Hacker News

104 Comments:
Cantbekhan said 2 months ago:

Nobody seems to be talking about the actual reason Chinese doctors found chloroquine (and HCQ) interesting and it has nothing to do with it's immunosuppressing effect:

1) Chloroquine (and HCQ) is a zinc ionophore: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/

2) Zinc seems to inhibit RNA polymerase of Coronaviruses in vitro https://www.researchgate.net/publication/47794995_Zn_Inhibit...

Their conclusion was that chloroquine could indeed allow zinc to enter the cell and then inhibit replication (and therefore that the treatment needed to be administered early).

Nobody seems to be talking about a very easy way to verify chloroquine (and HCQ) efficiency by just using the same method used in China:

Cross-check the list of patients infected with Lupus (lupus erythematosus) and with chronic HCQ treatment (they take it for years) with the list of known infected COVID19 patients.

In China (and specifically in Wuhan), this is how they (team of Dr Zhang Zhan) found out about the efficiency of HCQ. They noticed that there were no patients with chronic HCQ treatment for lupus (lupus erythematosus) infected with covid19. This was in peoples Hospital of Wuhan University (source: https://www.jqknews.com/news/388543-The_novel_coronavirus_pn...)

This alone would be enough to prove some efficiency even as prophyalxis (as they are advocating officially in India). This should be quite trivial to check with the current amount of confirmed infection.

These details were all explained in this medcram vid: https://www.youtube.com/watch?v=Eeh054-Hx1U

said 2 months ago:
[deleted]
nradov said 2 months ago:

In principle that would be a great thing to check but due to lack of clinical systems interoperability it's not at all trivial to check. Surescripts and the various pharmacy chains have data on who has been taking chloroquine but researchers will still have to get access, and then do a bunch of record linkage work to compare outcomes. In the hardest hit areas I suspect healthcare providers have also fallen behind on data entry so there's going to be a data quality problem.

Cantbekhan said 2 months ago:

Yes ... And it seems this issue is a global one. We seem to have the ability to put half the world in lockdowns but we don't have ability to crosscheck a bunch of different patient databases that could already contain the answer to this whole HCQ debate.

viggity said 2 months ago:

Korea has released all of their data and I think this is possible to cross check

https://hira-covid19.net/

Cantbekhan said 2 months ago:

It's not open registration tho ... I tried and it needs "admin confirmation" and I'm not sure the data is in English which would make this rather "complicated" for a non-Korean.

I'm also not sure they'll give out all patient detailed history but we'll see...

ruggi said 2 months ago:

An interesting hint could come from this pre-print study: https://www.biorxiv.org/content/10.1101/2020.03.29.014407v1 They tried different administration modalities of HCQ to in-vitro infected cells: some cells got nothing (control), some got HCQ only before infection, some got HCQ only after infection, some got HCQ both before and after infection. THe cells that got HCQ only before or only after infection had just slightly better outcome than control (they appear as heavily infected), while cells that received HCQ both before and after contagion were in much healthier conditions. If that would be the same in vivo as in vitro, that would entail that it would be possible to use HCQ as prophylaxis, given that the patients never stop taking the drug. Of course the caveat is "IF that would be the same in vivo as in vitro", that they didn't (yet) tested.

majormajor said 2 months ago:

> Their conclusion was that chloroquine could indeed allow zinc to enter the cell and then inhibit replication (and therefore that the treatment needed to be administered early).

Where does the "if it inhibits replication it needs to be administered early" line come from? I've seen it elsewhere too, but why wouldn't inhibit replication lead to => continually declining amounts in the body => easier recovery at any stage?

Cantbekhan said 2 months ago:

Because they didn't intend to use chloroquine as a way to reduce the immune response to cytokine storms.

They intended to use it to prevent virus replication in the cells at the early stages of the immune response to allow the immune system to build up a response at a slower pace.

The amount of treatment proposed in Europe is around 5 days of HCQ with about 800mg on D1 and then 400mg on D2-5. This is an incredibly low dosage and will have very little immunosuppressant effect. It takes a very long time to act as an efficient immunosuppressant (1 to 3 months for Lupus).

Expecting HCQ to suppress the immune system for cytokine storms in a matter of hours seems very strange.

As that controversial French doctor said in multiple interviews. If you are already in need of a respirator then your issue is no longer the virus but your own immune system killing you (cytokine storm or added bacterial pneumonia). At that stage, HCQ is not very useful. Not in these dosages at least.

Most people are only focusing on the immunosuppressing effect of HCQ for some reason which is very strange to me.

It takes time for chloroquine to act as a zinc ionophore as well and for zinc to enter the cells (and it needs to be in the cells to inhibit RNA polymerase). As you can see in the studies I posted. Between 24 and 72 hours it seems.

If the virus cannot replicate correctly (with the zinc idea), it might give more time to "flatten the curve" for the immune system. To build up antibodies and respond to the disease without inducing a cytokine storm.

