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Saturday, March 21, 2020

Hydroxychloroquine and azithromycin

1. Sure, hydroxychloroquine/azithromycin is promising. However I fear Trump is overselling it. It's far from a panacea at this point in time. Maybe that'll change in the future, but the problem is it's still to be determined. (Edit: A Stanford pathologist's opinion.)

2. In other words, hydroxychloroquine/azithromycin in combination to treat COVID-19 still needs to be proven through clinical trials. That's the standard to ensure safety and efficacy. However, right now, the evidence for hydroxychloroquine/azithromycin is primarily based on case reports. Case reports have sometimes or perhaps often fallen by the wayside in light of further investigation.

3. Same goes for other hopefuls like chloroquine, remdesivir, lopinavir-ritonavir, etc. These likewise need to undergo the gauntlet of clinical trials to demonstrate safety and efficacy. And some of these antivirals are already undergoing clinical trials (e.g. I've mentioned Stanford and remdesivir in the past).

4. By contrast, there already exists a reasonable therapy to tide us over until we can develop antivirals or a vaccine. It's called convalescent plasma therapy (serum antibodies). I think it'd be better to prioritize (in the interim) convalescent plasma therapy. I've described this in the past (e.g. here). Basically what plasma therapy would entail is taking the antibodies of someone who has already recovered from COVID-19 and transferring the antibodies to someone else. This can be done for treatment and/or prophylaxis. Plasma therapy would confer passive immunity to people. This is what infectious disease experts like Ian Lipkin (Columbia University), Peter Hotez (Baylor College), and Amesh Adalja (Johns Hopkins University) have been saying for weeks now.

We could do this for health care workers on the frontlines, the elderly, the immunocompromised. They're at higher risk than the general public of developing COVID-19 and dying. It'd likely be a monthly injection.

Again, plasma therapy is available right now. It's not theory, but reality. There's no large scale clinical trials required. We can start implementing it today.

To be fair, there are some medical issues to be dealt with in certain patients (e.g. allergic reaction), but that's outweighed by its tremendous benefits.

The real challenges are not in the medical technology but logistics (e.g. obtaining enough blood donations from those who have recovered from COVID-19, setting up blood banks, distribution).

23 comments:

  1. To be fair, Trump is “overselling” the FDA to “move mountains” to put these into use. He is not saying to throw them out there Willy-nilly. As far as the trials being in a disarray, that doesn’t change the fact that the course of the disease HAS been interrupted by this combination of drugs.

    In addition, Trump has been a strong advocate of “right to try”. A person who is gasping for breath is less likely to want to uphold “scientific standards of evidence” than to want to try something that is going to help them through the hardest parts of this illness if it’s possible.

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    1. "To be fair, Trump is “overselling” the FDA to “move mountains” to put these into use. He is not saying to throw them out there Willy-nilly. As far as the trials being in a disarray, that doesn’t change the fact that the course of the disease HAS been interrupted by this combination of drugs. In addition, Trump has been a strong advocate of “right to try”. A person who is gasping for breath is less likely to want to uphold “scientific standards of evidence” than to want to try something that is going to help them through the hardest parts of this illness if it’s possible."

      1. I'm not criticizing Trump's efforts so much as I'm criticizing the safety and efficacy of the drug (i.e. hydroxychloroquine/azithromycin).

      2. The fact is case reports aren't equivalent to clinical trials. There are certain ethical and scientific standards we shouldn't drop or waive even in the midst of our current pandemic.

      3. I already mentioned a perfectly acceptable alternative that would save lives today.

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    2. In the press conference today, Trump said that a whole bunch of it is being sent to New York, and his thought was, "what do we have to lose?" It's not as if chloroquine is a new drug. It already has a lot of history. It is known not to have many side effects. If it doesn't work, it just doesn't work. But if it does, it could be very helpful to a lot of people.

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    3. “ It's not as if chloroquine is a new drug.”

      Chloroquine is not the same as hydroxychloroquine/azithromycin.

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    4. “It already has a lot of history.”

      All these drugs have a lot of history. That’s not the point. The point is will they likewise work in Covid-19 patients in which they do not have a lot of history?

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    5. And keep in mind I did say the drug combination is promising. That’s already more positive than many if not most medical experts are saying about it. And also keep in mind I did say it needs to undergo clinical trials. So I’m obviously not against what Trump is doing.

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    6. It’s getting good press: https://youtu.be/e7y6xwQq-us

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    7. Thanks. Yeah, I saw that. William Grace is an oncologist at Lennox Hill, not an infectious disease physician. However these days apparently anyone with MD after their name gets an interview with a major news network! :) But seriously he brings up some good points. However I've also brought up some of the same points he brought up in this very post! :)

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  2. I really do appreciate what both of you have said here. It would be great if we could subject quinone/azyth to clinical studies if we had ample time.

