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Comparing HydroxyChloroquine Trials

One minor side effect of the pandemic is that perhaps more people will learn about what drug research and clinical trials can really be like. Today’s example: we have a clinical trial of hydroxychloroquine from Wuhan that has just published on a preprint server. What’s good is that this one is blinded, randomized, and controlled (like the earlier hydroxychloroquine which one I blogged about here from Zhejiang University, so we can actually talk about it rather than just spend all our time wondering what the heck is going on.

This time there were 31 patients in the treatment group and 31 in the control group. Median age was 44.7 years, male-female ratio almost even. Both groups got standard-of-care (oxygen therapy, antiviral drugs, antibiotics – presumably against suspected bacterial pneumonia – and immunoglobulin, with or without corticosteroids). In addition, the treatment group got 5 days of hydroxychloroquine, 200 mg b.i.d. All were diagnosed with (relatively) mild illness, but all had pneumonia by CT scan. More patients in the treatment group presented with fever and cough as compared to the control group.

After five days of treatment, the treatment group showed significant improvements in comparison to the controls in fever, in cough, and in pneumonia (by CT scan). This is actually the first controlled study to show any benefit for chloroquine or hydroxychloroquine therapy against the coronavirus – it may sound odd to say that, but all the positive reports we have had up to now are anecdotal reports and open-label studies without control groups. The one controlled study we have seen, as mentioned, showed no effect. Here’s a comparison between the two:

So you can see that these two came out rather differently, with the Zhejiang study showing no detectable difference on treatment and the Wuhan one showing what looks like a real effect, especially on radiological progression of pneumonia (which I have to say is a very strong endpoint to measure). Here, then, is a good exercise in interpreting clinical trial statistics: we are now one-and-one after two small hydroxychloroquine trials: which one (if either) reflects the real-world situation?

Update, for medicinal chemists et al.: people have asked about the once-a-day dosing in the Zhejiang study versus splitting to twice-a-day in the Wuhan one. The human pharmacokinetics of hydroxychloroquine are well worked out (as they should be for a drug of that vintage). A 200mg oral dose hits its Cmax in the 3-hour range, but boy, does it tail off slowly after that: plasma half-life is 123 days (!) with a large volume of distribution (extensive uptake in tissue). About 10% of the dose is excreted as parent, with metabolites still showing up in urine after three months. The metabolites peak in the blood about the same time as the parent compound after a dose, so it’s not that the compound doesn’t get metabolized – that long half-life is due to distribution. Kinetics were linear after 155mg and 310mg i.v. doses, so you’d figure 200 and 400 oral would likely compare in the same way. I believe that toxicity and QT prolongation are CMax driven, and that’s the likely reason for dosing b.i.d. Since we don’t have a good idea of the mechanism for any antiviral effects, it’s hard to say if those are more CMax or more AUC driven, though.

You could argue that overall we’re seeing either no benefit or some benefit here, which is good. As for adverse events, neither trial reported anything serious, But both of them excluded patients with any sort of cardiac arrhythmias, a wise precaution since one of the most acute worries with high doses of hydroxychloroquine is QT-interval prolongation, and you don’t want to do that to anyone with any underlying problems. So as long as such patients are excluded, for now hydroxychloroquine is in the “might do nothing, might do some good” category, which under the current conditions seems sufficient for treating patients, pending further data. You will notice that we are not exactly in the “total cure” category that the Marseilles group has been putting itself in, but frankly, these results from China are more like what I expect from the clinic (at best!) when using a repurposed drug against such a pathogen.

One thing to note about the clinical data in this situation: fatality rates are notoriously hard to estimate in an epidemic, and often only become clear after things have completely settled down. But you would probably not go far wrong estimating this one for the total infected population as around 1% – maybe a bit better, maybe a bit worse. It’s higher when you look at the patients who are admitted into hospitals, naturally, and it most certainly gets higher as you stratify by age groups. So if you want to see how many people you’re keeping from dying with any given therapy, you need a larger sample than anything we’ve seen so far. Getting people out of the hospital more quickly, or keeping them out of the ICU or off ventilators, though, are very worthy goals in themselves, and if HCQ treatment can help with those it’ll be most welcome. We have little or no data on these yet.

There are some things that need to be noted about this latest work, though. As Leonid Schneider has commented on PubPeer, the original trial as registered in China looks quite different from what we see here. Update: see this comment as well. The design was for 100 control patients, another 100 patients to receive one dose of hydroxychloroquine, and 100 more to receive a higher dose. What we have, though, are only two groups of 31 patients each, which suggests that there were problems with the inclusion criteria for the trial and/or with patient recruitment. The trial design also called for endpoints of negative results for viral RNA, and for “T cell recovery time”, to be collected by sputum and throat swabs and by blood samples, respectively, and none of this shows up in the preprint at all.

Now, it may be that the 100-patient size numbers were in there as a placeholder and meant “Up to this many depending on how many people we can enroll”. But the endpoints and sample collections seem to have changed pretty thoroughly, and it would be good to know more about that, why these decisions were made, whether any of these data were collected and what they were like. So my opinion of this latest study is “cautious approval”, and that probably sums up my feelings about hydroxychloroquine as a therapy in the Covid-19 epidemic in general. It’s a long way from “This is the cure and it’s unethical to disagree”, that’s for sure. More data will be coming, and we’ll revisit the topic then.

155 comments on “Comparing HydroxyChloroquine Trials”

  1. Tom Boyer says:

    Sounds like it’s the first real controlled trial, since the previous China trial was a mess. And the first controlled-trial data is, well, hopeful.

    It’s got to be really hard to recruit volunteers — in China or in New York — as soon as you tell them they might get the potentially live-saving treatment, they might get the placebo. Gov. Cuomo tried to solve that problem by decreeing that no one would have access to chloroquine unless they volunteered for a study. That seems a big coercive.

    1. Lynn says:

      I’m surprised an IRB or bioethics committee would approve such a clause.

    2. Jeff Hill says:

      When using hydroxychloroquine as a prophylactic for Covid-19, is there an known absolute minimum dose? The mechanisms of action is entirely different between malaria and coronovirus. With Covid-19 it facilitates zinc transport into the cell which interferes with RNA replication of the virus.
      Hydroxychloroquine has a half life of 22 days. Is it conceivable that a load dose of 200mg followed by as little as 20mg daily plus some zinc lozenges would stop infection from taking hold?

      1. Dr Vikram Saxena says:

        Sounds most logical I’d say! But with 20 mg what would be the blood level of the drug? Will it fall in the effective therapeutic range? Don’t think so I’m afraid!

        1. Fred Harris says:

          Every doctor I’ve seen report what they considered excellent results were using HCQ AND zinc, along with azithromycin to ward off bacterial infections. If the zinc is what stops replication but can’t penetrate the cells on its own, and the HCQ is what opens the door, why would they do a study without zinc?
          Call it anecdotal. Call it anything you like. But when thousands of patients who have been treated with this triple combo are resulting in better than 90% success when treated early, despite the lack of a control group, these numbers can’t be ignored. Considering that there seems to be no danger in trying this as long as there’s no pre-existing condition that conflicts with the HCQ, why are state and federal legislators making decisions that doctors should be making on a case by case basis? That patient has their life to gain & nothing to lose.

          1. tomaso says:

            You’ve been paying attention – WHY are so many people not – it seems deliberately controlled that people omit zinc so often!

        2. Jeff Hill says:

          What blood level of the drug does it take to be an ionophore for zink which is the goal? What ever the dose for on label use it has no relationship at all to the dose as an ionophore except to show the upper limit. I suggested 20mg but why not 2mg. The point is if one doesn’t know they don’t know. Sometimes it takes a long time to find the limits of minimum effective dose. Meanwhile, I take Quercetin.

    3. Steven P. Bradford says:

      This wasn’t a controlled study..it was flawed. “There are some things that need to be noted about this latest work, though. As Leonid Schneider has commented on PubPeer, the original trial as registered in China looks quite different from what we see here. Update: see this comment as well. The design was for 100 control patients, another 100 patients to receive one dose of hydroxychloroquine, and 100 more to receive a higher dose. What we have, though, are only two groups of 31 patients each, which suggests that there were problems with the inclusion criteria for the trial and/or with patient recruitment. The trial design also called for endpoints of negative results for viral RNA, and for “T cell recovery time”, to be collected by sputum and throat swabs and by blood samples, respectively, and none of this shows up in the preprint at all.”

