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Hard Data on Remdesivir, and on Hydroxychloroquine

Let’s catch up with some things that (by this point) feel a bit like old news. But it’s important to do it, because (A) the big reason they feel that way is because of the bizarre world we’ve been living in the last few months, and (B) the pace of medical discovery is not set to human preferences, anyway. I’m talking about remdesivir and hydroxychloroquine. And yes, I know that I said I wasn’t going to mention the latter one again, but I figured the points being made today are important enough to justify it. I might regret that.

The New England Journal of Medicine today has the final report from the team studying remdesivir in a >1000 patient randomized controlled trial. This group was randomized and divided roughly half-and-half to standard of care plus remdesivir versus standard of care plus placebo, blinded. So this is the most solid look we have at the drug’s efficacy in coronavirus patients. The good news is that the patients receiving the drug had a shorter time to recovery (9 to 11 days, in the 95% confidence interval, versus 13 to 18 days with non-remdesivir standard of care. That’s real, but it’s not real dramatic, either, which is what you would realistically expect from a single broad-spectrum antiviral drug. This ain’t sofosbuvir clearing out hepatitis C, and even that one doesn’t do the job by itself.

As for the hardest endpoint of all, mortality by Day 29 for these patients was 11.4% with remdesivir therapy as compared to 15.2% with the controls. So again, that’s a real improvement and very much worth having, but it’s not a Miracle Drug, either. Adverse events were actually lower in the treatment group, which is of course good news. You can see that these were indeed at-risk patients – the overall mortality rate in the general population for coronavirus infections is nowhere near those rates, and it’s a damn good thing it isn’t. The mean age of the patients was 59 years, 64% male, with 50% of them having hypertension, 45% of them obese, and 30% with Type 2 diabetes. So even though they were characterized as mild-to-moderate on enrollment, this was just the sort of group that you’d worry about as a physician.

So remdesivir is indeed a worthwhile drug, especially when given to people in higher-risk patient groups. This confirms the preliminary reports, and (to be honest) is somewhat better than some of the early reads. Not everything gets worse when you look at it closely! But you have to look at it closely and rigorously – there is no substitute and there are no shortcuts.

That point is illustrated by a second paper in the same issue of NEJM, the report from the RECOVERY study on hydroxychloroquine. In this one, 1561 patients got HCQ plus standard of care, versus 3155 who had standard of care without it. There would have been even more treatment patients, but enrollment was closed in early June after an interim analysis showed a strong likelihood of no benefit. Both cohorts were followed thereafter, with 28-day mortality as the primary endpoint.

The HCQ-treated patients did not survive better than those not getting the drug: 27% of them died within 28 days, versus 25% in the standard of care group. The data are shown below:

Overall, 59.6% of the HCQ patients were discharged during that 28-day period versus 62.9% of the control group. Meanwhile, 30.7% of the HCQ group ended up on ventilators during that period (none were, at entry into the trial) versus 26.9% of the control patients. Every single one of these trends is in the wrong direction and every single one of them was seen in all the pre-specified patient subgroups. As for adverse effects, there were numerically more cardiac events in the HCQ group, but it was not statistically significant. Note that patients with existing QT prolongation were excluded from the study.

I’m not in a mood to be subtle. Hydroxychloroquine treatment for coronavirus does not work. It is not beneficial, and in fact appears to be actively harmful. As far as I’m concerned, administering it to infected patients now constitutes medical malpractice. I have no interest in goalpost-moving efforts to say that they didn’t administer zinc or azithromycin, or they picked the wrong patients or the wrong loading dose or whatever. No. This is special pleading, and it is not backed up by any hard data. None of the countries or regions where HCQ was enthusiastically adopted, with or without the addition of zinc, azithromycin or what have you have seen discernable benefits. It. Does. Not. Work. Give it up.

215 comments on “Hard Data on Remdesivir, and on Hydroxychloroquine”

  1. Matthew says:

    And now MK4482 is moving along in trials. Although Rick Bright had some safety concerns about that compound.

    1. confused says:

      Could you link to a source to learn more about this please?

      And what phase of trial is it at?

    2. confused says:

      (The wikipedia article on MK-4482 says that Merck “announced its intention” to start “late stage trials beginning in September 2020”. The article mentions a Phase II trial before that, so presumably “late stage” means Phase III – but it’s October now, did that actually happen?)

      1. Matthew says:

        Look it up on ClinicalTrials dot gov

        Phase ii/iii

      2. Erik Dienemann says:

        Here’s what I posted on FB the other day.

        Speaking of my old company, Merck/FDA announced details of its upcoming combined phase II/III trial with its new antiviral compound MK-4482 (formerly EIDD-2801), as we recently partnered with Ridgeback to test/produce this drug. The trial will be a randomized, double-blind, placebo controlled (can’t do a “blinded control” vs. remdesivir, which is IV) study in 1450 non-hospitalized COVID patients, starting in about 3 weeks, evaluating 3 different doses in phase II and then taking the best one forward into a larger phase III trial. There will hopefully be interim results by the end of the year or early next year (that could support an emergency use authorization if it looks very good).

        A lot of optimism around this drug, since it’s orally bioavailable, meaning it can be dosed in tablet form, whereas remdesivir can only be dosed by IV in a hospital and it’s very potent in vitro and in animal models. This is the program I was just brought out of retirement to work on, part-time, helping out with various aspects of process development and filing with regulatory agencies, as we do the transfer to manufacturing.

        https://clinicaltrials.gov/ct2/show/NCT04575597

        1. This sounds like a suboptimally-designed trial.

          Blinded trials of IV versus PO drugs are perfectly feasible. Some patients get active pills and placebo IVs, others get placebo pills and active IVs. In the absence of blinding, special pains must be taken with endpoint selection & evaluation.

        2. David E. Young, MD says:

          It is frustrating that it takes so long, but at least they are doing it. As an oncologist, I will note that we are reprimanded to accruing only 5 percent of our patients to clinical trials. What percent of Covid19 patients are submitted to trials? My guess is that it is 0.2 to 0.3 percent. You would think that 1,000 patients could be accrued in a week if you had the means. As it is, it will take 2 to 3 months.

    3. David E. Young, MD says:

      It looks like they finally have a “vir” name for MK4482 (EIDD 2801).

      The drug is called: Molnuparivir

      I wish them the best.

      1. David E. Young, MD says:

        Whoops, spelled it wrong

        Molnupiravir

        That’s it

  2. Mark says:

    Thank you for your work in tracking these developments. You’re performing a real service.

  3. Alex says:

    “Chloroquine is a Zinc Ionophore”, reads the title of research in 2014 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877 ). In patients with poor zinc/copper levels, hydroxychloroquine likely suppresses infection-fighting inflammation without providing antiviral benefit.

    Zinc is also a rate-limiting cofactor for thymus hormone to trigger t-cell maturation. Poor COVID outcomes are closely linked to low t-cell activity.

    Low zinc levels are independently tied to sepsis, for example “Zinc and Sepsis” (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115943/ ) and “Persistent Low Serum Zinc is Associated with Recurrent Sepsis in Critically Ill Patients”(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417428/ )

    The second paper explains, “Hypozincemia is a well observed phenomenon in sepsis patients. In acute phase response zinc is redistributed to the liver and other organs, leading to a transient decrease in serum zinc levels. This mechanism is an important feature of host immune defense to limit availability of essential micronutrients to pathogens.”

    Severely infected COVID patients are likely to experience low serum zinc levels. Hydroxychloroquine’s activity depends on zinc.

    1. Thomas says:

      My car does not run if the gas tank is empty. Once there is some fuel in, it runs. Doesn’t matter if there is just enough fuel or it is topped up. It also doesn’t run better with extra fuel in the passenger compartment.
      This is the same with nutrients and vitamins. Enough zinc is needed to allow enzymes to be formed and be functional. But having more zinc doesn’t mean more T-cells or more active T-cells – it will just be sloshing around, hopefully not messing something up.
      FWIW zinc is in many foods, it is unlikely to have shortages.

      1. theasdgamer says:

        The body has all kinds of control systems. It can tell when zinc is low and favors primary uses like providing energy over secondary uses like immunity. So low serum zinc levels can have a major impact on immunity. This has been well-established in the literature.

        1. theasdgamer says:

          “Zn functions as a modulator of the immune response through its availability, which is tightly regulated by several transporters and regulators. When this mechanism is disturbed, Zn availability is reduced, altering survival, proliferation and differentiation of the cells of different organs and systems and, in particular, cells of the immune system.”

          https://pubmed.ncbi.nlm.nih.gov/25462582/

          The car analogy isn’t very good.

          1. Dave Kielpinski says:

            Is there a reason theasdgamer is tolerated on this site? Derek specifically called out their zinc bullshit in the OP. They write like a Russian bot.

      2. Charles H. says:

        I have definitely seen reports that excessive zinc damages the immune reaction. But they were in the popular science press, and about a decade ago. I don’t know of recent studies, and (I’m a programmer) I haven’t seen medically oriented reports. So your “hopefully not messing something up” seems to be very dose dependent.

  4. Why the lies on HCQ? The RECOVERY study used ludicrous dosages, dosing that would beat up an elephant with predictable effects…and of course without zinc. https://hcqtrial.com/

    1. David E. Young, MD says:

      Those are the doses that gave blood levels on par with what was felt to be needed to kill the virus. If I take Amoxicillin for a urinary tract infection, it is unlikely that if I double the dose, the Amoxicillin would no longer effectively treat the infection.

      1. theasdgamer says:

        Dr. Young,

        If taking toxic levels of Amoxycillin caused you to vomit so severely that blood came out, you might stop taking it.

        Prescribing toxic levels of a drug doesn’t bring confidence to any study.

        Also, giving an antiviral after viral replication is done doesn’t bring confidence.

        Days 1-5…incubation

        Days 6-13…immune response…virus is dead in most patients and there is no further significant viral replication…peak is typically on day 8

        Days 14-28…damage from the immune system occurs…ARDS, etc.

        I got this from Marik’s video.

      2. theasdgamer says:

        Dr. Young,

        Could you please try the RECOVERY dosage on yourself and report back to us your experience and whether you discontinued the dosing or ended up in the ED? (That’s 2400 mg over 24 hours. Zelenko doses at 200 mg bid.)

        Thanks.

      3. Jacob Friedman says:

        Your argument, sir, is akin to sophistry.

        The counter-argument is that if you’d administer an overdose of the antibiotic (or any medicine) then the patient will die before you have a chance to analyze if the medicine works.

        And now to address all the Nay-sayers:

        Personally, over the recent few months, i have invested over 100 hours(!) researching online very numerous cases and reports mentioning HCQ. (Encompassing tens of thousands of individuals, via medical professional’s and personal accounts including interviews studies and trials.)

        The findings are consistent, WITHOUT exception;

        1) The failures did not follow the simple protocol.
        2) And those that did follow it, rarely, if ever, ended with death.

        Go ahead, search yourself.
        Mocking and belittling won’t change the facts.

        p.s.
        I am employed in a Nursing Home.
        We’ve lost a few dozen residents/patients back in March and April.
        However, since we’ve implemented the HCQ-protocol, we have not lost a single patient to Covid-19.

    2. Terry says:

      The ongoing demonization of HCQ, like many other things in the Trump era, isn’t related to anything rational, and in fact contradicts the evidence.

      1. will says:

        HCQ cost nothing, remdesivir etc cost 1000USD+ thats why.

        Its sad that we can’t get proper and trusted testing though. Maybe HCQ isnt so great f.e. but apparently we’re okay with having people die just to make people richer so we don’t know. I wish articles like this were more critical about the testing process rather than just report their opinion. This has so much filler and you’re better served clicking the report directly (then be sad that the testing vs HCQ isn’t valid since no zink and over dosage – and people died over this)

        1. Terry says:

          I had another reply that didn’t post, probably because I included a website. It was mainly about another study:

          Early treatment study Source Study Page
          Sulaiman et al., medRxiv, doi:10.1101/2020.09.09.20184143 (Preprint)
          The Effect of Early Hydroxychloroquine-based Therapy in COVID-19 Patients in Ambulatory Care Settings: A Nationwide Prospective Cohort Study
          Observational prospective 5,541 patients, adjusted HCQ mortality odds ratio OR 0.36, p = 0.012. Adjusted hospitalization OR 0.57, p < 0.001. Zinc supplementation was used in all cases. Early treatment in ambulatory fever clinics in Saudi Arabia.
          death, ↓63.7%, p=0.01
          hosp., ↓38.6%, p=0.001
          (odds ratio converted to relative risk)

          There are many such studies at the site, c19study dot com.

