The paper that appears to have triggered the Trump administration’s obsession with hydroxychloroquine as a treatment for infection with the novel coronavirus has received a statement of concern from the society that publishes the journal in which the work appeared.
The April 3, 2020, notice, from the International Journal of Antimicrobial Agents, states that the March 20 article, “Hydroxychloroquine and azithromycin as a treatment of Covid-19: results of an open-label non-randomized clinical trial”
does not meet the [International Society of Antimicrobial Chemotherapy’s] expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety.
The notice, which is from the ISAC and not the journal itself, is a bit ambiguous. The society says it “shares the concerns” about the paper, but it doesn’t appear to be taking additional action.
The study was led by Didier Raoult, of the University of Marseille, whose publication history has come under scrutiny.
Last month, Elisabeth Bik took a close look at the IJAA article and detailed a long list of serious problems with the study, including questions about its ethical underpinnings, messy confounding variables, missing patients, rushed and conflicted peer review, and confusing data.
Others have used PubPeer to report additional issues with the Raoult article.
Raoult has not responded to a request for comment from Retraction Watch.
Of course, the horse has left the proverbial barn on this one. An untold number of patients have been receiving hydroxychloroquine, as well as chloroquine, for Covid-19 infection, thanks in large part to cheerleading for the drugs from President Trump.
Although a certain amount of haste is to be expected in a medical crisis, and sometimes spitballing may be a viable option, the use of poorly investigated therapies is hardly risk free. In this case, not only do the drugs carry significant side effects, but they are critical treatments for people with lupus and rheumatoid arthritis — patients who now have to hope that they can still get access to medications that are keeping them alive. (Now come reports that states are hoarding hydroxychloroquine and chloroquine for precisely these people.)
In other words, although the president might be narrowly correct when he says that Covid-19 patients have “nothing to lose” by taking the drugs, the game is zero-sum.
And we are likely to see lots of “promising” but ultimately unhelpful treatments in the days and weeks ahead. As we wrote the other day in Wired:
When it comes to findings, the Covid-19 train is an express, while the rigorous science coach is a local. Until that local arrives at its final destination, it may be wise to label all this research—preprints, peer-reviewed papers, and for goodness’ sake, pronouncements from Donald Trump— with a black-box warning: “There is some evidence for this now. It will likely turn out to be at least partially wrong.”
Update, 1900 UTC, 4/12/20: Elsevier is now investigating the paper.
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This posting distorts the available evidence supporting safety and effectiveness of the hydroxychloroquine treatment. Here is the advice from a highly knowledgeable doctor who has used it for decades in his treatment of lupus ( https://detroit.cbslocal.com/video/4505709-dr-oz-asks-rheumatologist-dr-daniel-wallace-if-any-of-his-patients-with-lupus-have-contracted-covid-19/ )
So Covid19 is similar to Lupus now? Both gourds of patients are in the equitable physical state and could be used together in a control group for testing? That’s like saying apples and baseballs are both round and could be used in a pie. Super scientific thanks.
Don’t turn this into a snarky twitter argument.
The idea is to treat an overexuberant inflammatory response, that’s relevant for both cases.
That’s not at all what this article is implying. Maybe study up on Chlorquione first and understand how it affects cells and why this medication works in autoimmune diseases and why it could possibly work for Covid. Possibilities should be explored, however the science backing and safety and efficacy need to be shown first.
What “available evidence?” A Dr Oz TV interview? There is NO peer reviewed evidence of HCQ value in active nCov-2 infection. Not one.
THE KEY TO DEFEATING COVID-19 ALREADY EXISTS. WE NEED TO START USING IT – Harvey A. Risch, MD, PhD As professor of epidemiology at Yale School of Public Health, I have authored over
300 peer-reviewed publications and currently hold senior positions on the editorial boards of several leading journals. I am usually accustomed to advocating for positions within the mainstream of medicine, so have been flummoxed to find that, in the midst of a crisis, I am fighting for a treatment that the data fully support but
which, for reasons having nothing to do with a correct understanding of the science, has been pushed to the sidelines. As a result, tens of thousands of patients with COVID-19 are dying unnecessarily. Fortunately, the situation can be reversed easily and quickly.