  2. cirby says:

    It would have been nice if they’d done something more than an HCQ-only study – the more dramatic results claimed by others have been with HCQ + AZ as a combination therapy, sometimes with a zinc add-on.

    Basically, the most this shows is that, even with a partial treatment, they’ve getting some actual good results.

    They do also mention that all of the patients who progressed to severe disease were in the control group, which is a pretty big data point on its own.

    1. Mo says:

      Reduction in fever/cough when the treatment group presented with more fever/cough at the beginning isn’t really helpful, regression to the mean and all that. Only serious progression in the control arm sounds like it might have value though. Unless only 3 progressed to more serious condition in which case it is useless.

    2. David Young MD says:

      Once you have established that Hydroxychloroquine is helpful, you can then add on another drug. For example, you can then run a study comparing HydroxyC by itself, HydroxyC with zinie, Hydroxy C with Azithromycin and HydroxyC with both Zine and Azithromycin. Granted, you would need about 100 subjects on each arm to see if there really is a difference, but in this study, everybody gets HydroxyC (there is not a “no treatment” arm).

      1. Nate says:

        Is it possible the difference here is between necessary and sufficient conditions? I.e., HCQ is a necessary but not a sufficient condition to show improvement, thus in order for HCQ to demonstrate effectiveness it must be partnered with other drug(s).

        1. Smut Clyde says:

          The hypothesis that “HCQ + some second drug is effective against COVID pneumonia” is too unfalsifiable for my tastes.

        2. David Young MD says:

          I don’t think that you can find an example in known drugs for other diseases where “Drug A is an excellent drug against Disease X but you have to also give generally worthless Drug B in order for Drug A to work at all.” We do have cases where Drug B makes Drug A work better. For example Leucovorin to make Fluorouracil work better against colon cancer, or Clavulanate with Amoxicillin to make Augmentin. In both these case the first of the two drugs are not helpful at all by themselves but they make the second drug more effective. There is also the possibility for synergism where two drugs that have modest activity against a disease show much better than additive effects when combined. We, as oncologists, have talked for decades about synergist in treating cancer. We now know that synergism has never been proven “in vivo.” In regards to HydroxyC…. most of us would find it hard to believe that you need Azithromycin in order for the HydroxyC to work. Too much voodoo.

          1. Robert Bryant III says:

            The zithromax is for a potential secondary infection, not treatment of COVID-19.

          2. Antony Dobson says:

            My understanding was that it is zinc that is particularly effective, in that it inhibits the action of the viral replicase. The reason for including Hydroxychloroquine as part of the treatment is that it is an ionophore, which allows the zinc to enter cells more easily. Hydroxychloroquine might also affect the pH inside the cell, which might also inhibit the replication of the enzyme.

          3. Bob K says:

            For HCV cocktails, individual drugs may show a drop in viral loads, but usually have no clinical value. Only when combined do they have clinical value.

          4. Leena says:

            My question would be why this would work at all and who thought of using it to treat a virus?

            What are the mechanics of this virus and what makes Hydroxychloroquin effective in treating it?

          5. Phil says:

            To Leena

            Because it had been looked at as far back as 2005. Strange how no one knows how to look this up themselves, just read what the media puts out as of late.

            Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

            https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/

          6. James says:

            Anxiety asthma seems like voodoo as it gave respiratory distress with inflammation but no infection to treat as shown by tests. Normal hospital treatment for asthma plus Azithromycin with observation for 24 hours after ER visit was the treatment. I only lacked the Zpack or I could have treated myself at home. However the fear of Covid-19 illness plus a disturbing stress filled week with my sister combined into anxiety and four days later produced an asthma attack that mimicked Covid-19 symptoms enough to be admitted to the hospital.

        3. loupgarous says:

          Has anyone studied azithromycin without hydroxychloroquine? There’s a documented anti-inflammatory effect that (now we’re not scared of anti-inflammatory drugs per se in COVID-19) might help enough that chloroquine’s known toxicity outweighs its value in addition to azithromycin.

        4. Jeff Hill says:

          Of course. The research 15 yrs ago showed that in the lab HCQ was a potent ionophore for zinc which is the actual medication that kills the virus. Not focusing on a zinc ionophore for 15 yrs that costs 69 cents and kills SARS almost seems deliberate or at best incompetent. I’m not a researcher but I can’t imagine seeing that and not getting $5,000,000 almost overnight to study it. Current reaction to HCQ doesn’t help.

      2. Peter A Gillespie says:

        From the French doctors Renault concerning the malaria drugs. Use it early prior to full blown pneumonia. This is where we need to change. HC and Zinc provide benefit in the early stages to avoid the viral replication. Once they are in the hospital the Cytocline storm is already compromised their immune systems. Covid patients are told to stay at home unless they have trouble breathing. According to the below this is almost too late to start this treatment.

        The second: hydroxychloroquine proves effective but under very specific conditions. In “people who are moderately ill, diagnosed early” . Before warning: “We must be careful, when it is too late, it is too late. It is at the beginning that we must fight against viruses, once the lesions are done, they are a little irreversible and we can’t stop them anymore.”

        1. Dave Kielpinski says:

          See Derek’s earlier debunking of Raoult’s claims on this same blog.

          1. theasdgamer says:

            What do Raoult’s claims have to do with the HCQ/zinc cocktail?

        2. mark says:

          I wonder if these trials are comparing apples and oranges. Are they all at the same stage when given the med? Are there enough markers for stages to even know this? The pattern seems to be that people have symptoms for a while and then there is a sudden decline. Are they catching people early enough? I am doubting it.

    3. Johnathon says:

      I’ve heard of success with HCQ and AZ and I’ve heard of success with HCQ and Zinc. You mentioned “sometimes with a zinc add-on”, where can I read about using all three at once? Thanks

      1. Johnathon says:

        I found this: https://techstartups.com/2020/04/05/new-updates-dr-vladimir-zelenko-cocktail-hydroxychloroquine-zinc-sulfate-azithromycin-showing-phenomenon-results-900-coronavirus-patients-treated-must-watch-video/

        Looks promising on the surface. Are HCQ+AZ+zinc in combination being studied in New York or other places around the world? Is there anywhere else I can read about it? Thanks.

  3. Smut Clyde says:

    The trial registration mentions no secondary endpoints. The ones used in the preprint appear to be ad-hoc, chosen at the end of the trial when subjects’ conditions were known.

    1. Dave Kielpinski says:

      Smut Clyde! I haven’t seen you online for like 10 years. I followed your blog for ages. Still writing?

      1. Smut Clyde says:

        Blogging is sporadic, and increasingly boring. Focused more on pointing and laughing at bad science, these days.

        1. Dave Kielpinski says:

          Have one on me down at The Old Entomologist!

  4. KazooChemist says:

    Derek: In the second paragraph you wrote that the treatment group received chloroquine. Shouldn’t that be hydroxychloroquine?

    1. Derek Lowe says:

      Fixed that and the title of the post, too – thanks!

  5. Matt says:

    Hopefully, David Boulware’s trial that is currently recruiting will give us a lot more good data to tell whether HC works or does not work.

    https://clinicaltrials.gov/ct2/show/NCT04308668?term=boulware&cond=COVID-19&draw=2&rank=1

    1. charlie says:

      How does one do a placebo with Hydroxychloroquine? I mean it taste, well, very distinctive.

      1. HU says:

        Bitrex pills?

      2. Ar says:

        Put pill inside an empty capsule. In the placebo group put an artificial sweatener inside the empty capsule. Empty capsules are cheap, you buy them open and could be handled by hand quickly

  6. KAG 20020 says:

    Take the drug, virus goes down! Can’t explain that!

    1. matt says:

      Ever heard of a post hoc fallacy?

    2. Dr Horse says:

      It’s so effective the virus goes down in both groups! Miracle cure

  7. Bryan L Roth says:

    I. note the B.I.D. vs Q.D. dosing in the two studies which could be important going forward

  8. Tom Boyer says:

    Now I’m really excited about the Minnesota and British trials re prophylactic use among health workers. Hopefully they can get volunteers since they’re not asking sick people to risk missing out on life-saving treatment. And the world gets data on pre-infection or early-stage infection instead of just late-stage.