        2. David Eugene Young says:

          …but apparently we’re okay with having people die just to make people richer so we don’t know..

          Well, I’m not okay with that. I don’t know anyone who is okay with that. Certainly the CEOs of pharma are not okay with that. So, you are entering conspiracy theory territory here. I think that HCQ just doesn’t work, either by itself or with zinc.

          Strange, for six+ months now people have been raving about HCQ. But you don’t do the RCT trial to find out. Look, do the trial. What are you waiting for? You’ve had six months to run a proper clinical trial and yet you won’t.

          1. Marko says:

            “But you don’t do the RCT trial to find out. Look, do the trial. What are you waiting for? You’ve had six months to run a proper clinical trial and yet you won’t.”

            Multiple clinical trials were ongoing at the time of the Surgisphere data publication which were halted based on those “compelling” results indicating no benefit and likely harm. You can imagine the difficulty in recruitment that must have ensued for any trial that attempted to continue after the retraction.

            https://www.theguardian.com/world/2020/may/29/covid-19-surgisphere-hydroxychloroquine-study-lancet-coronavirus-who-questioned-by-researchers-medical-professionals

          2. theasdgamer says:

            Good point Marko. Why weren’t trials restarted? How did Surgisphere pass peer review? How can anyone not smell a rat in all this mess?

            The well was poisoned by Surgisphere by design and the retraction didn’t register with most scientists. Science proves that scientists are irrational.

          3. Eddy P says:

            Well check out what’s happening in the Netherlands right now:
            https://www.news1.news/2020/10/zwolle-doctors-investigated-how-malaria-medicine-hcq-can-still-help-with-corona.html

            Just saying, but it could be game-changing. And íf these doctors turn out to be right, who’s going to take responsibility explaining the deaths that cóuld have been prevented?

            Im saying “if”. Only sharing what I see happening here the last two days.

        3. David says:

          will: “HCQ cost nothing, remdesivir etc cost 1000USD+ thats why.”

          And yet, the people recognize that all blinded / controlled studies of HCQ have failed readily accept that dexamethasone, also a cheap drug, works.

          Leaping to veiled accusations of financial corruption is a poor argument strategy.

        4. Dan says:

          these studies never use the zinc with the hydroxychloroquine. but imagine if they did and it was found to work (which it does). what would the American people do to Fauci, Twitter, and all the politicians and media that would at that point be considered murderers? and what about the host of this blog? I trust the opinion of Harvey Risch much more than the in the pipeline guy.

          1. drsnowboard says:

            Harvey Risch may be an eminent cancer epidemiologist.
            But his colleagues have doubts over the studies he bases his opinion on.
            https://www.medpagetoday.com/infectiousdisease/covid19/87844

          2. SteveM says:

            Re: drsnowboard, “Harvey Risch may be an eminent cancer epidemiologist. But his colleagues have doubts over the studies he bases his opinion on.”

            I can agree with the criticism of the studies Dr. Risch cites, but the criticism is based on the cititations not linked to RCT’s, not proof of lack of efficacy under the protocols of the treating physicians.

            So I inquire again if any trials using the exact protocols specified by the clinical physician-advocates of HCQ therapy have been conducted? I.e., HCQ + Zinc + Azithromycin at initial diagnosis of Covid. That’s a real, not a rhetorical question.

            Given that 30,000+ people are diagnosed with Covid every day in the U.S., an RCT with % transition to in-patient status being an endpoint versus placebo could be done in a few weeks.

          3. theasdgamer says:

            drsnowboard,

            Dr. Risch’s colleagues have difficulty reading scientific articles. They rely on Boulware and Cavalcanti. I have already explained why Boulware should not be used even though Watanabe showed significant prophylactic benefit from Boulware.

            Cavalcanti stated in his paper that since hydroxychloroquine was being widely prescribed in the hospitals where the study occurred, he couldn’t rely on the control group not having received it. Cavalcanti hence modified his inclusion parameter to absence of dosing with HC for some period. This is a mountain.

    3. Michel Nita says:

      What lies are you on about?
      There is hard data in the article. Address that. Get on topic.

      1. Charles H. says:

        There will always be corner cases that aren’t addressed. I’m quite willing to believe that in people suffering from a zinc deficiency, added zinc is useful. And I can see plausibility that sufficient zinc could prevent the cytokine storm, as I’ve seen reports that excess zinc damages the immune system. Of course, then you’re left with a damaged immune system until the zinc levels return to normal….perhaps some cleating treatment would help…

        That doesn’t mean that I think this is a good approach, though. I consider a “slightly above the RDA” of zinc to be desirable, and couple this with “slightly above the RDA or vitamin D”. And don’t consider this a treatment, but rather a health measure. It might result in a milder case of COVID if I catch it. I’m also watching my blood sugar levels carefully. (Well, I’m an obese male diabetic older than 60.) But really what I’m trying to do is avoid it until a reliable vaccine is available … but that sure doesn’t mean one rushed out before Nov. 3.

    4. Miles says:

      Please do not try to fool us with hcqtrial.com – its junk and you are a fool or a crook.

    5. David B. Collum says:

      I concur. The trials keep falling short on one of two critical features: initiated too late in the disease state or omission of azithromycin AND zinc. If they only had zinc, this would have sealed the deal. As it stands, it appears to leave yet another gap. How many of us have witnessed a failed reaction because one of the supposedly key ingredients was left out. That student would be sent back to the lab with the instructions to do it correctly. This is very disappointing.

  5. Terry says:

    That’s interesting, but it’s only one study. Others have had heavily contradictory results, for instance:

    Early treatment study Source Study Page
    Sulaiman et al., medRxiv, doi:10.1101/2020.09.09.20184143 (Preprint)
    The Effect of Early Hydroxychloroquine-based Therapy in COVID-19 Patients in Ambulatory Care Settings: A Nationwide Prospective Cohort Study
    Observational prospective 5,541 patients, adjusted HCQ mortality odds ratio OR 0.36, p = 0.012. Adjusted hospitalization OR 0.57, p < 0.001. Zinc supplementation was used in all cases. Early treatment in ambulatory fever clinics in Saudi Arabia.
    death, ↓63.7%, p=0.01
    hosp., ↓38.6%, p=0.001
    (odds ratio converted to relative risk)

    Many more studies at c19study.com…

  6. failed scientist and incel says:

    Derek works for the Rand Corporation (in addition to his regular gig) and speaks fluent Chinese. Connect the dots!

    1. johnnyboy says:

      Says the one who works for Big Zinc.

      1. PDINV says:

        Hahahahahah

    2. Harvey 6'3.5" says:

      Derek,
      Please remove “failed scientist and incel”‘s post. Some of the other posts above are also unreasonable in disagreeing with you on HCQ, but that post is just ad hominem absurdity.
      Thanks.

      1. Successful Scientist and Married (So Also Incel) says:

        Harvey,

        He was being sarcastic.

  7. Rhenium says:

    As soon as I saw the title I expected a great chemistry write up and good awful comments…
    I was not disappointed on either front.

    1. Magrinho says:

      Exactly – crackpot comments coming in 3….2….1….

      Sometimes I wonder why even try to explain but I keep trying.

  8. Philip says:

    Derek, thanks for the update on remdesivir. I hope you never feel the urge to write about hydroxychloroquine with respect to a virus again.

    I still feel that we have not seen results from a good trial for any of the antiviral therapies, including remdesivir. Without giving antivirals very soon after infection, I do not believe that we are giving them a chance to show their full potential as a treatment.

    I know that study design is much harder when you have to have daily testing for the subjects. It is also more costly. You could argue that any trial requiring daily testing would not be a “real world” trial. I still want to see frequent testing trials for antivirals so that we know which ones stand a chance of working.

    Even if we get high quality trials that show that mono clonal antibodies and remdesivir work fantastically, we still have problems. How do we get enough Rapid Antigen Tests (RATs) or Home Everyday Antigen Rapid Tests (HEARTs) to the right people so that we could start treatment early enough to be of great benefit? Even if we get the tests, we still have a problem on knowing who to treat and having enough of the treatments on hand. Maybe the link below will help us know who to treat.

    SARS-CoV-2 is a nasty virus. The long presymptomatic phase makes testing and tracing hard. Poor testing and tracing renders antivirals almost useless. The timing of treatments is a real PITA for physicians. Add in the thrombotic disorders caused by SARS-CoV-2 and you see why it is not just a flu.

    https://blogs.sciencemag.org/pipeline/archives/2020/09/28/interferon-and-the-coronavirus

    1. theasdgamer says:

      The presymptomatic phase lasts about 5 days per Marik. The initial immune response phase lasts the next 8 days per Marik. After that possibly comes the immune hyper-response phase.

  9. sam says:

    I agree with making a firm “NO to Hydroxychloroquine” statement — too often we say that “there is no evidence to support,” which is confusing to non-scientists. I look forward to getting to a firm YES to something (might the next yes be monoclonal antibodies??).

    1. confused says:

      Is this not a firm yes to remdesivir?

      Sure it’s not a *super dramatic* effect, but 11.4% vs 15.2% would mean it reduces risk of death by ~25% (at least in high risk populations, which is where it really matters IMO)

      But yeah I am *very* interested in monoclonal antibodies, hope the public hears more soon.

      I wonder if the fact that one of these therapies was given to the President might suggest that the *company* has decent data not yet public, as I’d expect that they’d be very worried about an “our experimental treatment killed the President” headline.

      1. Daniel Barkalow says:

        If you try to come up with a treatment plan using remdesivir, it’s hard to get one where the benefit/cost of using it beats other things you could be doing with that money. After earmarking a bunch of money for supportive care, it makes sense as another thing to also do, but it’s not at a level of effectiveness where it makes sense to redirect resources such that it would be available to everyone who tests positive.

        As far as Trump getting antibodies, I expect that the company has data that shows that the rate of serious adverse events attributable to the treatment is low, like there’s a 1 in 10000 chance of killing the president. What they probably don’t know is whether it helps at all, but the difference between it having no effect and not being 100% effective doesn’t really change the “fails to save the president” headline, and there’s like an 85% chance of him surviving even if it does nothing. It wouldn’t be good public policy as a standard treatment, but it’s not like “president gets experimental drug, can’t afford oxygen, dies” is going to happen.

        1. confused says:

          This is probably an ignorant question, but why is “it does nothing” a plausible outcome?

          This is an artificially-produced version of a human anti-COVID antibody that works when patients naturally produce it, isn’t it? I can see how it could potentially do harm (antibody-dependent enhancement), so I can see the need for trials, but if it is an antibody that is known to have anti-COVID activity in the human body, why is “no effect” (neither benefit nor harm) plausible?

      2. Marko says:

        ” Sure it’s not a *super dramatic* effect, but 11.4% vs 15.2% would mean it reduces risk of death by ~25% …”

        If that was a statistically significant effect , sure. It wasn’t. Close , but no cigar.

        It’s funny how Derek and many others are willing to tout a non-significant mortality benefit for remdesivir but get the vapors when others do the same about hydroxychloroquine.

        1. theasdgamer says:

          Marko,

          I don’t see how any study of HC will directly yield mortality benefits because of the problem of significance. I would expect it to yield a benefit in reduction of hospitalization (80% in Zelenko and Heras). You would have to infer a benefit in mortality reduction.

          1. Marko says:

            Agreed , but my point was merely to illustrate the double standard at play here. The remdesivir trial was also under-powered to demonstrate a mortality benefit in the pre–specified statistical analysis. The mortality benefit claims here are based on post-hoc analysis , and mainly focused on a single subgroup , both practices which are normally disparaged on this site – correctly – as being bad science. Not only that , the upper confidence intervals in several of the subgroups run to relative risk ratios of 1.9 – 4 , suggesting that in a new trial , you might even demonstrate a mortality increase in those subgroups.

            Yet Derek touts the “hard endpoint” mortality benefit without qualification , going further than even the Gilead CEO was willing to go. I just wish there was a consistent and unbiased review of trial data here , and that is clearly not the case.

