS on HCQ vs. in the control group was 1.14, with 95% confidence interval of 0.65 - 2.00. That means that 95% of the time, the relative risk will fall between those two guardrails. If we take the single-sided probability, then the relative risk will be less 0.65 2.5% of the time. "Reducing the onset by half" means a relative risk of 0.5, which is less than the lower 95% confidence interval bound.
No, this is a standard example of a claim you cannot make with frequentist statistics, and can only make with a Bayesian credible interval.
In frequentist statistics, the true population parameter is fixed, not random, so the claim "the relative risk will be less 0.65 2.5% of the time" has no meaning. The 95% claim is that if we repeatedly sample new data, 95% of the time we will generate a confidence interval covering the true parameter; but that does not say anything about the individual confidence interval in this specific case, about which we have no probability claim. Indeed, it's not clear what a 95% chance would mean for a specific interval, since probability in frequentist statistics is defined in terms of long-run probabilities over repeated samples of data.
But the impulse to interpret confidence intervals in a Bayesian way is common, since it's the question we want confidence intervals to answer. You can find a lot of academic papers arguing about this as a sign of the inadequacy of frequentist statistics.
Title of the paper could (with a tongue firmly in cheek) be called, "Weak evidence for effectiveness of hydroxychloroquine but our sample was likely too small for it to pass a T-test"
> Title of the paper could (with a tongue firmly in cheek) be called, "Weak evidence for effectiveness of hydroxychloroquine but our sample was likely too small for it to pass a T-test"
It would be irresponsible to choose an experimental design (like significance level) and then use wishy-washy language ("weak evidence") to work around it when the study criteria aren't met.
This would be more akin to the headline from the press release for the study from the university PR office.
> In the US the phrase "tongue-in-cheek" means "kidding."
I took that to mean they obviously weren't suggesting something so conversational as the actual title, but the takeaway is the same and shouldn't be a conclusion taken from the OP comment.
Well, given the time constraints, and the fact that the previous paper was had a much weaker setup yet claimed efficacy, I think this paper is a good idea. Incidentally, it's not the only such paper; a chinese analysis from the early days came to a comparable conclusion.
Even based just on this evidence, the case for HCQ looks very, very weak. The only positive report was riddled with caveats that could easily explain a false-positive, and other reports see next to no effect.
Note that it's perhaps not so interesting whether it has some effect; for this to really matter, it needs to be somewhat significant effect (in the real-world impact sense, not the statistically measurable sense). And even a small sample can reliably detect large effects; several studies have now not found such an effect; ergo: it doesn't exist.
If HCQ has any benefit whatsoever as applied once very sick, the benefit is likely too small to matter much in terms of mortality. And it's unlikely to be relevant whether it works beforehand; there's no way to make enough to give it to everyone which is what you'd need to do if you wanted to significantly impact the pandemic if HCQ were prophylactic.
It seems very unlikely at this point that HCQ is going to matter much in the course of the pandemic.
It is weak evidence for the effectiveness of hydroxychloroquine. e.g. if you ran this as a Bayesian analysis you would find that these results should shift your beliefs towards it being more likely that hydroxychloroquine reduces deaths + ICU visits.
However you are correct that the medical community has decided to be conservative to reduce the likelihood people make decisions based on weak evidence. That may be the correct decision from a overall social welfare perspective. In that framework all we can say is "this experiment did not generate enough evidence to reject the null hypothesis".
"Weak evidence for effectiveness of hydroxychloroquine but our sample was likely too small for it to pass a T-test but it has a compound that was championed by a politician so it will be trumpeted far and wide by those who don't understand any of it and it will trampled upon similarly by those who don't understand any of it. "
There are two potential benefits of hcq people are hoping to prove: first as an antiviral, secondly as an immuno modulator for the IL-6 pathway. As a nonspecific antiviral any benefit tends to be for the early stage of the disease, possibly as a prophylaxis or preventive. So to me this trial mostly shows that there is no discernible benefit for hcq as an immuno-modulator. That is disappointing but not too surprising. I hear people with autoimmune problems say that it takes a month or two for the drug's effect to kick in. That is about 12g of cumulative dose, too big to reach in a short time without acute toxicity. I wonder here if also people of the high risk group could benefit from prophylactic use. Is there any truth to the claim that lupus patients on hcq don't suffer from covid? This claim should be easy to check now that we have so many cases of covid around the world.
Excellent point - this study does add to our knowledge - the case is now pretty much closed on the efficacy of HCQ as an immuno modulator for COVID-19.
"In the weighted analysis, 20.2% patients in the HCQ group were transferred to the ICU or died within 7 days vs 22.1% in the no-HCQ group (16 vs 21 events, relative risk [RR] 0.91, 95% CI 0.47-1.80)."
Qt prolongation does not mean you have arrhythmias. You don't get tachycardia or atrial flutter or necessarily sympthoms. Clinically if it means there is a risk if the QT interval gets to long that you will have a fatal arrhythmia - torsades de pointes. So you need to know how bad the Qt prolongation is. In the paper 2 patients had serious side effects - one with QT prolongation over 500ms and the second with a first-degree atrioventricular block. Another maybe had a left bundle branch (not great, but not fatal). They resolved by stopping HCQ treatment.
Wouldn’t ecg changes be plausibly the result of the virus itself? I haven’t read the paper so maybe they go into greater detail but it would be important to know whether such changes were seen in the control group as attrition/discontinuance is critically important to any study.
Well they're the most frequently occurring serious side effect of HCQ, so I'm not sure why you're leaping to blame the virus when the drug they're giving is well-known for causing exactly those problems.
Those ECG changes aren't generally observed just in people who have COVID-19; it's the drug that we know does that, doing that.
Okay but there are actually good reasons to test hydroxychloroquine, as it is effective against viruses with relevant similarities to Covid-19. The same is not true for chocolate milk.
To address the elephant in the room: yes, Trump did come out in favor of hydroxychloroquine, but his opinion on medical issues is literally meaningless noise in both the informational and auditory senses of the phrase. We certainly shouldn't be pursuing hydroxychloroquine because Trump said to, but there are other good reasons to at least investigate it.
Exactly. One virus which is has been proven effective against in vitro is SARS-CoV. Which is probably why it is being tried against SARS-CoV-2. The two are similar, but with clinical differences (big surprise).
> Other commenters are correct that large randomized trials will be more definitive.
The reason they aren't doing large randomised controlled trials is because the hydroxychloroquine itself is killing people, and it's unethical to continue.
People have said they'd rather have malaria than take it, and that should tell you something. The side-effects for hydroxychloroquine include death, which is not immediately obvious from reading HN.
Doctors aren't just making this up and ignoring evidence, the drug is bad, and not effective for covid-19
I have a friend who takes it for lupus, and has taken it for years. Clearly, he hasn't died, in part because it is a prescription drug and requires a doctor's script. He understands the risks and the benefits. He has taken it for years, as I mentioned, so your "people have said" is clearly not inclusive of a large number of people. The medicine is made by several manufacturers, and if there wasn't a market, that wouldn't happen.
There's a very strict set of people that prescriptions are given to - i.e. not a routine treatment for viruses like this.
There's a reason it's not licensed for viruses, and why only a tiny number of people take it, and there's a reason why wide scale trials are being cancelled. There isn't a huge anti-hydroxychloroquine conspiracy here
This is absolutely true. But the reason that a bland non-result is newsworthy is precisely because various public entities decided to treat the previous result as much more significant than it was. And it absolutely does serve as a refutation of that rhetoric.
And this we now have the opposite problem, where a potential option is treated like it has the legitimacy of crystal healing, depending on the political side you sit on.
Sorry, who exactly is likening chloroquines to crystal healing? I hear this all the time, but frankly it's a giant strawman. No one serious (i.e. a public figure with media coverage) is arguing against the efficacy of chloroquines.
Boosting unproven drugs is dangerous and irresponsible, and arguing that fact is not the same thing as arguing that the drug is ineffective.
Would it be the same thing to do 1,000 small studies like this one as doing one LARGE study with 1000x more people? Would the results be considered just as useful?
That isn't the same as the studies are likely to be different. If one study is old people, another young, another those with diabetes, and so on. Some may have data but it is clouded by a biased sample...
Putting this all together is done in meta analysis which is complex and finds things in small studies that don't show up but it isn't trivial to do them.
Also, it's extremely hard to account for all kinds of biases and systematic errors in a meta-analysis. I'd take most meta-analyses, even by renowned statiticians, very, very skeptically. Teasing out small effects from samples that need corrections for lots of confounding factors, and then trying do combine many such results is next to impossible.
If your effect is small enough that you need a meta-analysis in the first place, that's a warning sign.
Obviously it's sometimes possible to do this right, but the reproducibiility crisis didn't appear out of nowhere; it's best to be wary of overly clever statistics; hard to know what you don't know.
Magic potions do not work, we all should know that in 2020 and wait for the scientific trials step by step... as for corona, today the most promising way before a vaccine, if any, is tailored therapy aimed at containing symptoms so that your body and immune system can fight off the virus at full strength... and we are starting to see a great number of cases that actually improve and can help similar cases (for age, sex, comorbidities, etc.) worldwide, so more hope today than one month ago even if infection numbers are still rising up.
I do not think this argument is relevant to estimating effect sizes, rather than binary outcomes as the Less Wrong post does.
If the claim had been "no patients treated hydroxychloroquine recover", and the study found no patients that recovered, the argument would apply: there's no evidence that patients recover, which starts to suggest that indeed, patients do not recover.
But here we are interested in estimating the size of the effect, which can take any continuous value. The statistical result is that the relative risk of death is, with 95% confidence, somewhere between 0.13 and 2.89. You can't interpret that as evidence relative risk is exactly 1 (equal risk with or without the drug) -- if you could, you could also take it as evidence the relative risk is 1.2, or 2.7, or 0.75.
In this case it really is not evidence of an absence of an effect. In fact it should increase your belief that the treatment has an effect (e.g. if you did a Bayesian analysis), since the treated group did have lower death and ICU usage than the untreated. However this evidence does not rise to the 1% or 5% that we traditionally use, so it's fair to conclude that we don't know if the drug works or not.
This experiment is so small that it had virtually no chance of ever being able to detect an effect on the probability of death (what statisticians call the "statistical power" of the experiment is only 10% whereas a well designed study should aim for power above 80%). Even if the drug cured 100% of people it was given to, a study this small would not be able to statistically conclude whether the drug works. Since the baseline death rate is only 4%, it takes fairly large samples to be able to detect any change. A 200 person experiment has basically no hope of being able to detect a difference in the death endpoint (there is a bit more hope for the more common ICU endpoint).