This at least is their hypothesis. And it has not been confirmed in any other way than by observing that those with chronic Lupus+HCQ treatment seemed to be "immune" to the disease. And this was only done in Wuhan as far as I know.

Unfortunately Dr Zhan Zhang has not yet published his full results except for this preliminary https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v...

Which doesn't go into much detail about anything except that "it seems to work". Unfortunately ... Yet I do see logic in the idea.

I just wish people (with access to patient files in major hospital centers) would also look into this and they could maybe confirm this "once and for all" without even needing a full blown trial.

touisteur said 2 months ago:

Do we know of any case of severe covid-19 that was taking immunosuppresors (post-transplant, so cyclosporine or tacrolimus?). Haven't heard of one and the doctors my wife talks to (who follow hundreds of those) haven't heard of one. Yet.

touisteur said 2 months ago:

Correction, sorry, seems we have (in France) over a 100 adult hospitalized patients infected, that are post renal transplant (less than 5 years post transplant it seems). Not heard of liver transplant cases, or even child transplant cases (even more fragile).

contravariant said 2 months ago:

I'm in no way qualified to explain this, but going by kurtzgezagt's explanation[1] the main cause of damage isn't the virus replicating itself but rather the severe reaction of the immune system, which isn't directly proportional to the amount of viruses (although it does eventually go down in the absence of viruses). When you're too late with administering then the immune system has already done most of its work in destroying the virus (as well as the surrounding tissue) and it takes a while for things to go back to normal, if things go well.

[1]: https://www.youtube.com/watch?v=BtN-goy9VOY

AstralStorm said 2 months ago:

It's both. Viral replication gets the immune system into NK and T cell mediated killing mood, destroying even more of the remaining lungs and causing all results of cytokine storm.

Reducing viral replication would also stop the storm (with some delay).

Apparently these drugs are not especially effective at it.

giardini said 2 months ago:

Yes, reducing viral replication at any time would make recovery easier.

But if the virus replicates sufficiently before chloroquine + zinc is administered then much damage is already done.

So it's a race between the virus and the "cure". Get the "cure" in quickly and the virus stops replication before much harm occurs; get the "cure" in late and the virus has run most of its course and maximal damage is done.

Also, since the viral damage opens the door to opportunistic bacterial infections (e.g., pneumonia), antibiotics may be given to prevent bacteria from taking hold.

Cantbekhan said 2 months ago:

Which might be the reason some countries such as India decided to advise HCQ as prophylaxis for healthcare personnel, Source: https://www.mohfw.gov.in/pdf/AdvisoryontheuseofHydroxychloro...

3fe9a03ccd14ca5 said 2 months ago:

We should be doing the same here as well. Unfortunate HCQ has suddenly become some political casualty in our hyper polarized world.

OniBait said 2 months ago:

Nobody is going to point out that of the 11 patients, "8 had significant comorbidities associated with poor outcomes (obesity: 2; solid cancer: 3; hematological cancer: 2; HIV-infection: 1)"?

I don't even understand what the point of this study was except as a rebuttal to the prior study. I mean, if people thought the prior study was cherry picking results. I don't even know what I'd call this...

There's _some_ anecdotal evidence that it _may_ work if treated early. Hopefully there are some real studies that are being done on that.

raphlinus said 2 months ago:

A really excellent review, published today, of the current state of knowledge on HCQ: https://blogs.sciencemag.org/pipeline/archives/2020/04/06/hy...

Note this is by Derek Lowe of "Things I won't work with" fame, an extremely informative series about entertainingly dangerous chemicals.

And here's a new piece of candy for people who want to get their hopes up about a promising treatment: https://stm.sciencemag.org/content/early/2020/04/03/scitrans...

(h/t Helen Branswell of STAT news, who is very much worth following, who retweeted Timothy Sheahan)

dang said 2 months ago:

That review article was posted at https://news.ycombinator.com/item?id=22794850. We'll put it in the second-chance pool (https://news.ycombinator.com/item?id=11662380), so it will get a random placement on HN's front page. Thanks!

robocat said 2 months ago:

> a promising treatment https://stm.sciencemag.org/content/early/2020/04/03/scitrans...

That is frightening. Increasing the mutation rate must carry a large unknown risk. Also surely the first thing to mutate will be self-defeating resistance to that drug...

raphlinus said 2 months ago:

The thought occurred to me as well, I got a strong sense of "playing with fire." However, viruses have a very high mutation rate as it is [1], so I'm not sure how much difference it makes.

Btw, one of the best markers for overconfident but uninformed analysis is overinterpreting the fact that we have all these strains of SARS-CoV-2 as suggesting they have different degrees of infectiousness or health impacts. Certainly the different flu strains do, and, thanks to fine-grained sequencing efforts (Nextstrain in particular is doing awesome work) we can see lots of strains of this one, but Trevor Bedford has estimated that we have about a year or more before the variation in strains has an impact other than being able to "fingerprint" the chains of transmission.