    2. Charles H. says:

      AFAIKT, monoclonal antibodies are also only a “moderately effective treatment”, not a magic bullet. Possibly polyclonal antibodies are needed, but it’s also possible that TCells are the main defense, and antibodies can only affect how serious the case is. (OTOH, perhaps inhaled antibodies is a good treatment and injected antibodies are sub-optimal, or perhaps you need both.)

      Don’t take this seriously, as I’m not medic, but this is based on various reports I’ve read about things being tried. (And, of course, the way I remembered the reports.)

      But I still have a real question as to how durable an immunity can be created. IIUC, antibodies are transient, but TCells seem (in similar diseases) to create a durable immunity…but not a sterilizing immunity. So you can catch it more than once, but second cases will be milder. OTOH, one reported second case was more serious.

  10. Big Mike says:

    The real weakness of the RECOVERY study is that cases were treated *after* hospitalization for COVID-19. The successful protocol was hydroxychloroquine + ZINC + azithromycin given *EARLY* (certainly prior to hospitalization) in the course of the disease.

    So the RECOVERY study, like many other studies using HCL, waited until patients had advanced COVID-19, hospitalized them, then gave them a protocol doomed to failure b/c it was too late.

    Patients in successful studies using the HCL+ZINC+ZITHROMAX protocol avoided hospitalization. For example, in one of Zev Zelenko’s studies , only 4 of 141 of his patients needed to be hospitalized:

    https://www.prnewswire.com/news-releases/newly-published-outpatient-study-finds-that-early-use-of-zinc-hydroxychloroquine-and-azithromycin-is-associated-with-less-hospitalizations-and-death-301094237.html

    1. bob says:

      Multiple flaws in Zelenko’s study unfortunately and when HCQ is tried in a proper RCT it seems to produce no decent results… Here’s one with Zinc even:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384270/
      We all wanted it to work (I know someone will claim that just because Trump promoted it all scientists worldwide suddenly developed a bias against HCQ), but unfortunately results just aren’t there.

      1. David E. Young, MD says:

        I don’t understand Zelenko’s data. On about July 1st, he said that he had treated 2,200 Covid19 patients with HCQ/Zinc/Az. That would mean, if he saw patients in follow up, that he would have to see 100 covid19 patients in his office every day. That could not happen.

        1. theasdgamer says:

          Dr Young,

          2200 patients / x days = 100/ day

          So you think that Zelenko had only seen patients for 22 days?

          (Zelenko triaged his patients. Low risk were sent home with no care, but were followed up, I suppose.)

          Zelenko was reporting having seen 700 patients back in April. 700 in two weeks is doable, especially if he’s doing telemedicine from home and patients go to his clinic to be seen by his staff and a lot of the patients are low risk and require no prescription. Low risk patients require maybe 5 minutes at most.

          1. David E. Young, MD says:

            You have to follow patients up. You don’t just see them once. I figure that you would have to see each patient AT LEAST four times for proper follow up. There is no way on earth that Zelenko could properly assess those patients with just one visit. ARE YOU KIDDING ME? 8,800 patient visits over 15 weeks. That is a lot of patients per day.

          2. theasdgamer says:

            Maybe Dr. Zelenko has NPs and/or PAs working for him?

        2. chiz says:

          Zelenko treated more covid19 patients than actually existed:

          As of last Thursday, Orange County, where both Kiryas Joel and Monroe are located, had officially reported a total of 68 positive cases of coronavirus. Zelenko, however, claims that he has treated 350 coronavirus patients from Kiryas Joel alone and nearly 150 more from nearby areas.

          He’s a liar and a charlatan.

          1. theasdgamer says:

            Reports are often dilatory. But thanks for playing.

      2. SteveM says:

        Re: “Multiple flaws in Zelenko’s study unfortunately and when HCQ is tried in a proper RCT it seems to produce no decent results… Here’s one with Zinc even:”

        From the link: “Intervention: Oral hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days) or masked placebo.

        I don’t see Zinc there. Hard to believe that a HCQ + Zinc + Azithromycin at initial diagnosis trial has not been done. With the number of new daily cases in the tens of thousands, it could be completed in 2 weeks. Does anybody know if that trial has actually been done and the results published?

        1. theasdgamer says:

          When people are afraid of a drug, albeit unreasonably, enrollment is difficult.

      3. Dan says:

        “here’s one with zinc even”
        there’s no zinc in that study.

        1. Eric B. says:

          Zinc is directly mentioned three times on the page linked by Bob, and Table 2 of the PDF attached as supplemental data gives their results and commentary about both Zinc and Vitamin C.

          It almost reads as, “We were double checking someone else’s anecdotal information, and found nothing. We went ahead and checked for the possible secondary contributors while we were in there, to see if there is any point in researching the combinations. Alas but we must conclude ‘nope'”.

          1. Dan says:

            the zinc and vitamin C numbers in the article referred to “self-reported use. ”
            useless.

          2. debinski says:

            And about 30% of both treatment groups took zinc on their own (who knows how much or when). Interestingly, if you look at the subanalysis of the groups that did not take zinc, the hydroxychloroquine group did better than placebo (based on 95% CI). There are several other subgroup analyses that favor HDCQ but as the authors point out, they appear to be spurious. However, there is a trend for HDCQ doing better in older patients that they think warrants further study. See supplemental table 2.

      4. theasdgamer says:

        Just stop with paying attention to Boulware. His study is meaningless.

      5. theasdgamer says:

        No, the reduction is hospitalization is a real, significant benefit, never mind the problems with the control group. Substitute any similar control group and Zelenko’s results are _significantly_ better.

        Zelenko’s results were confirmed by Heras. In spades, since the median age in Heras was 85+.

    2. Simon Auclair the Great and Terrible says:

      Oh, yeah hydrochloric acid, thatl cure em even better than chugging bleach. Genius!

    3. David Eugene Young says:

      Your link is to a press release with no details. There is a link that tells me that the original study was retrospective and therefore worthless. Anyone can select out a series of patients with Covid19 who did well, better than average. Using retrospective comparison I can prove that popcorn cures covid19.

      Please,…. do the proper randomized clinical trial first and then we’ll talk.

      1. theasdgamer says:

        Show me a RCT that provided a solution to a novel viral infectious disease and then we’ll talk.

        SARS, MERS, H1N1, ebola…how important were RCTs in those cases?

      2. Dan says:

        I hope you are not like Fauci and okay with people dying while we wait a study you like to be performed.

    4. Derek Lowe says:

      Zelenko did not actually conduct “studies” in the way that most people use that term, from what I can see.

      1. theasdgamer says:

        Derek, anyone can see that Zelenko’s post hoc study produced significant reduction in hospitalization if you use any comparable populations for comparison.

        Heras used much older patients than Zelenko (Heras’ patients were median age 85+) and achieved similar reductions in hospitalization.

        The evidence for HC is very strong. Not overwhelming, but very strong, even if they are post hoc.

  11. Bill says:

    “In conclusion, in this large nationwide observational study of patients hospitalised with COVID-19, HCQ monotherapy administered at a dosage of 2400 mg over 5 days was independently associated with a significant decrease in mortality compared with patients not treated with HCQ.”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444610/

    1. Bell says:

      If you read it carefully, the non-HCQ patients were, on average, 10 year older in that study. That’s why you do double-blind studies: to eliminate, among other things, various sampling biases.

  12. David E. Young, MD says:

    Remdesivir, by itself for hospitalized patients with Covid19 is not a miracle drug, but it does help. Perhaps it would work better given earlier in the disease course. (At least) two trials are being done to address that. I have said it before, and would like to mention it again: I would like to see trials of combination antivirals. Not necessarily combined on every day but with some over lap. Say, for instance, Remdesivir intravenously on days 1 and 2 with Favipiravir or MK4482 (EIDD-2801) given orally days 3 to 7. Or similar combinations. (days 1 to 3 of Remdes and days 2 to 7 with an oral antiviral as another example). Such combinations could be tested in vitro, I suppose, but as far as I know has not been done. If shown to be (at least ) additive, if not synergist, such a combination could be very attractive for outpatient treatment for anyone with early Covid19, at risk due to age or comorbidities.

    Sorry that such a trial has not been started yet.

    1. Thomas says:

      Favipiravir might be teratogenic, according to Wikipedia. I don’t know whether that matters a lot of r a drug like this? Especially as the risk groups (elderly and male) are not likely to be pregnant.

      1. David E. Young, MD says:

        Favipiravir is likely to be teratogenic, as far as I know. That would make a difference here in the US and would require a REMS (probably mandatory pregnancy testing in women of childbearing age and instructions to keep the medicine out of other’s hands), and it might be restricted to older individuals.

        1. David Eugene Young says:

          Don’t misunderstand me. I believe that Favipiravir is a valid and valuable drug for Covid19. I strongly regret that the US has all but ignored Favipiravir. And I don’t know why. It is not as though scientists are refuting the data, or claiming bias in the randomized study. I hate to think it but is it not being studied here because it is off patent and inexpensive to manufacture?

  13. Fraud Guy says:

    As I saw elsewhere, in addition to the mortality benefits of remdesivir, cutting the hospitalization time of patients means that we create less capacity stress on hospitals treating COVID patients, which means more can be treated:

    “Remisdivir is another way of expanding hospital capacity. A bed and the attached staff can be ~50% more productive by adding a drug to the treatment regimen for some patients.

    We saw in the spring that mortality was massively elevated when hospitals were slammed. Expanding capacity by both the construction and staffing of new surge beds and improving the productivity of each current bed will delay if not completely avoid the possibility of local hospital systems getting overwhelmed this fall and winter. Remisdivir should be prioritized for regions that are approaching or over sustainable hospital capacity in order to minimize the total number of deaths. We, as a society, should be willing to pay through the nose for Remisdivir and other drugs that have a good evidence base to reduce mortality and hospital stays when it is used in highly stressed systems and concurrently, we should be willing to pay very little when it is used in regions with thousands of spare hospital beds.”

  14. SteveM says:

    Below is an email I sent to Derek inviting a discussion. I titled the subject “Big Pharma, Big Politics and Big Money”. Guess I’ll start it here to see if it animates anyone:

    I saw this article in the Washington Post related to Remdesivir:

    https://www.washingtonpost.com/business/2020/09/30/remdesivir-drug-coronavirus-gilead/

    $3,170 per treatment with modest clinical value.

    Also recent articles related to the Russia formulation of Favipiravir (Avifavir) for use as a Covid treatment:

    https://economictimes.indiatimes.com/news/international/world-news/russia-to-supply-avifavir-drug-to-17-nations-for-coronavirus-treatment/articleshow/78293556.cms

    http://avifavir.info/

    Favipiravir is taken as a tablet. The per tablet price in India is $1.40. At that price, if the drug works, I imagine it could be prescribed when Covid is initially diagnosed.

    The anti-Russia animus in the U.S. for political reasons is obvious. There are also the Big Money reasons for Big Pharma to actively subvert acceptance of Avifavir by FDA. I’m wondering if this would be worth starting a discussion from your end about how those exogenous factors that may impact access to clinically and cost effective treatments in the U.S.

    I mean Favipiravir was developed in Japan and is generic. Would/should a Russian Covid proof of concept of a Favipiravir formulation prevent its registration in the U.S. because it came from Russia and is also dirt cheap?

    1. 13enster says:

      It doesn’t matter how cheap an API is in India. If it got FDA approval for a new indication, especially one where the standard of care sucks, then there would be an associated period of regulatory exclusivity for the new indication where the company behind the trials + approval would be able to charge a significant premium. If it worked, a pharma company would be all over it and profit from it in the process.

    2. Matthew says:

      In the US, those extra hospital days that remdesivir saves cost a lot more than $3170. If beds are scarce, they could cost lives.

    3. Phong Nguyen says:

      Russia’s death rate has not been reduced, so I think that drug only helps a very little or none. Let’s wait until it passes phase 3.

  15. Another Guy says:

    I fail to see how adding zinc or azithromycin will magically make hydroxychloroquine more effective. In my experience, if drug A works a little, and drug B works a bit, then combining the two gives you a better result than using A or B alone. In contrary, if drug A does nothing for the patient, and drug B does something good, then any benefits to the patient are purely drug B and drug A is just an expensive placebo at best.