> "no evidence of efficacy" does not imply evidence of no efficacy, and in fact the uncertainty in this study is quite large. The sample size is small enough that it would be very hard for this study to detect the effect of hydroxychloroquine unless that effect is very, very large.
What you're saying might be correct but misses the point of the parent (and perhaps statistics) completely.
By that logic, you could just not do the study at all and claim it as evidence of absence. Statistically, it's the same problem. You need data (and lots of it, relative to the noise) to provide evidence of anything.
Personally I'm witholding judgment until the results of the PATCH trial (https://clinicaltrials.gov/ct2/show/NCT04329923) arrive, as it'll finally give us some decent statistical power, and be a full, double-blind RCT. It also has multiple study arms (health-care worker prophylaxis, home-quarantined early stage, hospitalized later-stage), so if it turns out that HCQ is effective but that by the time patients are hospitalized it's too late, as some are now suggesting, we should finally know with some degree of certainty.
Yeah, the devil is really in the details about exactly when and how you administer it.
Doctors are already saying that it's definitely no magic bullet, but they debate whether it is effective at a certain stage of illness.
What I don't understand is why we're focusing so much on this specific drug when there are some great antivirals out thee that have a more effective theoretical mechanism of action. (eg Remdesivir)
Remdesivir could be great, and there are a lot of studies ongoing about it. However, it has a long production time
- Gilead says 6 to 8 months: see https://www.gilead.com/purpose/advancing-global-health/covid.... They're only projecting to have 500,000 treatment courses by October, so it could only help a relatively small fraction of the people that will have coronavirus.
Even a small volume of an effective treatment could still be helpful. Usage could be restricted just to patients with cases serious enough to otherwise require ventilators, for instance, which would both ease the strain on limited ICU resources and save lots of people who would otherwise die (since only around 10-30% of ventilated patients survive even with that treatment).
By the time we have lots of it, we will have good statistics on demographics of people most likely to need it, so you could make educated guesses and still see a benefit.
To offer some perspective, in Montgomery County, just north of Philly (a suburban metro county harder hit than most), 10% of positive tests have been admitted to hospital, and 2.6% of positive tests have gone on ventilators.
So the subpopulation needing remdesivir is probably less than 5% of the positive cases (or 1250 of the 25,000 who tested positive here). BTW, the county population is 900,000.
Right, but it isn't a random sampling of that population that ends up on ventilators. For men over 65 with hypertension, it's about 50% of those who test positive.
...so a targeted application of anti-virals is definitely worthwhile.
Remdesivir (and other antivirals / T-inhibitors on trial) are all extremely difficult to manufacture (and expensive) compared to hydroxychloroquine. Most hospitals and countries will be unable to acquire the amounts required for even small trials. It will be many months before we can begin to see results for these drugs.
It's being focused on in the news, but the others are also being tested. The big problem is like the GP raised, we need proper testing to really be able to say much about the ability of any of these drugs to help.
Honestly, if this were not linked so tightly at this point to a certain U.S. politician, then I doubt that it would receive much media attention at all. And it would probably be the sort of thing that HN and Reddit would view favorably.
It would be same as Remdesivir, nitric oxide, and favipiravir. They all have clinical trials going on and anecdotal evidence of efficacy . Most people have never heard of any of these treatments. Like most drug trials, they will probably show a limited or no improvement over the control group. We can get our hopes up, but we should be planning that there will be no effective and/or viable treatment deployed before a vaccine is released.
The difference of course is that HCQ is part of the existing treatment plan of SK, France, and other countries. At the very least we’ll have a large sample size in the next few months.
And how funny is it (at least to me) that this is only because Trump came down on one side initially. If he had come out saying exactly the opposite, that HCQ was bad and we should be skeptical, everyone hoping it doesn’t work now would be looking for the 10 person studies saying it totally works and defending its use.
It’s almost beyond reason how hyper partisan this specific issue is.
Maybe we run in different circles but the two main sides I've seen are "This drug is a miracle cure" and "Maybe let's wait for some evidence". If the first side flipped to "This drug is terrible" then the other side would still be saying "Maybe let's wait for some evidence". I haven't seen very many people actively hoping the drug doesn't work just to spite the president.
For some issues there's plenty of partisan hackery to go around, but in this instance there is clearly one person to blame for turning this into a partisan issue. Politicians should not be offering their opinions on drug efficacy, full stop.
This is not accurate and kind of exposes your own bias.
If you listen to virologist podcast, TWIV, they talk about the effectiveness of HCQ. They aren't all "it's amazing!", but they do not make the claim that it doesn't work.
Sorry, I don’t buy into pole riding / hero worship, nor do I believe that theoretical-you on the theoretical-“other side” wouldn’t have an equal but opposing argument.
It’s all game, do you really not see that? ... If you’ve been following this topic, shouldn’t you be able to make the steelman argument for it?
Because it's easy to make, there's tons of it lying around already, and it doesn't need human safety trials (we already know safe dosages). If it works, it'll be a near-miracle.
Because this drug can be cheaply manufactured out of patent. Let's say Remdesivir is the only drug that works, it's basically an admission that Gilead is going to have us over a barrel.
> it's basically an admission that Gilead is going to have us over a barrel
That's absolutely not what would happen. I was chatting with a family member who used to work in biotech/pharma and posed the question what would happen if Remdesivir is found to have efficacy against covid-19. What they said is basically there would be licensing done immediately to other pharma companies which would run manufacturing in parallel with what Gilead is doing. Gilead will be getting profits from each pharma company that gets a license. I am unsure why the lead time is so long, however it may be that the company does not want to create a huge supply of a drug that may not be effective. But this is very interesting, the pentagon is getting lots of remdesivir for troops so there must be some info that leadership has about its success rate:
https://qz.com/1834939/how-the-military-secured-experimental...
So the reward for spending millions on neglected tropical diseases is nothing. That's a great motivator for the company that cured HIV and Hep C to keep working.
The post I was responding to had the strong implication of a Mafiosi stopping by a store and saying "Nice store you have here - it would be a shame if something happened to it". "You might want to consider our needs and sell us stuff at what we consider a good price".
My comment was specifically in regards to extortion, and you'd need the court of public opinion on your side to do it anyways. The US government still does use eminent domain to do stuff people don't want - see recent examples involving the Keystone XL pipeline and the border fence where everyone from native american tribesfolk to ranchers have had their property seized by the government against their wishes.
That's how the USA behaves literally all the time with other countries and foreign companies. It seems like a weird time to choose to play nice for once?
Yes, different arms will have data available at different times. The prophylaxis one might take longer than the others, but for the ones involving sick people, once they hit their target enrollment (which probably won't take long at all), those people will either get better or they won't.
I wouldn't expect a given prophylaxis case to take more than ~2 weeks to assess (the recommended quarantine time), and I would expect there to be significantly more eligible participants for that arm than the others. Am I missing something?
Prophylaxis is for people who are currently negative (it's pre-exposure, not post). You need to give them the medication (or a placebo) and then wait long enough for a significant fraction of each group to have had an opportunity to become infected, so you can meaningfully compare the trial group with the control group. They're all wearing PPE and such anyway (both groups), so not that many are going to seroconvert even in the control group in just a couple of weeks.
I don't see how any of this would increase the time to evaluate a given study participant beyond ~2 weeks? Regarding what you said about prophylaxis, the study page specifies that participants will either:
* Have had close contact with a known positive individual within the past 4 days (but not have any symptoms themselves yet).
* Have developed symptoms (and tested positive) within the past 4 days.
Technically that's not really a prophylaxis, but it's early enough that it's practically the same thing. It's also more representative of how we would be likely to employ the medication in the real world. (Also I don't see how it would be ethical to intentionally expose people, and waiting for people to be inadvertently exposed seems impractical for a number of reasons).
> Worryingly, significant risks are identified for combination users of HCQ+AZM even in the short-term as proposed for COVID19 management, with a 15-20% increased risk of angina/chest pain and heart failure, and a two-fold risk of cardiovascular mortality in the first month of treatment.
Based on that, azithromycin would appear to be a decidedly bad choice of antibiotic to use in conjunction with HCQ. Luckily there are many others available.
Other antibiotics than azithromycin have been used, e.g., doxycycline. The antibiotic's purpose is to halt opportunistic bacterial infection; many antibiotics are available to do that.
But azithromycin has an ACE2 inhibitory effect and its use in disease modulation is postulated to decrease viral entry to the cell in a similar mechanism to HCQ, hence the discussion of dual therapy there.
The opportunistic bacterial infection is separate (although you’re correct that it has a role here)
> so if it turns out that HCQ is effective but that by the time patients are hospitalized it's too late
What's the mechanism supposed to be here? If it suppresses replication of the virus, shouldn't that be effective up to close to the point of death - once replication is slowed enough, viral load should fall off, and recovery should happen?
There's some evidence now that viral load peaks in the first week, and it's the second week that tends to be a problem for people with very serious cases. By the time many of these patients are hospitalized, their viral load is already going down on its own, and their serious complications are either due to immune overreaction (the so-called "cytokine storm"), or some sort of opportunistic co-infection like bacterial pneumonia.
It's decently likely from what I've been reading that there might end up being effective pharmaceuticals for each stage, but that they'll be totally different from one another: maybe HCQ and antivirals like remdesivir or favipiravir early, and maybe immune-modulators like tocilizumab or even corticosteroids in this second phase. But again, the devil will be in the details, as it looks like HCQ doesn't work late, and steroids or other immune modulators might be actively harmful in that first stage when the virus is still surging.
As for mechanism: nobody is really sure. HCQ does have some immune-modulating effects (that's what makes it useful for lupus), but there's also speculation that it might have some effect on the interaction between the ACE2 receptor and the coronavirus spike protein, and so somehow inhibit viral entry (see, e.g., https://www.nature.com/articles/s41421-020-0156-0).
Hydroxycholorquine is an immunosuppresant not an anti-viral, so the theory here is the problem isn't the virus, but reacting to it. It's not quite as silly as it sounds - this does, rarely, work, specifically with malaria. But, it is pretty silly when you contrast the likelihood of it being a meaningful thereapeutic versus the significance it's taken on
From my understanding it does something to the virus membrane which then allows a high dose of zinc to actually disrupt the virus. I think the antibiotic component is to suppress risk of a secondary infection due to the suppressant effect.