[1]: https://jvi.asm.org/content/92/14/e01031-17

robocat said 2 months ago:

Here is a paper which suggests they found a different strain: https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....

“In this report we describe the first major evolutionary event of the SARS-CoV-2 virus following its emergence into the human population. Although the biological consequences of this deletion remain unknown, the alteration of the N gene transcription would suggest this may have an impact on virus phenotype.“

However they don’t speculate on whether that strain is more likely to spread (it clearly is a viable mutation).

robocat said 2 months ago:

I would have thought any variation that has a significantly increased transmission rate should dominate within time.

Detecting small differences in effects between different genetic variants of the virus would require large statistical populations, and wide testing for the different genetic variants.

Without that, Trevor is only making an educated guess?

raphlinus said 2 months ago:

I'm not qualified to say either way, but here's the relevant thread: https://twitter.com/trvrb/status/1244750382338719745

Also, for people who don't know, Trevor is arguably the single most expert person in the world to weigh in on this.

And here's the specific thread where he predicts it will take a few years for the virus to mutate enough to significantly hinder a vaccine: https://twitter.com/trvrb/status/1242628550563250176

robocat said 2 months ago:

Awesome thanks. Trevor Bedford‘s key comments:

“There have been only 11 mutations to proteins that are widely distributed. These are potentially functionally distinct variants that deserve attention and experimental and clinical follow up. But my expectation would be most have ‘little effect’ without further data“.

“in terms of immunity, there is a single widely circulating mutation in spike protein (D614G). Spike is present on the surface of the virus and is what the immune system sees“

“If you follow a transmission chain in which one person with flu infects another person and they infect another person and so on, you'll find that the virus mutates about once every 10 days across its genome. Almost all of these mutations will have little to no effect on virus function. Evolution weeds out the mutations that ‘break’ the virus and mutations that make a virus replicate better are extremely rare.”

The effects of the OP drug increasing the mutation rate would need to be modelled to understand risks.

said 2 months ago:
[deleted]
perl4ever said 2 months ago:

I have no medical expertise, but there's something that is confusing me. From what I read, typically, you get the virus, then an opportunistic bacterium gives you pneumonia, and that's what you die from. But this study seems to be saying "someone else found these meds reduced the virus and we didn't". But the meds are more or less antibiotics, aren't they? So could the explanation simply be that while the virus is the same, the bacteria are not, in the two tests?

Gibbon1 said 2 months ago:

My understanding is what you said is true for influenza and to a lesser extent colds. Those virus tend infect the upper respiratory system. COVID19 though can infect the lower lungs and directly causes pneumonia. And viral pneumonia is no joke even before COVID19.

jfnixon said 2 months ago:

Some antibacterials have antiviral properties.

https://erj.ersjournals.com/content/36/3/646

sunsu said 2 months ago:

By the time it's severe, it's often too late: https://twitter.com/yishan/status/1244717172871409666?s=20

said 2 months ago:
[deleted]
uncoder0 said 2 months ago:

I am not in any way qualified in the medical domain but these methods look similar to the other Study that was viewed as flawed that showed it did work. Seems there is no solid data either way.

archgoon said 2 months ago:

Which, in itself, is probably a valuable take-away.

malpighien said 2 months ago:

Well this one seems more rigorous. They monitored concentration in blood for 4 days, they checked viral presence two following days at the end. They don't mention viral load though and I don't know if they have a threshold for cycles in QPCR to estimate that. This kind of paper is not here to say here is the proof it works or it does not work, it is meant to say: this what we had with us, this how we did it, this is the results we observed and whether or not it validates the hypothesis stated.

arrrg said 2 months ago:

These studies tell me mostly that if there is an effect it’s probably not a large one.

podgaj said 2 months ago:

If the patients have a zinc deficient they can make all the zinc channels they want, it won't matter.

It is one thing to inhibit the virus, but zinc is needed to reduce the over active immune response,

webmobdev said 2 months ago:

Wonder when the Indian Council of Medical Research will release more papers - there were a few patients who responded positively under their suggested treatment plan:

> “We used a combo of Lopinavir and Ritonavir drugs which are usually given as a second line of treatment for HIV with drugs meant for curing malaria and swine flu. We administered this line of treatment to a 70-year-old Italian woman, who had come as a tourist to Rajasthan, who tested positive and was being treated by us, as well as another Italian, who is 69-year-old,” said Dr Sudhir Bhandari.

> ... “The team of doctors under the leadership of Dr Sudhir Bhandari, Principal of SMS Medical College held consultations with the ICMR and tried a combination medicines given for malaria, swine flu (Tamiflu) along with drugs for HIV and it worked well. All three persons including the Italians were cured this way,” said Rohit Kumar Singh, additional chief secretary, health of Rajasthan government.

Source: https://www.nationalheraldindia.com/india/three-coronavirus-...

> ... The three persons who tested positive were administered a combination of 200mg Lopinavir and 50 mg of Ritonavir twice a day besides Oseltamivir and Chloroquine that are given to the swine flu and malaria patients.

