Stupid question in case anyone here has a medical background.
I was under the impression that covid19 was a two step process. First the virus infects and attacks the protective layer of the lungs (causing cough and fever). Then, the damage done to the protective layer of the lungs results in an infection / pneumonia, and that's where people have respiratory problems and may be in critical condition. But at this stage the viral load is low and the virus isn't the problem anymore, the pneumonia is [1].
This is why I thought Pr Raoult was advocating for the use of chloroquine in the early days of the disease, combined with prompt testing.
But it seems that anti-virals (like the study mentioned in this post and other studies in the US and Europe) are tested on patients in critical phase, i.e. with serious cases of pneumonia. Am I missing something or should we not expect anti-virals to be of much use in those cases, as it is too late, we are not dealing with a virus but with a pneumonia?
We don't have data to really address this, but it's likely a flawed picture in that it's an uncommon progression even for severe cases. The reasoning is that antibiotics don't seem to be very effective for the most severe cases, and at least anecdotally among physicians, the evidence for secondary infection is usually weak. There seems to be a lot of primary damage caused by the virus itself to the point of diminished lung function.
Without getting overly technical, there's also some atypical results in some of the labs that seems to indicate that the virus is just overwhelming parts of their immune system, which are in collapse. This can drive up other parts that are inflammatory in nature leading to the cytokine storm and ARDS which comes on very rapidly. However, the fact that things like steroids are leading to WORSE outcomes suggests that the immune suppression is very unhelpful which suggests the problem is more that tissues are just getting overwhelmed with virus.
Sorry for the ignorant question but you mentioned steroids and immune suppression. Does that imply that steroids suppress the immune system in some way?
I’ve tried googling but came up empty besides a paper on “ glucocorticoids” which seems to be something to do with cortisol shots for reduced inflammation, which has immune suppression tendencies.
Is that what you mean? And if yes, is this for all levels of steroids or just some particular types? (IE steroids in an asthma inhaler vs cortisol shot vs anabolic steroids).
> Does that imply that steroids suppress the immune system in some way?
Yes. This is the reason why they're used in the first place.
> steroids in an asthma inhaler
Yes, but an entire year's worth of asthma inhaler is like one dose of oral prednisone, so the impact is quite low and you should not stop using your inhaler.
Steroids are an entire class of chemicals that have a specific pattern in their structure.
Hormones are signalling molecules that get transported throughout your body.
Steroid hormones are chemicals that are both a steroid and a hormone. Not all steroids are hormones (ex cholesterol) and not all hormones are steroids.
A subgroup of steroid hormones is corticosteroids. A subgroup of corticosteroids is glucocorticoids, (most of?) which exhibit strong effects on the immune system (roughly speaking, they suppress the immune system and reduce inflammation).
Corticosteroids suppress the immune system, as do anabolic steroids, but it's not a property inherent to steroids. For instance estrogen is also a steroid and doesn't suppress the immune system.
There's a trial[1] whose objective is to determine if chloroquine is actually useful early on in the infection.
With a target sample size of 3000 individuals it would have at least sufficient numbers to show if it's actually viable, helps a little, or does not help at all.
I'm also looking forward to this study. Kudos to U of M to get this kicked off quickly. I find it interesting to see how fast they were able to marshal a response. Basically, we go from nothing to something started in 10 days. I've been reflecting on how western culture does not seem as effective as China in suppression of the disease, but the west's ability to do "start up" type activity is amazing, and a place for hope.
https://www.twincities.com/2020/03/18/preventing-coronavirus...
Tho they've focused mostly on care instead of the science (they don't believe in randomized trials), and it's going to be hard to know if the treatment is efficient from those (the EU and Michigan studies should help figuring that out).
In the absence of other viable treatments, the efficiency isn't really important.
Frankly, if it is only modestly effective, it should still be given to everyone without contraindications.
Efficiency only becomes important in a year or two when there are competing therapies.
When the choices are Chloroquine or Hopes and Prayers, Chloroquine is the obvious choice (for those that don't have the contraindications, of course -- for those patients, you'd need more evidence to know that the benefits outweighed the risks)
There's a very interesting hypothesis that lung inflammation is a secondary effect caused by the virus damaging red blood cells, making them unable to transport oxygen. See this thread:
What would be the mechanism for damaging the red blood cells, considering that they don't have a nucleus, and therefore the virus cannot replicate in them?
The title of the article for those curious is: "COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism"
It is not a stupid question at all but nobody has a legit answer yet, with so many tentative protocols under way all over the world. Some people recover because of non-standard drugs reducing the most critical effects, some other recover because they get non-standard cocktails at early stage, some other die because prolonged fever leads to multiorgan failure or infections. Gilead is making its part, which is laudable.