——————————
I am referring, of course, to the medication hydroxychloroquine. When this inexpensive oral medication is given very early in the course of illness, before the virus has had time to multiply beyond control, it has shown to be highly effective, especially when given in combination with the antibiotics azithromycin or doxycycline and the nutritional supplement zinc.
——————————
On May 27, I published an article in the American Journal of Epidemiology (AJE) entitled, “Early Outpatient Treatment of Symptomatic, High-Risk COVID-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis.” That article, published in the world’s leading epidemiology journal, analyzed five studies, demonstrating clear-cut and significant benefits to treated patients, plus other very large studies that showed the medication safety.
——————————
Physicians who have been using these medications in the face of widespread skepticism have been truly heroic. They have done what the science shows is best for their patients, often at great personal risk. I myself know of two doctors who have saved the lives of hundreds of patients with these medications, but are now
fighting state medical boards to save their licenses and reputations.
——————————
READ THIS ARTICLE IN IT’S ENTIRETY AT;
https://www.newsweek.com/key-defeating-covid-19-already-exists-we-need-start-using-it-opinion-1519535?fbclid=IwAR1P6aYpdSqZh_WWuovM77tR5Oe59mdCgUxC2eH4SbCs1LzjS-rIXIEh1pE
Dr. Oz is a well-known fraud and quack, so I’d be pretty skeptical of any doctor citing appearing on his how or citing his show. He has a long, well-documented history of hocking fake cures for cash.
– https://sciencebasedmedicine.org/lies-fraud-conflicts-of-interest-and-bogus-science-the-real-dr-oz-effect/
– https://www.livescience.com/50576-dr-oz-miracle-claims.html
– https://www.thedailybeast.com/why-is-alleged-quack-dr-oz-giving-coronavirus-advice-on-the-today-show
– https://www.latimes.com/science/sciencenow/la-sci-sn-dr-oz-claims-fact-check-bmj-20141219-story.html
– https://www.healthnewsreview.org/2018/02/pulling-back-the-curtain-on-the-doctors-and-the-dr-oz-show-what-our-analysis-reveals/
So better use it given the life saving benefits against harms.
What I find most surprising is the fact that otherwise reputable periodicals of Medical Science would publish something that sounds quite dodgy in its methodology, and thus, in its results. This is not the first time something like this has happened: One cannot help but be reminded of the article in The Lancet regarding the link between the MMR Vaccine and Autism, and which, perhaps more than anything else, seems to have given the anti-vaccine movement its current driving impetus. Aren’t these papers properly peer-reviewed before being considered for publication? If they were peer-reviewed, then what is going on with the peer review process that such egregious mistakes are occurring?
Drive by political comments are becoming somewhat more common on Retraction Watch. This demeans the otherwise sterling work of RW.
Trump may well have been influenced by this paper, but the concept of quinine/related products having an antiviral effect is well known. Even the likely mechanism of action (hence the other “obsession” with Zinc) is entirely plausible and quite well established. Chloroquine and relatives appearing to be effective against SARS-Cov2 was evident many weeks before a presidential tweet.
Where are the stats for chloroquine treated lupus and RA patients referencing SARS-Cov2? Are there any positives at all in this cohort?
But it is a strange idea to explore whether people already on these Rxs have contracted Covid-19… which is being touted for its anti-inflammatory effects – which might be there – but it is NOT at all credible to imagine that it might prevent acquiring the virus!
Yes it is “credible to imagine that it might prevent acquiring the virus!” CQ and HCQ are ionophores for zinc. Zinc inhibits viral polymerases, including RNA-dependent RNA-polymerase in RNA viruses like coronavirus in addition to other polymerases. (1) https://jvi.asm.org/content/jvi/91/21/e00754-17.full.pdf (2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2973827/ (3) https://www.sciencedirect.com/science/article/abs/pii/004268227890274X (4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/
All 4 references are experiments in vitro, are there any clinical trials in COVID-19?
The global alliance of rheumatology against covid19 published on Twitter the first series of 110 reumatologi patients with covid19. Chronic treatment with hydroxychloroquine didn’t seem to exert a protective effect. 5% lethality with or without it. In addition, the global alliance recommends against hcq off label use for methodological flaws of the evidence (Kim, Ann int med)
The game is worse than zero-sum if the drugs are ineffective for treating COVID-19 but social demand for them impacts lupus sufferers
Other “experts in the field” had enough time and enough patients to test these findings, why haven’t they done so? The science is all about testing results. Please stop judging this paper and conduct your own trial, so we will all have benefits, but also elucidate this important issue!