    And dosing. What if a very low dose is a highly effective prophylactic or highly effective in the first 3-4 days of infection? If you could combine that with cheap and rapid testing (just around the corner, I’m sure), then all of a sudden you apply time-tested public health measures — test everybody, trace contacts, treat anybody exposed — and this thing could be under control by late summer. I have memories of those sugar cubes we got in elementary school which stopped polio. Dare we dream?

    1. Diego Manuel Fleitas says:

      Good

    2. Gunther Schadow says:

      The dosage of the HCQ studies so far is way too low.

      Didn’t we know from the in-vitro that we should be having at least 10 if not 20 uM concentration? HCQ sulfate has a molar mass of 434 g/mol, so 400 mg has 922 umol, right? So that means if we take basic aqueous distribution volume (70% of ideal body mass) we get some 18 uM maximum at peak, but take off of that the bioavailability, so with 200 mg dose you’re not hitting the spot.

      The issue with the long half time is deceptive IMO, because high distribution volume means the initial dose is sunk into that compartment. Look at the lupus dosage 400 mg and taken every week, for a long time. If this wasn’t siphoned off into a fat compartment, it would reach massive plasma concentration after a few weeks.

      I don’t understand why they are not giving at the very least the malaria dosing scheme 800 mg, then 400 mg at 6 hr, 24 hr, and 48 hr after initial dose to boost initial concentration! To me this makes no sense at all. And I don’t understand this extreme anxiety about QT intervals. There is no reason not to give 800 mg if you are already having the patient in ECG control.

      It’s annoying to see that studies that didn’t really go in and possibly suffer from low dose problems are sucking the air out of the informational space and giving false negative impressions.

      By the way, my hypothesis is that the benefit of azythromycin which Didier Raoult saw in the Marseille study could be at least partially due to pharmacokinetic interactions raising the available tissue concentrations of the HCQ, which he too applied in a rather low dose. IMO early trials should (have) run with frequent HCQ plasma level tests.

      1. drsnowboard says:

        I would counter with the virus doesn’t exert it’s antiviral effect in plasma, so plasma concentration is a poor surrogate for concentration at the site of action, which is the inner surface of the lung? In which case, high volume is helping not hindering. Of course as a basic drug it could be being trapped in lysosomes, but that is a different argument.

    3. Stephanie says:

      What about asking those of us in the autoimmune community that have been on HCQ for years?

  9. Omar Stradella says:

    “Pre-clinical studies in animals as well as the first data from clinical studies show that hydroxychloroquine kills the coronavirus,” Novartis Chief Executive Vas Narasimhan said.

    Does anybody know what studies and how did he reach that conclusion?

  10. Lawrence Mayer MD says:

    This trial and the other Chinese Trials are worthless. They have released no details and no data. The single trial for which there is data shows no effect.

    The College of Clinical Toxicologists warned yesterday that there is no evidence HCQ works and it is potentially toxic.

    The results are allegedly published in Chinese. We translated the paper and it gives no details.

    We have a Facebook group Covid19 Clinical Epidemiology Discussion Group. Made up of Epidemiologists and Frontline clinicians. We welcome people to join.

    1. David says:

      I’m having trouble finding this group, could you post a link?

      1. Lauren Dowell says:

        Here is the group: https://www.facebook.com/groups/covidnerds . The title is “Clinical Epidemiological Discussion of COVID19 Pandemic Group”.

        1. David says:

          Cheers 🙂

    2. Tom Boyer says:

      Maybe the College of Clinical Toxicologist could use someone who has been thoroughly trained in the use of Google and Twitter.

      https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v1

      Not in Chinese, and as a bonus, below the summary there is a very nice analysis/summary of the study posted by someone from the Sinai Immunol Review Project.

      “Despite its limitations, the study design has good rigor as a double blind RCT and consistent symptom checks on each day of the trail. Now that the FDA has approved HCQ for treatment of COVID-19 in the USA, this study supports the efficacy of HCQ use early in treatment of patients showing mild symptoms, to improve time to clinical recovery, and possibly reduce disease progression. “

  11. Daniel Barkalow says:

    It would be worth knowing whether the antibiotic included in the standard-of-care portion was azithromycin. It seems like a reasonable choice for potential bacterial secondary infections, and using it in particular in a HCQ trial would help to identify whether the combination is particularly effective against COVID-19, or if AZ is just a good idea for patients who are going to be particularly at risk from bacterial infections.

    1. Robert Clark says:

      Yes. I would have liked to see which drugs were given to the control group as well. They may have some effectiveness against the disease on their own since even the control groups showed 55% improvement.

      Robert Clark

  12. Smut Clyde says:

    What we have, though, are only two groups of 31 patients each, which suggests that there were problems with the inclusion criteria for the trial and/or with patient recruitment

    It is also worth looking at this press release from 18 February. https://www.jqknews.com/news/388543-The_novel_coronavirus_pneumonia_has_short_term_curative_effect_on_the_treatment_of_new_crown_pneumonia.html

    They had already recruited 20 patients by then (in the intervention group – no mention of any placebo group) with the pneumonia improving in 19 cases. In the subsequent 10 days (before the cutoff of the trial design) they recruited another 11 Intervention patients, of whom 6 improved.

  13. Todd says:

    Not ideal, but no one has time for ideal. At least now we know that hydroxychloroquine might help, and definitely won’t harm. Now is the time to go up the ladder with the trials.

  14. Jo Chloro says:

    Is there anyone somewhere doing a proper clinical trials with the full treatment, i.e. HCQ + Azithromycin +zinc? That’s what is being used with apparently great succes; and that’s what we would need to validate ASAP.

    1. Smut Clyde says:

      HCQ + Azithromycin +zinc

      How did this become the “full treatment”? You seem to be telling us that trials which omit zinc – like Raoult’s, or like the present study – are meaningless, and if they report positive results then it’s by accident or faked. I’m happy with that.

      Perhaps it is up to the person who invented “HCQ + Azithromycin +zinc” as the full treatment to test it a clinical trial.

      1. Mlb says:

        Exactly hydro…high dose zinc…. azithromycin…hydro opens pathway in cells for zinc to stop viral replication. How can people be running trials without the zinc this is completely irresponsible almost like they don’t want the results to be positive because the whole treatment cost $20

      2. theasdgamer says:

        Zelenko is a clinician who is actually helping patients immediately, which distinguishes him from any of us.

      3. Dina Goldin, Ph.D. says:

        In his interview on 4/20 Zelenko said that he has a JAMA paper in the pipeline, with results from treating 1450 patients with HCQ+Azt+Zinc.

  15. Onegoodperson says:

    Turns out the mask has some benefits, but as you know we have to lie to people for the good of society.

  16. Sollé says:

    I’m french, excuse my bad english.
    Here’s the article about the recent chinese study on hydroxychloroquine :
    https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v2?fbclid=IwAR2ra_0QqTR5XPCa0pM3ShXGRNHQK_N59jpMCTHPeDaxlls8_ERlniGZYjU
    The daily dose was 400mg/day and not 200mg as said.
    The treatment applied in France in IHU Marseille Infection by Pr Didier Raoult and his team with great success (even if not recognized by the government for x reason) is the following :
    « For all infected patients, many of whom are not very symptomatic and have pulmonary lesions on the CT scan, to propose treatment with hydroxychloroquine combination as soon as possible after diagnosis (200 mg x 3 per day for 10 days) + azithromycin (500 mg on the 1st day then 250 mg per day for 5 more days), as part of the precautions for use of this combination (with in particular an electrocardiogram on D0 and D2), and without marketing authorization (AMM). In cases of severe pneumonia, a broad-spectrum antibiotic is also used. »
    The IHU gives daily his results in Covid-19 treatment. It has been seen that out of 1283 patients treated with this protocol, the IHU team only had one death.
    Here’s their link :
    https://www.mediterranee-infection.com/covid-19/

    1. Derek Lowe says:

      200mg bid means twice a day, or 400mg/day total.