> I was under the impression that covid19 was a two step process. First the virus infects and attacks the protective layer of the lungs (causing cough and fever). Then, the damage done to the protective layer of the lungs results in an infection / pneumonia, and that's where people have respiratory problems and may be in critical condition. But at this stage the viral load is low and the virus isn't the problem anymore, the pneumonia is [1].
There are apparently a large number of cases that work differently, with hypoxemia prior to any evidence of severe lung dysfunction:
Yeah, in the last two days there is increasing evidence that there's something else going on in at least some patients beyond "pneumonia resulting in ARDS"
That tweet is interesting. Some folks are starting the theorize that many of the pneumonia (especially, bilateral) diagnoses based on CXR might be mistaken.
The most interesting hypothesis I have encountered (way too little evidence yet to do anything but study it) is that the virus is directly interfering with haemoglobin saturation, and that the abnormal CXR is actually looking at tissue damage caused by haemoglobin degradation somewhat akin to that found in Malaria patients.
That hypothesis intends to explain the apparent efficacy of chloroquine, magnified when taken by patients early in the disease, by hypothesizing a similar mechanism of action in COVID as in Malaria -- not by being antiviral, but by inhibiting heme polymerase.
The apparent antiviral properties of the treatment are then merely keeping the patient healthy and lung-damage-free while the immune system does its thing.
If that were true, then treating COVID patients for pneumonia could be highly counterproductive.
Of course, even if the hypothesis is correct, there might be some COVID patients who do develop a bacterial secondary pneumonia -- that is an uncommon-but-not-rare complication of all respiratory illnesses. That might also explain why Azithromycin seems to make Chloroquine more effective -- each drug helping a different subset of patients, rather than actually as a combined effect.
As I say, though, there is nowhere near enough evidence yet for this hypothesis -- but it is pretty interesting. It is probably worth a study or two to evaluate.
It is a neat hypothesis in that it takes a wide variety of disparate and otherwise apparently contradictory datapoints from clinical experience and weaves them together into a coherent narrative.
Of course, that it makes a good narrative is in no way evidence for it's truth, no matter how much we humans love good narratives.
If that hypothesis is correct then hyperbaric oxygen therapy (HBOT) should be effective. However there are very few hyperbaric chambers available and little prospect of building more quickly.
I don't know the answer to the best time to give antivirals, but the lung inflammation happens for some, but not all patients. A non-trivial amount have relatively normal lungs, low oxygen saturation, and an extremely high heartrate.
The reasons for this are unknown, but it is an active area of research. Some doctors are beginning to call for treating covid patients like they altitude sickness.[1]
It's not super clear yet what the mechanism of Chloroquine (and derivatives like HCQ) is in combating COVID-19 / Coronavirus, and I imagine people are not sure about Remdesivir either, except that it was previously developed as an Ebola treatment (ineffective), but also shown to be effective in some in vitro studies on SARS-COV-1.
Disclaimer: I'm not a doctor or an expert.
Chloroquine is suspected to have general prophylactic abilities (like Remdesivir), but also hypothesized that if taken with Zinc, [1] acts as an ionophore with which Zn2+ ions can inactivate the first part of the viral replication step. But at this time, clinical trials for HCQ have been somewhat mixed, with small N-size studies reporting weak benefits or lack of benefits. I don't know of any RCTs that include Zn2+ in the treatment group along with HCQ. It's still as yet unclear.
With untested drugs, the risk-benefit is considered such that only people who are certainly going to die without intervention can be treated without incurring further liability. So only "terminal" cases get remdesivir in the first place.
To use HIV as an example, every infected T cell releases ~50,000 virions when it bursts. So that's ~10^4 times the number of infected cells. So during an infection only 10^9 of your 10^13 cells would need to be infected to get up into the 10^13 range. That's obviously a TINY fraction at 10^9/10^13 = 10^-4. So saying there's trillions of viruses in your body during a major infection like COVID is hardly an exaggeration. 10^15 may or may not be though, in fairness.
Compare that to the amount of virus you'd be exposed to in the air though in a COVID ward and its just totally negligible. Unless you're getting injected with virions, it's just not relevant to the progression of your infection when you're already a week into it. I'd be shocked if you could daily environmental viral loads above 10^6.
So fine I'll revise it to 6-9 orders of magnitude. The point stands though, it's just not relevant to your immune system compared to the virus it has to deal with from your own cells.
Right, with this and chloroquine, assuming it works to prevent the virus from binding to ACE2, you'd want it to be in the early stages, before massive damage to the lungs, liver, intestines and brains are done (all of these are targeted by this virus). All other countries that are testing these are giving the drugs to patients in both the early and late stage of the infection. In the US alone, trials are only being done in the very late stage, after permanent damage has been done, and it's less likely to be of much use.