> However, the doctors at the SMS Hospital warned that this was only an emergency treatment and the HIV medicines were used only as an emergency measure that could help in regaining normalcy.

Source: https://www.nationalheraldindia.com/india/covid-19-magic-med...

webmobdev said 2 months ago:

Update: The Indian Council of Medical Research has also given the go ahead to try out plasma therapy for the really serious, and some hospitals and institute are waiting for clearance of the same from the Drug Controller General of India:

> ... Blood for the plasma therapy will be collected from recovered patients at SCTIMST and the medical colleges and donated to critical patients with sanction from Blood Transfusion Council. Plasma would be separated from blood and taken to other hospitals under refrigeration.

> ... When a person suffers from COVID-19, antibodies are created in his or her body as defence. Such B lymphocytes would be present in plasma. After a patient recovers from the disease, these antibodies remain in blood to prevent another attack by the virus. The plasma collected from such people and given to another patient would have antibodies which target the virus and prevent the recipient from slipping into a more serious condition. According to researches, plasma taken from one donor would have sufficient doses for two patients.

Source: https://english.manoramaonline.com/news/kerala/2020/04/09/ke...

ruggi said 2 months ago:

An in-vitro pre-print study ( https://www.biorxiv.org/content/10.1101/2020.03.29.014407v1 ) showed that administering Hydroxychloroquine only after Covid-19 infection is not helping much, while administering it both before the infection and after the infection gives great outcomes. They tried different administration modalities of HCQ to in-vitro infected cells: some cells got nothing (control), some got HCQ only before infection, some got HCQ only after infection, some got HCQ both before and after infection. THe cells that got HCQ only before or only after infection had just slightly better outcome than control (they appear as heavily infected), while cells that received HCQ both before and after contagion were in much healthier conditions. If that would be the same in vivo as in vitro, that would entail that it would be possible to use HCQ as prophylaxis, given that the patients never stop taking the drug. Of course the caveat is "IF that would be the same in vivo as in vitro", that they didn't (yet) tested.

rpiguy said 2 months ago:

COVID-19 attacks hemoglobin and that is how it damages the lungs. With your hemoglobin unable to exchange oxygen with blood in the lungs, it causes terrible damage.

https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surf...

Chloroquine prevents the virus from affecting hemoglobin, or reduces the effect. This is also how Chloroquine treats malaria.

The problem with a study on severe cases is that the damage is already done and the hemoglobin is already compromised.

It is best to start treatment with chloroquine prior to reaching the severe stage. By the time you are severe you’ve gotten permanent lung damage and the immune system is in a race condition unable to keep up with the virus.

If you want to detour into tinfoil hat territory, you could posit that these studies on severe patients were designed knowing it would show low or no efficacy, because it’s too late to protect the patient’s hemoglobin.

Azithromycin slows ribosonal RNA replication in bacteria. It is unclear how it helps with a Covid.

Antivirals are much more promising for severe cases, but even they can’t heal ground glass in the lungs.

praeter said 2 months ago:

COVID-19 is not a normal respiratory infection. It seems to prevent your RBCs from holding onto O2 and CO2 mimicking high altitude sickness. The disease acts like HAPE (high altitude pulmonary edema). The damage and inflammation is coming from the blood's inability to properly perform gas exchange in the lungs. Other damage could actually be coming from ventilators with pressure set too high (lungs of patients are mechanically normal, atypical for ARDS). Patient oxygen stats are also weird, they're hypoxic, but not necessarily short of breath.

https://vimeo.com/402537849

https://twitter.com/EricLeeMD/status/1245054768185303041?s=1...

https://twitter.com/cameronks/status/1243582723945566208?s=1...

https://www.cureus.com/articles/29004-acetazolamide-nifedipi...

jo6gwb said 2 months ago:

Thank you for posting this - some of the other comments didn't quite capture it. See the twitter of Cameron Kyle-Sidell who is working at Maimonides Hospital in Brooklyn for additional info. https://twitter.com/cameronks/status/1246765252307533825 https://www.medscape.com/viewarticle/928156

KaiserPro said 2 months ago:

> Chloroquine prevents the virus from affecting hemoglobin

This virus attacks the cells that live in the throat and lungs. The "spike" as far as I'm aware does not attach to haemoglobin.

> damage is already done and the hemoglobin is already compromised.

Its the lungs that are damaged, not the blood. The reason why people die is because they drown in thier own fluids, as the cells walls of the lungs are broken down by the patient's immune system.

If Chloroquine was effective, it would stop the virus reproducing. This would lead to a detectable change in viral load.

Sure, it could already be to late by then, the damage is done. But, the viral load would have a measurable change. These studies don't really show anything conclusive.

This means that its unlikley to work as a prophylactic as its not actually stopping the virus from attaching or reproducing.

> Azithromycin

Thats there to stop any opportunistic bacteria from causing more damage. Typically when someone is admitted to ICU for covid they have a lower than expected white cell count.