  17. Tom says:

    The tidbit in the study about how 80 lupus patients on long term (much higher accumulated dose) HCQ inside their survey were not seen to have gotten Covid-19 is also very interesting, particularly since they’d otherwise be assumed to be immune compromised …

    1. Robert Clark says:

      Good point. There is an upcoming study to see if HCQ is protective against Covid-19 for family members of those with the disease. This will take 2 months though and enroll only 2,000 people.

      But we already have millions of people taking HCQ for lupus and rheumatoid arthritis. This should provide confidence at high sigma level if it is protective against the disease. Moreover, it would be low cost rather than have to conduct a research study recruiting patients and giving medications. This instead would require reviewing of medical records to see if Covid-19 patients were on HCQ because of prior conditions.

      Robert Clark

      1. Nick says:

        Exactly. I really don’t understand, why there are no statistical studies of people who were already taking HCQ (for example lupus patients) vs the general population of the same demographics. Percentage of infected/seriously/infected/ICU and so on.

        This data can provide to a big degree an answer, is HCQ effective or not.

        1. Smut Clyde says:

          “Over 25% of patients who developed a COVID-19 were on HCQ at the time of diagnosis”.

          https://twitter.com/rheum_covid/status/1245754373076115456

          1. Robert Clark says:

            Thanks for the link. That provides a good data point. We need to explore that data further though on rheumatoid arthritis patients with COVID-19. I found some recommended dosage numbers of HCQ for rheumatoid arthritis and lupus:

            ______________________________________________________________
            Rheumatoid Arthritis

            Indicated for treatment of acute and chronic rheumatoid arthritis
            400-600 mg/day (310-465 mg base/day) PO as a qDay or in BID
            When a good response is obtained, reduce dosage by 50% and continue maintenance dose of 200-400 mg/day (155-310 mg base/day) PO as a qDay or in BID; not exceed 600 mg or 6.5 mg/kg (5 mg/kg base) per day, whichever is lower, as the incidence of retinopathy has been reported to be higher when this maintenance dose is exceeded
            Use corticosteroids and salicylates in conjunction with hydroxychloroquine; gradually decrease dosage or eliminate after a maintenance dose has been achieved

            Systemic Lupus Erythematosus

            Indicated for treatment of chronic discoid lupus erythematosus and systemic lupus erythematosus
            200-400 mg/day (155-310 mg base/day) PO as a single daily dose or in two divided doses
            Doses >400 mg/day are not recommended
            Incidence of retinopathy has been reported to be higher when this maintenance dose is exceeded
            _________________________________________________________

            The maintenance dose for rheumatoid arthritis is reduced by 50% off of the initial dose of 400 mg per day. That might make it too low to be protective against Covid-19. It would interesting to find out what was the dosage of HCQ for rheumatoid arthritis patients who do get the virus and those that don’t.

            So also for lupus.

            Robert Clark

    2. HA Lurker says:

      Wasn’t there something about the possibility of (some categories of) immunosuppressed people being immune to the effects of the virus (and unbeknownst to them, superspreaders)?

  18. Robert Clark says:

    Thanks for the link to the article. A few points: I wish they would have said which antivirals and antibacterials were given to the control group. Just calling it the “control group” gives the impression no drugs were given to them.

    This is important because even in the control group the improvement was 55%. This may mean the antivirals and antibacterials given to the controls also have some effectiveness against the disease.

    Also, if they had compared HCQ to the case of patients given no medicine at all the effectiveness of HCQ might have been shown more clearly.

    Finally, the French researchers actually included AZT with the HCQ, which they say improves its effectiveness. Then the HCQ effectiveness in this Wuhan study may have been even higher if they had also included AZT.

    Robert Clark

  19. DrOcto says:

    These results have moved me from ‘completely dismissive’ up to ‘strongly pessimistic’.

    I understand that medical facilities are under great strain right now, and that collecting some of the data needed to support the studies is simply not a top priority, but the raw data is exactly what is needed to evaluate these results properly.

    How strong are these results, statistically speaking, with respect to expected patient to patient variations?

  20. Robert Clark says:

    A point of clarity of the prior Chinese study at Zhejiang University, discussed here:

    https://blogs.sciencemag.org/pipeline/archives/2020/03/24/the-latest-coronavirus-clinical-trials

    It’s been commonly interpreted as showing HCQ showed no improvement.

    This is the wrong takeaway from the study. Discussion on the study has been so much on whether or not HCQ is effective that the most important fact about it was completely overlooked: 100% of the 30 patients in both test group and control group showed no virus after two weeks. There was effectively 100% cure rate in both groups in two weeks.

    It’s important to keep in mind the “conventional treatment” group, i.e., the control group, mentioned in that study does not mean they did not also receive medications. In fact both groups the HCQ and the controls received additional antiviral medications.

    Different patients received different drug combinations in the study. But since there was 100% improvement in all patients, the question must be asked what was the common denominator? It turns out that ALL patients both test and controls received interferon alpha, a potent antiviral.

    THAT is what the main focus of the articles reporting on that research should have been about, that they may be a medication that allowed 100% recovery of hospitalized Covid-19 patients, and that drug is interferon alpha.

    Aside, from the fact that interferon alpha might provide a cure, it should be noted you really can not draw any conclusions from the study about the effectiveness of HCQ. The interferon alpha showed 100% effectiveness. It’s pretty hard to improve on 100% effective!

    The HCQ could be 0% effective, it could be 50%, it could be 100%, just like interferon alpha. You can’t tell because it was always combined with a medication that was always 100% effective.

    But if interferon alpha is indeed 100% effective, would HCQ have any use even if it also has a high effectiveness rate? It could. For instance millions of lupus and rheumatoid arthritis patients have been taking it as a daily medication for years. Then it would be better characterized as a daily medication for protection against Covid-19 than interferon alpha is.

    By the way, a google search turns up reports interferon of all three types, alpha, beta, and gamma, showed effectiveness against the prior corona-type viruses SARS and MERS.

    Robert Clark

    1. P One says:

      Is there a trial of interferon alpha underway, with a proper control group?

      1. Robert Clark says:

        I don’t know that but this treatment containing interferon alpha was part of what was called “conventional treatment” in that Chinese study. Perhaps the authors can be contacted if that is indeed commonly prescribed in China for COVID-19 patients.

        Robert Clark

      2. Robert Clark says:

        After a web search I found other interferon trials for COVID-19 being undertaken now. This article has links to some of them:

        https://www.trialsitenews.com/covid-19-arrives-in-guyana-and-a-different-request-for-an-interferon-based-drug-then-reports-of-40-countries-follow/

        Robert Clark

    2. P One says:

      Does anyone have an English translation of the Zhejiang University hydroxychloroquine study? The abstract is in English, but I would like to read through regarding the use of interferon alpha.

      1. Derek Lowe says:

        Download the PDF, then go to translate.google.com and use the Documents option, pointing to the file on your own drive. Works pretty well!

      2. Ar says:

        Yandex translate can handle PDF documents

      3. Robert Clark says:

        As Mr. Lowe suggested you can download the article in Chinese then send it to translate.google.com.

        But I like this article in English by Tara Haelle that provides a good summary of the study:

        https://www.forbes.com/sites/tarahaelle/2020/03/25/chloroquine-use-for-covid-19-shows-no-benefit-in-first-small-but-limited-controlled-trial/

        Again, I don’t like the title there, but that has been the general take on what the research shows. I don’t agree it shows that. I think you can’t draw that conclusion since all patients including the test group received medicines that resulted in 100% cure rate.

        Here’s the passage in the article by Ms. Haelle where it is explained all patients, test and control, received interferon alpha:

        *Usual care included bed rest, oxygen inhalation, and antiviral or antibiotic drugs as needed or recommended according to the hospital’s treatment plan. All patients in both groups received interferon alpha with a nebulizer, and umifenovir—an antiviral treatment approved in China for influenza—was administered to 67% of the usual care patients and 80% of the patients receiving hydroxychloroquine. Two patients received lopinavir-ritonavir, an anti-viral normally used to treat HIV infections.*

        Robert Clark

        1. Ben says:

          Robert you sound pretty knowledgeable. Could we agree that those N95 masks are for changing cat litter and not deadly virus protection? From experience working in dusty conditions, air easily travels around the mask, by the nose, as noted by black marks once removed. Also being that the eyes are a mucus membrane… hospital staff are completely wearing the wrong ppe and this is the primary reason they’re being infected. A full face respirator should be minimum, with full face and supply-air being the ideal. Would you agree?