There is a large-scale clinical trial with 3000 participants (https://clinicaltrials.gov/ct2/show/NCT04308668) to see if chloroquine prevents progression to severe disease when given shortly after exposure, because when patients are symptomatic it was proved to be completely useless.
There isn't a shortage of participants, and at that scale we'll know soon enough if Trump's wonder drug does something. Probably it won't.
Remdesivir was one of the earliest promising candidates to treat covid-19 since it had promising results - in the lab - against other coronaviruses like SARS and MERS. It did not have results in humans because those viruses went away before in vivo testing could be performed.
Will it work? If it was a runaway success, I would have expected any of the current clinical trials to be cut short as the difference between placebo and non-placebo patients would have been obvious. That hadn't happened. I'm still hoping it has some positive effect.
The drug also had to administered through an IV over several days. It is not a pill you take. If it works, this makes treatment a little bit more difficult. You can't just give patients a pill and send them home.
Gilead is providing the entirety of this existing supply at no cost, to treat patients with the most severe symptoms of COVID-19. The 1.5 million individual doses are available for compassionate use, expanded access and clinical trials and will be donated for broader distribution following any potential future regulatory authorizations. These doses are for treating patients with severe symptoms, through daily intravenous infusions in a hospital setting. Having a potential treatment in our hands comes with significant responsibility. Providing our existing supplies at no charge is the right thing to do, to facilitate access to patients as quickly as possible and in recognition of the public emergency posed by this pandemic.
>The safety and efficacy are not yet known so while we feel the greatest sense of urgency in our work with remdesivir, we must take the responsible, ethical approach of determining whether it is indeed a safe, effective treatment.
>we continue to provide remdesivir on an individual compassionate use basis for children and pregnant women.
Can someone explain this logic to me? The safety and efficacy is not known, so we're going to give it to the most vulnerable people first?
These are already patients who are in serious condition and this may be their last hope. AFAIK (at least pre-COVID rule changes), experimental treatments like these are only used at a patient's last resort, as stated by the FDA.
As with anything pharmaceutical - they still need to make sure it doesn't have long term side effects. As horrible as it is to prevent treatment and prolong suffering, it would be more horrible if thousands of people suffer from unknown side effects if they would have recovered without it.
My takeaway that this drug was for folks that are literally on their “last leg”. I don’t think potential aide effects are going to deter such a patient, at least it wouldn’t deter myself.
It’s tough to worry about a future when you don’t have one.
> Remdesivir is still an investigational medicine and has not been approved by regulatory authorities anywhere in the world. The safety and efficacy are not yet known so while we feel the greatest sense of urgency in our work with remdesivir, we must take the responsible, ethical approach of determining whether it is indeed a safe, effective treatment. This is why multiple clinical trials for remdesivir are underway, involving thousands of patients with COVID-19 across the world.
I’m not too glad. From the description, it sounds like it’s a massive expense to produce the drug, and if public attitudes force companies to give the results away for free, then there is no expectation of profits for pharma companies to invest for future preparedness for pandemics. I’d like them to charge a lot and make a killing. Governments can subsidize if they want.
Perhaps pharma companies shouldn't be the ones planning for pandemic preparedness? Maybe some sort of societal structure that operates at a level above individual companies could bear this responsibility.
That being said, I think it is fine if the government buys these supplies. I also think it is fine if a company wants to donate.
My guess regarding why they have a stockpile of this drug is that they were hoping to be able to sell it for ebola, for which it's ineffective, and have subsequently been trying to figure out how to sell it. Here, they're able to get clinical trial information (and lots of goodwill) with a potentially small marginal expenditure.
It's also not entirely clear what it means to provide the drugs "at no cost" (later on it says "no charge", but in a separate sentence), nor is it clear how long this promise will last.
Why don't we just get the drugs now and figure out payment when there isn't an emergency going on? When there's a potential for thousands of people dying, I'd rather get the medicine produced and in the hands of the people who need it immediately. I agree that if the drug helps they should be compensated well, but there's a time and place for everything.
You should be glad. Pharma companies are well-known historically to have milked monopolies to their own financial favor at the cost of public health, well-being, and welfare. They are not traditionally seen nor acting in congruence with altruism. If a company has decided to do so, that is great. But I think seeing this as some sort of a slippery slope seems completely backwards to me. It's about time pharma companies cut a little of their profits for the benefit of people. The cost of research is far outweighed by their excessive profits that come after the fact.
I don't know how you can complain about "excessive profits" for entirely novel products that a drug company brings into existence, essentially, starting from nothingness. No amount of profit is excessive - the profit is the motivation for them to invest in further research and we should all hope it continues to be so. "Profit" directly represents how much value to society their drug produced. If someone cures cancer, are you going to whine about how much money they make from it? Are you going to claim that, because they produced something extremely valuable, society has the right to take it from them for less than it's worth?