    1. theasdgamer says:

      In the same vein, using 13 meaningless late studies of antivirals does nothing. Adding one with a hyped name like RECOVERY is somehow supposed to change things.

    2. Charles H. says:

      Sorry, that’s a bad argument. Often a combination of drugs works better (or worse) than either drug alone. Cellular chemistry is complex, and simple models of what’s happening will often mislead you. (OTOH, we still don’t have any good and workable models….I suppose you could call quantum mechanics a good model, but it’s not workable in that context.)

      This doesn’t mean I accept the argument. Just that saying “a combination is necessary to achieve the desired result” is not inherently wrong. But the number of possible combinations is so huge that it’s impossible to test most of them…so you only test the ones that seem (to you or your sponsor) the most plausible.

    3. Geeknerdly says:

      One thing to understand is that HCQ’s primary antiviral activity was original determined in culture to be due to driving intracellular zinc concentrations above normal levels and zinc poisoning effect on the RNA polymerase of COV preventing replication. (It was actually originally noted with pyrithione as the ionosphere and SARS if memory serves). So, without Zinc, HCQ is worthless.

      1. Fleury says:

        I do not understand, if HCQ is able to carry Zn inside the cell across membranes, it does so even if initially the concentration outside the cell is at homeostatic value. You do not forcibly need to provide additional zinc, there should be enough zinc round there in the first place, the concentration of zinc around cells is not zero in the absence of zinc supplement

  16. MB says:

    I don’t really care one way or another about HCQ, but I will say this, Trump did not prescribe the treatments. Tens of Thousands of doctors thought it worthwhile to try. Do I think these doctors were morons or duped by Trump? No. I wonder if Derek does. The politics of Covid-19 are absolutely moronic.

    1. dr. fancypants says:

      No one faults the doctors who initially tried HCQ out, back when we had no idea what treatments would work. The issue is that some people (see, e.g., earlier in this thread) insist on pushing it as a treatment long after the evidence has come down pretty strongly against it.

      1. MB says:

        In your opinion, when should have doctors stopped prescribing it?

        1. Semichemist says:

          After data shows it kills more people than the control seems like a good time

          1. theasdgamer says:

            Oh, you mean the Lancet study that was retracted?

      2. theasdgamer says:

        Giving an antiviral after replication has been stopped is meaningful somehow?

      3. theasdgamer says:

        All the evidence against early treatment with HC is from the land of make believe. Surgisphere, RECOVERY, etc.

  17. DrivingToTheBar says:

    Let’s all try to do Derek a small favor and not link to this blog when quoting the result about HCQ. Use the direct link to the NEJM paper.
    For myself, I’m trying to remind the self not to get into another online idiotfest about HCQ.

    Oddly enough, normal levels of zinc and vitamin D do seem to be beneficial. That’s normal range, not megadoses promoted on social media.

    PS a thx to the author for this post. This is the one place I trust to find reliable and non-politicized info on such topics.

  18. I understand Remdesivir inhibits TMPRSS2 which along with ACE2 allows the entry of COVID-19 into cells.

    BUT

    Researchers have found a second protein that SARS-CoV-2 uses to enter human cells, potentially offering a new target for vaccines and drugs.

    The SARS-CoV-2 protein called Spike is known to attach to a human protein called ACE2, which allows the virus to enter cells. Two teams of researchers have now found that the human protein neuropilin-1 (NRP1) also aids viral invasion.

    The Simons team also found that in mice, NRP1 assists the entry of virus-sized particles

    into the central nervous system.

    The studies suggest that blocking the interaction between the virus and NRP1 could provide a way to combat coronavirus infection.

    https://www.nature.com/articles/d41586-020-00502-w

    Vesencumab? It already exists and has been used for other diseases.

    1. Barry says:

      Remdesivir inhibits viral RNA synthesis; it has nothing to do with ACE2 or with viral entry to host cells.

    2. theasdgamer says:

      Check out protein 157 as well. SARS-2 may bind to it.

      1. theasdgamer says:

        Sorry, that’s Protein CD147.

  19. li zhi says:

    I am pretty sure that since April or May, the advocates (aka “fanboys”) of HCQ have been claiming that 1) it must be used “early” and 2) if must be accompanied by Zn (and many also would add azithromycin to that cocktail). I have no position on whether HCQ works or not, and it seems clear that claiming that it needs those things is, indeed, special pleading. But it also seems to me like the old saw about paranoia: just because you’re paranoid, doesn’t mean someone isn’t out to get you. That is, just because it is special pleading, doesn’t mean it is wrong. So, I’d like to see DL actually address this, but based on his posts, he’s dug into his categorical position and isn’t likely to move. What specifically am I curious about? Well, first what does “early” mean (in terms of when HCQ needs to start)? What is the criteria that they advocate which should trigger HCQ+Zn admin.? And for how long? And at what dose? Second, how practical is it to require an intervention be “early” when the presymptomatic period is long? Just wondering.

    1. Marko says:

      Agreed. I don’t know if hydroxychloroquine works , and I don’t really care. To be completely honest , if I had any bias at all , it appeared when Trump declared Hcq a “game changer”. Since I despise Trump , my bias , if any , would have been for Hcq to flop. But I wouldn’t want bias like that to impact scientific evaluations of the benefit of a drug for a disease like COV2 , and that is exactly what has happened. The Surgisphere study is the smoking gun. Numbers made up out of whole cloth , designed to shut down studies of Hcq’s potential benefit , and it was successful at doing so. Out of 250 listed clinical trials , only a few have generated results. The rest are either suspended , “still recruiting” , “not yet recruiting” , etc. In other words , the trials are toast.

      Hcq was investigated early on because of in vitro antiviral effects , and previous hints of efficacy vs SARS as well as similar results vs COV2 out of China. However , if there is indeed any benefit , it could as easily be due to immunomodulatory effects as to antiviral effects , or to a combination of both. After all , Hcq is widely prescribed for RA and lupus , presumably because of those immune modulating properties.

      If it turns out that the main effect is as an immune modulator , you can throw out most of the “prophylaxis” trials. The endpoint there is generally infection , not severe disease or death. Also , you can throw out the high-dose trials designed to achieve the comparable in vitro antiviral drug concentrations -conveniently perhaps — since those concentrations are also going to give you the cardiac side effects. What you want to look at is the trials modeled after the RA and lupus experience , not the in vitro experience.

      There’s more , but suffice to say , this has been a blight on medical science in the Western world. There is no independent , unbiased evaluation of anything , anywhere , ever. It’s all polluted by politics and money. The fact that the Surgisphere folks are not behind bars right now is just one painful , raised middle-finger reminder of this reality.

      1. Dan says:

        what Trump has accomplished in the middle east in three years far surpasses Obama’s entire presidency. at this point democrats are nothing more than a corrupt and dishonest party offering zero transparency on their plans for the future because they know the people don’t want their globalist agenda.

    2. theasdgamer says:

      Digging in to positions is fine as long as you have some way of determining when to abandon them.

      Joseph Priestly, the discoverer of oxygen, was a bad example of this. He went to his grave clinging to the Theory of Phlogiston and denying the Theory of Oxidation.

    3. theasdgamer says:

      li zhi,

      Great questions! Zelenko’s protocol is what needs to be tested. Read his paper if you want specifics about everything. It answers your questions.

  20. anon says:

    If HCQ were actually useful, Trump would have gotten it at Walter Reed. The fact that he didn’t take it when his own life was on the line tells you something.

    1. JasonP says:

      @anon
      Ding, ding, ding!

      For me this says it all! If HCQ were of any use then the dude that touted it as a “game changer” early on would have INSISTED on its use when he contracted COVID-19. After all most writers on this forum proclaim that Trump was directing his treatment, so the fact it wasn’t used speaks volumes.

      Surprised that this point was missed by the always astute author here. Then again, perhaps political expediency and not wanting to stir the pot came into play?

      None-the-less HCQ is off my list of interventions.

      1. Chris Phillips says:

        Not only that, but from the details that were issued of what he was taking regularly (including Vitamin D, for example), it’s clear that even if he had been taking hydroxychloroquine at one time, he had stopped.

        The remaining believers are trying to be “more royalist than the king”.

      2. Robert Clark says:

        Obviously, his doctors were convinced by the anti-HCQ hype just as much as anyone else.

        That doesn’t mean that it doesn’t actually work.

        Robert Clark

    2. theasdgamer says:

      Trump stopped taking HC in May. The fact that he got covid after stopping prophylaxis should tell you something, too. lol

      1. Chris Phillips says:

        Interesting syllogism.

        (1) Trump stopped taking hydroxychloroquine in May.
        (2) Trump got COVID-19 in October.
        (3) That should “tell us something” about hydroxychloroquine.

        1. theasdgamer says:

          What is “mockery by imitation” for 400, Alex?

  21. Blaine White M.D. says:

    In part I respectfully disagree with Derek Lowe’s evaluation here. I want to make clear I am no fan of Mr. Trump and strongly support the unprecedented editorial action of the New England Journal of Medicine in their call for his defeat in the coming election. But there is substantial evidence that HCQ treatment has been helpful in published real world studies of series totaling (at least) 27,746 patients from
    (1) Henry Ford Hospital in Detroit (2,541 patients – Internat J Infectious Diseases 2020; doi.org/10.1016/j.ijid.2020.06.099),
    (2) the New York Icahn SOM/Mt. Sinai Hospital system review of 6,493 Covid-19 patients (J Gen Intern Med 2020; doi: 10.1007/s11606-020-05983-z),
    (3) An even larger study of 8,075 patients (4,542 with HCQ monotherapy and 3,533 with no HCQ) in Belgium (Internat J Antimicrobial Agents 2020; doi.org/10.1016/j.ijantimicag.2020.106144)
    (4) An Italian study of 3,451 Covid-19 patients (European J Internal Medicine 2020; doi.org/10.1016/j.ejim.2020.08.019)
    (5) A prospective cohort study of 5,541 confirmed Covid-19 patients from 238 ambulatory fever clinics in Saudi Arabia with 28-day followup (MedRxiv 2020; doi.org/10.1101/2020.09.09.20184143)
    (6) and from Spain another large study of 1,645 Covid-19 patients (MedRxiv 2020; https://doi.org/10.1101/2020.07.17.20155960).
    Although every study can be criticized, that is a lot of doctors, patients, and nations to blow-off as anecdotal evidence, and unlike the first widely discussed negative study from Mehra et al. (Lancet 2020; S0140-6736(20)31180-6), they appear to be free of fraud.

    Derek referred to the Oxford RECOVERY RCT, which first garnered substantial public attention by announcing to news media on June 5 results indicating no HCQ efficacy with no significant difference in 28-day mortality in 1,542 HCQ patients compared with 3,132 similar patients without HCQ. I’m probably just picky to note those group numbers have now changed to 1,561 and 3,155. In any event that data didn’t appear in a preprint (MedRxiv 2020; doi.org/10.1101/2020.07.15.20151852) until July 15, and the study was immediately criticized for an excess of patients over 70 in the HCQ group and their use of unusually high doses of HCQ that may be acutely immunosuppressive. It’s now in an October journal. I am unconvinced by the generalized interpretation. There are more convincing negative studies that HCQ is ineffective as prophylaxis (NEJM 2020; doi: 10.1056/NEJMoa2016638) and in the advanced stages of Covid-19 (NEJM 2020; doi: 10.1056/NEJMoa2012410). But on balance the real world data from 27,746 patients suggests HCQ can be helpful in early management of the infection. There is no evidence that it is harmful when used carefully at appropriate doses (Am J Epidemiol 2020; doi: 10.1093/aje/kwaa093).

    I also have difficulty being confident remdesivir is well separated from marketing hype. Remdesivir was developed in the Ebola epidemic to interfere with viral RNA-dependent RNA polymerase but did not perform well clinically. Computer modeling predicts remdesivir is also likely to form a stable interaction in an active site groove of CoV Nsp1 (ChemRxiv 2020; doi.org/10.26434/chemrxiv.12091356.v1). This suggests patients treated with remdesivir should be studied for recovery of interferon levels since Nsp1 knockout prevents coronavirus suppression of interferon production; that has not been done. RCT remdesivir data from Beigel et al. (NEJM 2020; DOI: 10.1056/NEJMoa2007764) found among 1,059 hospitalized Covid-19 patients the total of 469 SICK patients (246 placebo and 223 remdesivir) had essentially identical recovery curves over 29 days. Similarly, Spinner et al. reported another RCT of remdesivir in 596 patients with no evidence of an effect on mortality (JAMA. 2020; doi:10.1001/jama.2020.16349).

