WHO launches global megatrial of the four most promising coronavirus treatments
sciencemag.org
sciencemag.org
"On 17 March 2020, Chinese officials suggested that Favipiravir seemed to be effective in treating COVID-19 in Wuhan and Shenzhen.[31][32][33]
A study on 80 patients comparing it to lopinavir/ritonavir found that it significantly reduced viral clearance time to 4 days, compared to 11 for the control group, and that 91.43% of patients had improved CT scans with few side effects."
I'm sure they'll test the drug in the future though, there are likely plans to test it as we speak, and if it works really well there are lots of ways to get expedited approval, especially in a state of emergency
You just have to do the science, there's no way around it. And realistically we may not have time.
In the current state of knowledge about both ARDS and Covid and given the time available, clinicians rely on traditional teachings to care for covid-related ARDS until solid evidence can be provided.
if you want some interesting details from American MDs there's this podcast
http://www.microbe.tv/twiv/twiv-593/
lots of subtle details that you can't get on simplified stats
https://www.thelancet.com/journals/lancet/article/PIIS0140-6...
Significant lung and myocardial injury and papers have honed in on ARDS as a real problem.
My understanding is that most deaths are in the elderly, and that those deaths are due to pneumonia.
If this helps https://en.wikipedia.org/wiki/Cytokine_storm
"It is believed that cytokine storms were responsible for the disproportionate number of healthy young adult deaths during the 1918 influenza pandemic, which killed 50 to 100 million people.[16] In this case, a healthy immune system may have been a liability rather than an asset."
1. Remdesivir (Ebola drug).
2. Chroloquine and Hydroxychroloquine (Malaria drug).
3. Ritonavir/lopinavir (AIDS drug).
4. Ritonavir/lopinavir + interferon beta (virus signaling protein).
This allows it to engage in uncontrolled replication for up to two weeks before the adaptive response brings it under control.
This massive viral load greatly contributes to transmission.
(Or at least SARS does this.)
It should be possible to supply a large part of the worlds population with (hydroxy)chloroquinine if that is deemed a solution, but the others seem less ideal candidates for that, or am I wrong?
The hoarding is even happening among my lesser scientifically-reasonable md colleagues. This has to stop. Now.
I hope when this is over, someone will look into this behaviour from the MDs. It's eroding trust in the system when they claim potentially vital resources for themselves.
Our bosses were still laughing at us for worrying on Monday evening, and now they're pissing their pants. Idiots.
Obviously I don't want anyone with lupus / malaria / etc to be adversely affected, but I think the people being forced to work the front lines do deserve to be somehow prioritized just from a "how do we keep the system operating efficiently" standpoint, and it doesn't really seem like the people who could manage supplies to make sure both parties needs are balanced, e.g. hospital administrations and regional governments, are going to take much responsibility for that.
<50yo: all MDs understand and have been vocal about it for weeks.
>50yo: nah, this can't happen to us great minds. Let's start preparing when the first patients are already in the ICU.
Link in dutch: https://eenvandaag.avrotros.nl/item/fabrikant-van-coronamedi...
So, yes, if we lived in India in the mid-to-late 1800s, drinking tonic water might help, at least for the things that quinine helps.
But modern tonic water isn't really anything like that.
Regardless, WHO should be doing trials on more over-the-counter products. It's dumb that they put out a statement warning people that there was no evidence that Garlic could be used as an antiviral, despite the fact that literally two days ago the FDA granted emergency expanded access for some multi-million dollar inhaled nitric oxide device based on the fact that nitric oxide has been shown to block the replication of SARS-CoV in vitro. (Guess the mechanism of action by which eating raw garlic nearly instantly lowers your blood pressure.)
Sources here: https://www.reddit.com/r/covid19stack/
And the article you're referencing chooses to link press releases, but only vaguely mention studies not only without linking but without even providing enough information to identify them - which hardly inspires confidence.