          1. Robert Clark says:

            I admit I haven’t read much in regards to the effectiveness of the N95 masks. There have been several widespread viral outbreaks before. I imagine there have to have been studies determining the level of effectiveness of these masks to limit viral transmission of disease.

            Robert Clark

    3. DrOcto says:

      Statistics. If 1% of people die and your trial was only 30 people, then there is a 70% chance that your trial didn’t include an expected fatality.
      And that’s assuming no bias in patient selection, which I expect will be hard for a doctor on the front line to accomplish, given the grizzly nature of what they are facing.

  21. Erik Kobal says:

    The question I have is if antivirals are given to everyone in the study, doesn’t that throw off the test of hydroxychloroquine?

    1. Robert Clark says:

      Yes, it does. I’m guessing that since these were hospitalized patients, for ethical reasons they did not just want to give the test group HCQ alone since it was an unproven medication. But the fact all patients received other drugs does make it difficult to untangle the effectiveness of the HCQ.

      But I think a statement in the more recent Chinese study from Wuhan that the researchers weren’t seeing lupus patients is really key. This suggests we already have a ready made set of cases counting in the millions of lupus and rheumatoid arthritis patients to see if HCQ is protective against COVID-19. In view of the urgency, the fact no additional testing is required you just have to collate existing medical records to see if any of them contracted COVID-19 is also important since it can be done rapidly.

      This should be doable in just days. All doctors in the U.S. prescribing HCQ to some patients for any earlier condition forward to a central repository medical info on whether they contracted COVID-19. Medical confidentiality could be maintained by providing each patient a randomized number.

      Additionally, each doctor could ask those patients they prescribed HCQ to to also do a coronavirus test, since so many cases show no symptoms. How many of them had been infected? Is it much lower than the general population? How many of those that are infected progress to actual illness? Is that much lower than the general population?

      Robert Clark

      1. Ted Carey MD says:

        I do not see in the Wuhan preprint that it was placebo controlled, just that it was “blinded” and randomized. Am I missing something?

        1. Derek Lowe says:

          Exactly – it was controlled to standard-of-care.

  22. Nick says:

    Aren’t current protocols great?

    Long after the peak of pandemic we will finally have an answer, can we use HCQ or not. Of course it would be of no use, because 90% of the damage would be done already and dozens of thousands people dead without treatmant, but drug trials are not about minimizing deaths, they are about, well, science.

    1. Med(iocre) Chemist says:

      That’s quite the hot take, given that a number of these trials were done in a matter of weeks and that the peak of the pandemic is still to come (at least in the U.S.). We could have known in time whether these drugs are useful – if any of these trials had been done properly the first time. Now we’re relying on overworked frontline clinicians (many of whom took one statistics course 10+ years ago) to interpret murky data from slapdash trials.

      Funny how everyone talks up “evidence-based medicine” until it actually comes time to apply it, then we revert back to “doctor knows best”.

  23. NMH says:

    Hate to say this, but I really don’t think you can trust any “scientific/acadxmic” work coming out of China. The motivations of the researchers have been largely compromised by self interest. Sorry to say it.

    https://forbetterscience.com/2020/01/24/the-full-service-paper-mill-and-its-chinese-customers/

    1. Tom Boyer says:

      Good thing trials have been started by trustworthy American researchers who have absolutely no interest in career advancement! I wonder whether we will have their results in time for this pandemic or the next pandemic.

  24. Ralph says:

    Can’t someone in the US consult directly with the researchers in China. As I recall, Trump was kicking all Chinese medical researchers out of the US so maybe that makes “cooperation” more difficult.

  25. Simon Auclair the Great and Terrible says:

    Another untested hypothesis!

    https://asiatimes.com/2020/04/map-suggests-tb-vaccine-may-help-prevent-covid-19/

  26. Charles H. says:

    One thing that bothers me….
    There have been reports that patients that have been on a respirator and “recovered” frequently die shortly afterwards of unexpected heart attacks. And HQC is associated with heart arrhythmias.

    If people are going to start being given HQC, this needs to be investigated. Perhaps if the virus is suppressed early this isn’t a problem, but …

  27. I did not see any discussion here of p-values. It seems to me the Wuhan result is just not statistically strong enough to say anything. The random standard deviation on 31 patients is 5.6. Assuming the null hypothesis (no effect), then the best estimate of the mean (placebo) improvement is the average of the two, thus 68%, or a total of 21 patients expected per group of 31 on average.
    For a two-trial ensemble of 31 patients each, the fluctuation down to 17 patients (55%) is -0.8 sigma, and the fluctuation up to 25 patients (81%) is about +0.8 sigma. The net result is a bit over 1 sigma, happening very often at random, and statistically insignificant.

    I suppose the original study also reported p-values, and perhaps there is a nuance here that I am missing. I hate to be a buzzkill, but this is not nearly enough to prove anything yet.

    1. Nunca Frequentista says:

      Regarding their p-value of 0.0476 in Table 2, the manuscript doesn’t provide adequate information on its computation. All I can determine is:

      – They used Graphpad Prism, version 6.0

      – They seem to have used a χ2 test for Table 2

      – Table 2 contains a single p-value, so it’s some kind of omnibus test.

      A few thoughts:

      – The omnibus p-value simply says that the counts aren’t random, which isn’t very useful. It doesn’t say whether the treatment is working.

      – Using a Chi-squared test isn’t great because some outcome counts are small (e.g., 2, 4, 5), so the estimated p-value won’t be terrific. If they really wanted an omnibus test, Fisher’s exact test would have been more appropriate.

      – Note the inconsistent responses between the improved subgroups:

      control moderatelyImproved 12
      control significantlyImproved 5

      treated moderatelyImproved 6
      treated significantlyImproved 19

      – I couldn’t get near their p-value using a Chi-square or Fisher’s exact test using the data in Table 2 (code below)

      – Aggregating the data into two categories: not improved (exacerbated, unchanged) and improved (moderate, significant), hints at a useful effect:

      notImproved improved
      control 14 17
      treated 6 25

      – Using a Fisher exact test, that aggregation produces a p-value = 0.05584

      Conclusions:

      – Their stats aren’t ready for a peer-review pub.

      – I might be doing something wrong, but I can’t recreate their p-value

      – Aggregating the four outcomes to non-improved/improved hints at a beneficial effect.

      – For those who (still) like frequentist hypothesis testing, the aggregated result isn’t statistically significant.

      —-
      ## stats experiments with:
      ##
      ## medRxiv preprint doi: https://doi.org/10.1101/2020.03.22.20040758 .
      ##
      ## Efficacy of hydroxychloroquine in patients with COVID-19: results of a
      ## randomized clinical trial. Zhaowei Chen, Jijia Hu, Zongwei Zhang, Shan Jiang,
      ## Shoumeng Han, Dandan Yan, Ruhong Zhuang, Ben Hu and Zhan Zhang
      ##

      dfRaw <- data.frame(exacerbated=c(9, 2), unchanged=c(5,4),
      moderatelyImproved=c(12,6), significantlyImproved=c(5,19))

      rownames(dfRaw) <- c('control', 'treated')

      dfRaw

      stopifnot(rowSums(dfRaw) == 31)

      fisher.test(dfRaw, hybrid=FALSE)

      chisq.test(dfRaw)

      ## aggregate 4 outcomes to: not improved vs improved
      dfAggregated <- data.frame(notImproved=dfRaw$exacerbated + dfRaw$unchanged,
      improved=dfRaw$moderatelyImproved + dfRaw$significantlyImproved,
      row.names=rownames(dfRaw))

      dfAggregated

      stopifnot(rowSums(dfAggregated) == 31)

      fisher.test(dfAggregated, hybrid=FALSE)

      1. Robert Clark says:

        Talk about your p-values, imagine if we had millions of cases to evaluate and compare for their susceptibility to COVID-19 by looking at the millions of lupus and rheumatoid arthritis patients that take HCQ on a daily basis.

        Far larger, easier, faster, and cheaper to do than conducting another research study and giving HCQ to test subjects. In fact, it probably could be completed in days.