    Derek and I probably agree that so far data for single-drug anti-viral treatment of Covid-19 shows modest effects. We wouldn’t dream of treating serious bacterial infections with one antibiotic, and almost all of the patients in these studies have in reality received multiple drug interventions as doctors worked very hard to save lives. That greatly complicates attempts at RCTs in this pandemic and makes blanket statements about efficacy inappropriate. What is appropriate are well-founded measures for prevention – like wearing masks. Perhaps President Trump’s experience will help him understand this – a bit late.

    1. Dan says:

      if two pills, hcq and zinc, were served at dinner in all of the nursing homes for the past eight months there would have been much less death. but Fauci et al said we needed to wait for RCT studies.

    2. theasdgamer says:

      Dr. White,

      Boulware’s study has sooo many problems. It was totally online and no clinical interaction. It totally relied on patient reports with no possibility of verification. The patients were health care professionals who could easily identify whether they were getting HC or placebo. The data was broken out by how long they took HC after exposure in order to reduce significance and make confidence more difficult. The data were from April and testing was dodgy (and really still is). No clinical interaction + relying solely on dodgy tests?

      If you group the data from table S-1 on your own, you get significance from days 1-3 post exposure. But really, the study is so dodgy why would you care?

      Let’s not bring up Trump. He’s irrelevant to this post.

  22. theasdgamer says:

    I’m not of a mind to be subtle. Chemists don’t know much about antivirals. They don’t work when given late in toxic amounts.

    And has RECOVERY released its data yet? We’re still waiting….

    1. Some idiot says:

      You really don’t seem to care about the pharmacodynamics of this drug, and therefore continuously repeating the lie “toxic dose” doesn’t make it less of a lie. The HCQ arm had _lower_ side effects than placebo, which doesn’t tie up very well with your oft quoted lie of “toxic “ doses. Yes, very high at the start, then lower. Designed to give it the best chance of working.
      If another antiviral works in trials, why shouldn’t HCQ?

      1. theasdgamer says:

        You try taking the “non-toxic” dose and report back to us. You can get nausea and diarrhea from 200 mg of HC bid. What do you think will happen if you dose with 6x that amount in 24 hours?

        And, pray tell, what is the cutoff day after symptom onset for expecting antivirals to work?

        1. Some idiot says:

          If it was something that would significantly decrease the severity of the disease, then I would gladly take it!!! It is only for high doses for a few days to get the pharmacokinetics working. And anyway, there are close to millions of people around the world who have worse treatments (think cancer). So let’s get rid of the nonsense about it being partially toxic, ok?

          1. theasdgamer says:

            Mr. I,

            So have you tried dosing yourself with the RECOVERY dose yet?

          2. Some idiot says:

            Seriously, what is the point of that question??? I have already said that if it was a useful treatment against serious illness or death (or if it was part of a clinical trial testing this, by extension), then yes, I would…! It doesn’t for COVID-19, but if it was found to be so for some other condition that I had that needed treating, then yes I would.

            I have a feeling hat you actually have no clue as to what pharmacokinetics are, and so therefore why they doses like they did. If that is the case, learn. If that is not the case, at least be honest about it and don’t pretend it doesn’t exist.

          3. theasdgamer says:

            Mr. I,

            Show me the trials that show that HC is safe at the levels in RECOVERY that also measure compliance with confirmation of compliance.

            You won’t try it yourself and that speaks volumes.

          4. Some idiot says:

            Oh for crying out loud, you are twisting my words so they come out backwards… Are you in the common practice of taking medication you don’t need? Because I’m not. If it was a useful treatment for a condition I had, or if I was enrolled in a clinical trial, I would take it.

            And you still haven’t answered about the pharmacokinetics. But I can understand that we really shouldn’t expect people like you to understand that…

          5. theasdgamer says:

            Pharmacodynamics mean so much when people trash the med. lol

            I made my point and I’m done here.

          6. Some idiot says:

            You have made an assumption that is not backed up by anything at all.

            You are totally done here.

        2. theasdgamer says:

          It’s worth noting that the Brazil study that was roundly criticized for giving toxic doses of chloroquine to patients never exceeded 1.2 grams per day. By way of contrast, RECOVERY gave 2.4 grams the first day.

          Neither dose has undergone FDA safety testing to my knowledge.

          Zelenko was criticized for unsafe practices for giving 2 grams over 5 days. lol. Even at low levels, Zelenko reported some nausea/vomiting.

          Where is the evidence that there was compliance from patients and the meds weren’t trashed?

          1. Some idiot says:

            Ok… incredible claims need incredible proof… If you are claiming that the trial recipients are selectively trashing their medications, then you will need to prove that… Otherwise your point here is as useless as the rest of your thread here…

          2. theasdgamer says:

            “Incredible claims need incredible proof”

            Why do people think that Hume’s fatuous chestnut mean anything?

            All you ever need is an adequate proof for anything. Incredibility is irrelevant.

          3. Some idiot says:

            When you have an incredible and spurious point like yours, you need to put your money where your mouth is. But you probably won’t, because you usually don’t.

      2. theasdgamer says:

        Mr. I,

        I think you’re missing the human factor as well as taking into account the standard dosage for HC. People will throw pills in the trash to avoid side effects. Side effects will be minimal, lol. Also primary effects from the drug.

        RECOVERY explained that they couldn’t get HC in larger doses and had to prescribe it in standard 200 mg pill form and I detected a note of surprise.

        1. Some idiot says:

          Just to repeat from what I said above, incredible claims need incredible proof… If you are claiming that the trial recipients are selectively trashing their medications, then you will need to prove that… Otherwise your point here is as useless as the rest of your thread here…

          1. theasdgamer says:

            You have things exactly backwards. People can figure out that they are being given toxic levels of medications and connect that with what to them are severe side effects.”

            RECOVERY would have to prove that the patients actually took the toxic levels of drugs.

            Of course, it’s all irrelevant since HC was given after viral replication had already stopped in over half the patients. But you have been studiously ignoring that point.

          2. Some idiot says:

            You are the one claiming that the patients trashed their medications. This is an extraordinary claim. You need to show this otherwise you are (again) just talking through your rear orifice.

            But I wouldn’t expect people like you to understand this…

          3. Some idiot says:

            Sorry, the last bit was over the top, but you get my meaning.

            But there is one thing that we agree about, and that is that if something is an antiviral, it makes sense to give it early in the process, not later on when the main problem is the immune response…

          4. theasdgamer says:

            Perhaps we agree that the RECOVERY trial was meaningless.’

            How is it an extraordinary claim that patients trashed poisons rather than taking them?

            RECOVERY gave HC at moderately toxic levels. They were toxic because of the way they were administered–the pharmacodynamics are accompanied by toxic effects. HC goes fairly quickly to the tissues or is eliminated because of redistribution and metabolism. Ramping up is what causes the toxic effect.

          5. Some idiot says:

            We certainly do not agree. The RECOVERY trial (and SOLIDARITY backed it up 100%) showed very clearly that HCQ given at that time has no positive effect. Full stop.

            One of things in your behaviour that irritates me immensely is your attempt to smear anything/anyone who comes up with something that disagrees with the world view you are trying to push. Which means using very emotionally-laden language such as “taking their poisons” instead of rational, scientific discussion. You are very good at it, but I annoy myself when you succeed in dragging me down to your level. The manner in which you insult and lampoon others on this blog also shows a distinct lack of respect, more like a spoilt child when being caught lying.

            And no, it is not reasonable to suggest that all/most people were deliberately trashing their medications. But I can understand why you came up with that explanation, since your other lines of argument died.

            Yes, many medications have toxicity related to their use, but in this case it was simply a high loading dose to get the pharmacokinetics running. Yes, I am quite sure there would have been side-effects, but only for around 2 days or similar. And please, stop emotionally smearing the trials, and stop using words like “poisons”. Play the ball, not the man. And if you want to talk high toxicity, talk to many cancer patients, who have to put up with far, far worse, week in week out.

  23. Sulphonamide says:

    We’re within a month or two of seeing the vaccine data and the outcome of the most incredible real-time biomedical experiment ever (counter examples welcome). We told pharma, biotech and biomedical scientists to stop squabbling about who should get the Nobel prize, to forget their cynical price rises and come down out of their ivory towers, to take all we had learned in 300 years and rise to the greatest medical challenge of our times (sort of) and show us what they could do. They reminded us it would normally take 10 to 12 years, we said we could give them 10 to 12 months – don’t fail, tens of millions of lives and billions of livelihoods depend on you…and maybe just maybe they have achieved the impossible…has there ever been a more important or exciting set of results? And yet people are still squabbling about chloroquine and zinc!? I genuinely don’t get it. Why? It might make a small difference, but nothing compared to what we are (maybe) just about to see…. I mean those who feel that every story needs a conspiracy theory need look no further than vaccines… It being the season for a visit to Alice’s Restaurant: “I mean, I mean, I mean I’m sittin here on the Group W bench…”.

  24. micoan says:

    Is there some data about favipiravir yet?

    1. SteveM says:

      Here is a September 23 link to a limited Phase 3 trial by the Japanese version of Favipirivir (Avigan):
      https://www.precisionvaccinations.com/japans-antiviral-flu-drug-found-effective-against-covid-19-infection

      And a August 9 Phase 2 brief report (pdf) of the Russian version Avifavir:
      https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1176/5890024

      Both with positive results. The MSM seems be much more interested in reporting about new and novel compounds that happen to cost a lot more money.

      Given the scope of Covid 19 infections I think that benefit / cost considerations when evaluating alternative therapies should be much more explicit. E.g., what is the cost of the Regeneron Cocktail that President Trump has promised to everybody for “free”?

  25. KarelM says:

    The dutch news site (public radio) reports today : “Discussion on HCQ gets a new impulse”
    https://nos.nl/artikel/2351726-discussie-over-hydroxychloroquine-krijgt-nieuwe-impuls.html
    I include some fragments of their communication , translated from Dutch with ‘Google translate’

    The long-standing anti-malarial drug hydroxychloroquine (HCQ) may well have a beneficial effect on corona patients if they receive it from the first day of their hospitalization. A study in fourteen Dutch hospitals shows that patients who received the drug had a lower risk of ending up in ICU by more than half. Use of HCQ did not reduce covid-19 mortality.
    The study was led by internist-infectiologists Jolanda Lammers and Paul Groeneveld from Isala in Zwolle. Lammers and Groeneveld are convinced that the beneficial effect is a result of the early administration of HCQ. In patients receiving the related chloroquine, there was no significant effect on the number of IC admissions compared to standard care.

    Both infectiologists emphasize that their research results must be confirmed in a randomized controlled trial, a study in which comparable patients are blindly divided between a treatment group and one or more control groups. The article by the Zwolle researchers has already been peer-reviewed and assessed for value by colleagues.
    ……

    Non-preventive
    HCQ does not appear to have a preventive protective effect against the corona virus. Care workers who received preventive HCQ for eight weeks contracted covid-19 no less often than colleagues who were not treated. However, it is a study with only 125 participants.

    1. Marko says:

      The pdf of the full study ( in English ) is available here :

      https://www.sciencedirect.com/science/article/pii/S1201971220321755

  26. RGB says:

    1. In the non-US country I live in, the national health authorities did use HCQ and stopped doing so. I have a reasonable amount of confidence in both their competence and independence so I tend to think they have a solid basis for their decision.

    2. That said, I do not understand why Derek and others seem to ignor the fact that these HCQ trials do not (AFAICT) administer HCQ early. I was once given an antiviral medication, but was told that it may not do anything because it needs to be administered within the first 48 hours of the infection.

    3. Moreover, the Surgisphere fiasco is an example of the type of event that undermines public trust in Big Pharma. Yet, as far as I know, noone has suffered any consequences: not the authors of the paper using the fake data, not the Lancet editors, and not even the “Surgisphere” people themselves. Why not?

  27. Chris says:

    Every
    Single
    Advocate
    Of HCQ
    FROM THE BEGINNING
    has been adamant that to get the benefit you have to combine it with Zinc. So what do you do? You shovel out this garbage study that didn’t use Zinc. I pretty much have to believe it’s a conspiracy at this point.

