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Comment by mhandley | Hacker News Reader

From the paper: "Interpretation: We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19."

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It's important to keep in mind the study's limitations section, too:

"Our study has several limitations. The association of decreased survival with hydroxychloroquine or chloro-quine treatment regimens should be interpreted cautiously. Due to the observational study design, we cannot exclude the possibility of unmeasured con-founding factors, although we have reassuringly noted consistency between the primary analysis and the propensity score matched analyses. Nevertheless, a cause-and-effect relationship between drug therapy and survival should not be inferred. These data do not apply to the use of any treatment regimen used in the ambulatory, out-of-hospital setting. Randomised clinical trials will be required before any conclusion can be reached regarding benefit or harm of these agents in COVID-19 patients. We also note that although we evaluated the relationship of the drug treatment regimens with the occurrence of ventricular arrhyth-mias, we did not measure QT intervals, nor did we stratify the arrhythmia pattern (such as torsade de pointes). We also did not establish if the association of increased risk of in-hospital death with use of the drug regimens is linked directly to their cardiovascular risk, nor did we conduct a drug dose-response analysis of the observed risks. Even if these limitations suggest a conservative interpretation of the findings, we believe that the absence of any observed benefit could still represent a reasonable explanation.In summary, this multinational, observational, real-world study of patients with COVID-19 requiring hospitalisation found that the use of a regimen con-taining hydroxychloroquine or chloroquine (with or without a macrolide) was associated with no evidence of benefit, but instead was associated with an increase in the risk of ventricular arrhythmias and a greater hazard for in-hospital death with COVID-19. These findings suggest that these drug regimens should not be used outside of clinical trials and urgent confirmation from randomised clinical trials is needed."

Has anyone seen good randomized clinical trials yet?

I guess that's the end of the road for hydroxychloroquine/chloroquine as a treatment for COVID-19.

Yes it's probably the end medically, but it's not the end of its use as a political wedge.

To people who believe the current political rhetoric promoting hydroxychloroquine, a study in a medical journal doesn't change anything, as their interest in it was never based its medical efficacy, but rather as a symbol used to rally around their leader and their movement. Just look at the anti-vaccination movement, which continues despite being debunked for years.

And we shouldn't so quickly dismiss this phenomenon. We underestimate the power of that kind of fictional narrative group-think to our peril. The only way to fight falsehood based narrative is truth based narrative. The dry statistical or scientifically derived truth that eggheads like most of us wish would prevail is largely powerless. Stories are what ultimately wins.

Exactly. What, you think these hucksters like Laura Ingraham are going to apologize for their dangerous bullshit (spoiler - no: https://www.thedailybeast.com/laura-ingraham-trashes-promisi... )? Of course not. Apologies are for losers, instead when the facts are against you, you just double down and demonize those who try to convince you with those facts as nefarious enemies.

Those of us who live in the world of reality need to realize the only way to fight this "demon haunted world" is to make a scarier demon, not try to fight with facts.

It's been absurd that I have people on my Twitter feed attributing the low death rate in India to India's "widespread daily use of HCQ".

31 years in India and I've never even heard of it!

Easy to explain. HCQ as treatment is questionable. Always was. Even the Chinese retracted their recommendation in End of February. But it is still recommended as prevention, and there is a Indian study confirming its suitability as prevention. That's how it always worked. India is also the sole manufacturer of it, for their malaria problem. It's still in widespread use there.

Europeans were extra stupid to try it as treatment. If you read the early original Chinese reports they always mentioned that it worked as prevention, Lupus patients had an advantage.

And those two disliked presidents always promoted its usage as prevention, not treatment. But reading is apparently a rare skill.

I suspect this was people thinking “chloroquine is a malaria drug and India has malaria, therefore it’s used in India”. Which sounds vaguely convincing at first glance, but malaria in India has been immune for decades.