Part of the reason I'm suspicious of hydroxycloroquine and zinc is because for decades zinc and cloroquine have been fringe quack medicine staples for treating/preventing colds and flu.
From what I understand, in the late stages of the disease, it's not necessarily the virus that's killing the patient. Often, the virus has been cleared and it's the patient's own immune response that's doing the damage.
This matches what I've read, too. It's less about the virus during the later stages and more about the infected person's immune system. If they've entered a state of amplified immune response, colloquially called a "cytokine storm," organs are damaged when their cells are mistakenly attacked.
If you can moderate the immune system's reaction you can prevent significant damage. HCQ is useful for this type of immuno-suppression.
Here's a pre-print of an article from a few years back which talks about HCQ and cytokine storms:
Scott W. Canna, Edward M. Behrens. Making Sense of the Cytokine Storm: a conceptual framework for understanding, diagnosing and treating hemophagocytic syndromes. Pediatric Clinics of North America [Preprint]. April 2012.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368378/
My understanding is that tocilizumab is roughly 100 times as expensive as hydroxychloroquine and has intensive storage requirements. I don't see how the drug scales.
That link says the primary completion date won't be until April 1, 2021, a year from now. Seems like we should be able to collect valuable information much sooner than that because of the volume of patients, right?
They should have data already on this. Basically, is the current rather large population of people already taking HQC under representing in the Covid-19 patient data.
Given that I need hydroxychloroquine to treat my rheumatoid arthritis, I'd like this hypothesis to be either proven or disproven as rapidly and as unambiguously as possible.
Because HCQ’s efficacy was briefly endorsed by a controversial political figure I fear that there’s no evidence in either direction will convince the true believers. This is now a political issue, like global warming. Hopefully someone is ramping up production so availability improves for those that actually need it.
Yup - and said controversial political figure jumped on the guess before the science was in and heavily endorsed it - this is likely leading to widespread misuse of a drug which is know to cause extreme damage to organs including kidneys, livers and eyes when misdosed and taken in excess.
The science may be apolitical, but the choice to accept or reject the science can depend on your politics. I think the anti-vaccination movement has shown that no amount of evidence is sufficient if someone is strongly attached to a belief for ideological reasons.
Imagine if Obama had "endorsed" Biden using the same language. Would you have considered it an endorsement? I find the interpretation of what he said to be very peculiar.
What is the comparison being made here? Endorsing the frontrunner for political candidacy isn't remotely the same as endorsing an unproven drug to treat an ongoing pandemic.
HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real chance to be one of the biggest game changers in the history of medicine. The FDA has moved mountains - Thank You! Hopefully they will BOTH (H works better with A, International Journal of Antimicrobial Agents).........be put in use IMMEDIATELY. PEOPLE ARE DYING, MOVE FAST, and GOD BLESS EVERYONE! @US_FDA @SteveFDA @CDCgov @DHSgov
For a comparison (to the original point made above):
Joe Biden has a real chance to be one of the biggest game changers in the history of this country. The Democratic party has moved mountains in their support of them - Thank You! Hopefully he will take office IMMEDIATELY. PEOPLE ARE LOSING FAITH, MOVE FAST, and GOD BLESS EVERYONE! @US_DNC @JoeBidenPrez @POTUS @IowaElections
The base rate probability for an arbitrary drug to treat a disease with no treatments is probably extremely low, < 1%. There are thousands of drugs; at most a few treat COVID-19. Suggesting that any single drug has a significant chance of a positive effect puts it well ahead of the pack.
By contrast, the base rate for a former Senator doing an okay job with the Presidency is probably in the range 20-80%. Suggesting that Biden would do as well as any other former Senator (may or may not) is not an endorsement, but suggesting he would do much better than the base rate is definitely an endorsement.
My mother, a pharmacist by training, has repeatedly communicated her impression that "this whole coronavirus thing would be gone in a week if we just gave everyone HCQ!"
She got that impression from somewhere, but certainly not from any of the studies I've read, leaving the conservative news sphere as the likely source. Whoever is making the exaggerations, they're egregious.
I'm not at all sure I would like millions of doses of Joe Biden to be placed in the federal stockpile of emergency medical supplies, even if those doses were for the sole use of the federal government. It sounds kind of expensive and I don't think anyone knows what the effect of Joe on the coronavirus actually is.
They will do that with vaccines before they are approved as well as a preparatory step. They likely will do it with more than one vaccine formulation, even if only one is ultimately approved. Stockpiling isn't an endorsement.
My wife is feeling the same anxiety - she'd usually get 90 day fills at the pharmacy and they've scaled it back to 30 day fills... which is great because folks with autoimmune diseases really should be going to the pharmacy more often.
I don't believe that the sentence pattern which I used attributes sentiments to others.
"You want ..." functions as as rhetorical idiom.
"You want X or else Y" roughly means "Unless X, Y, thus you will be objectively disadvantaged".
The sentiment, if there is one, remains mine; on the other hand, this "ghoulish" is in fact an external interpretation of sentiment being ascribed to me.
I don't know you enough to call you "ghoulish" and wouldn't be inclined to, but the sentiment itself hopes that a treatment for an illness killing tens of thousands of people per week will fail in order to secure supplies for a chronic but nonfatal ailment. I feel like the absolute morality of that sentiment is something we can actually evaluate.
(It's all hypothetical, of course, because in fact HCQ does not appear to be effective for C19).
Have you considered that I might be thinking of the problem that it will be hoarded up by some individuals who have neither the illness nor the ailment? Few who needs it for any reason will be able to get their hands on it. That's my thinking, more or less.
Hoping a treatment for C19 won't work --- in essence, rooting for the virus --- is a bad look. That's as far as the analysis goes. And, again, it's a moot point.
This whole debate is insane to me -- some people that so-called "experts" don't like mentioned HCQ as a possible treatment for coronavirus, and we've ended up in some bizarro world where everyone is shouting and fingers are being pointed over something that really shouldn't be controversial or perceived as some sinister plot to destroy clever society.
1. HCQ has been used for many decades
2. The side effects are generally known
3. It may have a positive impact on COVID-19, and it may not.
4. Nobody is suggesting long term high doses for anyone, COVID patients or otherwise.
5. If people are severe patients of COVID-19, this should certainly be tried as a treatment as long as the patient (or immediate family) is briefed on the potential side effects. The alternative, potential death, makes this a worthy discussion for a doctor/patient to have, with families being allowed to err on the side of right-to-try. HCQ is cheap, available, and has been used for decades.
The fact that "no evidence HCQ works!!" has 200 points of upvotes and counting when the sample size for this study is 181 patients only just shows how high the temperature has become.
Everyone just calm down. As capnrefsmmat has eloquently pointed out, "absence of evidence" does not mean "evidence of absence".
If you enjoy the thrill of debates for debates sake, here are other potential topics for you: Whether masks are effective, condoms, seatbelts, helmets, or even parachutes[0]:
Results We were unable to identify any randomised controlled trials of parachute intervention.
Conclusions As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute.
Why in the world would you quote "experts" and clearly you know nothing about statistics if you look at 181 patients and immediately think "oh well that's just too small!"
You can have significant results with as little as 10 random samples. People are mad because this is getting pushed as a treatment for COVID-19. The only correct response is: "We do not have evidence that this a treatment for COVID-19."
As more research is done we can update our knowledge on this, but instead you talk about the "experts" like they you know more than they do. Typical anti-academic rhetoric.
2. They are known but they are by no means mild. A trial in Brazil just got aborted due to severe heart problems.
3. So does almost everything. If that's your threshold for taking a drug then I have a lot of homeopathic remedies to sell you!
4. Actually the doses given for COVID are often higher. Not sure what long-term has to do with anything.
5. That assumes that the risk of side effects is zero. It's not. Also, there is an opportunity cost to taking HCQ instead of something else.
I totally agree with you that we should do proper trials on this and see what happens. But right now there is zero evidence that it actually works, and some (admittedly low-quality) evidence that it might not.
> Actually the doses given for COVID are often higher.
Not just higher. The original article (the one out of China) that mentioned that there might be some positive effects reportedly suggested using doses that were a whopping 5 times higher than the usually prescribed amounts: 500mg/day vs the usual 100mg/day.
What more, the same article put forward that the drug was considered generally safe and without any potentially troublesome side effects. That raised more than a few eyebrows amongst the medical staff who knew the drug.
When faced with death as an alternative? Of course! The hypocrisy is that all the shouters and screamers would likely make the decision to try HCQ if it was them in that situation.
> some people that so-called "experts" don't like mentioned HCQ as a possible treatment for coronavirus
Let's call a spade a spade. Trump, not 'some people'. Trump's medical training amounts to what, exactly? He heard that a drug has some beneficial effects on a similar disease and is all aboard, and HE is the one "some people say it's an amazing drug", "it can't hurt you" (except when it can), "I'm seeing people who will die without it" (based on what, exactly?). Oh, "and I directly profit from it".
People aren't screaming that HCQ "shouldn't be used", but that a President shouldn't be using his position (and complete lack of medical training) to be promising things that are at best unproven, and at worst, factually incorrect.
I would add: HCQ is most effective at the onset of symptoms. It stops the virus from replicating, it does not repair cell damage. Also, it must be used with zinc together, since HCQ opens the cells to absorb zinc and zinc must be present.
This study is specifically about patients sick enough to be put on oxygen. The top ranked comments don't seem to address that detail.
Some thoughts:
My understanding is this is a powerful alkaloid. My experience has been that similar compounds can help combat inflammation. They also can work to help kill infection at times.
By the time people with Covid19 need oxygen, inflammation doesn't seem to be the primary problem. So I wouldn't think it would be particularly helpful at that point.
Ventilators get prescribed in part on the assumption that inflammation in the lungs is a major impediment to getting sufficient oxygen. Ventilators are failing at a shockingly high rate, with a death rate up around 80% or so. Some doctors are moving away from ventilators because the death rate is so high.
I spoke recently with a researcher who suggested impaired vasodilation was a possible explanation for the reports of low oxygen combined with a surprising lack of pneumonia and inflammation in some cases and that makes a lot of sense to me. The mechanism causing low oxygen does not appear to be the obvious answer of "lung inflammation and pneumonia."
That doesn't mean this drug can't play a meaningful role at some stage. It mostly means it's not the magic bullet solution for advanced cases that they were hoping for.
This in no way surprises me because the things it actually treats do not appear to be the cause of low oxygen in advanced covid19 cases.