And the subreddit from which you're getting it is...wow. Just an absolute heap of fear-driven misinformation, and while I'm not without compassion for the people there who feel the urge to do something to protect themselves in the face of a very frightening situation, it's important to try to keep a clear enough head to understand the difference between developing knowledge and multiplying tiny probabilities into meaningless, misleading rumors. That subreddit is doing the second one of those, not the first. For the sake of your own emotional wellbeing, please consider taking it less seriously.
edit: Oh, sorry, I hadn't noticed that the people posting in that subreddit are basically 90% you. So, I guess I'm warning everybody else off it, and asking you to consider doing less of this, in the cause of everyone else's emotional wellbeing.
The vast majority of links are just to metastudies and literature reviews. If you think the Cochrane review studies or whatever are fear-driven misinformation then you should complain to them for creating them, not me for posting them.
Literally today Trump put out a statement saying that he's considering just sending everyone back to work and letting everyone get it all at once.[1] If that happens then the medical system basically won't even exist for 90% of people. What exactly do you propose that people should do in that scenario, just sit around drinking Gatorade and waiting to die?
[1] https://www.nytimes.com/2020/03/23/us/politics/trump-coronav...
It’s helpful in the short term, but not effective for longer than a few weeks apparently. Also there may be scaling issues?
> It’s not a vaccine. Think about it as the administration of a protein, it’s a liquid that is given to people that gives them immunity.
> Right. Because the vaccine would provoke the recipient’s antibodies. You'll have the antibodies, but they won't be your antibodies—though it'll do the same thing.
And many more reasons...
1. Where are the high costs coming from? Distribution? Storage? People? Most of these seem shared for other drugs.
2. Blood transfusion seems to be one of the most common treatments there is (https://en.wikipedia.org/wiki/Blood_transfusion#Frequency_of...). Safety concerns seem to stem from so far unknown pathogens that are not tested for in the blood of donors.
3. Production facilities are every hospital. Nothing needs to be produced or what do you refer to?
Right now, chloroquine is cheap. I suspect that will change. As for plasma yes, every step from collection to administration is expensive if you want to keep with the current safety level. And other people need plasma too...
Plasma toxicity worries currently comes more from transfusion-related reactions than from infection.
Hospitals have very limited capacity in term of production. Just starting with the fact that you'd have to find enough volunteers in the first place, but even so a hospital is not a factory.
I’m curious /excited to rare how this dynamic changes once we get serological tests online. Maybe all of the mild cases amongst youth can give enough serum to treat the harder hit individuals.
Here’s a recent discussion about serum:
https://www.globalhealthnow.org/2020-03/covid-19s-stop-gap-s...
And the linked study:
Exponential growth messes everything up, basically. All our intuition about how things work tends to be wrong in subtle ways.
[1] https://www.imperial.ac.uk/media/imperial-college/medicine/s...
A vaccine triggers an active immune response. That includes the differentiation of aptly-called "memory" B cells. Those can lie dormant for decades and spring into action when needed.
FWIW, it seems at least plausible to me that a recovered patient who was treated with serum may not generate as many protective antibodies as a naturally recovered patient. For example, Rh antibodies are used during pregnancy specifically to prevent an immune response. I don’t know if this would apply to COVID-19 or if giving serum only after symptoms become severe would prevent this outcome.
https://techcrunch.com/2020/03/19/french-study-finds-anti-ma...
Ventilator-associated pneumonia (VAP) is a type of lung infection that occurs in people who are on mechanical ventilation breathing machines in hospitals. ... Between 8 and 28% of patients receiving mechanical ventilation are affected by VAP
https://en.wikipedia.org/wiki/Ventilator-associated_pneumoni...
I would recommend this post: https://blogs.sciencemag.org/pipeline/archives/2020/03/19/co...
... and most anything that Derek Lowe has to say about small molecule drugs. He's apparently had a bit of time at home recently to blog more, and is rather focused currently on Corona virus.
"Enrolling subjects in SOLIDARITY will be easy. When a person with a confirmed case of COVID-19 is deemed eligible, the physician can enter the patient’s data into a WHO website, including any underlying condition that could change the course of the disease, such as diabetes or HIV infection. The participant has to sign an informed consent form that is scanned and sent to WHO electronically. After the physician states which drugs are available at his or her hospital, the website will randomize the patient to one of the drugs available or to the local standard care for COVID-19."