> Antivirals are much more promising

yes because they actually disrupt the virus replicating. Chloroquine doesn't appear to do that. This is the problem with making drugs. Something that works in the petridish doesn't always work in the body. This is why Gilead's new wonder drug wasn't in production, because it was designed to target ebola, but didn't really work.

Threeve303 said 2 months ago:

> as the cells walls of the lungs are broken down by the patient's immune system

If there is actually a real statistical anomaly that Lupus and other immune comprised people are less susceptible to certain parts of the virus, perhaps it's not the medication they take at all. It could simply be that someone who is immune compromised would not have as strong as a reaction as a healthy person and then may actually survive as a result. Less fluid, etc. Also, I am in no way qualified medically, it's just a quarantine showerthought.

KaiserPro said 2 months ago:

I have heard of two patients in london who were immuno compromised and recovered quicker than a "normal" person.

The real damage occurs when the immune system ramps up to attack the virus, but ends up attacking the cells they are living in as well. Now, most of the time this is fine an normal, but it can also trigger https://en.wikipedia.org/wiki/Cytokine_release_syndrome which is a nasty feedback loop.

There are experiments to give immuno-suppressants at key times to try and limit the damage. But its tricky and dangerous.

rpiguy said 2 months ago:

COVID-19 is not a normal respiratory infection. It seems to prevent your RBCs from holding onto O2 and CO2 mimicking high altitude sickness. The disease acts like HAPE (high altitude pulmonary edema). The damage and inflammation is coming from the blood's inability to properly perform gas exchange in the lungs. Other damage could actually be coming from ventilators with pressure set too high (lungs of patients are mechanically normal, atypical for ARDS). Patient oxygen stats are also weird, they're hypoxic, but not necessarily short of breath. https://vimeo.com/402537849 https://twitter.com/EricLeeMD/status/1245054768185303041?s=1.... https://twitter.com/cameronks/status/1243582723945566208?s=1.... https://www.cureus.com/articles/29004-acetazolamide-nifedipi....

tonfa said 2 months ago:

> If you want to detour into tinfoil hat territory, you could posit that these studies on severe patients were designed knowing it would show low or no efficacy, because it’s too late to protect the patient’s hemoglobin.

I would think it is still useful because from what I've read, this protocol is often used for severe cases at the moment, so it's useful to know if it has no impact.

rpiguy said 2 months ago:

Very true. It does make sense to look at those in the most dire need first. That did not occur to me.

nodamage said 2 months ago:

Isn't that paper highly theoretical at this point since it's based on computer simulations? Are there any studies on actual humans confirming the virus's effect on hemoglobin?

nradov said 2 months ago:

If that hypothesis correct then we should be able to test it with blood transfusions, or possibly hyperbaric oxygen therapy (HBOT). HBOT can be used to treat patients with severe carbon monoxide poisoning. Even though their hemoglobin is unavailable, enough oxygen dissolves into the blood to prevent ischemia.

KaiserPro said 2 months ago:

That only works if the lungs are viable. In this case they are so damaged they just fill up with fluid. Thats the issue.

effectively the patients drown. Its not like CO poisoning at all.

podgaj said 2 months ago:

"COVID-19 attacks hemoglobin and that is how it damages the lungs."

COVID-19 is not the virus, it is a disease cause by SARS-CoV-2.

And no, SARS2 does not "attack hemoglobin". The lungs are filled with fluid from an overly zealous cytokine response and the bacterial infections that follow.

ricardobeat said 2 months ago:

See this comment, with sources: https://news.ycombinator.com/item?id=22798543

gmaster1440 said 2 months ago:

Azithromycin helps with pneumonia which is a common progression of covid.

stevespang said 2 months ago:

Totally agreed.

deadmetheny said 2 months ago:

There's literally no proof of this. It's based on a paper that's purely untested conjecture and hypothesis right now.

sdiq said 2 months ago:

https://abc7news.com/amp/coronavirus-drug-covid-19-malaria-h...

Not a study but just another anecdote. Using zinc this time round rather than azithromycin.

snapetom said 2 months ago:

Yeah, I don't know what's the point of these studies that don't look at HCQ+zinc when the hypothesis is that HCQ promotes zinc absorption.

pengaru said 2 months ago:

Isn't there always going to be some ambient zinc available even without additional supplementing?

I imagine there'd be some evidence of efficacy regardless, but this is nowhere near my area of expertise.

HarryHirsch said 2 months ago:

The hypothesis is that hydroxychloroquin interferes with glycosylation of cell surface proteins that are essential for entry of the virus into the cell. The zinc notion is total bunk, intracellular zinc concentration is tightly controlled. Random zinc excursions just don't happen, if they did they would result in death.

podgaj said 2 months ago:

This is so wrong I do not know where to start.

ADAM17 is responsible for shedding of ACE2 from the cell which creates soluble ACE2. If ACE2 is not ON the cell the virus cannot infect the cell.

ADAM17, like ACE2 is a zinc finger protein and uses zinc as a cofactor.