Don't even get me started on the people hoarding tonic water because it has quinine in it

It goes both ways. There are studies showing it is a statistically and clinically significant treatment [1]. Whether those results are reproducible or not remains to be seen. Most of these studies you never hear about because many people on the left want Trump to be wrong or have a knee jerk reaction to anything he says. It even has a name: Trump derangement syndrome.

Irrational behavior in both directions is indefensible.

[1] https://www.medrxiv.org/content/10.1101/2020.05.02.20080036v...

[2] https://pubmed.ncbi.nlm.nih.gov/32335560/

> Irrational behavior in both directions is indefensible.

Agreed that any political side is capable of false narratives, but that's hardly what's going on here. Nobody with the fundamental desire for a treatment for themselves and those they care about should they fall severely ill would want any proven effective treatment to be dismissed for political reasons, whether that is hydroxychloroquine or anything else.

The problem is that what should have been left as an investigation into a medication with no political colors was turned into a political wedge by the US president who seemingly aspired to use it to regain relevance during this crisis.

The same thing has also happened for the various promotions of very preliminary vaccines, or of a fictional nationally deployed testing website that was claimed by POTUS to be under development by Google. This follows the basic principle guiding this administration and its leader that there is no such thing as bad publicity. And to a certain extent, they might even be right. Time will tell.

Every reference I've seen to Hydroxychloroquine in the media is quick to denounce it as a dangerous, discredited treatment. So I think this is not just irrationality on the part of the left, but an example of the gated institutional narrative suppressing ideas. Not to take away from the irrationality of blind faith in anything Trump says seen on the right.

If you look at the experts, they're still designing studies to test it, and there are some papers suggesting it does work. The jury is very much still out on this subject.

> If you look at the experts, they're still designing studies to test it, and there are some papers suggesting it does work. The jury is very much still out on this subject.

I'd like nothing more than for hydroxychloroquine to be an effective treatment, so we can end this crisis. It should continue to be explored and investigated. At the very least we might learn something new that will help with its known effective use in treating malaria or autoimmune diseases like lupus.

But it should never have been turned into a political football, and the person responsible for that is unmistakably the POTUS.

Yep, with you there. POTUS should not be making recommendations outside his field of expertise, unless he's merely quoting the experts.

Not necessarily. Some discussions[1] of potential mechanism focuses on hydroxychloroquine working as an ionophore to drive zinc into cells - so this potentially only works when given in conjunction with zinc. There are a few studies that suggest it is effective used that way. Whether those results hold up over time is an open question.

[1] (video) https://fast.wistia.net/embed/medias/td0v8taipc

The effective use is applying it 3 weeks before the infection. Not two days after. That's not enough time to fill up the cells with zinc.

Unfortunately, probably not; the general public won’t read this, and some people won’t believe it when they see news media’s take on it.

There was an article the other day that interviewed someone who’d been on long-term treatment with the drug (for lupus) they were shocked when they got covid, because they believed that the drug was a prophylactic. No reputable scientist ever claimed that, as far as I know; it was a popular myth encouraged by unscrupulous news outlets, which won’t go away just because of a study or two.

"We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2"

It may be the end of the road for hospitalized patients with heavy viral loads but, considering the fact that zinc is mentioned nowhere in the full text, it is not the end of the road for prophylaxis. Early action before hospitalization is necessary... see below.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6...

Zinc does the hard work of inhibiting viral replication; HCQ is the zinc ionophore that lights the pathway. "First used in 1967, the term ionophore refers to the molecule’s ability to bind a metal ion and facilitate its transport across cellular membranes." In order to inhibit viral replication, zinc must enter the cell... HCQ and other zinc ionophores can facilitate this.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896753/

Pasting my previous comment below with slight modifications:

Hydroxychloroquine is just one of several zinc ionophores that inhibit viral replication. "Zinc Ionophores Pyrithione Inhibits Herpes Simplex Virus Replication" https://pubmed.ncbi.nlm.nih.gov/23867132/

"... the virus replicative cycle can be divided into 10 steps (Fig. 52-1): (1) adsorption, (2) penetration, (3) uncoating, (4) early transcription, (5) early translation, (6) replication of the viral genome, (7) late transcription, (8) late translation, (9) assembly, and (10) release of new virus particles."