You might find this thread interesting (“There's a growing body of data to strongly suggest #COVID19 predisposes to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilization and diffuse intravascular coagulation.”)
Thank you. It is interesting stuff and fits with some of my impression that they are overlooking important blood-related issues. Anemia (a blood disorder) is also a cause of low oxygen. That's not exclusive to lung function.
Glad to see some doctors are working on that angle. (crosses fingers, hopes for better treatments soon)
Given the study's small sample size, it seems the only way it would have produced a conclusive result is if the effect size was huge (i.e. miracle cure). The study found some evidence of efficacy, but it was not significant given the sample size.
A better headline would say something like: "study finds that HCQ is not a miracle cure for already-hospitalized covid-19 patients".
Your point doesn't really make sense, because the purpose of a study like this is not for making treatment decisions; it's for making research decisions.
I don't see anything in the study that discredits HCQ as a potential treatment, and therefore it makes sense to keep researching.
No. This study found no evidence of effectiveness as a treatment for COVID-19 in patients who need it.
A sample size of 20 is sufficient to satisfy a .05 statistical significance threshold that hydrochloroquine had even the slightest positive effect. In this population, it did not.
All therapeutic drugs are developed using in vitro and pre-clinical (non human animal) treatment groups no bigger than 20. When a well controlled and randomized study comparng two groups that are each four times larger than 20, we have a VERY strong indication that this drug delivers not only too little effect to be a useful treatment for COVID-19, but it very likely delivered absolutely NO EFFECT AT ALL in hospitalized patients. Don't expect any reputable physician or scientist to dismiss this evidence.
This is very bad news for the prospect for treating patients who need it using this drug -- those people who are likeliest to die or endure lasting harm. The other 80% of positive patients don't need any therapy except time.
This trial wasn't randomized, but a quasi randomized trial for HCQ whose preprint was leaked is here:https://www.dropbox.com/s/8b2govfsa6n0xbq/NEJM_Clinical%20Ou...
Study indicates that one adverse effect of HCQ (on top of not improving patient outcomes) is increased ventilator times.
A total of 63 patients were included with 32 in the hydroxychloroquine arm.
Hydroxychloroquine administration was associated with a need for escalation of respiratory support level compared to those that did not receive hydroxychloroquine at 5 days (p=0.013).
The same findings were observed in a baseline-matched subgroup analysis. Absolute lymphocyte change in the
hydroxychloroquine group was no different than supportive care alone (p=0.413).
Hydroxychloroquine use trended towards worsening neutrophil-to-lymphocyte ratio compared to supportive care alone
(+9.59 vs +1.58, p=0.51) as well as a higher risk for intubation (p=0.051).
> Hydroxychloroquine administration was associated with a need for escalation of respiratory support level compared to those that did not receive hydroxychloroquine at 5 days (p=0.013).
> was no different than supportive care alone (p=0.413).
Yes, exactly, p=0.413 corresponds to a coin toss, or as the authors of the paper put it "no different".
The p=0.51 figure seems to be a typo in the abstract. If you read the content of the paper, it says
> The hydroxychloroquine group also had a strong but not statistically significant trend towards worsening NLR (p=0.051).
So I believe they just accidentally moved the decimal place, and they are correctly avoiding calling the result statistically significant, but it is close.
That study has been widely condemned as lacking any sort of rigour – the journal that published it has since issued a statement of concern around the methods.
For example, their "control" group were just arbitrarily-chosen patients treated at different hospitals, not people treated in the same hospital as where the study was conducted.
If I recall right, they removed people who got worst and needed ICU from study. (Study was based on taking samples and since it was impossible to take samples, people did not counted.)
That's my main take-away at this point. I have seen enough reports saying it worked, and enough saying it didn't that I believe the answer is probably somewhere in the middle.
My understanding is the best guess for how it works is by keeping the viral infection from becoming serious enough to require hospitalization. Similar to how proper treatment of wounds early on keeps them from getting to the gangrene stage where you need amputation.
Unfortunately, politics. So the Left wants it to be completely no use at all, and the Right wants it to be a miracle drug. Most of the population really probably just wants effective treatments if they end up getting sick.
It’s somewhat more complex: one political faction claims that the other wants more people to die so that side can have a political victory. Supposedly, one side wants ‘the cure’ not to work, which means the other side can play victims. Nothing new, it’s just like claiming that liberals want to sell out to communists or Satan or whatever.
I think the point is that the stated reason for opposition is all rational and proper but the suspicion (based on current year political sentiments) is that it is nevertheless a cover for an altogether irrational hope that the the drug is proven ineffective.
A problem in my view, with attributing a strategy to the opposition, is that without hindsight, when Trump makes a weird/nonsensical/hyperbolic statement like this, you can't know if it's going to vanish without a trace or be doubled down on and become a huge thing.
At the time, who could say if his opinion was based on anything, he would be proven right, anyone would take it seriously, etc.? The public and media don't know these things.
It's "irrational" to oppose an idea just because it comes from someone you despise. It's not like this is coming from the National Enquirer--he has access to some of the brightest minds in the world.
The efficacy picture on these drugs is quite confusing, and it's not out of the question that they will turn out to be crucially useful. Giving up on them without further investigation doesn't seem wise at this point.
Beyond that, sometimes being a leader means giving people hope, even if that might involve shading things. Trump may not be an Adama, but I do think he's pretty good at making people feel better, or at least distracting them from their troubles. And right now, that probably is saving lives.
It's "irrational" to oppose an idea just because it comes from someone you despise.
Giving up on them without further investigation doesn't seem wise at this point.
I don't disagree with these ideas on the surface, but they seem largely strawmen-style arguments. I'm not convinced a significant number of people somehow "hate" hydroxychloroquine or are against research solely on the basis that Trump mentioned it.
Let's say Trump instead proposed that people taking, I don't know, silver supplements was a proper treatment for covid-19.
Would you say it's irrational to oppose that idea? I mean it's not been proven to not work, so you gotta try anything you can, right? And he's giving people hope.
If a lot of scientists world-wide were looking at it, yes, I would think that irrational to not consider silver supplements. As far as I know, Trump has never advocated taking any drug without medical guidance.
We were (and largely still are) dealing with a lot of unknowns. As far as I'm concerned, everything is on the table, as a possible improvement.
Isn't one of his quotes "It's been out there for a long time. What do you have to lose?" though I guess he does followup by saying he will talk to his doctor before he takes it. But the overall sentiment makes me pretty uncomfortable.
"It's not like this is coming from the National Enquirer"
It could be! I mean, his ideas presumably don't come from taking a random issue of the National Enquirer at face value, but he has or had a widely reported close relationship with the publisher, so it seems entirely plausible he might have been influenced by, say, David Pecker's opinions.
I'm dubious, but who knows? If the scientists and doctors think it looks promising, I don't much care who suggested it.
Trump isn't much to watch, but he does end up being right on some of his wacky-sounding calls more than I would have thought. I wouldn't bet my money against him.
I generally try hard to stay out of politics and to intentionally not get caught up in the Trump bashing that is quite common in my Twitter feed.
I'm having a really hard time trying to abide by that rule in this case.
I will suggest that you may have cause and effect backwards in at least some cases. Some people may be bitterly opposed to him because of nonsense like this rather than thinking this is nonsense because they bitterly oppose him.
He's the president of the US (aka the most powerful political leader in the world). Whatever one's personal feelings about the man, him touting something unproven while in such a powerful role is bound to get a rise out of people.
He has an obligation to look out for his people. This is not how you do that. This is the opposite of responsible behavior.
I'm quite upset about the whole thing, not because I'm anti Trump, but because it's a global pandemic. This isn't run of the mill, business as usual bullshit where political things like cronyism and glad handing make any sense whatsoever.
Yeah, I think we're all pretty unnerved. And we're far from knowing just how deep this rabbit hole is going to be. (Or how shallow.)
If you look at the charts of per-capita deaths in various countries, there's not much of a pattern, in terms of places we'd think of as having "good" government and/or public health versus "bad". Belgium, for example, is the worst right now (or among them), and many European countries are doing quite badly.
My personal suspicion is that in a case like this, there isn't really that much difference in in-the-moment governing across countries.
Sadly, people who get it right are frequently remembered as "lucky" after the fact or even sometimes get maligned in some manner.
When I took archery in college, I was the only one in class who could consistently hit the bullseye. I also practiced up to two hours a day.
A classmate who didn't practice, who had terrible form and was holding the bow all wrong and who couldn't manage to hit the target at all snidely informed me one day that it was all luck. He completely dismissed the idea that either proper form or practice made any difference whatsoever.
I know that in complicated situations, it can be quite hard to determine what actually worked and why. This is why humanity has practices like deferring to experts with a solid track record of success as evidence that they know whereof they speak, even if it basically looks like stuff and nonsense to most of the rest of us because we don't all have a PhD in that subject and a zillion years of experience like them.
I think it’d be far more accurate to say that the left wants Trump to stop spreading misinformation on the topic than to say the left is so Machiavellian that it isn’t interested in a cure. For the most part the left seems very happy to just amplify anything Fauci says.
A proven successful use of this drug would be very inconvenient for multiple media outlets who jumped at the (described as) unfounded claim. It would mean that either (a) the authorities had more information than they did, or that (b) the authorities bet successfully with the same amount of information, which doesn't align with their constant reporting of idiocy.
You are right, but b) has an obvious logical fallacy. It assumes essentially that only intelligent people can win the lottery. Of course, this won't matter for the political discourse.
> A proven successful use of this drug would be very inconvenient for multiple media outlets who jumped at the (described as) unfounded claim.
Eh? Even if it did turn out to work, it would still have been an unfounded claim for Trump to claim it did without evidence, and a stupid and dangerous thing to do. That's what 'unfounded' means.
President Trump encouraged trying hydroxycloroquine early on when there were early indications it might work. The problem is that he is considered such a villain by the left that they want it not to work just to prove him wrong. Such is the state of politics in the US.
IMHO he was right to lean on the FDA to find out if its effective. Since it's already available, it would make sense for doctors to try it, but most are not trained in doing controlled trials so the results are all over the map.
Most noticable to me is that when referring to this issue/drug, the media always points out that HCQ is not approved for covid-19. They neglect to point out that there is no approved treatment at all. It seems like an attempt to make Trump look reckless and irresponsible.
You do realize that, yes, "most [doctors] are not trained in doing controlled trials" because they have another job, the job of being a doctor? Running large RCTs takes time and a different sort of education.