Also, zinc is widely understood to lower the immune response by affecting interferon levels.

It is not only about intracellular zinc. But in a deficiency intracellular zinc has even less chance of being brought into the cell, right?

To say that zinc does not matter because hydroxychloroquin is absurd.

giardini said 2 months ago:

HarryHirsch says "The zinc notion is total bunk..."

I am unclear what you mean here but this in-vitro experiment. which studied interaction of zinc ions with chloroquine in a human ovarian cancer cell line. shows far more zinc entering cells that are exposed to chloroquine:

"Chloroquine Is a Zinc Ionophore": https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/

klipt said 2 months ago:

I hate the way this drug has been politicized by Trump yapping it up before there were any good studies.

Politicians should shut up about unproven medicines and leave it to the professionals to actually practice, you know, evidence based medicine.

betterunix2 said 2 months ago:

"Politicians should shut up and leave it to the professionals"

FTFY.

giardini said 2 months ago:

A political leader's role is not to choose medications but to give people hope and to keep the wheels of society rolling. But no matter what, there will always be more questions about what will be done. I think Trump was sufficiently vague yet optimistic in his answers, as befits his role.

Consider how different it would have been had he said "We know of nothing that works against this virus." or even worse, "We're screwed! Go home and tell your children we're all gonna die!".

anigbrowl said 2 months ago:

The lack of productive discussion around a potential treatment tells us more about our bad decision-making under anxiety conditions than it does about the efficacy or not of the medical proposal. Although I posted a preprint of the French micro-study to HN a few weeks ago when this first became a topic of discussion, I now regret doing so due to the subsequent public confusion and imho very irresponsible promotion of it as a harm-free prophylactic by Trump.

libpcap said 2 months ago:

Prescribe it before it gets severe then.

sna1l said 2 months ago:

n = 11?

dang said 2 months ago:

"Please don't post shallow dismissals, especially of other people's work. A good critical comment teaches us something."

https://news.ycombinator.com/newsguidelines.html

hpcjoe said 2 months ago:

That's not a shallow dismissal. Fundamentally, what I read was a cohort size of 11. 1 died. No control group. No double blind (as no control group).

There's no aspect of this that would be statistically distinguishable from noise.

Then again, the original study suffered from this as well.

n=11 may be succinct, but it is not shallow. There is a world of statistical DoE, analytics, etc. behind this.

My concern is the rush to headlines about studies without any real resolving power. The bad part of this is that we don't have time to do proper studies (this takes months and many people to make work). The n=11 comment actually infers this issue.

Sort of like -1 = exp(sqrt(-1)*pi), you don't need many letters to convey a tremendous amount of meaning.

dang said 2 months ago:

Somehow the hivemind decided a few years ago (it would be interesting to trace how and when) that every study with a small sample size is worthless and merely mentioning sample size is enough to cancel it, and whoever is first to bring this up in a thread wins. It's a gotcha response.

Obviously there are statistical concerns with small samples. Equally obviously, not every such study is worthless and the authors are not all idiots who knows less than any internet commenter. So to get substantive discussion, we need to engage with the specifics of a particular study, not post a generic dismissal. "n = 11?" looks specific but it isn't. It's a template instantiation, as stock as "Correlation is not causation".

The answer to "the rush to headlines about studies" is not the opposite reflex, it's to slow down and reflect, and then maybe post if one has something thoughtful to say. https://hn.algolia.com/?dateRange=all&page=0&prefix=true&que...

I don't mean to pick on the GP commenter. Maybe they had something else in mind. The issue is how such a comment plugs into a known shallow-discussion dynamic. The problem is at the group level, not the individual, and we all suffer from this reflexiveness, so none of us gets to feel smug.

elcomet said 2 months ago:

It is shallow because it doesn't teach anything to people that are not already familiar with this kind of work.

Something not shallow would be like "only eleven people participated in this study, this is too little to get a clear result that's not due to luck."

dang said 2 months ago:

That would be just as shallow. The issue isn't brevity, it's genericness. Are we really making the assumption that every study with a small sample is worthless, and that our reflexes know better than the people who worked on it? Obviously we need to do better than that. Generic discussion is shallow discussion (https://hn.algolia.com/?dateRange=all&page=0&prefix=false&qu...).

Here's a comparable comment that at least begins to engage with the specifics: https://news.ycombinator.com/item?id=22798031. I don't know if it's a good point, but it's at least actually about this particular study. We wouldn't moderate such a comment.

klmadfejno said 2 months ago:

I'm not sure I agree with this. Would you feel the same way if the sample size was 1? 5?

11 is very small, and useful only for evaluating the presence of very very prominent effect sizes, regardless of domain. A comment saying n=11 is not a novel insight, but I believe it is useful, similar to people who add "in mice" to articles whose headlines might imply the test was on humans. I appreciate those comments.