If using HCQ as a zinc ionophore which targets replication, "antiviral drug treatment should be started early, before irreversible tissue damage occurs. Such timely treatment is not possible without early and accurate diagnosis, which is difficult for many viral infections (such as infections of the respiratory tract)" https://www.ncbi.nlm.nih.gov/books/NBK8119/

The end of the science road perhaps, but there's still political obstacles to setting it aside. It's not obvious why Trump is pushing it so hard.

https://www.vox.com/2020/4/7/21211872/trump-coronavirus-hydr...

Does anyone know if zinc a macrolide? All the data I have seen on successful use of hydroxycholoroquine required the use of zinc along side. Also chloroquine is the drug that causes heart issues not hydroxychloroquine. The two are different. If zinc is not a `macrolide` I wouldn’t give this paper much credit as they didn’t test the treatment properly.

Edit: Wow, how the HN community has fallen. Downvoting a simple, honest question into oblivion.

I’d suggest it’s the other way around and those that suggest Zinc is important need to actually demonstrate that. I’d also suggest a dose of humility if you’re promoting it particularly if you aren’t able to quickly find out what a macrolide is and whether Zinc would be one.

"Results: The addition of zinc sulfate did not impact the length of hospitalization, duration of ventilation, or ICU duration. In univariate analyses, zinc sulfate increased the frequency of patients being discharged home, and decreased the need for ventilation, admission to the ICU, and mortality or transfer to hospice for patients who were never admitted to the ICU"

HCQ is an enabler; zinc does the heavy lifting but only if administered early.

See my other comment downvoted to oblivion below.

https://www.medrxiv.org/content/10.1101/2020.05.02.20080036v...

Your precious study is full of holes:

https://twitter.com/JamesTodaroMD/status/1266108861259210753...

Admit you were wrong.

Effectiveness of Zinc against RNA viruses is demonstrated multiple times already. For example: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2973827/

Well that one is in vitro so still needs to be demonstrated in humans. Also what relevance does it have to the efficacy of the treatments attempted in the study?

Recent Indian studies did that.

https://www.thelancet.com/journals/laninf/article/PIIS1473-3... is an overview of the counter criticism on it, with a link to the study.

I am programmer not a medical professional, how do you expect me to find that out for myself? Not sure how ask a simple question about something I am not an expert at means I need more humility. Nice projection though.

> If zinc is not a `macrolide` I wouldn’t give this paper much credit as they didn’t test the treatment properly.

A computer programmer suggesting a medical study shouldn't be given much credit based on a question they self-admittedly don't understand is pretty far from my definition of humility.

"Asking a simple question" is different from "asking a question and supplying your own assumed answer and throwing the whole thing out as a result."

It’s not the question that requires humility (although tbf this is a pretty easily Googlable one if you combine it with a high school level of chemistry) but the conclusion you drew that the study “doesn’t deserve much credit” as you baselessly claim Zinc is important.

I based my conclusion to not give the study much credit because it didn’t involve the inclusion of zinc or use of the therapy as a prophylactic. Which, from my understanding, is the actual claim that started the HCQ discussion in the first place. I am sure this paper is accurate in regards to the data they did look at. I am just saying I think it is the wrong data to look at to answer this question.

Just because the study doesn't answer the questions you want doesn't mean its without credit.

Exactly, you aren't a medical professional and you don't have the skills or knowledge to be evaluating the soundness of this journal article (for that matter neither do I), yet you said this:

> If zinc is not a `macrolide` I wouldn’t give this paper much credit as they didn’t test the treatment properly.

wow, ok. I never said that zinc and HCQ works or should be taken by anyone. I wouldn’t risk it myself. I also never said anything about the technical soundness of the journal. I was simply saying the HCQ+zinc was the treatment that first gained anecdotal notoriety. It doesn’t take a medical professional tp understand that in order for an experiment to be useful it should test the exact actual treatment that had anecdotal success.