Source: married to a physician who usually has a 1,200 patient panel, with a diversity of conditions; said physician spouse was at one point recruited to run an RCT for a drug company and did a lot of work to prepare and then pulled out because spouse figured out they'd not be allowed the latitude to improve the study design, and felt that the study design was slanted inappropriately to supporting the efficacy of the drug (it was not being compared to standard of care but instead to a demonstrably inferior treatment, a previous standard of care).
Yeah, objectivity and politics don't mix. There are people who do RCTs and do them well, and they're not just random doctors kind of scattering drugs among their patient panel.
>> You do realize that, yes, "most [doctors] are not trained in doing controlled trials" because they have another job...
Absolutely. It wasn't a criticism, just the way things are. For example, one doctor is claiming HCQ + zinc + antibiotic has treated over 700 covid-19 patients without a single death. I think it would be appropriate for someone to audit his records to see if that's true (was it even covid? or just some cold going around in his area?). If another doctor wanted to replicate his alleged success, I could easily see them using a slightly different protocol (skipping the zinc, using a different antibiotic, changing when or how much to administer, etc) and then claiming he's wrong when it doesn't work for them. That's just how a lot of people behave unless they've been trained otherwise.
The problem wasn't that Trump encouraged trying it, but that he clearly exaggerated what we knew about its effects and continued to do so for a long time even after having been confronted about it.
I can personally discount everything he says, that doesn't make it any less legitimate to say that the President of the United States shouldn't hold press conferences in which he over-hypes the proven effectiveness of certain drugs during a pandemic.
Otherwise anyone can just claim anything whenever they want without any proof whatsoever.
Independent of whether that is actually right, where did I consider them to be connected in this discussion? I'm not even inferring a political motive, I'm just stating that it is a dumb thing to say.
So everyone, including frightened elderly people, is supposed to have a prior that the president is a liar and should be ignored, and thus it is acceptable for Trump to say what he wants? That's a frankly bizarre approach.
It's like they think we don't remember hearing about how he was the only honest, incorruptible candidate in the field because he was self-funded and "said what he thought," rather than "talking like a politician." Or how his competence as a businessman and hard-as-nails negotiator was worth more than any amount of political expertise.
We don't even hear about four-dimensional chess or "draining the swamp" anymore.
> That's my main take-away at this point. I have seen enough reports saying it worked, and enough saying it didn't that I believe the answer is probably somewhere in the middle.
The initial study indicating HCQ was effective was recently withdrawn by the publisher for failing to meet their journal's publishing standards [1]. And for good reason, as the study conveniently dropped patients that deteriorated from their final numbers. None of the follow up studies I have seen (including the one in the OP) have shown anywhere near the same level of effectiveness.
> Unfortunately, politics. So the Left wants it to be completely no use at all
That is such a twisted, uncharitable interpretation of the situation that I have to wonder if it is intentional. Do you really think "the Left" would rather have the drug be completely ineffective so the entire planet has to keep this lockdown going? Really?
I guarantee you every single fucking person on this planet, left, right, or center, would love to have an effective drug against this virus right now.
The primary point I've seen made by "the Left" on this matter is the President of the United States should not be tweeting out unproven drug combinations until their efficacy has been demonstrated by clinical trials. Particularly when: 1) such drug combinations can potentially increase the risk of heart failure [2], and 2) people rushing out to buy these drugs has constrained the supply for patients who actually need it to treat their existing illnesses.
Unfortunately, politics, indeed. The world has gone insane when the position of "don't taken unproven drugs with risky side effects without medical supervision" is construed as a "leftist position" instead of COMMON SENSE.
And to put this interpretation into perspective, people that need this drug for diseases that it has proven to have a large effect on are losing access to it because it may or may not help with COVID-19.
You may as well delete it. My point was to caution against the continued enthusiam of using this drug for COVID-19 despite the consequences of doing so.
The original article has no such problem. Yet the person I replied to could be interpreted as "wait, maybe its still good!". My comment makes zero sense as a reply to the original article.
That's why I included a pointer to your comment's original context.
This is mostly a technical problem of how comment trees that get extremely heavy having no natural way to divide themselves. Sometimes we prune them, and when we do that, we try to do it in a non-lossy way.
It cites someone from Lupus UK. Their page at http://www.lupusuk.org.uk/uk-azathioprine-supply/ says "we have received reports from a number of people with lupus who have been unable to fulfil their prescription of azathioprine" and that "stocks are in the process of being replenished and should be available in the UK in mid-April".
Comment from an HN'er:
"For several weeks my mother hasn't been able to fill her regular prescription for hydroxychloroquine that has been an important part of managing her lupus for >30 years." - https://news.ycombinator.com/item?id=22793293
Is this shortage universal? Have there been shortages before, either universal or local? Is there evidence that this particular local shortage is due specifically to coronavirus demand?
It may be that the answer to these questions is "yes," but that answer seems to be being assumed right now.
I believe my citations answer your questions sufficiently.
Since the questions #1 and #2 can be answered both "yes" and "no", with equal merit, I suggest that perhaps they are not useful questions.
That is, not every pharmacy in every country is out, and sometimes a pharmacy is out of a medicine. If that's what you mean by "universal" and "local shortage before" then you're being absurd.
Bear in mind that I was answering beaner's question, not making some broader statement.
I think characterizing my questions as absurd is itself revealing of a bias. There is no judgment in my questions, I'm just trying to get at the answers.
I did not characterize your questions as absurd. I pointed out that your first two questions can be answered both "yes" and "no" with equal validity, and presented the absurd case to demonstrate why.
Did you really mean "universal" to mean every pharmacy in the world, and did you really mean "Have there been shortages" to include a single pharmacy somewhere running out? No. But how am I supposed to know what you do mean?
Your questions did not seem informed by the information in the links I presented, which suggests a different sort of bias.
This is perhaps anecdotal, but one of the articles I saw, said that a person who was denied their medication was specifically told it was because it was being reserved for COVID-19 victims.
So while you could doubt such a story for other reasons, the causal linkage is being made explicitly in at least some instances.
HCQ is an off-patent drug that is produced in every major country in the world. In fact, many countries have stockpiles of it because of its efficacy at preventing malaria.
If there’s a risk of a supply run, it would definitely not last very long. For many people there’s alternatives for treating arthritis and lupus.
If it’s shown even to improve the patient’s outcome by even just 10% or more (as this study suggests), every country should be ramping up production of it right now instead of letting it be politicized.
> If there’s a risk of a supply run, it would definitely not last very long. For many people there’s alternatives for treating arthritis.
As of the last time I talked to her a couple days ago, my mother still hasn't been able to fill her hydroxychloroquine prescription that she has used to treat lupus for over 30 years. The alternative medications are steroids such as prednisone, which have previously caused dangerous side effects. Due to the useless panic buying, she's is now at severe risk of a bad autoimmune reaction if anything activates her immune system (even from a mild cold; covid-19 would be fatal).
> every country should be ramping up production of it right now instead of letting it be politicized
Yes, they should, but before that happens while supplies are limited, there are people that need the drug for well-established reasons.
It's already been politicized, it's too late. The minute that politicians started advocating for a treatment before there was any scientific backing, that ship sailed.
Also, this study does NOT suggest that patient outcome is improved by 10% or more. Not in any way. Fewer patients died within the timeframe of this study, but more patients on the drug experienced ARDS; not to mention that 9 patients had to be removed from the study due to cardiac effects of the drug.
> It's already been politicized, it's too late. The minute that politicians started advocating for a treatment before there was any scientific backing, that ship sailed.
In general, that doesn't mean we should simply abandon all attempts to de-politicize it. In fact, it means just the opposite - we should put aside any political aspects and focus on objective data.
Agreed, of course. The difficulty is when one side of the argument is saying "take this medicine, it will help you," and the other side is saying "no, we don't know that yet." So, effectively, one side of the argument is arguing not to politicize the issue, the other side is doubling down on focusing on anecdotal data.
Then why are lupus patients struggling to get HCQ right now?
Sure in the long run it may be relatively easy to manufacture enough HCQ. But right now stocks are running extremely low because people are trying to use it for COVID without any scientific basis.
How is this about regulation? Factories and supply chains can't just suddenly ramp up their production by an order of magnitude or more. You need to build new machines, hire new workers, source new supplies, and figure out how to distribute it all. That can't just happen from one day or another, no matter how little regulation there is on the product.
So that's why it's so hard to find things like flour or toilet paper right now? Nothing to do with supply chains and manufacturing, just too much regulation? Can't wait until we repeal the 4-ply rule!
It really lasted about 4 weeks of hoarding before the supply chain caught up. Costco today had those products as far as the eye can see.
Besides, by requiring a prescription you’re negating the ability for people to hoard. And a single pallet of HCQ is enough to treat thousands of people.
I really hope you look into how easy to manufacture and abundant HCQ is. It’s important to combat media scaremongering.
I haven’t looked at why flour or toilet paper have shortages and don’t know the primary factors there[1]. I’ve done all I that I care to to inform you.
1: It’s probably the bullwhip effect and hysteresis in the supply chain but that’s speculation on my part.
> Go talk to a generics drug manufacturer in India yourself.
You mean the country that, more than a month ago, restricted exports of many drugs and chemicals used to make drugs (the so-called Active Pharmaceutical Ingredients). Your local end of the pharmaceutical supply chain can't deliver drugs that can't be made anymore.
> Face masks have been shown to be effective at controlling pandemics, and apparently no one (in many western countries) thought to stockpile those.
You're dropping the context of the hard decisions nations and governments actually deal in day to day, year to year when it comes to budgets. That's why not a single country had a proper stockpile of N95 masks for a pandemic like this. That isn't an exaggeration: literally not one nation had enough of a stockpile for this scenario, that includes South Korea, Japan, China.
To say that nobody thought to do it is outlandish. As one example Congress set aside funds in 2006 to stockpile 100 million N95 masks. That's not strange, as many people were aware of the need to maintain such a stockpile. There is a big difference between being aware of the need, proposing plans and spending for it, and actually getting billions of dollars on a recurring basis to maintain the necessary proper stockpile perpetually with no event to push it with (yeah but we had a flu pandemic in 1957! try selling that premise). That's the actual reality of budgets and governments.
It's expensive to maintain a persistent minimum stockpile of 1 billion non-expired N95 masks to cover the US population and the demand the US has seen. If it's a year-long pandemic, a billion masks isn't enough. You need several billion masks in that scenario. Coming out of the great recession, that is a very hard budget decision for all nations. And the fact is, most nations can't afford to do it at all. The easy retort of course is to say, well, look at the damage from this virus compared to that cost for masks. That's purely hindsight spouting that tries to pretend a comprehensive reality doesn't exist and that people who make budgets don't have to deal with difficult decisions every single year (while not factoring in every possible bad scenario every time they make a budget).