When the paper promoting a treatment is such crap, why should its critics have to conduct their own experiments?
It certainly helps when Raoult is also the editor in chief of that journal. This was likely an easy way to bypass any serious peer review process.
He is not ! (editor in chief )
His co author of the paper was
The co-author in question also being Raoult’s subordinate. Raoult effectively controls this journal. How else would a paper get “peer reviewed” in 24 hours ?
If hydroxychloroquine plus azithromycin plus zinc had 10 to 60 percent efficacy, the use would be as or more legitimate than flu vaccines, which have a similar range of efficacy. If 0.00001 percent of people would assist in the production of these meds, instead of whining that Trump mentioned them, there would be no shortage for patients who chronically take them. I see far too much investment in perpetuating the COVID 19 fear and quarantine. Why is this?
Why not just plow ahead, even if there is little evidence that the treatment works? Mobilize people to make the drugs, give them to everyone?
Because you are asking people to risk their lives making these drugs, when they could have sat safely at home. You are asking people to risk their lives taking them as well. One patient in the treatment arm of the original study died, and several more worsened their condition, and we *just don’t know* (given that it was not randomized) whether the outcomes were better or worse than they would have been without treatment. (There is plenty of precedent for good-sounding treatments that end up being worse than nothing: just look at the history of cancer-drug trials.)
Just to give a personal example, if you gave me a big dose of azithromycin while I was already ill, you would probably kill me; I’m desperately allergic to it. Luckily I already know this, but too bad if someone finds out for the first time while ill with COVID.
The researcher could have done a proper trial and gotten information we could rely on. He chose not to. I think this is very sad. Everyone wants to find a treatment for this disease, but a treatment that actually works, please! And for that you actually have to do the science. Just wanting it to work, however badly, isn’t enough. Rhetoric about “wanting people to be afraid” isn’t helping. We need to find something that can be shown to actually work, or we may throw a lot of lives away producing and using worthless or even harmful treatments. (Again, look at the history of cancer trials.)
I want to comment on this first–>>One patient in the treatment arm of the original study died, and several more worsened their condition, and we *just don’t know* (given that it was not randomized) whether the outcomes were better or worse than they would have been without treatment.
My comment: At what stage of the disease (stage 1, 2, or 3?-pls see the 3 stage mechanism of covid-19 below) was the treatment given to the patient that died? If it was give to the patient at stage 2 or 3, then it would most likely not help and the patient would certainly die. There are different repurposed treatments being tested right now for each stage of the virus so we can collect more data. Do we have any data on the number of people that died from taking hydroxycloroquine while being treated for covid-19? Was it the hydrocholoquine or the virus that killed them? Is it possible thatthis medication didn’t work because they
they were already at stage 2 or 3 of the disease? We need to collect more scientific data.
my question for anyone (assuming you are now positive of covid-19 and there is no shortage of hydroxychloroquine to compte with lupus patients ): Would you take these repurposed covid meds that have been proven to save some people’s lives if it’s going to save your life ( although its not 100% efficacy and just deal with the minor side effects that are not deadly) or not take any meds at all and risk dying?
I believe that we should stop the virus at at Stage 1.
I think that we should investigate viral infection/symptoms more over the late stage development of ARDS. If we can stop the onset of pneumonia by detecting the early signs of covid-19, then doctors can prescribed these repurposed covid meds that have been proven to save some people’s lives right away (although they are not 100% effective, just need to make sure they don’t have deadly side effects) and patients can take them immediately to prevent themselves from getting pneumonia.
If there is a way to stop COVID-19, it will be by blocking its proteins from hijacking, suppressing, and evading humans’ cellular machinery.
https://www.theatlantic.com/science/archive/2020/04/what-coronavirus-drug-will-look-like/609661/
STAGE I: STOP THE VIRUS FROM GETTING INTO A CELL
One possible mechanism for the much-hyped HYDROCHLOROQUINE, the malaria drug Trump is fixated on, may be inhibiting this spike-activation process.