Zinc is part of the theory of how HCQ is supposed to work. Medical practitioners are generally aware of this, and most of them were giving HCQ with zinc.

This isn’t an experiment it’s a survey of clinical outcomes from 671 hospitals across six continents where patients were given one of the treatments looked at within 48 hours of diagnosis. Also anecdote is not a sound way to conduct medicine.

@mehelevetyone I realize the study wasn’t an experiment in and of itself. The data they looked at though represented what essentially were experiments on real patients. It is a distinction without a difference so I see you’re more concerned with nitpicky details like this because you don’t have an actual response to my points.

Also where did I claim anecdote was a good way to conduct medical research? I did not. Anecdotal evidence is a completely valid source to find ideas that might be worth trying and testing with actual research.

Right but until this actual research surfaces I wouldn't be too concerned about the anecdote particularly when the data from actual research shows two out of three parts of the suggested treatment to be actively harmful.

I don't need any answer your points because you've not given any evidence to suggest they should be taken seriously versus the evidence that two-thirds of the treatment you suggest is still quite harmful.

@CydeWeys I never claimed to be an expert. I am human trying to survive on this planet like everyone else. I take in as much information as I can, with an open mind, and make the best choices I am able to.

Are you suggesting I should trust everything the government, media, or scientists says whole cloth simply because I am not an expert? Sorry, that is not how I operate or ever will operate. I take information on all sides of every topic seriously and come to the best conclusion I can for myself and I share what I’ve seen and learned with others.

If you don’t like that move to China and enjoy the CCP.

I totally agree with what you are saying here. It's funny how people who push science so hard also tell you to trust authority for anything you don't understand.

If you were an alien on another planet, would you blindly trust the local populace about things you did not understand? If not, why does that suddenly change when you are your own planet among your own people?

If you can't understand the logic of a solution posed to you, then logically you must not accept it as absolute fact.

Macrolides are just a family of antibiotics that includes azithromycin and a few others. Z-Pak is one.

to be fair, the answer to your query is trivially findable:

https://en.wikipedia.org/wiki/Macrolide

To be fair, I am not a medical expert so most things on that page are foreign to me.

Macrolides appear to be antibiotics like the azithromycin part of the very well-known trio HCQ + azithromycin "ZPac" + zinc. People have been discussing this trio for two or three full months now and there is no excuse for these scientists not to be aware of that. Even President Trump's famous statement a few days ago that he is taking HCQ mentions all three together. From their paper, these scientists appear to be skilled, but at the same time they are either disastrously ignorant of the space they are researching, or this paper is yet another propaganda job trying to convince people that HCQ is ineffective in any regimen (which maybe it is, but this paper does not show that).

Hydroxychloroquine is a zinc ionophore. It provides an ion channel that permits zinc to enter the cell and inhibit viral replication. In order to be effective, the zinc + ionophore antiviral should be administered early. Hospitalized ICU patients on ventilators are far from ideal candidates. Chinese (successful) studies used Zinc and Hydroxychloroquine; never Hydroxychloroquine without zinc.

Improving the efficacy of Chloroquine and Hydroxychloroquine against SARS-CoV-2 may require Zinc additives - A better synergy for future COVID-19 clinical trials https://digitalcommons.mtu.edu/michigantech-p/1795/

Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2973827/

Does Zinc Supplementation Enhance the Clinical Efficacy of Chloroquine/Hydroxychloroquine to Win Todays Battle Against COVID-19? https://www.preprints.org/manuscript/202004.0124/v1]

https://en.wikipedia.org/wiki/Ionophore Zinc ionophores have been shown to inhibit replication of various viruses in vitro:

Coxsackievirus

Equine viral arteritis

Hepatitis C virus

Herpes simplex virus

Human coronavirus

Human Immunodeficiency Virus

Mengovirus

MERS coronavirus

Rhinovirus

SARS coronavirus

Zika virus

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