And let's not pretend it's enough to stockpile masks, regarding spending allocations. If we're doing hindsight fantasy, let's be correct about it. You need to constantly maintain a lot of other gear and training for a pandemic, costing large sums of money. In an ideal scenario a nation the size of the US should probably have over a million ventilators stockpiled, just in case. We should probably maintain 2x or 3x the ICU capacity we have, on a persistent basis and at a large cost.
This isn't an argument against being more prepared. Of course every nation should have a vast magical stockpile of N95 masks that never depletes, even the ~140 poor nations of the world that can't afford to do it. The point is, it's difficult to convince any nation to do it at the required persistent scale, and most can't afford to do it regardless.
I think there is an alternative solution, though: Rather than maintaining a gigantic stockpile large enough to last a multi-year pandemic, it might be more efficient to maintain a modest stockpile sufficient for the breakout phase along with ready-to-deploy crash production capacity. This might be significantly cheaper.
This means that we need to ensure that we have the capacity to 100x, 1000x, 10,000x production--whatever is modeled to be enough to meet ongoing demand during a pandemic--within the time bought by drawing down the strategic reserve.
We don't need to maintain and refresh a complete stockpile of finished goods, or even a complete stockpile of production capacity (suitable factory floor space, meltblown nonwoven fabric equipment, etc.). We just need to know where such things exist that can be quickly directed to the desired use either with cooperation from the owner or with the DPA, how much exists naturally, and only if there is a deficit, to maintain a stockpile sufficient in combination with those identified supplies: Government-owned sterile factory floor space, for example, or spare production lines for meltblown nonwoven fabric.
We can even enlist private companies to maintain the stockpile for us. It makes way more sense to just subsidize e.g. 3M to have lots of extra meltblown nonwoven fabric production capacity. They are in the business, they maintain and operate the machinery and have the know-how and commercial connections to produce and distribute the material. They will have the capability to quickly respond to demand spikes if the capital requirements for increased production capacity already exist thanks to Uncle Sam's foresight.
Finally, what is maybe even more important than stockpiles or production capacity subsidies is the organization this exercise entails (knowing who makes what critical parts in the supply chain, where they are, what their production capacity is and how quickly it can grow, etc.), which gives an ability to rapidly marshal resources and eliminate inefficiencies to surge production as quickly as possible.
Why is the stockpiling function so centralized? How much supply does each individual hospital/medical center have on hand in reserve during the normal course of business?
Facemasks are only produced in a handful of countries. In fact we basically don’t even have the skill set or machinery here to convert factories to producing facemask even if we wanted to. Garment work was moved offshore decades ago.
It was observed that between 7% and 28% of hospitalized have acute myocardial injury [1-4]. When one looks at Epocrates (database for drugs which is why I'm not linking anything here) the severe adverse reactions of hydroxycholoroquine include QT prolongation, cardiomyopathy, and torsade de pointes. Just to define some things here, QT prolongation is the time from your Q wave to your T wave, or the start of an electrical depolarization on your cardiac ventricles to repolarizations. QT elongation usually leads to cardiac arrest. Torsade de pointes is a syndrome where your cardiac ventricles beat so quickly that your heart paradoxically cannot fill up with blood potentially, and usually, leading to sudden cardiac death.
Giving someone who has had essentially a heart attack (by definition COVID patients have elevated troponin which is the marker we use to assess if one has had a heart attack) is probably a bad idea so my question is: why would we celebrate a drug that has massive cardiac adverse effects as a side effect? Don't get me wrong I understand that there are drugs that are even worse. Cyclosporine is the first line immunosuppresant for kidney transplant. Do you know what one of the most common adverse effects of cyclosporine is? Kidney failure. But we don't know what is causing the kidney failure in a kidney transplant (rejection vs adverse effect) so we have to biopsy. Kidney biopsy is a very invasive procedure, FYI. My point is, maybe waiting for double blind placebo research here is the best case. Also, I made this exact same point on here a month ago and people told that they would take my dose if it came to that and at this point I will say go ahead.
> between 7% and 28% of hospitalized have acute myocardial injury
So, for a younger (< 60) otherwise healthy person whose chance of death with covid is less than 1%, it would seem ill advised to take this medication at the onset of symptoms, unless the the disease itself causes similar or higher rates of heart damage.
It's only advised if it actually works. If it doesn't work, then there's still no point in taking it because the side effects are still bad. And there's no good evidence that it even works, and some mild evidence that it doesn't.
Yes, and even if it did work to reduce severity of the illness (agreed that there is no evidence of this), it seems like for low-risk people, the risks of heart damage outweigh the benefits of taking it. After all, what's an extra week or two of illness vs a 7-28% chance of heart damage.
Yup. I'm in a relatively low risk factor group and got over COVID-19 at home, no hospitalization necessary and nothing stronger than acetaminophan needed. I don't think a decent change of permanent heart damage was what I needed through all this. Also, I would have had a higher chance of being hospitalized from the side effects of the HCQ than from the COVID-19, which is really not what the hospitals need right now.
The HCQ doesn't seem remotely merited based on its potential side effects unless you are in a higher risk factor for the disease, and of course even then, it's only merited it's actually efficacious (which it's seeming so far it isn't).
Potentially, yes. But again, we need more data before we can establish lucid guidelines on this therapy.
My hypothesis is that it's not going to be hydroxychloroquine that will be the miracle drug. There are better "hypothetical" alternatives that aren't getting as much mainstream attention but have a more realistic potential for working.
I think it's too bad that this drug has been so politicized. It's really unfortunate that its two original and most prominent champions are people that are so disliked. So many people spoke up (maybe prematurely) against it in a knee-jerk reaction to its advocates. Now many act as if they're more concerned about being right to ridicule the claims all along, than they are about whether the drug is actually helpful in fighting COVID-19. Which, for the rest of us without a stake in their stupid political feuds, is all that matters. And because of this idiotic battle of the egos we could be passing on something useful.
So here we all are, hanging by the edge of our seats, waiting for definitive proof that HCQ does not help in fighting COVID-19 and we keep getting these half-assed reports, seemingly more aimed at pushing a narrative than to present (or eliminate) an option in a fight.
One of the latest examples is the account of Rita Wilson (wife of Tom Hanks) who survived what seems like a difficult case of COVID-19 and shared her experience with the media: she felt very tired, extremely achy, uncomfortable, didn't want to be touched, on the ninth day her fever climbed up to 102 and she had chills like she'd "never had before" (her words), she lost her sense of taste and smell. Then she was given chloroquine, her fever broke (it's not clear how long after). She goes on to warn against the "extreme" (her word) side-effects she attributes to chloroquine: she was completely nauseous, she had vertigo, she could not walk and her muscles felt very weak. She then concludes that although her fever broke after been given chloroquine, she doesn't know if it helped or if it was just time, which is fair. What do you imagine the headline for that story should be? Well, to save you the trouble, most read like this Rita Wilson warns against "extreme" side-effects of chloroquine.
Are HCQ/CQ effective? We're still sitting here like idiots not knowing. If they are, should they be taken carelessly? Definitely not, we already got that, thanks, but that is not the point. We can't afford to have an "all or nothing" mindset with these drugs as we did with masks. Simply proclaiming that HCQ is useless because it is shown not to reduce viral load is just the best way to pass on some other ways it might be helping. If it is shown to have other palliative effects that actually help patients in their fight, such as reducing inflammation or helping cope with high fever long enough for your immune system to do the job, it's not nothing. It's information. It's an option.
It's important to note that this study did not evaluate or note that Hydroxychloroquine had no effect on all people in all situations with COVID-19.
This was a targeted study looking at a specific circumstance. The situation was "all adults in 4 French hospitals with documented SARS-CoV-2 pneumonia and requiring oxygen ≥ 2 L/min"
So, adults who were not on oxygen are not included in the study. How does it pertain to them? That's not covered by this.
It reads like it's saying people who are in bad shape and on ventilators did not have a positive impact by Hydroxychloroquine.
This still leaves open questions like, can the use of Hydroxychloroquine lower the rate of needing to get on a ventilator.
I look forward to someone reproducing this study and looking into the other areas.
"collected data to emulate a target trial"
I take it this means it's not an actual clinical trial, just a virtual trial? What's the point?
Of all the people that died, none were saved by the drug. Sounds like an insurance ad.
The study is way underpowered (too small a sample). Based on the raw numbers, the HCQ group had less deaths and less ICU admissions, but the numbers we're talking about are 3 vs. 4 deaths and 16 vs. 21 ICU admissions (group sizes were different).
These numbers simply aren't enough to make a determination one way or the other. On mortality, the 95% confidence interval allows for a range of HCQ reducing death rates by 87% up to it increasing death rates by 2.9x.
That may be, but it's gonna be harder logistically to do a study commencing from onset of symptoms vs at moment of hospitalization.
There's also the fact that study makes it less likely that pre-hospitalization HCQ will have any effect either. Applying a Bayesian analysis here, it's now likelier that the true ground truth is simply that HCQ doesn't do anything to COVID-19 at all, not necessarily that it works only in a narrow early window. HCQ has severe side effects too, that require close monitoring and can be fatal. If it's not clearly doing good then it definitely shouldn't be being given to COVID-19 patients.
Personally, my hopes are more on remdesivir and favipiravir, both of which are actual antivirals (HCQ is not) and thus were always more promising. HCQ was never the most promising drug candidate, and the only reason we're even talking about it as much as we are is that, for whatever random reason, that's the one Trump heard about first and then fixated on.
The study that made me think there might be something to it was looking at people taking it for unrelated illnesses and finding that they weren't tending to show up hospitalized with Covid-19.
I'd agree that we really don't have any evidence that giving it to hospitalized patients helps at all. Most antivirals have to be taken at the early stages of an infection.
The best looking treatment for people seriously ill with Covid-19 right now seems to be IL-6 inhibitors. That won't stop you from getting sick but might let you avoid intubation.
This could be correlation. People taking HCQ have autoimmune problems like lupus, and therefore would be more cautious and practicing social distancing earlier, therefore not getting infected in the first place. It also might be true that people who are agoraphobic shut ins are not contracting covid. But that doesn't tell us much about how covid interacts with agoraphobia.