This is not the same as, say, an ISP making excessive profits by manipulating the market and building themselves a quasi-monopoly, or a bank harvesting profits by taking huge risks with the understanding that the Federal Reserve will bail them out if everything blows up. The ISP isn't innovating, isn't creating anything, they're merely an engine for spending and allocating resources. The bank isn't creating anything either, they're just moving money around and playing social engineering games with society. Complaints about profits in these industries are totally reasonable, since these companies are basically just middlemen sucking money from the economy in order to maintain the plumbing.
But to complain about excessive profits in an industry whose entire purpose is to discover new things? That makes no sense to me. What alternative would you prefer?
> The bank isn't creating anything either, they're just moving money around and playing social engineering games with society
How would you react to a situation in which small companies discovered new drugs for ~$10 million, building on public research, and then were purchased by larger pharma companies for ~$300 million, and in which the large pharma companies aimed to earn ~$1-5 billion before the patents on the small company's invention expire?
I would say that there is a common misunderstanding of:
A) the viability initial drug discovery and subsequent development costs, and
B) The time value of money.
For A) success rates of 5000:1 are not uncommon. Discovery is at the very beginning of this process [1],which can take 12–15 years and cost in excess of $1 billion [2]
B) A 1 to 5 billion dollar return on a 300 million acquisition is likely a loosing proposition for most pharma companies due to risk and the time value of money. If you have a 300m acquisition, 700m additional dev costs, a 50% time discount, and a 50% chance of success, you are already up to 4 billion in revenue needed to break even. This article [3] provides a balanced overview of the finical aspect and is written by a scientist trying to give away a cure for his terminal wife.
I agree with your comment in general, but I would just underline that the discovery component of a drug is often not paid for by the eventual vendor of the drug, but is instead paid for by taxpayers, other granting agencies, and venture capitalists. Thus the eventual vendor of a drug won't necessarily have 5000:1 odds, but instead will be able to review and purchase the most promising candidate drugs based on data generated by other companies.
It's definitely true that companies also attempt to make new drugs in-house, but I can't readily recall a recent blockbuster drug made in this way.
The expensive part of bringing new drugs to market is testing in humans. Perhaps the US could bear some of these costs while, in exchange, shortening or eliminating patent protections.
>I agree with your comment in general, but I would just underline that the discovery component of a drug is often not paid for by the eventual vendor of the drug, but is instead paid for by taxpayers, other granting agencies, and venture capitalists.
In the case of the taxpayers and grants, i think it is important to keep in mind that these are explicitly given without strings attached or rights reserved because society decided that we want to encourage private research. It is fair to argue that perhaps we should change the model moving forward, but I find it fairly offensive when folk claim a retroactive ownership on this basis.
>Thus the eventual vendor of a drug won't necessarily have 5000:1 odds, but instead will be able to review and purchase the most promising candidate drugs based on data generated by other companies.
I wholeheartedly agree. the long >5000:1 is at discovery, i.e. the basic research that is often publicly funded. Once drugs have gone through enough screening to be used, the probability of approval is up to about 10:1 [1]. A lot of the bigger sales take place between phase 1 and 2, which probability of approval is up to perhaps 25%. Research institutions and early developers get paid based on the potential value and risk, and are not taken advantage of. The fact that companies often outsource early develop doesn't invalidate the their claim to their profits.
>The expensive part of bringing new drugs to market is testing in humans. Perhaps the US could bear some of these costs while, in exchange, shortening or eliminating patent protections.
This is an interesting idea. Two additional options that you may want to consider that wouldn't stifle development are expedited approval and government manufacture of generics. Due to the time value of money, faster approval increases the profitability of new drug development and without increasing prices to consumers. For generics, drug profits after loss of exclusivity are so far out that they don't significantly weigh in on the decision to develop a product or not.
There are a ton of studies ongoing, stock pumping PR campaigns like this aren't responsible until the data is in, and there should be studies breaking their blinds this week. It's fine to ramp up production just in case, but that hardly justifies a press release by the CEO.
I was under the impression that covid19 was a two step process. First the virus infects and attacks the protective layer of the lungs (causing cough and fever). Then, the damage done to the protective layer of the lungs results in an infection / pneumonia, and that's where people have respiratory problems and may be in critical condition. But at this stage the viral load is low and the virus isn't the problem anymore, the pneumonia is [1].
This is why I thought Pr Raoult was advocating for the use of chloroquine in the early days of the disease, combined with prompt testing.
But it seems that anti-virals (like the study mentioned in this post and other studies in the US and Europe) are tested on patients in critical phase, i.e. with serious cases of pneumonia. Am I missing something or should we not expect anti-virals to be of much use in those cases, as it is too late, we are not dealing with a virus but with a pneumonia?
[1] see this useful video: https://www.youtube.com/watch?v=BtN-goy9VOY