    But I do see John's point. Our nation is panicked. I can easily see why Trump would promote a less than optimal treatment in light of all this drama.

    Antibody therapy is also a great idea, but no matter what we do, it appears we need to consider all our options.

    Thanks to both of you.

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    1. Thanks, Coreysan. However, please keep in mind I am arguing for using every means possible - antivirals, vaccines, plasma therapy, etc. But antivirals and vaccines take a long time to develop.

      Anyway, don’t listen to me or John, because we’re nobodies, but listen to medical experts like Ian Lipkin or Amesh Adalja. See what they’re saying.

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  3. A few more things I wanted to add:

    1. I definitely agree we should be working on any and all viable therapies including but not limited to hydroxychloroquine/azithromycin. Remdesivir is another one that's already undergoing clinical trials at places like Stanford University (as I've pointed out in the past). There are several others (e.g. chloroquine, tocilizumab).

    2. My main concern in terms of "policy" was Trump seems to be preferencing hydroxychloroquine/azithromycin over the other drugs we're working on. Like I've said, I'm not against him doing this, per se, but I'm not sure what it's based on. Why hydroxychloroquine/azithromycin rather than (say) remdesivir? But maybe he knows something I don't. That's entirely possible since he's the president and I'm a lowly nobody.

    3. Anyway so I definitely agree we should be pursuing any and all potential therapies against COVID-19, including antivirals, but of course antivirals are still some ways away. Not as far away as a vaccine, but still not available today or tomorrow. At least if we do things as we've always done things and make sure to ensure efficacy and safety in representative populations.

    4. By contrast, convalescent plasma therapy using serum antibodies from those who have recovered from COVID-19 is available today (in terms of the medicine, not logistics). In fact, this isn't anything new. It's been known about at least in broad strokes since the Spanish flu in 1918, though obviously medical science and technology were far cruder back then than it is today.

    5. However, if (to take an extreme position) we want to forego clinical trials, and start using hydroxychloroquine/azithromycin on everyone with COVID-19 without undergoing clinical trials, based on what "seems" to have worked among Chinese or French or other COVID-19 patients (who do not necessarily have the same demographics including health demographics as we do, for one thing), then that's extremely risky. For all we know at this point, it could just as well result in the deaths of as many as we cure.

    If desperate times call for desperate measures, and we do something like this, then I would argue we should likewise suspend malpractice lawsuits against physicians, nurses, and other health care providers when it comes to using hydroxychloroquine/azithromycin. That's because it would not be fair to them if as a society we ask (demand?) them to use hydroxychloroquine/azithromycin without the drug combination having undergone adequate safety and efficacy checks, in case it ends up killing or seriously harming many COVID-19 patients.

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    1. And don't take my word for it. Ian Lipkin (Columbia University) talked about plasma therapy nearly weeks ago! Perhaps even longer. See this for example:

      https://twitter.com/LouDobbs/status/1237892870331191297

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    2. A few more things I'd like to add:

      1. The "Marseille" study (which also took place in Nice and Avignon) with Didier Raoult is the "best" of the studies out there on this. However, the thing is, the Marseille study was a nonrandomized and unblinded study with a small sample size as well as dropouts and no longer-term follow-ups. So it's certainly promising, but even Raoult himself recognizes these limitations.

      2. As far as clinical trials for safety and efficacy. To take an almost absurd example, we might know a particular drug is safe and effective when used for high blood pressure, but we don't necessarily know it's safe and effective when used for pneumonia. The same drug could have different effects on different diseases or diseases states or the like. So with regard to our drug in question, it's true it's safe and effective as an anti-malarial drug as well as with a rheum disease like lupus. However that's not the same as being safe and effective in COVID-19. What we're basically trying to do is re-purpose a drug for use in a different disease (COVID-19) but we don't know if it will be safe or effective, though as I've said it is "promising".

      3. In fact, because hydroxychloroquine and azithromycin are known drugs, their side effects or adverse effects are also known. For example, hydroxychloroquine and in fact azithromycin can both have issues with what's known as QT prolongation. The problem is that QT prolongation can lead to fatal cardiac arrhythmias ("heart attacks"). So a concern physicians have is will this likewise be the case in COVID-19 patients?

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  4. Isn't there a danger with plasma therapy that the virus might still be in the bloodstream somewhere even if the person is ostensibly recovered and has antibodies as well? In which case, especially if it were used for prevention, could it actually spread the disease?

    And as a treatment--correct me if I'm misremembering here, but isn't it a 1/1 ratio of donor to patient? If it's anything close to that, it would be really inefficient. You'd have to get a *lot* of willing donors who qualify in other ways to treat patients.