In this case I think it is fair to conclude that the headline "Severe Covid-19 Cases Don't Respond to..." is an accurate takeaway purely because the sample size is so small. With this sample size you can, at best, conclude that these combinations of drugs don't reliably cure the disease in severe cases, which is a very different idea.

dang said 2 months ago:

Why not? It depends on the study. I agree with you about misleading headlines and the mice thing. It's an interesting point to compare.

While I have you: could you please stop creating accounts for every few comments you post? We ban accounts that do that, and in fact this account was banned. This is in the site guidelines: https://news.ycombinator.com/newsguidelines.html.

You needn't use your real name, of course, but for HN to be a community, users need some identity for others to relate to. Otherwise we may as well have no usernames and no community, and that would be a different kind of forum. https://hn.algolia.com/?query=by:dang%20community%20identity...

klmadfejno said 2 months ago:

Yes

dang said 2 months ago:

Appreciated! (I only just saw this.)

dooglius said 2 months ago:

Succinctness does not imply shallowness

dang said 2 months ago:

Certainly not. Mechanically repeating a stock criticism does. This one is currently the internet's cliché way to dismiss a study.

Generic discussion is shallow discussion.

kilbuz said 2 months ago:

Imagine a treatment that would being people back to life. Surely if you saw that 11 times you would believe it worked. In fact, after n = 1, you would be so amazed you'd be thinking there is a trick. The point is that, while N is important, the N needed to uncover a signal differs wildly with the outcome you're trying to affect, specifically the outcome's variance. If one of these drug cocktails 'works' (which has many different definitions in clinical research), the signal may be obvious enough that n = 11 is enough to hone in on a promising treatment for further study. It's complicated.

onlyrealcuzzo said 2 months ago:

I can only think in the context of A/B testing, but I really don't get it. Can anyone explain how you can have any confidence with these small sample sizes?

Imagine you have a purchase form that converts at 0.1%. You test a new change, and with the first 22 users (11 in each group), if the control group randomly gets a conversion, it will have AT LEAST a ~9% CVR now. Okay, maybe you ignore that data, since you can just compare to historical data. Whatever.

Even if the new form is dramatically better and has a 30% CVR -- There's a 3% chance it would show a ~9% CVR also, and about the same that it would show a 0% CVR. Similarly, there's about a 6% chance it would show a 91%+ CVR -- skewing your results just as badly in the opposite direction. There's only like a 30% chance you get close to the "true" CVR.

Unless these hydroxycloroquine is close to 100% effective (and that doesn't seem to be what any of these studies say) I just don't understand how there's any confidence with small sample sizes.

Does anyone have a link to how this works? I've asked a few friends in medicine, and they haven't given a good answer. Haven't found anything on Wikipedia. Probably don't know what to search for.

kilbuz said 2 months ago:

You're thinking about things correctly. The statistical and scientific methodology of clinical trials are by and large the same thing as A/B tests. I don't think anyone is drawing much from this sample of n = 11 except to say it's definitely not a miracle cure. No approval would normally be given to a new treatment for any study of this size.

If an A/B test took a form from almost 0% conversion to almost 100% conversion, you might only need 11 users to show that. But even in that case, the devil is in the details. Were your users really a completely random sample from your population, etc?

The other side of the coin is, can we say these are non-interesting treatments with only 11 subjects? Or are the studies too underpowered to say much of all?

simondw said 2 months ago:

I don't think your scenario is as different as you think.

Depending on what we mean by "back to life", a trick is in fact much more likely than something thought to be biologically impossible.

If we eliminated the possibility of a trick -- that is, proved beyond a doubt that 11 people were dead, and then alive -- I would absolutely not be ready to attribute it to some new treatment. Natural law is being violated here! I would instead start checking for other possibilities, like:

- Are other people spontaneously reanimating around the world, or just in this study?

- Did these 11 people have anything else in common? Extraterrestrial origin, perhaps? Unusual religious beliefs?

- Hang on, let's double (triple, quadruple, etc.) check that they were really dead. And then go back and check again.

- And by all means, start a proper clinical trial of the new treatment while we're trying to understand how resurrection is even possible.

dooglius said 2 months ago:

That wouldn't really be n=11 because there is a huge implicit control group of people who haven't come back to life, and if you do the math it would very strongly reject the null hypothesis.

michael_storm said 2 months ago:

Believe it or not, it's pretty hard to conduct a large-scale study in the middle of the largest pandemic in modern history.

MikeTheGreat said 2 months ago:

Is it too morbid to joke about it actually being a great time to get a lot of samples for a study?

I mean, that plus Zoom and you're like halfway to a world-wide sample size, more-or-less

On a serious note: I'm extremely grateful for everyone who's working to solve this big and complicated problem, and (like the other poster said) it's entirely reasonable that it's really difficult to get larger studies going.

SpicyLemonZest said 2 months ago:

I don’t believe it. Studying how to effectively treat coronavirus patients is literally the most important problem in the world right now, and I’m sure a lot more than 11 severe cases are being treated with hydrochloroquine.

kilbuz said 2 months ago:

While your point is a good one, meaningful clinical research is hard enough under normal conditions. Forms, enrollment, protocols, data collection, statistical analysis plans, reporting, etc. It's an entire industry used to operating in scales that often span years for a single meaningful study.