> There's also the fact that study makes it less likely that pre-hospitalization HCQ will have any effect either.
We'll see with the U of Minnesota trial, which attempts to use it as post-exposure prophylaxis. Data (hopefully) will tell us.
On favipiravir, the data on the Chinese study wasn't exceptional, but wasn't that bad either. Perhaps the Japanese phase 3 study will be more enlightening.
I don't think it is moving the goalpost. The french doctor who first advocated this molecule pushed from the outset for testing and treating early rather than waiting for respiratory problems as we currently do [1]. In fact he later mentioned that when people had severe respiratory problems, the viral load was low and an anti-viral treatment wouldn't really help.
I don't think we wasted too much time and money on chloroquine. It looked promising in early trials. The proper thing to do is follow up on that. If it helped even just a little it would save literally thousands of lives. Having a well known drug be even slightly effective is pretty close to the best case scenario. Not following up on such leads would be stupid.
The Trump thing is a huge distraction. Doctors in China and Europe were already singing its praises before Trump got involved. These tests aren't happening because Trump got excited about it.
This study is basically garbage. It applies to people who're so damaged from Covid they need at least 2 liters of oxygen per minute. It studies treatment with pure hydroxychloroquine--no zinc, no azithromycin/doxycycline/ivermectin.
Hydroxychloroquine.
Patients who get their treatment from doctors less fraudulent than the authors of this study almost certainly see better outcomes.
When the Covid crisis is over, one of the strangest sub- plots will have been the fracas around Hydroxychloroquine. Starting from medical practitioners worldwide adopting its usage in a ‘cargo cult’ way, mimicking what other doctors were doing, to Raoult’s low- quality study. Then people in Silicon Valley (notably Elon Musk) picking up the idea. Followed by the explosion in the political sphere, from Trump pushing it at the White House podium, to Indian PM Modi reversing an HCQ export ban for Trump, to French PM Macron talking it up.
All the while HCQ remained unproven for Covid use, while people trying it got hurt by cardiac side- effects (and one couple in a prominent incident mistakenly took different chemicals with a similar name), and patients with other conditions ran out of HCQ due to shortages.
Maybe HCQ will be part of the standard of care for Covid- 19 in the future, but it’s seeming less and less likely. Meanwhile it’s definitely not a miracle cure, so the frenzied advocacy and adoption of this medicine will turn out to have been a bizarre story.
The recent reports about low benefits of HCQ didn't stop Raoult from appearing in a video about the state of HCQ and covid-19 in his clinic. Sadly he seems to be yet again using very wide statistics to justify his views (covid is of no importance compared to yearly stats [0]) and digress into political attacks (his past interactions with pharma labs that weren't conflict of interests).
I still can't say if he's a low hanging troll [1] or if he's just so far above the pack that everybody else is braining wrong. That's also his motto... he likes to discuss disruption and paradigm shift in his classes and talks about how every past paradigm was considered gold standard and only people breaking the mold advanced the state of the art.
[0] unsurprisingly Musk is also very fond of wide stats to justify his AutoPilot ~feature
[1] his lab specializes in repurposing well studied compounds for new diseases.. seems like leveraging past efforts to get success (if I go full paranoia :)
Even pre-covid, Raoult had a reputation for pumping out hundreds of really poor quality studies and making controversial public claims. It's a shame he's the one that's caught the attention of the general public, there's lots of good work going on with other potential treatments, but suddenly my social media is filled with armchair pharmacologists arguing about this one drug.
My understanding is that fish tank chloroquine phosphate is the exact same molecule as the pharmaceutical. You shouldn’t take it because it doesn’t have pharmaceutical quality standards and is very tricky to dose.
Politically, yes, there was/is a cargo cult. Both for those convinced it's a cure, and the anti-cargo-cult opposing party convinced it's somewhere between useless and actively harmful.
From a medical practice standpoint, you have a widely-available drug with well-known side effects that can be administered in a medical setting with low risk, and potential life-saving upside. When the research is early but potentially promising, it's not irrational to administer in cases where the side effects should be well-tolerated, even if later research shows no or low benefit.
The problem arises from self-administration without medical supervision, or with inadequate medical supervision.
The problem with 'low risk / high upside' is that it can apply to anything. We can try lemonade since it has low risk and high upside. But at some point we have to start wondering if we should all be obsessed with lemonade right?
Even when doctors were using HCQ before the politicians and random outsiders picked up on it, there were other drugs in the mix that they were also considering (Lopinavir, Remdesivir, etc). Incidentally Remdesivir trials have also come out lately seeming pretty weak. But there is still nowhere near the level of frenzy around Remdesivir as there has been around HCQ to the extent of advocacy at White House press briefings, international diplomatic incidents... it's beginning to seem like a very strange mass hallucination.
If there is a serious suggestion that lemonade works we should try it in medical settings. So far the only suggestions come from those who point to alternate theories without any science - even a case study. If you get a doctor to try it and it works ill be more interested. Until then it is quacks and I'm not.
Remdesivir is very difficult and expensive to synthesize, and it’s patented by Gilead. HCQ is dirt cheap and generic. Of course we should be testing anything that shows enough promise and has a well understood safety profile, but it’s obvious why the cheap generic drug working would be better.
> anti-cargo-cult opposing party convinced it's somewhere between useless and actively harmful.
Can you name some prominent members of this cult and their statements that match this framing? Serious question. I don't think anyone really matches that description. Pretty much everyone horrified at the cloroquine boosterism was horrified because it was irresponsible and dangerous, not because they had strong feelings about the drug itself.
A handful of friends/acquaintances on fb - so, no, sorry. It's clear they're less informed than most, and I've certainly seen plenty of more appropriate responses along the lines of what you describe.
To clarify a bit: it's certainly not the position of the opposing party as a whole, but those I saw who were vehemently opposed to it were ideologically motivated.
So... you consider a handful of people in your social media circle rhetorically equivalent to an "opposing party" made up of most of the major media figures on the biggest news channel on TV and the president of the United States?
I don’t understand who gets to decide and how, which of these people receive / don’t receive a specific treatment.
I’ve always loved medical studies, but now the crisis got me to thinking about the moral decision (playing god?)
The answer is, by and large, doctors. Within the hospitals they really do have the power of life and death, deciding who gets treatment when supplies are thin. Generally the decisions are made using the heuristic of "With this limited stock of X, who should we give it to to save the maximum possible number and quality of lives?"
It's not playing god, it's just making rational decisions in times of scarcity. That's something humans do constantly, no god necessary.
> This note addresses in more detail the relationship between our guidance and those patients who are elderly or who have disabilities. It emphasises that neither age nor disability are in themselves relevant criteria for making decisions about treatment.
Aside from these results, what is the proposed mechanism of benefit here?
And why are we expecting a mechanism with hydroxychloroquine against this virus when essentially no small molecule therapies are effective against viruses in general?
Hydroxychloroquine is an immune suppressant and may help reduce the cytokine storm effect. How that interacts with the "you have to start it early" issue is unclear to me.
And it might keep you from getting malaria while you have COVID19.
The way HCQ is by accumulating in cells. It inhibits the replication of viruses by interfering with endosome/lysosome trafficking or viral protein maturation during virion maturation. (basically stops the virus from replicating)
The original study that set off this flap ran for a period of 6 days. I don't know that 6 days is long enough for significant accumulation. Beyond that, unless someone has published something significant that I haven't seen, any hypothesis on the drug's effect on coronavirus is pure speculation.
That's because it's not hydroxychloroquine that helps them. It's Zinc. It just allows for much better absorption of the Zinc. Same can be achieved by combining Quercetin and Zinc.
I know this study doesn’t put anything to bed, but one has to understand that the basis for the HCQ and CQ (+/- zinc) thing is the same as x kills cancer in vitro. Then, you get a motivated researcher who publishes a single arm study of essentially OK patients claiming zero deaths. Game changer? We’ll see. But I imagine there are hospitals that are already using this as a first line treatment and there’s no positive reviews from the front line.
Beyond that, we do have the ability to perform small sample studies (cf. Student) and decide whether we’re headed in the right direction. Are we in a lull in statistics where we can’t even use statistics to guide future research?
TLDR: French publication, non randomized 181 patients (hospitalized with pneumonia and O2 requirement) with control group (84 with HCQ, 97 without HCQ), no efficacy but adverse effects for some.
All the HQC results other than the heart problems (a known side effect) were slightly better, just not enough so to be statistically significant, I guess.
They are also quite likely correlated. If, by random chance, you have healthier people in one group than the other, it's likely they will have better outcomes in most categories.
full title "No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen:..."
from the article:
"We used data collected from routine care of all adults in 4 French hospitals with documented SARS-CoV-2 pneumonia and requiring oxygen ≥ 2 L/min to emulate a target trial aimed at assessing the effectiveness of HCQ at 600 mg/day...
This study included 181 patients with SARS-CoV-2 pneumonia; 84 received HCQ within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group).
The median age of patients was 60 years ..."
"...[Patients were from] four French tertiary care centres providing care to patients with COVID-19 pneumonia. Adult patients were eligible in this study if they were aged between 18 years and 80 years, had PCR-confirmed SARS-CoV-2 infection, and required oxygen by mask or nasal prongs (corresponding to a WHO progression score of 5)."
"Among the 181 patients eligible for analysis, 84 received HCQ within 48 hours of admission and 97 did not (although 8 of them did receive HCQ later on)."
So, first of all, these patients were infected with Covid-19 _days_ prior and now had progressed to pneumonia. The up to two-day delay in the administration of HCQ after admittance to the study is disheartening.
I am surprised that, despite the experimentors selecting an elderly, pneumonic, oxygen-dependent cohort in advanced stages of the disease, these patients did as well as they did. Its a credit to the human body.
But timing is everything...
Once a Covid-19 patient has developed pneumonia, it is too late for hydroxychloroquine to affect the Covid-19 virus' replication process significantly. The patient's body is saturated with the virus.
In a patient who has developed pneumonia the disease has progressed to a second phase wherein the virus and other opportunistic pathogens (e.g., bacteria) attack the lungs and other tissue. Antibiotics may help at this point. But it is quite clear that the patients in this study arrived too late to gain any benefit from hydroxychloroquine which, when coupled with zinc sulfate, slows or halts viral replication _early_ in the disease, delays or halts the virus' progress and allows the body time to develop an immunological response to the virus.
The study's conclusion states explicitly that " These results ... do not support the use of HCQ in patients hospitalised for a documented SARS-CoV-2 pneumonia."