        Robert Clark

          1. Christo says:

            They have a database of 110 patients. They haven’t systematically analyzed anything at all, unless you have a link to a more robust study they have conducted.

          2. Janelle says:

            There is a report that says 25% of people taking Plaquenil got Covid-19. I think that we should also look at whether or not they were also taking an immunosuppressants. Some patients are only taking Plaquenil, and others are taking a cocktail of meds. Also, we must remember that some Lupus and RA patients already have heart problems and/or lung problems due to these disorders. If we’re going use them as a test study, I think they should divided them into three categories: only Plaquenil, Plaquenil+immunosuppressant, and those with damaged heart and lungs.

        1. Richard H. says:

          They mention in this preprint that in a follow-up survey none of their 80 SLE patients on long-term oral HCQ had been confirmed to have SARS-CoV-2 or related symptoms.

  28. Jim Palmer says:

    “No evidence of benefit” is often misinterpreted as “evidence of no benefit” — which makes it an insidious phrase. Beware august bodies that hide behind this disingenuous facade. Saying “We don’t know if it works” is not the same as “We know it does not work,” after all. The jury will remain out on HCQ (plus co-factors that may well enhance its effectiveness) but we can certainly conclude that no one has yet proved it fails.

    1. Robert Clark says:

      Very good point. It’s a shame but it really does seem for political reasons the difference between “Not proven to work” and “Proven not to work” is being overlooked.

      Robert Clark

  29. The effects of HydroxyChloroquine on the Corona virus was first discovered in china by observing lupus patients who couldn’t get sick. Here we wait till pneumonia sets in then try to cure pneumonia after it sets in. Pneumonia is a result of the terrible damage already done from the disease.

    It just seems to me it should be used earlier as the prevention at earliest detection not latter as the cure.

    P.S. Dr. David Price in New York on the front line of the epidemic says, 99 percent are getting the disease from hands to mouth contamination not airborne like many believe.

    P.P.S. If it’s true What Dr. David says I believe the fastest cure is prevention.
    Don’t touch your face!

  30. An Old Chemist says:

    Unlike FDA, European regulators refuse to clear chloroquine for COVID-19 without data

    https://www.fiercepharma.com/pharma/europe-locks-down-chloroquine-scripts-as-researchers-china-report-positive-controlled-covid

  31. TMS says:

    I know this is a real problem with privacy, but with the all of the data Express Scripts, Walgreens and CVS have in their prescription database and the knowledge of who the COVID-19 patients are, wouldn’t it be possible to see if their is or isn’t any statistical basis for people taking HCQ being less susceptible to Covid-19. It would seem that the Regional authorities in China would be able to do this more easily and less hesitantly.

    1. Tom Boyer says:

      Maybe New York medical insurers would have enough cases to data-mine this right now. Select two groups — people over 40 with a previous insurance claims for chloroquine, and people over 40 with no chloroquine in their claims. How many have insurance claims for breathing support? It might take a few more weeks for enough insurance claims to be filed to answer the question.

  32. Nunca Frequentista says:

    That would be a great real-world observational study and I’d love to see it done. Two immediate issues come up (in addition to privacy that you mentioned):

    1) Databases of medical records are a mess, and lots of smart people have been working on this problem for ages. On the other hand, you don’t need to integrate the world’s medical data; rather, you could start small and build if there’s evidence of a correlation. For example, you could join CVS’s prescription data to a large hospital chain’s medical records and look for relationships. That’s all doable with enough software development resources and data management expertise.

    2) The gnarlier problem can’t easily be fixed: This is fundamentally an observational study, which means that anything could be confounding its findings. For example, in a lupus population, a genetic trait could exacerbate the need for HCQ, and, at the same time, confer a reduced likelihood of dying from coronavirus.

    Anything can totally confound an observational study such as age, gender, ethnicity, behavior, geography, favorite soda, really anything at all. There are statistical fixes that sorta help but an observational study can’t infer cause like a randomized experiment can.

    All that said, I’d love to see the study done, the results could support continued research on the HCQ hypothesis. But everyone should approach an observational study their eyes wide open, aware of its fundamental limitations.

  33. SVC says:

    What is your opinion on the tobacco leaf-based covid-19 vaccine? I have not really seen much of a discussion in the scientific community related to this option.

    1. Derek Lowe says:

      Wasn’t aware of that one! It looks like yet another method for protein production to make antigens, though, not a new vaccine technology per se.

      1. SVC says:

        Thanks for the reply!

  34. Lane Simonian says:

    This recent “negative” study came out of Paris (apologies if it has already been posted on this site).

    “A second French group, led by Jean-Michel Molina, has now tested the hydroxychloroquine-azithromycin combination treatment in 11 patients at the Hôpital Saint-Louis in Paris, France, and their results were strikingly different.

    Like the Marseille study, the Molina trial was also a small pilot study. Molina and colleagues used the same dosing regimen as Gautret. In contrast, however, to the Gautret study, eight of the 11 patients had underlying health conditions, and 10 of 11 had fevers and were quite ill at the time the dosing began.

    These Paris researchers found that after five to six days of treatment with hydroxychloroquine (600 mg per day for 10 days) and azithromycin (500 mg on day 1 and 250 mg on days 2 to 5), eight of the 10 patients still tested positive for COVID-19. Of these 10 patients, one patient died, two were transferred to the ICU and another had to be removed from the treatment due to serious complications.”

    https://theconversation.com/a-small-trial-finds-that-hydroxychloroquine-is-not-effective-for-treating-coronavirus-135484

    It is premarture to say with any certainty, but if this treatment works at all it may only work early on.

  35. JP Leonard says:

    I’ve read a lot about this and this is what I’ve gathered.
    Like previous commenters noted, HCQ works in the early stages. We’re seeing authorities (such as in France) saying it should only be used as a last resort. So they get negative results there.
    It is important to find drugs that will protect people from getting into the critical stage. ICU’s are in short supply and many patients can’t be saved that late.
    I was trying to find some confirmation on the NY village doctor who said he is saving patients with a combination of HydroxyChloroquine (HCQ) and zinc. All I could find was a post where a scientist says that it’s actually the zinc that cures people, that HCQ synthetic quinine only helps transport it into the cells:
    “being a ++ ion, extracellular zinc requires active transport to pass across the cell membrane. It so happens that chloroquine is a zinc ionophore, thus provides zinc++ with the transport mechanism…. In this instance, chloroquine has no drug action. It is the zinc that is in play.” https://www.researchgate.net/post/Is_a_combo_of_chloroquine_and_Zinc_a_cure_for_coronavirus
    So much effort is spent on developing vaccines that won’t be ready until after the pandemic is over, yet no one can find time to make a full scale trial of a promising drug combination.
    Or at least take steps to confirm or deny the stories of doctors who swear by it? Seems like this should be a good scoop for an inquiring reporter.

    1. Toni says:

      In the meantime it is uncritically proclaimed everywhere that chloroquines are zinc-ionophores and that this property provides the antiviral effect. If you take a look at the few original data, you have to say that they are rather poor.

      1. JP Leonard says:

        I googled on chloroquines zinc-ionophores and the first hit is this
        Chloroquine Is a Zinc Ionophore
        “chloroquine is a zinc ionophore that targets zinc to cellular lysosomes”
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/

        1. Toni says:

          Look at the dates. For example, Figure 2 A and B.
          That’s more than questionable. And watch out for concentrations of zinc and chloroquine needed.

      2. JP Leonard says:

        Zinc as a Gatekeeper of Immune Function
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748737/
        “After the discovery of zinc deficiency in the 1960s, it soon became clear that zinc is essential for the function of the immune system. Zinc ions are involved in regulating intracellular signaling pathways in innate and adaptive immune cells. Zinc homeostasis is largely controlled via the expression and action of zinc “importers” (ZIP 1–14), zinc “exporters” (ZnT 1–10), and zinc-binding proteins. … Here, we report molecular mechanisms underlying the development of a pro-inflammatory phenotype during zinc deficiency. Furthermore, we describe links between altered zinc homeostasis and disease development. Consequently, the benefits of zinc supplementation for a malfunctioning immune system become clear.”