> A global data safety monitoring board will look at interim results at regular intervals and decide whether any member of the quartet has a clear effect, or whether one can be dropped because it clearly does not. Several other drugs, including the influenza drug favipiravir, produced by Japan’s Toyama Chemical, may be added to the trial.
I'm not finding the original statement/source from WHO, I'm sure they gives more reasons there around why some drugs are not included (yet)
Japanese government only allows it to be used as a backup, Chinese licensed the design but the government only allows it to be used when all other avenues are exhausted.
Favilavir is accepted only in Japan and China.
Still seems chloroquine is required to meet a higher bar than the others which continues to be odd.
I mean...it seems likely that some of the boosters who have been astroturfing it do actually have a stake.
A number of zero-medical-experience personalities have become mini-celebrities with their boosting of it. For those who saw the movie "Contagion", their behavior is shockingly similar to the Jude Law character and its boosting of Forsythia. Some of these people are active on HN, and it's amazing how often absolute trash science is heralded like it's some suppressed truth.
A few days back Trump was retweeting one such huckster. A guy who has repeatedly tried to recreate his own Wikipedia page (to be deleted again for non-notability). Who has a pretty standard hustler-and-exploiter bio. Now he's claiming that he's at the forefront of "working with companies" to get this magical treatment to the streets. It is deplorable.
People who need it for medical conditions are finding it impossible to find. Not sure how large the production is.
Any treatment that is found to actually be effective in real studies is pretty clearly going to be nationalized, recreated by countries around the globe, and mass produced overnight.
It's large, or can be easily scaled up. Novartis is pledging 130M tablets, Teva 16M, Mylan is planning on ramping production up to 50M.
0: https://www.fiercepharma.com/pharma/new-commitments-mylan-an...
I doubt that these people have financial stake in any of these products. Sometimes, the substance might be relevant to some opinion they hold dear. The guy recommending garlic might consider all modern medicine a conspiracy of the pharmaceutical industry. A significant number of people on HN and reddit have also been really into cytokines for the last few years, the reason for which eludes me (maybe it’s the one bit of biology they heard of at some point and they are still enamored by their smartitude and want everyone to take notice).
Quinine and similar might have just been popular for the funny Gin&Tonic tie-in. Then, the US president read about, called it “the biggest discovery in medicine” or similar on Twitter, and now the alt-right has a stake in its success.
http://bannerhealth.mediaroom.com/trending-now-at-banner?ite...
Does the article say anything about different bars for the different treatments? I must have missed that. What are you referring to?
Main researchers and leaders were still laughing at us for worrying on Monday evening.
It's the same all across the western part of the continent.
for example, if you have a few medications, you might start by trying them all equally at random and then as data comes in, use a bandit algorithm to gradually shift more and more new patients onto the ones that prove most effective, in a way that optimally trades off accurately estimating the effects with wasting time testing the less effective drugs.
interestingly, the first formulation of the problem is due to Dr. Thompson at the Yale Pathology Department in the 1930s; he came up with Thompson sampling. So these are techniques that were originally designed for medical trials.
I think that designers of medical trials probably do have a good grasp of this stuff (some statistical estimators that originated in the medical world have even been successfully imported into reinforcement learning/MAB research) so probably they would be using a bandit-like technique if they felt it made sense.
For example, in Thompson sampling probability of choosing option is equal to probability of that option being the best option given evidence so far.
Aim is to maximize reward (successful treatments), while spending little as possible time on exploration (testing less effective treatments).
An example of how machine learning goes wrong is if a treatment slows down the progression but increases the death rate. Given exponential ramp up in the incoming cases, it will look good until the final horrifying numbers are in. You need to slice and dice the numbers by cohort to detect/react to this.
Suppose that the treatment increased deaths by 50% but delayed death by a week. And we have a doubling rate for the disease of 1 week.
Back of the envelope that means that the treatment will have 1.5x the deaths from when the disease happened 0.5 times as much for 0.75 of the deaths at any point in time. It looks like it saves 25% of lives when in fact it kills 50% more people. The raw numbers will look good until you look at a cohort over time.
Current doubling time for deaths has been about 3 days. My assumption of a week is therefore optimistic. Perhaps we get there with social distancing.