    1. theasdgamer says:

      If zinc levels are adequate to begin with, zinc administration isn’t necessary. But you have to test for zinc levels in your study, which Raoult did in his later studies. RECOVERY was a joke. Toxic doses of an antiviral given after the disease had progressed past the immune response phase with no attention paid to zinc levels or vitamin D levels. (Got to pay attention to that Nature article where the researchers cultured virus from patients at various intervals to see how the disease progressed, combined with PCR tests. h/t Marik)

      Days 1-5 incubation phase…then the body responds

      Days 6-13 immune response phase…infectious viral levels are insignificant after this phase

      Days 14-28 immune hyper-response phase…this is predominantly what kills patients…cytokine storm, etc.

      It’s interesting that research shows that zinc deficiency increases cytokine levels.

      1. passionlessDrone says:

        asdgamerkid – You really seem to want to latch onto the fact that the study mentioned was for hospitalized patients, but we have RCTs on the population you think should show changes and they seem to be negative; i.e.,

        https://www.acpjournals.org/doi/10.7326/M20-4207 — given within four days of symptom onset and none of the group was hospitalized. No effects noted.

        https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1009/5872589#.XxCYlMdGoJM — non severe cases with less than five days of symptoms. No effects noted.

        https://www.nejm.org/doi/full/10.1056/NEJMoa2016638 — used after exposure for prophylaxis with high risk (i.e., someone in the house got it). No effects noted

        Do you have any thoughts why *these* studies failed to show effect?

        Also, Zev is clearly a nut job if you spend five seconds looking at his twitter page the dude is clearly off his rocker. No idea why you would put faith into anything he says on any subject.

        1. WST says:

          Your first reference:

          “With placebo, 10 hospitalizations occurred (2 non–COVID-19–related), including 1 hospitalized death. With hydroxychloroquine, 4 hospitalizations occurred plus 1 nonhospitalized death (P = 0.29).

          Limitations:
          Only 58% of participants received SARS-CoV-2 testing because of severe U.S. testing shortages.

          Conclusion:
          Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19.”

          I could be wrong but it seems that the HCQ group had 2 times less hospitalisations,does not seem to prove your point, good you did not cherry pick your studies!

        2. WST says:

          Second study show a small improvement in hospitalisation and duration in HCQ group but without statistical significance.

          Boulware study, did you read it ? It’s full of unknowns , nobody was tested, really uncertain if anything can be concluded from it.

          1. passionlessDrone says:

            @WST –

            |I could be wrong but it seems that the HCQ group had 2 times less hospitalisations,does not seem to prove your point, good you did not cherry pick your studies!

            In a further response you indicate you understand the value of statistical significance, so why not here where the p value is .2? I mean, if you’ve got a proposed mechanism by which HCL fails to show reduction in symptoms, but does show a reduction in hospitalization, that would be an interesting theory!

            For the second study, the endpoint that asdgamer seems to be so sure of, that giving this antiviral early in the game will reduce viral replication, again seems to be at odds with available evidence:

            “For the primary outcome of reduction of the viral load in nasopharyngeal swabs, there were no significant differences between the control arm and the intervention arm at day 3 or 7. ”

            So again, we have a situation wherein we observe no difference in what should be indicative of effect, you see something that looks like statistical noise and now want to talk about trends. If the trend was real, presumably based on interfering with viral replication, shouldn’t we have observed a reduction in viral load in the HCL group? What is the proposed mechanism by which we can not slow down viral replication but observe effect?

            Regarding Boulware, 20 people did have confirmed COVID via testing (see table 2). HCL group had 11 confirmed cases, placebo had 9. Both groups had a single hospitalization.

          2. WST says:

            Well, frankly all these studies are strange, first one, 20% not tested, Boulware, 20% tested, this is not serious. First two too small to get any significance for the rare phenomenon under inquiry.
            IMHO none says anything useful either way.

          3. Marko says:

            “What is the proposed mechanism by which we can not slow down viral replication but observe effect?”

            The same mechanism that explains the routine use of Hcq for RA and lupus : immune modulation ( i.e. prevention of subsequent dysregulation , aka “cytokine storm” ).

            If there is a direct antiviral effect of Hcq alone , it is clearly modest. Prescribed at the correct dosage ( lower than that used by Boulware ) , and combined with zinc , you may get the immune modulating effect as well as a more substantial direct antiviral effect. Regardless , if the immune modulating effect alone is sufficient to reduce severe disease outcomes , it’s still worth pursuing.

            Both of the first two studies you posted showed a trend towards a Hcq benefit , and the failure to achieve significance could simply reflect a too-small sample size. IOW , it was “hypothesis-generating” , and should prompt larger trials to sort out the real effect , much like the assumed, yet unproven , mortality benefit subscribed to remdesivir by Derek , above. If not for the trial-cancelling effect of the Surgisphere fraud , we might already have the answer to the Hcq question.

          4. passionlessDrone says:

            @Marko –

            > The same mechanism that explains the routine use of Hcq for RA and lupus : immune modulation ( i.e. prevention of subsequent dysregulation , aka “cytokine storm” ).

            But then we would be seeing benefit in exactly the places we *aren’t*, in hospitalized patients who are dealing with immune overload! The entire thing has been, ‘it must be given early’, ‘it works by disrupting viral replication’. But we don’t see that in the studies I referenced, we see the opposite of that.

            The term “immune modulation” is an expansive phrase, you might as well say “CNS modulating” as a reason why a drug prescribed for depression might help someone with migraines. I’d love to see if you have any references toward the notion that the cytokine storm seen in covid is in any way similar to what is seen in RA / Lupus. (?)

            > Regardless , if the immune modulating effect alone is sufficient to reduce severe disease outcomes , it’s still worth pursuing.

            But that has been pursued to death and no effects are shown; this is why asdgamer is so intent on spamming this board with the notion that it must be given *early* to have any effect; because supposedly, it is *inhibiting viral replication*.

            > IOW , it was “hypothesis-generating” , and should prompt larger trials to sort out the real effect , much like the assumed, yet unproven , mortality benefit subscribed to remdesivir by Derek , above.

            They were hypothesis generating toward these questions though:

            1) Does HCL decrease symptom severity in people when given within 5 days of symptoms. No.

            2) Does HCL decrease viral load when given within 4 days of symptoms? No.

            The recovery study referenced above and several others have consistently failed to show any effect on severe cases.

          5. Marko says:

            ” I’d love to see if you have any references toward the notion that the cytokine storm seen in covid is in any way similar to what is seen in RA / Lupus. (?) ”

            To take only one cytokine , Hcq is well known to reduce IL-6 levels , one of the primary cytokine markers that signals deterioration in Covid patients when levels increase. That’s why IL-6 blockers like toci have been used in severe cases. As far as references , do your own work There’s a million of them. Start with Wikipedia , and expand from there. Educate yourself , instead of expecting others to do it for you. Here’s one to get you started :

            Current and Future Use of Chloroquine and Hydroxychloroquine in Infectious,
            Immune, Neoplastic, and Neurological Diseases: A Mini-Review
            Article in Clinical Drug Investigation · May 2018

            “….these drugs have an antiproliferative effect on T cells [38, 39] and reduce the production
            of several pro-inflammatory cytokines, including interferon-c [40], tumor necrosis factor (TNF) [40–42], interleukin (IL)-1 [41–43], IL-6 [40, 42, 43], and IL-2 [39]. All these cytokines play a key role in the adaptive immune response. Furthermore, chloroquine has been shown to stimulate the production of nitric oxide in human endothelial cells, a putative mechanism explaining, at least partly, its antiproliferative effect [44]. Chloroquine and hydroxychloroquine also influence innate immunity. They are able to block the interaction of Toll-like receptors (TLRs) with nucleic acid ligands, reducing the innate immune activation [45]. ”

            Hcq is a mild immune suppressant ( modulator , whatever ) , which is why it’s preferred over something like methotrexate for autoimmune diseases like RA and lupus. If you can prevent subsequent immune dysregulation with early treatment , without shutting down the innate and adaptive response entirely , you might not have to try to rescue people later with drugs like dex and toci.

            Do me a favor , troll someone else.

          6. theasdgamer says:

            Drone,

            Watanabe showed significance in HC using Boulware. Have you read Watanabe’s paper?

            But, really, because of methodology, lack of clinical controls, verification, or followup, Boulware’s study is a joke.

        3. Tony M says:

          “Do you have any thoughts why *these* studies failed to show effect?”

          Open letter published on these three studies signed by statisticians, medical researchers, clinicians and other quantitative researchers.concluded:

          “Due to the importance of clinical trials in COVID-19 public decision making, we believe it is fundamental that these three studies correct their conclusions and publicize these corrections.”

          Worth a read if you have not read it!

          Source: https://drive.google.com/file/d/1NZOJ57fM0RTaHD1t_9w2iua7lUJhOgWT/view

  28. theasdgamer says:

    Derek,

    Please comment on the RECOVERY median beginning of dosing at 9 days post symptom onset and why you would expect that this is a valid trial given that viral replication is generally stopped by the patient’s immune system by day 8.

    1. Frank Wenner says:

      Possible Problem :
      http://jamanetwork.com/article.aspx?doi=10.1001/jamainternmed.2020.6319

      But: Perhaps a prophylaxis could work if the antiviral substance, which is effective in vitro, is delivered via a drug delivery system as e.g. liposomal aerosol (there are certainly already drug delivery systems that can do this). This could possibly also be tested for other antiviral drugs, e.g. ivermectin, niclosamide etc. Would sufficient antiviral bioavailability and the achievement of a sustained effective IC 50 be utopian? What could be done to slow down the elimination of the antiviral drug and to stop it falling below IC 50?

      Translated with http://www.DeepL.com/Translator (free version)

      1. theasdgamer says:

        PCR will show virus long after live virus has been eliminated. Check out “SARS-CoV-2 viral load in the upper respiratory tract of children and adults with early acute COVID-19 ”

    2. theasdgamer says:

      Correction to my previous comment. My memory said that there was no live virus after day 8. “SARS-CoV-2 viral load in the upper respiratory tract of children and adults with early acute COVID-19 ” says day 10.

  29. Flavio Abdenur says:

    The data from the HCQ outpatient randomized clinical trials show that the HCQ groups consistently did clinically better than the control groups. “Outpatient” means early treatment or prophylaxis before admission to hospital, as is practiced by Raoult’s IHU hospital in France, by Zelenko in NY, by India, by Senegal and much of Africa and so on (they do generally add azithromycin to HCQ, whereas the outpatient RCTs stick to HCQ monotherapy).

    This thread lays out the whole story, explains some of the nuances of the data, and literally draws a picture of the clinical outcomes:

    https://twitter.com/threadreaderapp/status/1314402749510021120?s=21

    1. Flavio Abdenur says:

      Link outside of Twitter:

      https://t.co/86eBmD6VTD

      Includes links to two two metanalyses of the outpatient RCT data. Both conclude that there is a ~20% relative benefit with p < 0.05

  30. Fleury says:

    It is sort of significant that in the US HCQ fanboys protest that HCQ would not work in trials without zinc, while in France, they protest that HCQ cannot work without Azithromycin.

    1. theasdgamer says:

      Actually, I think Raoult says that zinc may need supplementation.

    2. Thomas says:

      And in these times, pharma efficacy seems to be determined by popular opinion. Saves a lot on R&D!

      1. theasdgamer says:

        Your prince ain’t gonna show. He’s doing RCTs.

        Meanwhile, medical experts have tried and vouched for HC. You know, the family med physicians.

  31. Frank Wenner says:

    Possible Problem:
    http://jamanetwork.com/article.aspx?doi=10.1001/jamainternmed.2020.6319

    But: Perhaps a prophylaxis could work if the antiviral substance, which is effective in vitro, is delivered via a drug delivery system as e.g. liposomal aerosol (there are certainly already drug delivery systems that can do this). This could possibly also be tested for other antiviral drugs, e.g. ivermectin, niclosamide etc. Would sufficient antiviral bioavailability and the achievement of a sustained effective IC 50 be utopian? What could be done to slow down the elimination of the antiviral drug and to stop it falling below IC 50? I am thinking more of the biological half-life.