  36. John-Paul Leonard says:

    PS. So now I’m wondering if there is a correlation between zinc deficiency and coronavirus. What comes up is a piece https://www.cnet.com/news/zinc-supplements-wont-protect-you-from-the-coronavirus/ warning that zinc is not a silver bullet, but it does reduce respiratory virus symptoms.
    Now it should be possible to test this without any trials, just by looking at data from blood tests of coronavirus patients, to see if there is a significant correlation with zinc deficiency, compared with normal healthy populations.

  37. JP Leonard says:

    PPS. Checking further, it isn’t quite that easy. Zinc deficiency doesn’t show up in an ordinary blood test because zinc binds to proteins in your body. There are special tests for it. So we’d have to start testing for that among patients.

  38. Becky DeGrossa says:

    You all seem to actually know how to look at these things. Did you see this interview? https://techstartups.com/2020/03/28/dr-vladimir-zelenko-now-treated-699-coronavirus-patients-100-success-using-hydroxychloroquine-sulfate-zinc-z-pak-update/

    What are your thoughts. Hopeful or …?

    1. Derek Lowe says:

      Not hopeful, unfortunately.

  39. JP Leonard says:

    That zinc helps fight off respiratory viral infections is well established by many studies (it is often taken as cold relief lozenges).
    I’ve just rec’d corroboration from Dr. Eric Beeth, a Belgian physician, that HCQ works by making zinc bio-available within the cell. I heard of him through his article online https://www.globalresearch.ca/not-only-covid-19-virus-dangerous-how-our-body-reacts/5707304.
    He also advocates better nutrition for people in nursing homes, to support the immune system, plus Vitamin C, Vitamin D, hydration and similar therapies. I hope to translate his Covir treatment protocol from French into English. He does note that patients should have an EKG before taking HCQ, due to the contraindication in cases of arrhythmia.

    – It may be that failed HCQ trials occur when it’s given too late, as it should be used in an earlier phase.
    – Another cause of failure could be zinc deficiency, if HCQ needs zinc to work.

    In treating coronavirus, doctors can try testing for zinc deficiency. If the patient is zinc deficient, then supplement with zinc while treating with Hydroxychloroquine.
    The New York Post reported on a poll of 6000 doctors worldwide in a “survey, conducted by the global health care polling company Sermo” which found HCQ to be the most effective therapy for Covirus. https://nypost.com/2020/04/02/hydroxychloroquine-most-effective-coronavirus-treatment-poll
    If so many doctors are already using HCQ, then what official agencies like the WHO should be doing is not to rationalize that we don’t have enough trials to support this, but to go ahead and arrange for such trials quickly, as a matter of course.
    “Hydroxychloroquine was approved for medical use in the United States in 1955. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system,” says Wikipedia.

  40. Mlb says:

    Please see Rudy giuliani’s video with the Jewish doctor in upstate New York who is treated 600 plus with zinc hydro and azithromycin all older people doing better

  41. Mlb says:

    Arrhythmia one in 10,000 4 hcq doesn’t sound like a bad side effect risk

  42. ZenZig says:

    From what I can tell all the people with the highest mobility rates also have a high likelihood of having a zinc deficiency. I have assembled more than a few sources to back up this theory. Please take some time and watch the first video, if it piques your interest and you continue to read the rest of the research…maybe that will be a good thing

    View the following video https://www.youtube.com/watch?v=U7F1cnWup9M
    Link to NIH paper with more details: https://www.ncbi.nlm.nih.gov/pubmed/21079686

    Why is it that 35% of the deaths are from COVID19 are people with diabetes?

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407731/

    Why is it that the elderly have a much greater chance of dying from COVID19?
    https://www.ncbi.nlm.nih.gov/pubmed/18200755

    In vitro and in vivo effects of zinc on cytokine signaling in human T cells ..
    https://www.ncbi.nlm.nih.gov/pubmed/18249079

    Why does blood type matter?

    http://www.rroij.com/open-access/blood-group-diet-research-is-the-key-to-get-precise-results-toimprove-human-health.php?aid=59918

    Before you read the next article take a guess which blood type is likely to be deficient in zinc

    https://www.sciencealert.com/paper-suggests-certain-blood-types-might-be-slightly-more-susceptible-to-covid-19

    Also very interesting is your BMI

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681543/

    Guess who has a very high risk of death from C19

    https://nypost.com/2020/03/26/obesity-increases-risk-for-coronavirus-complications-report/

  43. Ajay Gupta says:

    Most clinicians don’t understand including CDC that when people dying and serious pandemic is on – RCT’s can’t be done. Even ethically if patients don’t want to take placebo then a physician can’t force them to take it. Either the drug has no benefit or has some benefit- in either case patient wins as there is no net loss for pt. Cardiac SE again is a hoax. In developing countries it is given so common, in my practice of >40 yrs no cardiac SE seen. Still if treating physician is concerned then they can withhold this med for people with cardiac co morbidity. is CDC is wrong on this and I totally agree with President Trump on this. !

  44. JP Leonard says:

    So to review
    1. https://www.ncbi.nlm.nih.gov/pubmed/21079686
    Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture.
    Zinc blocks coronavirus replication
    2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407731/
    beneficial effects of Zinc supplementation in patients with diabetes
    Diabetes is one of main co-morbidities with Covid19 (35% of death are in patients with diabetes)
    3. Why is it that the elderly have a much greater chance of dying from COVID19?
    https://www.ncbi.nlm.nih.gov/pubmed/18200755
    Zinc deficiency in the elderly
    4. https://www.sciencealert.com/paper-suggests-certain-blood-types-might-be-slightly-more-susceptible-to-covid-19 Type A blood is somewhat more susceptible to Covid19 – but I couldn’t find where is the link between blood type and zinc deficiency
    5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681543/
    Zinc Deficiency Exacerbates Macrophage Infiltration into Adipose Tissue
    https://nypost.com/2020/03/26/obesity-increases-risk-for-coronavirus-complications-report/
    and sum up:
    Zinc blocks coronavirus replication. Zinc deficiency is associated with old age, diabetes, and obesity, risk factors which are all associated with deaths from Covid19.
    In this light, Covid19 starts to look like an opportunistic infection that exploits zinc deficiency, which could be blocked by supplementation with bio-available zinc

  45. Mark Fisher says:

    With all the doctors and nurses dying from the virus, I have to assume that none of their own preferred methods of treatment, including this drug, had any beneficial effect.

    It doesn’t help, either, when the one account of, supposedly, perfect results, has something to do with Rudy Giuliani, and hence Donald Trump.

  46. JP Leonard says:

    All the doctors are dying?
    Does it matter if Trump endorses it?
    Our society has bigger problems than coronavirus, when promising therapies are turned into a political football instead of an action point.
    Last I heard, Dr. Zelenko was still alive and kicking. He claims 100% cure rate with HCQ, Azithromycin and Zinc supplementation.
    I tried to find confirmation of Zelenko’s claims. All one finds is the political right promoting his success and the left media ignoring it. I would have thought the CDC or Mayo Clinic or even a reporter or the WHO would look into it. If doctors are trying his prescription, apparently they are too busy to post about it.
    All I was able to figure out is that his claim is not illogical, because zinc is essential to the immune system, as I noted above. In fact, zinc deficiency is also related to the major coronavirus comorbidities, hypertension and heart conditions, as well as to complications from pneumonia. All this is on NIH.
    Also I found a paper there on NIH by Dr Raoult’s group on HCQ. It doesn’t mention zinc. So HCQ might work on its own as well as being a zinc ionophore. In fact, there may be a number of immunoregulatory substances that inhibit both viruses and inflammation. Even Vitamin D seems to have both effects. Azithromycin seems to be more for inflammation and later stage infection while HCQ helps more in the earlier stage. Zinc supplementation is needed as a prophylactic to improve immunity even earlier. So is proper nutrition. This is old hat.
    Of course zinc is only part of the picture. It’s not that zinc is a silver bullet. But zinc deficiency could make coronavirus into a lead bullet.
    Here is the press release on the survey of 6200 doctors with 37% favoring HCQ
    https://www.businesswire.com/news/home/20200402005460/en
    “The three most commonly prescribed treatments amongst COVID-19 treaters are 56% analgesics, 41% Azithromycin, and 33% Hydroxychloroquine”
    This is the website of the outfit that did the survey: https://www.sermo.com/ “6,200 doctors from 30 countries donate their time on a weekly basis to give us insights into the treatments they are using.”
    It would be nice to know what to take to keep from getting the virus. Here’s one view
    https://www.hsph.harvard.edu/nutritionsource/2020/04/01/ask-the-expert-the-role-of-diet-and-nutritional-supplements-during-covid-19/
    We need a means of preventing mild cases that become critical, so we can avoid the double catastrophe of health and economic disasters. For prevention, one could use remedies known to help with the common cold and flu for now.
    I’ll try and post some more links from NIH about zinc deficiency and coronavirus comorbidities.
    The coronavirus has an advantage over us, that it doesn’t care about politics. Focusing on what works instead of ideologies will help us defeat it.