Well, sure, but everything works best with immediate success-fail metrics. That's one of the most basic results from learning theory is that the longer the latency between stimulus and response the slower the learning rate can be. I'm not sure how multi-armed bandit is special in this regard in any particular dimension. All learning techniques are going to be susceptible to the problem you outline in your second paragraph.
This is one of those "there is no perfect solution" situations. It's really easy to say that out loud. It's quite difficult to internalize it.
(Also, just as a note to your other post, bear in mind that our hard-core "social distancing" efforts in the US are just about to reach approx. 1 incubation period. It is only just this week that we're going to start seeing the results of that, and it'll phase in as slowly as our efforts 1-2 weeks ago did. My state just went to full lockdown today, though we've been on a looser lockdown for a week before that.)
Which medicine looks effective? Which medicine gets people out of the hospital faster? What underlying conditions interacted badly with given medicines? These questions do not have to be asked up front. But they can be answered afterwards. And knowing the answers, matters.
Here is an example. Suppose that we find one medication that gets people out of bed faster but kills some. In areas with overwhelmed hospitals, cycling people through the bed may save net lives. If your hospital is not overwhelmed, you wouldn't want to give that medicine. Now I'm not saying that any of these medicines will come to a conclusion like that. But they could. And if one did, I definitely want human judgement to be applied about when to use it
Even if they were proposing it, there's no realistic chance of it happening.
I don't want people blindly copying "standard" scientific procedures either, where we run high-stastistical-power studies for months with double-blind scenarios then carefully peer-review it and come up with some result somewhere in 2022.
They'll probably use sequential stopping rules to take samples of incoming data.
If one of the treatments works much much better, then they'll almost certainly recommend that (but doctors will probably figure this out first, anyway).
https://www.cdc.gov/coronavirus/general-information.html
It seems that those keep coming back each year either because they mutate, or the antibodies produced by our bodies are no longer produced/effective after a year or so.
So even if we had a vaccine for SARS-CoV-2, would it lose its' potency after a year, and people need annual booster shots? Or would the virus mutate so that the specific vaccine no longer works?
Also, is the expectation that the mortality rate of SARS-CoV-2 will reduce over time because of evolutionary pressure? Is that really the case, given that much of the spreading happens in the first 1-2 weeks, before the host is potentially dead?
The answer is probably yes to both questions.
RNA viruses, like influenza, HIV or coronaviruses do mutate a lot. This is what makes them hard to eradicate, plus in the case of influenza at least we've got an endless reservoir from wild animals.
But a lot of people are already vaccinated for influenza every season and the availability of a vaccine that works for 6 months would make this very manageable, even for people that forget or refuse to vaccinate, due to herd immunity.
Mar 22, 2020,01:43pm EDT
"Two scientists at major university centers reviewed the French trial for me. They agreed, separately, that while the study is preliminary, small, and not without flaws, its findings were strong enough, given the drugs’ known safety records, to guide treatment decisions in a crisis.
“Despite the limitations of this study, in the absence of any effective treatment, in this urgent situation, this Plaquenil and Azithromycin combination therapy should be given to patients with COVID-19 as a treatment option,” Ying Zhang, a professor of microbiology at Johns Hopkins Bloomberg School of Public Health, wrote in an email. “For now, there is no time to wait."
Brian Fallon, a research scientist and clinical trials investigator at the Columbia University Irving Medical Center, agreed on the study’s overall merit despite the patients who dropped out. After analyzing the data and counting all six dropouts as treatment failures, he said the overall rate of improvement was still statistically significant for the entire group, though not for the hydroxychloroquine group alone."
https://www.forbes.com/sites/marybethpfeiffer/2020/03/22/one...
"The just-released French study reported that 70 percent of hydroxychloroquine-treated patients, or 14 of 20, were negative for the virus at day 6, as were all six patients who were treated with hydroxychloroquine and the antibiotic azithromycin (which Novins also received). But the study was small – 20 treated patients and 16 controls – and had other serious limitations."
Covid-19: India Recommends Hydroxychloroquine As Prophylaxis For Healthcare Providers, Patient Family Members
https://swarajyamag.com/insta/covid-19-india-recommends-hydr...