STAGE II: STOP THE VIRUS FROM REPLICATING
Replication is a relatively complicated step, which makes it a ripe target for antivirals. “There’s many, many proteins involved … there’s many potential targets,” says Melanie Ott, a virologist at the Gladstone Institutes and UCSF. For example, REMDESIVIR, an experimental antiviral that is in clinical trials for COVID-19, targets the viral protein that copies the RNA, so the genome-copying step goes awry.
Rather than directly fighting the virus, ACTEMRA is an anti-inflammatory drug that may help alleviate symptoms in COVID-19 patients. In particular, some severe cases have been marked by an overactive immune response that can damage the lungs. This testing will help answer if Actemra can help these patients. https://www.businessinsider.com/roche-actemra-coronavirus-trial-begins-enrolling-covid19-patients-2020-4
STAGE III: STOP THE IMMUNE SYSTEM FROM GOING HAYWIRE
Another way to treat COVID-19, then, is by treating the immune response, rather than the virus itself.
Drugs for quelling the immune system in these patients are now being repurposed in clinical trials for COVID-19. Randy Cron, a rheumatologist at the University of Alabama, is planning a small trial for ANAKINRA, an immunosuppressant currently approved to treat rheumatoid arthritis. Other trials are repurposing yet other drugs on the market, such as TOCILIZUMAB and RUXOLITINIB , which were originally developed for arthritis and diseases of the bone marrow, respectively. Treating a viral infection by tamping down the immune system is especially tricky to balance, because the patient still needs to clear the virus.
Please stay safe and healthy.
He Just finished an observational trial in 1060 patients.
What of this recent paper, finding great promise in Hydroxychloroquine’s ability to treat Covid-19?
https://www.unboundmedicine.com/medline/citation/32251731/Structural_and_molecular_modeling_studies_reveal_a_new_mechanism_of_action_of_chloroquine_and_hydroxychloroquine_against_SARS-CoV-2_infection.
Thank you for sharing this most interesting and detailed article. It certainly gives an abundance of chemical and biochemical information on how and why hydroxychloroquine should be efficacious in treating COVID19. I do appreciate the authors recommendation that urgent pt testing is needed.
This is a modeling study. It may provide a potential explanation if the mechanism by which hydroxychloroquine and/or chloroquine work is through blocking interaction with the ACE2 receptor, but this is far from clear to me. An in vitro study seems to suggest both drugs work at later stages – after uptake:
https://www.nature.com/articles/s41421-020-0156-0
An older paper on SARS-CoV also does not seem to support the mechanism proposed in this modeling paper, although it does find an effect on the ACE2 receptor:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/
Note in this respect that ammonium chloride has the same effect as chloroquine, which is rather difficult to explain if the active compound works by blocking receptor binding.
That article is suspect because it was the same team who did the original study which, as shown on RetractionWatch, was not a well done study.
Didn’t the freakin title of the paper give anyone a clue?
When the title of a paper proclaims that it’s reporting “results of an open-label non-randomized clinical trial” it should set the expectations. But then again, if we can use it to bash Trump . . .
Though the title makes it obvious that the article was not intended to report results of a non-blinded, non-randomized study, it should not be used to support the use of this therapy- but rather support the need of additional studies that are properly designed and peer-reviewed.. This is the quality of a paper I would expect of a third rate medical student.
The tone and slant of this article should surprise no one who has ever taken a glance at the social media pages of the author. Pretty sad.
Another research group in France, using the same dosing regimen reported in the paper of Gautret et al. on a different group of patients, found “No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection”: https://www.sciencedirect.com/science/article/pii/S0399077X20300858
Very low sample. Patients had high comorbidities.
I am surprised that the main reason for questioning the validity of the hydroxy chloroquine paper is that it has been supported by President Trump. Do you think he will be making this claim on his own? He would have been advised by the plethora of experts in this field.
I rate this as biased journalism.
Do you really believe that he has listened to the advice of experts in the field? Or just “Fox & Friends”, Dr. Oz (Mehmet Oz), and the likes?
Do you have any evidence “the main reason for questioning” is that Trump mentioned it?
From what I have noted on PubPeer, there was already quite a bit of criticism of the pre-print, well before Trump mentioned it.