  32. “. . . it’s not real dramatic, either, which is what you would realistically expect from a single broad-spectrum antiviral drug.”

    Doesn’t that sound like a conclusion-jump to assert that just because any *prospective* antiviral is intended to be broad-spectrum in nature, then it should show only very limited efficacy?

    With reference to this good survey-paper style response to the state of research on broad-spectrum antivirals:

    https://www.quora.com/Why-is-there-no-broad-spectrum-antiviral-for-viruses-like-there-are-broad-spectrum-antibiotics/answer/Tirumalai-Kamala?ch=10&share=77f4e109&srid=hoHc

    A highly broad yet effective antiviral might show toxicity for being so broad, but for brief episodes of antiviral therapy the attending physician is empowered to weigh the risks and conclude that a quantified and understood level of toxicity is acceptable for treating a life-threatening viral illness.

  33. CuriousAboutAnalysis says:

    Quick question regarding mortality in the Remdesevir trial:
    When looking at table S1, we can see that there is 24% of patients in the Remdesevir group that are under mechanical ventilation at the beginning of the trial, compared to 30% in the control group. In first approximation, if we consider that patients who are in this group will make most of the deaths (not too far from reality I think), wouldn’t the fact that the randomization attributed more critically ill patients to the control arm than to the Remdesevir arm explain most of the mortality difference (11% vs 15%)? I imagine that this would be adressed in the analysis but the 11.4% and 15.2% mortality figures are pretty close to simply raw number of deaths divided by number of patients in both groups (59/541=0.109% for treatment arm and 77/521=14.7% for control arm), so I’m unsure as how you would correct for the fact that patients most at risk of dying are unevenly represented in the two groups while getting figures so close to #deaths/#patients.
    Anyone can shine a light for me on this issue? 🙂

  34. theasdgamer says:

    Some of you might not know this, but a 5 g dose of hydroxychloroquine (or chloroquine) is almost always fatal. RECOVERY administered 2.5 g in 24 hours. Gonna be harder on the women than the men because of body weight.

    Hydroxychloroquine only comes in pill form, not IV. IV medications are generally administered by hospital staff, so there is little chance it won’t be given. Not so pills.

    If patients try hydroxychloroquine, and it leads to nausea, vomiting, and diarrhea, what percent of them will start trashing the pills when the nurse leaves them at bedside?

    And some of you lot talk about pharmacodynamics, lol.

    1. c says:

      Out of curiosity, what is your explanation for the fact that, despite HCQ’s apparently very strong case for efficacy in your opinion (at least enough to post a dozen comments within a few hours, almost as many as you mustered up in defense of Trump in the last thread), no nation on Earth has successfully deployed it?

      The two explanations that come to mind are a global case of incompetency or a global conspiracy. What’s your explanation?

      1. Marko says:

        “…no nation on Earth has successfully deployed it?”

        India is one country that has used it widely , and continues to do so AFAIK. Can you say definitively that they’ve been unsuccessful ? I don’t think you can.

        Neither could one casually make the claim that they’ve been successful without the data to back it up. Simply looking at current case counts and death rates doesn’t tell you much , given the importance of factoring in multiple other variables , like the population pyramid , level of and access to medical care , nutritional status , testing coverage , etc.

        India can’t afford to treat everyone with remdesivir and MAbs , even assuming they could access the supplies. It’s hard to blame such countries for using cheap drugs like ivermectin and hydroxychloroquine given their well-known safety profiles and suggestive – though not conclusive – evidence of efficacy in selected cohorts.

        1. c says:

          So the point stands that no country has successfully deployed it, thank you.

          If it is the miracle cocktail you people claim it is, why isn’t it being used?

          1. Marko says:

            Read my comment again. You can’t say that India , for example , has been unsuccessful.

            I’m not one of the “you people” who thinks Hcq is a “miracle drug” , in fact I’m certain it’s not. I think the jury is still out as to whether it might have some utility in the high-risk outpatient population , and to what extent , if any , zinc contributes to that utility. If Hcq or Hcq plus zinc could reduce hospitalization and/or subsequent death by only 20% in a high-risk outpatient cohort , it would be a valuable intervention , and unlike any other we have for that group right now. You can be sent home with Hcq and zinc by your doc or a clinic. You’ll only get remdesivir or Mab treatment when you’re beyond that stage.

          2. Robert Clark says:

            Actually, that is incorrect. Almost all of Asia and Africa use it. And they have 1/100th the death rates of the West.

            Researchers ponder why covid-19 appears deadlier in the U.S. and Europe than in Asia.
            https://www.washingtonpost.com/wp-apps/imrs.php?src=https://arc-anglerfish-washpost-prod-washpost.s3.amazonaws.com/public/OFJZCQU7RMI6VPQGV5KRJ3QDQU.jpg
            {graphic comparison}
            https://www.washingtonpost.com/world/researchers-ponder-why-covid-appears-more-deadly-in-the-us-and-europe-than-in-asia/2020/05/26/81889d06-8a9f-11ea-9759-6d20ba0f2c0e_story.html

            The pandemic appears to have spared Africa so far. Scientists are struggling to explain why
            By Linda NordlingAug. 11, 2020 , 3:15 PM
            https://www.sciencemag.org/news/2020/08/pandemic-appears-have-spared-africa-so-far-scientists-are-struggling-explain-why

            I don’t believe it is a coincidence.

            Robert Clark

      2. theasdgamer says:

        Do nations have to “successfully deploy” HC by eliminating mortality, or does reducing mortality by 75% count as successfully deploying it?

        Morocco, Turkey, Bahrain, Qatar, all over Africa, etc. have deployed it. Many, many nations have deployed it much far lower ifr than the US.

        1. Robert Clark says:

          Exactly. Most of the public and even most doctors in the West are unaware that in Asian and African countries, COVID-19 deaths are a small fraction of those in the West.

          And in almost all those countries HCQ use is widespread either for malaria or COVID-19.

          Robert Clark

          1. theasdgamer says:

            I’m not sure why some African and Asian countries show low covid deaths. Maybe they are just not diagnosing the disease or maybe the public health isn’t up to snuff.

            South Africa has a higher death rate than most of Africa and it should be investigated as to why.

            Morocco and Turkey are two countries I would look at if you want to make that kind of case because they have actually put public health resources to work on covid.

        2. Robert Clark says:

          Theasdgamer, the case for Morocco and Turkey has already been made:

          Moroccan Scientist: Morocco’s Chloroquine Success Reveals European Failures.
          Zemmouri believes 78% of Europe’s coronavirus-related deaths could have been avoided if European states had mirrored Morocco’s chloroquine strategy.
          https://www.moroccoworldnews.com/2020/06/306587/moroccan-scientist-moroccos-chloroquine-success-reveals-european-failures/

          And:

          Coronavirus: How Turkey took control of Covid-19 emergency.
          By Orla Guerin
          BBC International Correspondent, Istanbul
          * 29 May 2020
          Turkey embraces hydroxychloroquine.
          The country has public health lessons to offer, according to acting head of the World Health Organization (WHO) in Turkey, Dr Irshad Shaikh.
          “Initially we were worried,” he told the BBC. “They were having 3,500 positive cases per day. But what has worked is testing. And they did not have to wait five or six days for results.” He also credits the quarantine, isolation and contract tracing measures but says it’s too soon to judge Turkey’s treatment protocol for patients.
          Controversially that includes the anti-malarial drug, hydroxychloroquine, as standard. It’s much touted by President Donald Trump – but has been roundly rejected by the latest international research.
          The WHO has temporarily suspended it from their trial of possible treatments for the virus. That followed research published in the Lancet which suggested hydroxychloroquine can cause cardiac problems in Covid-19 patients, and could do more harm than good.
          * Why anti-malarial drugs are proving so controversial
          We were given access to a hospital where it has been part of the standard treatment for thousands of patients. The Dr Sehit Ilhan Varank hospital, a two-year old-state hospital, is also state of the art. It’s a bright, spacious battlefront against the virus.
          Turkey has been using the drug hydroxychloroquine to treat Covid-19 patients
          Chief doctor Nurettin Yiyit – whose art work is on the hospital walls – says it’s key to use hydroxychloroquine early. “Other countries are using this drug too late,” he says, “especially the United States. We only use it at the beginning. We have no hesitation about this drug. We believe it’s effective because we get the results.”
          https://www.bbc.com/news/world-europe-52831017

          Robert Clark

  35. cynical1 says:

    Hi Derek. Thanks for your blog because it is well written and informative. Prior to COVID-19, I really enjoyed the comment section as well because there was a very well-informed audience group who made salient points.

    However, lately, I find it curious and rather annoying that you will have one or two individuals who will literally highjack the comments section evidently on some crusade to convince the world that they are smarter than you and everyone else. I was wondering if there was a way you could limit any poster to just a few comments in the comment section. If they can’t make their point(s) in those few comments, then perhaps they should start their own blog and convince the world that they need their own audience. (Or, perhaps, they could set up a TikTok account and dance and sing while they rant?) Just a suggestion but, again, thank you for your blog. I think you have earned the respect of your regular audience. They should too.

  36. TallDave says:

    stopped paying attention to HCQ studies, at this point there are enough for anyone to cherrypick what they like from the data orchard, but unfortunately we do not as yet have very many drugs than can effectively treat politics, or even reliable testing

  37. Marko says:

    Inhaled hydroxychloroquine :

    “Taiwan Liposome Gets the Go-Ahead for a Hydroxychloroquine COVID-19 Study”

    https://247wallst.com/healthcare-business/2020/10/07/taiwan-liposome-gets-the-go-ahead-for-a-hydroxychloroquine-covid-19-study/

  38. Hólmsteinn Jónasson says:

    Clinical Trial of Ivermectin Plus Doxycycline for the Treatment of Confirmed Covid-19 Infection. https://clinicaltrials.gov/ct2/show/study/NCT04523831
    Listen to Professor Thomas Borody, about possible covid cure “Ivermectin, Doxicycline and zink”, the gastroenterologist responsible for developing the first antibiotic treatment for ulcers. Part 1 https://youtu.be/PyA_FlPCWUA
    Part 2 https://youtu.be/POfIMGS2D6A

  39. Daren Austin says:

    The HCQ dose was carefully chosen to get patients to steady-state by Day 2 instead of subject to a slow accumulation. From the first HCQ trials, the prospect of in vitro viral inhibition to in vivo translation was slim at best and did not come to pass in the trial.

    “HCQ group and their use of unusually high doses of HCQ that may be acutely immunosuppressive”

    Makes little sense, given that the dexamethasone dose that another treatment arm was given most definitely WAS immunosuppressive. And as stated, tolerability was better than placebo. As monotherapy, it simply does not work.

  40. WST says:

    RECOVERY did not say anything new or unexpected; HCQ was not expected to work in the second phase of covid, which has been confirmed by yet another study.
    If an RCT found that dexamethasone did not work in the first viral phase and was actually harmful, would a conclusion be:
    ” It. Does. Not. Work. Give it up” ?

    What RECOVERY did establish though is that HCQ is safe, overdosed treatment to severely sick patients (mortality rate 25% in controls) did not significantly increase mortality.

    Is it ethical to even consider testing a drug that is not intended for nor is expected to work for patients with 25% death risk? IMHO in such situations one should only consider drugs that have a good reasons to work better than the standard treatment, an approach similar to rules for clinical research in emergency rooms.

    “None of the countries or regions where HCQ was enthusiastically adopted, with or without the addition of zinc, azithromycin or what have you have seen discernable benefits.”
    Respectfully disagree, there is simply no hard data either way. These countries (2/3 of humanity) show 4-5 times lower mortality rates, and HCQ could be one of the reasons.
    But there are some intelligent estimates , with conclusion ;
    “The treatment group has a 72.3% lower death rate”

    hcqtrial.com

    1. Robert Clark says:

      Actually, in many of those countries in Asia who adopted HCQ for treatment early on during the crisis, the death rates are 1/100th those of the West:

      https://www.washingtonpost.com/wp-apps/imrs.php?src=https://arc-anglerfish-washpost-prod-washpost.s3.amazonaws.com/public/OFJZCQU7RMI6VPQGV5KRJ3QDQU.jpg

      Robert Clark

  41. Jan Mion says:

    The main reason people cannot give it up is because they have lost their trust in science. In too many places politics have been creeping into scientific studies. And that is probably also why so many are not replicable.
    So if you know that some studies are bad some people start to pick and choose what to believe. And if they want to believe that HCQ works, they will believe it.