So, the trick is to treat _early_ with HCQ+zinc sulfate+azithromycin.
There have been a variety of studies and reports, both for and against, the use of hydroxychloroquine. Is there any reason this particular study is so highly upvoted? Or is this just an attempt to dunk on Trump for suggesting the drug showed promise?
Hm, the pseudo-study (it was a after the fact data review) found a near halving of mortality rates in the HCQ group. Yet that is described as no evidence of efficacy. Odd.
There is an obvious pushback on hydroxychloroquine. Not enough money to be made so other "solutions" are preferred. Something that was used for more than 50 years is being tested for safety? What a joke.
I'm sure when vaccines arrive they'll be "safe and effective" and used all around the world from day one...
There is an obvious pushback for hydroxychloroquine. Something that was used for more than 50 years should've been widely adopted by now but there is not enough money to be made (and let's not forget political issues).
I'm sure when vaccine arrives it'll be "safe and effective" and widely used around the world from day one - no questions asked.
The sample was 185 patients. There are anecdotal evidences that support the medicine which claim to have more, the letter came from a French doctor too. The study is discouraging for sure though.
It really bothers me how hard both citizens and officials seem to be wanting Chloroquine to fail all because somebody they didn't like endorsed it publicly. Can't let him have that win, right? Like children.
The original studies that showed promise used combinations of Chloroquine, Azithromycin, and or zinc, and there is a speculated pathway by which these drugs interact to interfere with COVID replication. This study only looked at HCQ.
This kind of partisan, childlike pettiness is dangerous to all of us - what if Chloroquine works but we overlooked it because a couple shitty papers told us what we wanted to hear?
Was it appropriate to tweet about? Debatable. It is a presidents job to keep his people hopeful when possible, and this drug cocktail was in multiple (admittedly not perfect) papers at the time of the tweet. People need to be more objective when evaluating statements made by the president. That doesn't mean you have to like him.
I think there's a bunch of strawmen here. It's disingenuous to say that people who found [said person]'s comments to be a bad idea want it to fail.
Indeed, if that person had come up and said "there's a lot of promising treatments, such as ..." or "the experts are telling us that some studies involving [x, y, z] are showing some positive signs" or something of that ilk, nobody would have cared. Instead, the person multiple times touted something that is to date unproved. People find that irresponsible for a number of reasons, not least of which that there are legitimate users who need this and it's now in short supply.
So what people are protesting is someone not waiting for medical science and just causing noise.
Like many things, this person could have handled this all more responsibly.
"Have a real chance to be one of the biggest game changers"
Meanwhile the media response has been universally lamenting that a president would "tell people" [he didn't] to take this drug. How many outlets jumped on the single chloroquine phosphate overdose as proof of the president's responsibility? I encourage you to search "Trump" and "chloroquine" and find me a single headline that doesn't tear into Trump.
Like most people, your views have been warped by headlines and op-eds being touted as "news."
The fact that the president acts like a child doesn't mean our news should too. The petty editorialization of the daily briefings are an excellent example - the media's job in such a case is to be an objective first source - not to force their point of view through adversarial headlines that change every 5 seconds and "fact checking" only his alleged untruths. But this is where the majority of Americans get their news. It's shameful.
Edit: hell, look at this absolutely ridiculous headline at the top of the CNN "fact check" page: "Fact check: Trump denies saying another thing he said and makes more false claims at coronavirus briefing"
What kind of headline is that? Is anyone competent left at CNN? The media no longer deserves the soft power it wields. They lost that privilege when they strayed so far from any semblance of objectivity.
There were multiple papers out of Europe and China by then. This was already floating around before Trump latched onto it because it was indeed promising, which is exactly what Trump said.
What else do you think the words "hopefully" and "real chance" are here to communicate?
What do you think "move fast" means? Administer the cure to everyone, or figure out if it works?
This was a clearly promising avenue and as the head of the executive this is one of the few things that the man has done right. This vitriol is pure, irrational bias.
>it's neither vitriol nor irrational to expect a leader to yield to experts and to relay only reliable information.
And you want to tell me that from his tweet you already know he didn't get this information from so called experts? How exactly does this tweet indicate otherwise?
>What he did instead lacked context or information necessary to mass communicate. There's a way to communicate it and it wasn't this
Welcome to the new normal, where politicians communicate via tweet. I agree that it is inappropriate but this particular example is just being used to project the usual anger onto him with multiple plausible but ultimately inappropriate rationalizations. There was, again, nothing inappropriate about a passing mention of a safe, cheap, promising drug. He could have done the same in the middle of a speech for similar effect.
Besides, what did you expect him to do, cite the relevant studies on Twitter? Sure, ideally he would, but let's not pretend that more than, say, .01 percent of the population is even capable of reading studies...
> It really bothers me how hard both citizens and officials seem to be wanting Chloroquine to fail
No-one wants it to fail. However, right now there's no reason to think that it is useful, and the sooner there's a definitive answer either way the better. Certainly, no-one should be taking it outside trials right now, and the ambiguity (and unreasonable hope stoked by high-profile idiots) is causing people to take it, often without medical supervision. This will kill people.
Totally out of my depth here. I've been following Dr. Chris Martenson's daily covid-19 updates since late January. He is adamant this treatment is only effective in combination with zinc supplements.
So why doesn't this guy setup clinical trials instead of providing non-confirmed medical advice on the daily?
Probably cause he is lazy and more interested in selling and promoting himself than he is actually solving problems.
This guy knows the scientific method, I assume. he knows that something needs to be observable and replicated. Instead, he is asking us to trust his brilliance on something where the side effect might be death and blindness??
Who is Dr. Chris Martenson and which hospital does he work at? He seems to be suffering a name collision with some economics PhD guy who appears on Fox.
His PhD is in Neurotoxicology. Of all the things Martenson has been wrong about over the years, this particular event is a bit more in his wheelhouse than the economics or energy topics he typically covers.
He doesn't seem to have many biomedical or pharmaceutical qualifications for pronouncing on what treatments may or may not work?
Edit: Apparently he has a PhD in neurotoxicty (specifically "Acrylamide neurotoxicity: effect on neuronal growth cones and axonal fast transport") which does bolster his credentials.
I cannot tell if you are purposefully trolling, or this is sincere.
Regardless, let's wade in…
1. That's not's a study. That's not a metareview. That's a puff piece by people who have a strong, strong self-interest in promoting TCM, because they want to keep their department chairs.
2. Oh heck, I'll just quote the entire last paragraph:
"The safety of TCM in the treatment of emerging coronavirus diseases was not included in the observation on SARS patients. It was reported that some herbs used in TCM contain nephrotoxins and mutagens, while the toxicological features of the most of Chinese herbal medicines remain to be fully understood. Furthermore, herbs used in TCM can mimic, or magnify, or oppose the effect of conventional medicines. Thus, the safety of TCM used in treatment of emerging coronavirus infections should be carefully evaluated. It is particularly important to avoid toxicity or interfere with the efficacy of conventional treatment caused by herb-drug interaction."
So, in conclusion, we don't know if this works, and this stuff may be toxic, and it may have drug interactions, and oh by the way there's no quality control on this so you have no idea what's in the medications.
Might as well recommend acupuncture and getting your chakras aligned, couldn't hurt! (Probably less of a chance it hurting than taking a wild dose of unregulated herbal supplements.)
"Might as well recommend acupuncture and getting your chakras aligned, couldn't hurt!"
Indeed, it might help and it couldn't hurt.
"(Probably less of a chance it hurting than taking a wild dose of unregulated herbal supplements.)"
Or possibly a known drug with no real evidence of efficacy and a long list of known side effects?
Oh, and by the way, "That's a puff piece by people who have a strong, strong self-interest in promoting TCM, because they want to keep their department chairs," is both an hominem and describes all academic publications.
Thanks for sharing this, not sure why you're getting downvoted. TCM has its place, Artemisia Annua has been used as an anti-malarial treatment as well for hundreds of years, and again, is cheap, available, and side effects are known. I've had anecdotal experience that it's helpful for milder coronavirus symptoms.
> Thanks for sharing this, not sure why you're getting downvoted.
Because TCM is - charitably - pseudoscience. Many of its remedies involve grinding up endangered animals into concoctions that have no plausible mechanism of treating the thing they're meant to treat.
> I've had anecdotal experience that it's helpful for milder coronavirus symptoms.
I have anecdotal experience that my microsorium musifolium plant has been effective in preventing coronavirus infection in my household. Unfortunately, just like your statement, this doesn't qualify as evidence and shouldn't be used to make public health decisions.
You are mindreading my comment of "TCM has its place" and are wrongly confusing it in your own imagination of "used to make public health decisions". Please don't do that, it's insulting to folks trying to have open discussions, and it also makes you, the mindreader, stressed and anxious about things that are not happening.
> documented SARS-CoV-2 pneumonia and requiring oxygen ≥ 2 L/min to emulate a target trial aimed at assessing the effectiveness of HCQ at 600 mg/day
Well hydroxychoroquine is only useful before ventilators are needed (it attacks the full lungs) and is actually detrimental - we know that - after by its nature.
What kind of bad science is this study where you actually push patients through a known dangerous path to try to prove the non efficiency of a potential treatment.
>Well hydroxychoroquine is only useful before ventilators are needed (it attacks the full lungs) and is actually detrimental - we know that - after by its nature.
I’m worried that this has totally left the realm of science and is just pure politics... there is no evidence for a ‘magic window’ for HCQ in COVID-19 treatment, or any solid evidence of a positive role.
Secondly, having supplemental oxygen is not the same as being on a ventilator. I imagine most hospitalized COVID patients need oxygen (otherwise, they could be managed at home).
I hope we all avoid making comments (or even accepting comments) about medicine without either critical, independent study or background knowledge.
From the abstract:
> In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13-2.89), and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days (24 vs 23 events, RR 1.14, 95% CI 0.65-2.00).
The relative risks and confidence intervals are the important numbers here. For example, the relative risk for death is 0.61, meaning the observed risk of death was lower for patients treated with hydroxychloroquine -- but the confidence interval is 0.13 to 2.89, meaning the data is consistent with anything from the risk being much smaller to the risk being much larger. Since there were only 3 deaths in the treatment group and 4 deaths in the control group, it's very hard to draw precise conclusions about death rates.
I think we can interpret this result to mean that hydroxychloroquine doesn't have a miraculously large effect, but the evidence is weak. Other commenters are correct that large randomized trials will be more definitive.
(disclaimer: I am a statistician, not a doctor)