    1. Guessed says:

      The definition of looking into it is doing a controlled study of it.

      Everyone else is just using it because they think it might work.

      I would like to be able to look at line listings of all of Dr. Zalenko’s coronavirus patients. How old were they? How symptomatic? What co-morbidities? Were they also getting other experimental drugs or candidate drugs?

      Where do I find those details about his experience?

    2. Leena says:

      If there is an iron ion issue which is required to carry oxygen molecules throughout the body to the needed organs, vitamin C helps in red blood cells absorbing the iron. The organs are obviously starving of oxygen and shutting down whether by iron shedding or lung impairment. I’m thinking lung impairment is a secondary issue due to iron ion shedding being swept up in the lungs.

      Has anyone seen pneumonia like xrays showing equally in both lungs?

      1. theasdgamer says:

        Bilateral pulmonary damage isn’t typical of pneumonia.

        1. Derek Lowe says:

          As a person who had bilateral bacterial pneumonia three years ago, I beg to differ. Or maybe I’m even more unusual than I know.

          1. theasdgamer says:

            You are atypical. Some species of bacteria cause double pneumonia, but not most.

    1. Derek Lowe says:

      I tend to think so – it’s my hope that the Bayesian/adaptive nature of the trial will clear those out quickly?

      1. loupgarous says:

        Bayesian analysis would (optimally) change endpoint to identify what’s actually happening (like outcomes when supplemental zinc’s added to HQC therapy).

        I hope the stats guys can stand up to pressure to do another aducanumab re-submission – which looked to me like the “bad side of Bayesian analysis”. Like a knife, Bayesian can be abused – but we still need knives.

      2. loupgarous says:

        Getting to your point, Derek, yes, SINGULARITY can, potentially, give us worldwide datasets with meaningful numbers – and give the study organizers flexibility to look at endpoints they hadn’t foreseen (like adding zinc to HCQ).

        Bigger cohorts are what we need, fast, to eliminate therapies that don’t work as COVID-19 therapy. The scary thing is that there always seems to be supplemental zinc or something like it to keep HCQ/CQ alive as potential therapies. Done right, SINGULARITY can find out when HCQ and CQ work, and when they don’t.

        1. loupgarous says:

          OOPS! Meant to say “SOLIDARITY”, not “SINGULARITY”

  47. Jeremy Scott says:

    Dr. Zelenko lists his treatment regimen as follows:
    – HQC, 200mg, 2x a day for 5 days
    – AZ, 500mg, 1x per day for 5 days
    – Zinc, 220mg, 1x per day for 5 days

    Here’s the link to the video where he discusses it–specifics on dosing at 30:25 https://youtu.be/1TJdjhd_XG8

    1. Zinc agnostic but curious says:

      220mg of Zinc is 20X the RDA. I know RDA values were generated based on average dietary intake, rather than actual biological needs, but 20X seems to be more than would be required to guard against deficiency. I wonder where Zelenko got that number?

      1. psoun says:

        220 mg zinc sulfate is 50 mg elemental zinc. 11 mg elemental zinc is the RDV. See https://ods.od.nih.gov/factsheets/%20Zinc-HealthProfessional/

  48. Some citations:
    “Treating COVID-19—Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics ” https://jamanetwork.com/journals/jama/fullarticle/2763802

    “Lessons Learned: COVID-19 Protocols and Best Practices for addressing COVID-19 in the hospital setting” https://www.evergreenhealth.com/documents/Coronavirus/covid-19-lessons-learned.pdf

    “Why France is hiding a cheap and tested virus cure” https://asiatimes.com/2020/03/why-france-is-hiding-a-cheap-and-tested-virus-cure/

    “Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy” https://doi.org/10.1111/jth.14817

    “Urgent Guidance for Navigating and Circumventing the QTc Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for COVID-19” https://mayoclinicproceedings.org/pb/assets/raw/Health%20Advance/journals/jmcp/jmcp_covid19.pdf

    “Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19” https://www.nejm.org/doi/full/10.1056/NEJMsr2005760

    “ROS Signaling in the Pathogenesis of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS).” https://link.springer.com/chapter/10.1007%2F978-3-319-63245-2_8

    “Rapidly managing pneumonia in older people during a pandemic” https://www.cebm.net/covid-19/rapidly-managing-pneumonia-in-older-people-during-a-pandemic/

    “What’s Working for COVID-19 Patients” https://journals.lww.com/em-news/blog/breakingnews/pages/post.aspx?PostID=508

  49. BCF says:

    April 6th interview of a Los Angeles doctor Dr. Anthony Cardillo, where he confirms high efficacy of Zelenko’s HCQ, AZ, and Zinc combination:

    https://abc7.com/coronavirus-drug-covid-19-malaria-hydroxychloroquine/6079864/

    Key quote: “Every patient I’ve prescribed it to has been very, very ill and within 8 to 12 hours, they were basically symptom-free.” In the interview, Dr. Cardillo explicitly says the zinc supplementation is critical for efficacy.

    I have been waiting to see if this gets picked up by major national or international news, but amazingly nothing so far. This suggest HCQ trials without Zinc supplements would be expected to yield underwhelming results.

    1. theasdgamer says:

      I was looking for something like this. I’m still waiting for Zelenko deniers to come up with clinical trials to disprove his clinical success.

  50. theasdgamer says:

    No govt. is probably gonna push HCQ/zinc trials because zinc is a supplement, not a drug. It would look “weird.” And no private company is gonna push the trials because there’s no money in it. So it’s up to docs and private individuals to figure this thing out.

  51. theasdgamer says:

    Tony, can you point me to a paper that shows that Plaquenil’s ionophoric activity is low?

  52. DZed says:

    Did anyone else notice the really low SDs in the temperature duration and cough duration? If you have 29 patients with an average of 2 days–and just one of those patients has 1 day and one has 3 day duration, you get a SD of .25. Their SD is 0.2–lower than that. Seems odd or am I looking at it wrong?

  53. Leon Nash says:

    I have no medical qualifications nor knowledge but isn’t it possible that chloroquine, in addition to its possible help getting zinc into the cells, also assists as an immuno suppressant and thereby stops cykotine storms, which seems to be what is actually killing people?

  54. Matt says:

    Where is the use of zinc? Hydroxychloroquine is an ionophore, and zinc is the proposed method of stopping the virus RNA replication. Some of the case studies found that zinc is required for success, yet so many of the negative studies hitting the news did not have zinc as part of the regimen.

    I find that highly suspicious since the preferred treatment modality is a potentially dangerous vaccine or I guess an expensive recently patented medication like Gilead’s Remdesivir

    1. Leon Nash says:

      Exactly my thoughts too, Matt. Also, because the hydroxychloroquine and zinc combination possibly stop replication, it must be given in the early stages ….. not once they’re hospitalized with a massive viral load.

  55. Todd Louis says:

    Just reading articles and comments for my own info.
    I am curious, do we not already have a baseline group of people that have been on hydroxy. for lupis and other arthritics?
    Have any developed covid19?
    If so at the same percentages as the public?
    Lesser degree?
    I would think this info would be very easy to get, phone call?
    Might not be extremely useful, other than easy info to start with.
    I am not a Doctor or even any kind of college education. I am a Tradesman.( pipefitter)
    I have found over the years, sometimes a non professional points out the obvious that is overlooked.

  56. Joseph Clem says:

    Are there any studies where lupus and malaria patients treated with hydroxychloroquine get the C19 virus?

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