  42. Dan says:

    what’s interesting about this hydroxychloroquine business is the idea of a zinc ionophore suppressing viral activity. covid 19 is not the only virus this may or may not work for. it seems like a poorly understood, and crude, and potentially dangerous, way to fight a virus. but maybe it works. there seems to be something going on in the test tubes. quercetin and epigallocatechin gallate are suggested to work in a similar way to hydroxychloroquine for fighting covid. other zinc ionophores that you might not want to eat have shown promise in fighting a variety of viruses.

  43. Ogamol says:

    theasdgamer:
    The sequence is more like
    day 1-5: initial infection
    day 2-12+: patient is infectious
    split (roughly 80/20)
    if symptomatic (noticed in 2-4 days),
    day 2-4: worsening symptoms
    lethal version: catastrophe by day 6, followed by recovery through day 10, then organ failures.
    non-lethal: varies between major anoxic suffering and catastrophe by day 6, followed by recovery through days 12, with possible crises during recovery.
    if asymptomatic (unnoticed or very mild):
    often anosmia for 10-12 days, then recovery.

    So, you could have your timeline; or you could have the relatively quick 1 day infection, 1 day worsening symptoms, 2 days until crisis, 8 days of recovery, then catastrophic systems failure; or you could have the mild 2 days of onset, 12 days of loss of smell and being a spreader, then recovery; or any of the other standard or outlier results. Across the population, the stages overlap.

    1. theasdgamer says:

      Mr. O,

      Do you have a source? (I’m relying on Marik.)

    2. theasdgamer says:

      Mr. O,

      The key question is whether the virus is consistently dead by day 13 post infection. Again, I’m relying on Marik. If you can show that he’s wrong, I would appreciate it,

      1. theasdgamer says:

        The SARS-COV2 virus could not be cultured after day 8 (post symptom onset, I assume) according to the following study.

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185831/t

  44. Marko says:

    “Hard data” on remdesivir getting soft :

    https://www.ft.com/content/ee9b611f-2b4b-4572-afe1-b0b804d17a94

    “….Final analysis of the US NIH study of 1,062 patients, released last week in The New England Journal of Medicine, showed a decrease in hospital stays of about five days, from 15 to 10, but no significant mortality benefit for remdesivir.”

    1. emba says:

      What appear to be leaks from SOLIDARITY also showing no mortality benefit:
      https://www.ft.com/content/ee9b611f-2b4b-4572-afe1-b0b804d17a94

      All of this sure is difficult to reconcile for just about anyone.

      1. Marko says:

        Indeed , that is part of what I intended to convey , but the FT quote I included made it seem like I was talking about the NIH trial data. I deleted ( in error ) my statement preceding the quote that the FT was at least honest in not attributing a mortality benefit to remdesivir that is as yet unproven.

        1. emba says:

          Ah I see you had the same link, I missed it since the quote was about the NEJM study.

          1. Marko says:

            I’m glad you posted , otherwise my comment would have been confusing to anyone who followed the link. You gave me the chance to clarify.

  45. passionlessDrone says:

    @Marko –

    “Hcq is well known to reduce IL-6 levels , one of the primary cytokine markers that signals deterioration in Covid patients when levels increase.”

    But the entire thrust of my initial reply is that we keep hearing, “it has to be given early to disrupt vial replication”, and “none of the studies were given in early timeframes!”, far earlier than a cytokine storm / IL-6 would be present.

    “Educate yourself , instead of expecting others to do it for you.”

    You are the one who wants to talk about trending toward significance instead of statistical noise and why we should keep looking for new ways that we might be able to test this to see if it helps. When I ask for some rationale for why, for example, cytokine storm observed in covid is in any way similar to RA besides the presence of inflammatory cytokines, a milieu that exists in hundreds of conditions, you find a way to show me that HCL affects IL-6 and I’m told to educate myself.

    Hey, IL-6 is also found increased in migraines (coincidence?!?!?!), via immune modulation and reduction in IL6! Should we be trying cinnamon for covid? (Note: I do not work for Big Cinnamon)

    “The effect of cinnamon on migraine treatment and blood levels of CGRP and IL-6: A double-blinded randomized controlled clinical trial”

    “The serum concentrations of IL6 and NO were significantly reduced in the intervention group compared to the control group (P<0.05). However, the serum level of CGRP did not significantly change in both groups. The frequency, severity and duration of pain attacks significantly decreased in the intervention than the control group (P<0.05)."

    Yes, IL-6 is pro-inflammatory and rises in severe cases of COVID. Not a controversial statement. Yes, HCL is a mild immune modulator. Also not a controversial statement. It turns out, cinnamon is *also* a mild immune modulator with anti inflammatory properties (there are plenty of others besides what I listed). We should be exploring the use of cinnamon for covid due to it's immune modulating, anti-inflammatory effects. A dumb statement.

    There are a zillion compounds that act as immune modulators / subtle immune suppressants; if that is you rationale for HCL, as opposed to it's anti viral properties (as argued by asgamer), you are subsisting on extremely thin gruel.

    "Do me a favor , troll someone else."

    Earth to Marko: you responded to me initially.

  46. Digibom says:

    remdesivir very very good

  47. Robert Clark says:

    About the statement that countries where HCQ is used showed no benefit in combating COVID-19, actually the exact opposite is true. In both Asia and Africa where HCQ is widely used for malaria or COVID-19, they have COVID-19 death rates at 1/100th that of the West.

    So who has the better approach to combating COVID-19?

    Researchers ponder why covid-19 appears deadlier in the U.S. and Europe than in Asia.
    https://www.washingtonpost.com/wp-apps/imrs.php?src=https://arc-anglerfish-washpost-prod-washpost.s3.amazonaws.com/public/OFJZCQU7RMI6VPQGV5KRJ3QDQU.jpg
    https://www.washingtonpost.com/world/researchers-ponder-why-covid-appears-more-deadly-in-the-us-and-europe-than-in-asia/2020/05/26/81889d06-8a9f-11ea-9759-6d20ba0f2c0e_story.html

    The pandemic appears to have spared Africa so far. Scientists are struggling to explain why
    By Linda NordlingAug. 11, 2020 , 3:15 PM
    https://www.sciencemag.org/news/2020/08/pandemic-appears-have-spared-africa-so-far-scientists-are-struggling-explain-why

    Robert Clark

    1. theasdgamer says:

      South Africa and Egypt were much affected. Southern Africa has a young population.

      You can’t get valid comparisons of deaths/million for political entities at different stages of a pandemic. After the local epidemic is over, you can compare all such entities because they are at the same stage.

      There’s a similar case for cfr, but it’s easier to see trends much earlier. New York v. Utah, for example.

  48. Robert Clark says:

    RECOVERY report actually showed HCQ improved mortality specifically for invasive mechanically ventilated patients, i.e., intubated, but did not include this fact in their conclusions. The report did not give the numbers directly so we have to unwrap them from the data.

    See data in this table from the report:

    https://pbs.twimg.com/media/Ej8hDusWkAAe4u-?format=jpg

    As shown in this table, the report combined the number of intubated patients with the number of deaths, i.e., the union of the two sets. What we want though is the number of intubated patients who died, the intersection of the two sets.

    Use the formula |A ⋃ B| = |A| + |B| – |A ⋂ B|, which simply means the number in the union is found by adding the numbers in the two sets minus the number in the overlap.

    We want the number in the intersection though so we’ll turn it around to get:

    |A ⋂ B| = |A| + |B| – |A ⋃ B|

    For HCQ:
    |ventilated⋂deaths| = |ventilated| + |deaths| – |ventilated⋃deaths| = 128 + 311 – 399 = 40. So deaths on ventilator 40/128 = 0.312, 31.2%

    But for non-HCQ:
    |ventilated⋂deaths| = 225 + 574 – 705 = 94, so the rate of deaths on ventilator 94/225 = 0.417, or 41.7%.

    So for invasive mechanically ventilated patients, mortality cut on HCQ.

    From the report:

    Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.
    The RECOVERY Collaborative Group
    https://www.nejm.org/doi/full/10.1056/NEJMoa2022926

    Robert Clark

    1. theasdgamer says:

      Good work spotting the mortality decrease. Apparently the impact of HC on IL-6 DOES matter in late treatment. But RECOVERY was still supposed to provide political cover for Fauci and cause the termination of early treatment studies of HC.

  49. theasdgamer says:

    I travel to a city where there are old black men working in a hotel and they are doing fine. They don’t wear their masks properly, but so far haven’t been symptomatic for covid.

    Old black men are the group most at risk for covid mortality. These guys are taking zinc and vitamin C or D supplements. Working in the hospitality industry, they are very much exposed to covid. But they are all alive and asymptomatic.

    Older people typically have more problems with immune health, so supplementation is required. Older people are unsurprisingly more susceptible to covid.

    Older men tend to be zinc deficient, so they need to supplement zinc.

    About 40% of US adults are vitamin D deficient, and vitamin D adequacy is needed for immune health.

    People of color often avoid the sun in order to avoid getting darker. My wife is one such person. I have observed this to be the case generally. From this we should hypothesize that vitamin D deficiency may be more prevalent in people of color and they may need vitamin D supplementation.

  50. JC says:

    As always, the only barely interesting things to read in Mr. Tech Derek’s posts are the comments.

    And yes, he is living proof that you can have a nice writing style without any critical thinking skills. Always assertive, never pondering. That he still has a blog in AAAS is puzzling… or maybe not.

    Try Professor Nancy Cartwright for a glimpse of what is at stake here – both on RCT and why having a PhD in modern days equates to being a highly skilled technician rather than a full-fledged scientific researcher. Was the move from science to technoscience really worth it ?

    https://www.sciencedirect.com/science/article/pii/S0277953617307359
    +
    https://www.amazon.com/kindle-dbs/entity/author/B001IYZI7C?_encoding=UTF8&node=283155&offset=0&pageSize=12&searchAlias=stripbooks&sort=review-rank&page=1&langFilter=default#formatSelectorHeader

  51. theasdgamer says:

    The purpose of the RECOVERY and SOLIDARITY trials is to give political cover to all those who smeared HC–Fauci, et. al.

    No one ever thought that late treatment with antivirals was ever gonna work.

    There were many attacks on HC ostensibly in the name of science, but really they were aimed at poisoning the well.

    The VA “study” poisoned the well by studying late treatment. Surgisphere poisoned the well by showing increased risk based on manufactured data. The Brazil study where patients were given toxic doses of chloroquine poisoned the well by making it appear that HC was also dangerous. Boulware poisoned the well by separating benefits in order to reduce significance. Skipper poisoned the well by claiming early treatment when actually treatment was given outside of the antiviral window–to low risk participants.

    Lots of well poisoning was going on in order to smear HC and increase mortality.

    The only alternative is mass incompetence.

    Which theory do you think is more probable?

    1. David Eugene Young says:

      Well, does HCQ work late or not? Clark just said above that there was a study that showed HCQ worked late. Which is it?

      What I think is so amusing is that this all started with Didier Raoult, who make the biggest blunder in stating that it would be unethical to do a randomized clinical study. Raoult published a small observational study and got the ball rolling for Hydroxychloroquine. It is wasn’t for him……. But what is amusing is that Raoult’s observational study was in patients who were already quite sick with Covid19. Raoult made the claim that HCQ was excellent in treating advanced cases. And in March / April many people made claims about how great HCQ was in advanced Covid19. Now, when that is shown not to be true, you all claim that no antiviral is helpful for advanced cases and that made perfect sense. So why is Raoult still a hero? You are basically saying that his publication is a bunch of baloney. But it was his publication that started it all!!

  52. John Foutch says:

    Other than for HIV, I thought it was generally better to deliver antivirals early, rather than late. Lat’s take Tamiflu which is only given in the first 5 days with best benefits within the first 48 hours of symptom onset as an example. If we tried to study Tamiflu and only gave it to seriously ill hospitalized patients, would that not show Tamiflu as being ineffective? …and if our protocol was to only allow Tamiflu to be administered in a hospitalized setting (where all patients are way past 5 days of symptoms) would that not guarantee Tamiflu to be ineffective?

    I am not trying to argue or be a trouble-maker, I am genuinely curious.

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