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    1. "Isn't there a danger with plasma therapy that the virus might still be in the bloodstream somewhere even if the person is ostensibly recovered and has antibodies as well? In which case, especially if it were used for prevention, could it actually spread the disease?"

      That's a good question!

      1. In general blood transfusion from a donor to a recipient always carries some risk (e.g. allergic reaction, TRALI). One of these risks is, indeed, transmission of infectious agents. This is known as transfusion transmitted infection (TTI).

      2. This isn't only with regard to COVID-19, but it's true of blood transfusions in general.

      3. That said, the entire process includes processing or filtering the blood, testing for infectious agents, and eliminating them.

      4. We've done this for decades with regard to other viruses such as with the hepatitis B virus (HBV), the hepatitis C virus (HCV), HIV, etc. Not to mention other pathogens like certain bacteria.

      5. Of course, something could always slip through the cracks, but from what I've read the risk of TTI for HBV is approximately 1 in 2.5 million, for HCV approximately 1 in 50 million, and for HIV approximately 1 in 6.5 million. And HBV's size (diameter) is approximately 40 nm, HCV's is approximately 60 nm, and HIV's is approximately 120 nm. Our coronavirus, the SARS-2 virus, is approximately 120 nm in diameter (similar to HIV). I'm speaking on average, of course.

      6. One last thing I should note is that other therapies such as antivirals (including hydroxychloroquine/azithromycin) carry their own significant risks as well. Not necessarily TTI, but that depends on the therapy in question.

      "And as a treatment--correct me if I'm misremembering here, but isn't it a 1/1 ratio of donor to patient? If it's anything close to that, it would be really inefficient. You'd have to get a *lot* of willing donors who qualify in other ways to treat patients."

      1. There's evidently something of a debate over this. For example, as far as for therapy, I've heard Peter Hotez argue for a 1:1 ratio: "The kinds of numbers people are throwing out are 300-600 mLs for someone who is potentially seriously ill. So that looks like a 1:1 donor per patient."

      By contrast, I've heard Ian Lipkin argue it's closer to 1:3.

      2. That said, as far as prophylaxis, it looks like a much better ratio. As Hotez says in the same interview: "But for the prophylaxis, if we're talking 5 mLs, then a single donor could potentially prophylax dozens or maybe even a hundred individuals."

      3. And apparently the donation wouldn't be like a normal blood donation at (say) the Red Cross. Apparently it'd be much less taxing on donors.

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    2. In fairness, it's certainly possible I'm "overselling" this too (in the same or similar way Trump might be overselling hydroxychloroquine/azithromycin). If so, then I think at the very least we could add this therapy alongside other therapies (including hydroxychloroquine/azithromycin). Of course it's not a zero sum game. At least not as far as I can tell. I think we could be simultaneously pursuing all viable avenues of treatment without initially prioritizing any particular therapy. And we can always adjust and re-prioritize our options as we gain more information. In short, we could make it a both/and rather than an either/or situation with regard to finding best treatment options for COVID-19.

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  5. I haven't read this yet, just skimmed it, but it looks like a good overview of convalescent plasma therapy:

    https://www.jci.org/articles/view/138003

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  6. https://www.facebook.com/100001197885797/posts/2803035443079691/?d=n

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    1. That's good! I always respect Tim McGrew.

      Also, I've pointed out a few of the same things that Tim pointed out about how well South Korea has been doing. In fact, I even pointed out the use of chloroquine and hydroxychloroquine here. And it looks like Tim posted the FB comment on 3/18, while I posted my post on 3/17.

      I say all this not at all so that the focus might be on me or what I've said, but in response to you because you seem to think I'm unaware of these sorts of things (based on our previous debates among other things).

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    2. No, I only just saw it this morning. Not sure what time the update was. I posted it as a confirmation for what we’ve all been saying here and maybe as a hopeful sign for people who are just now tuning in.

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    3. "No, I only just saw it this morning. Not sure what time the update was. I posted it as a confirmation for what we’ve all been saying here and maybe as a hopeful sign for people who are just now tuning in."

      1. Well, this post and what we've all been saying here wasn't about South Korea.

      2. More to the point, you do realize, do you not, that you are a Triablogue member who can create his own posts? :)

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    4. The update was about the use of chloroquine and hydroxychloroquine as one of their "formal protocols". And that's really the most important and current part of the post by Tim. I don't really have anything more to add at this point.

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    5. "The update was about the use of chloroquine and hydroxychloroquine as one of their "formal protocols". And that's really the most important and current part of the post by Tim. I don't really have anything more to add at this point."

      1. My main point was that if you wanted to offer "a hopeful sign for people who are just now tuning in" then why not make it more visible by making your own post?

      2. The update is "the most important...part of the post"? An update about a drug therapy is more important than everything else he said about South Korea in the post?

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