Trump only listens to the experts at Fox.
Could you please take your anger and hate to Twitter.
Don’t pollute this internet board.
This article is nothing but an excuse to demean President Trump. A number of eminent physicians are also touting this therapy but only the Trump name is invoked (repeatedly) so immediately in my view this is mostly a political hack job.
BTW: “not only do the drugs carry significant side effects”…this statement (IMO) has less validity than Raoult’s paper! As clinicians we would be blessed if half the drugs we prescribe were as safe as these.
This paper did not test the patients that deteriorated – only those that improved – so not the positive result he presented in the paper. Also, a paper showed that the diabetic medication metformin + HQ or CQ was toxic to mice – 30-40% died.
https://www.biorxiv.org/content/10.1101/2020.03.31.018556v1
https://www.forbes.com/sites/victoriaforster/2020/04/05/researchers-warn-that-covid-19-treatment-touted-by-trump-may-be-toxic-when-combined-with-diabetes-drug/#3de42ea055f8
We need better science before touting the benefits of any of the potential therapeutics. Why Trump chose to so publicly tout this drug over any of the others with the same levels of unconvincing data, e.g. ACE inhibs/ARBs, remdisivir, favipiravir, kaletra, etc. is a mystery, but one suspects he just heard about it on Fox New or something. He certainly didn’t hear an endorsement from Fauci. IMO, as a real estate businessman, he just has a habit of reflexively touting overblown benefits, and ignoring detail. We should believe only about 5-10% of anything he says, especially now when he’s up against the ropes. Thanks to this publication for alerting us to the unsoundness of this source. Hoping everyone stays safe by following the best science available.
Could you please take your anger and hate to Twitter.
Don’t pollute this internet board.
Hydroxychloroquine may not be efficacious in severe infections. Gautret’s trial did not include patients with severe infections.
And since it also lacked a control group, we have no idea whether it is effective in patients with low-grade infection either.
We search for EXPLANATIONS. RCTs are completely overstated, do not explain anything, and do not deserve any special status. The goal is as many NEW , creative , improved testing as possible – all with an explanation to back it up. .Peer -review is nothing more than academicians getting n a circle and sniffing each others anuses and agreeing with the putrid scent like a pack of wild dogs. Progress is never made that way. Creativity and imagination fuel scientific progress. Medicine has a huge art component , too.
There are many articles by great scientists mentioning how RCTs failed miserably to deliver optimal treatment or flat out misled doctors. Search “Misunderstanding RCTs”. They are OVERRATED.
A much larger study by Raoult et. al.
2020-04-20: IHU Méditerranée Infection, Marseille, France: Early treatment of 1,061 COVID-19 patients with hydroxychloroquine and azithromycin (PDF)
https://www.mediterranee-infection.com/wp-content/uploads/2020/04/azithroquine_manuscript-soumis.pdf
Quotes:
BACKGROUND: Hydroxychloroquine (HCQ) and azithromycin (AZ) are promising drugs against COVID-19.
METHODS: We conducted an uncontrolled non-comparative observational study in a cohort of 1,061 infected patients treated with HCQ+AZ combination for at least three days.
RESULTS: Good clinical outcome and virological cure were obtained in 973 patients within 10 days (91.7%). Prolonged viral carriage was observed in 47 patients (4.4%) and was associated to a higher viral load at diagnosis (p < 10-2) but viral culture was negative at day 10. All but one were PCR-cleared at day 15.
A poor clinical outcome was observed for 46 patients (4.3%) and 8 died (0.75%) (74-95 years old).
Mortality was lower than in patients treated with other regimens in all Marseille public hospitals (p< 10-2). Five patients are still hospitalized (98.7% of patients cured so far). Poor clinical outcome was associated to older age (OR 1.11), initial higher severity (OR 10.05) and low HCQ serum concentration. Poor clinical and virological outcomes were associated to the use of selective beta-blocking agents and angiotensin II receptor blockers (P<0.05). No cardiac toxicity was observed.
CONCLUSION: *** Early HCQ+AZ combination is a safe and efficient treatment for COVID19. ***
— End quote —
Let’s wait and see.
At the exception of a few people like the Pr. Raoult, medical science is really just another social science.
Thanks for the demonstration.