SpicyLemonZest said 2 months ago:

And I agree with that as far as it goes, but I think it reflects the problem - clinical research contains a bunch of hurdles that have nothing to do with uncovering the truth. So in a sudden emergency, where clinical research starts to diverge from the treatment decisions of doctors and the drug supply actions of governments, I'm not going to put much weight on clinical research.

monadic2 said 2 months ago:

I'd estimate they were commenting on the quality of the results, not critiquing the personal efforts of the researchers.

lostmsu said 2 months ago:

Is it really in the age of ubiquitous Internet access?

A bit of self-promotion: https://news.ycombinator.com/item?id=22787162

In fact, I am impressed, this is not a thing yet.

rattray said 2 months ago:

Why is that?

crygin said 2 months ago:

Generally speaking, a criticism of a study that focuses only on something like this is uninteresting -- while it _may_ be a valid criticism, it is not always (many valid studies have very small samples!), and so stating it unsupported is actually more like evidence that you don't know how to critically evaluate a study. As Zeynep Tufekci said: 'Anybody immediately responds to a correlation with “but correlation does not imply causation” probably doesn’t know what they’re talking about. Don’t have much to say, throw around smart sounding cocktail phrase.'

SrslyJosh said 2 months ago:

Not very surprising given the quality of the studies that this fad is based on:

https://respectfulinsolence.com/2020/04/03/zelenko-smith-aba...

That's a long read, but it's pretty damning.

TL;DR: China says "hey, this stuff might work". French doctor conducts two very sketchy rapid-fire studies, then starts promoting himself on TV, including on Dr. Oz. No red flags there, right?

gridlockd said 2 months ago:

Pretty much every virologists I listened to said "this stuff might work", because it's entirely plausible that it might work.

> That's a long read, but it's pretty damning.

It actually isn't. All it says is that the evidence is poor and done by people with questionable reputation. It doesn't say "it doesn't work". What if it does work, but only in the early stages, when symptoms aren't severe (yet)? You wouldn't know.

Chloroquine and hydroxychloroquine are somewhat dangerous drugs and are therefore far more likely to only be given as a "last resort" rather than as a "precautionary measure", given their unproven status.

What are the odds that a reputable person is going to put their reputation on the line, doing such a dangerous trial on patients that aren't at high risk? Early on, a disreputable person is way more likely to do it. There won't be any good evidence for a while, in the meantime it's all a gamble.

This study is important, but limited in its scope. It shouldn't poison the well.

rodgerd said 2 months ago:

So a bunch of people who have medical conditions which actually respond to HCQ have lost access to it, for no benefit to anyone else.

Great.

transreal said 2 months ago:

Unfortunately, I'm one of those people. My last refill ran out last week, and my pharmacist doesn't think I can get a refill anytime soon :-(

Fortunately my condition is not life threatening or severe, but it's something I've been living with for many years, and the HCQ was just finally getting it under control, so it's a bummer that there is so much hoarding going on before we even know if it really works for Covid-19.

Also, it is not a risk free medication. While it's generally safe, my doctor makes me get frequent lab work & a vision test because the side effects can be pretty bad for a small minority of people.

tgafpc2 said 2 months ago:

Maybe don't let them get that severe? One can still starve after eating.

orwin said 2 months ago:

Thank you, i'm sure they are incompetent idiots that could not prevent their patients to die, after all they have graduated from a third world country and are probably not capable doctors. /s

ReptileMan said 2 months ago:

Some of the best medical minds with best education rejected evidence that washing hands before surgery saves lives for like 50 years.

Anyway X doesn't work on severe cases when there is compelling anecdotal evidence that X helps on medium cases to not progress to severe is, so give them X earlier is what I read in the OP word.

trhway said 2 months ago:

[IANAD] hydroxychloroquine is an immunosuppressant and shouldn't be combined even with vaccines ( https://www.medicinenet.com/hydroxychloroquine/article.htm#w... ), so using it when immune system is really fighting an infection may happen to be very antiproductive unless it is a case of COVID triggered cytokine storm (hyperinflammation) when such immunosuppressant is probably what you'd really want. May be it is a reason why in come cases of COVID it works and in some doesn't.

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

"However, in hyperinflammation, immunosuppression is likely to be beneficial. Re-analysis of data from a phase 3 randomised controlled trial of IL-1 blockade (anakinra) in sepsis, showed significant survival benefit in patients with hyperinflammation, without increased adverse events.8 A multicentre, randomised controlled trial of tocilizumab (IL-6 receptor blockade, licensed for cytokine release syndrome), has been approved in patients with COVID-19 pneumonia and elevated IL-6 in China "

Notable fact is that majority of the deaths of the second wave (the deadliest, which in addition to children/weak/elderly was also strongly hitting healthy 25-35 years old) of Spanish flu was due to cytokine storm.

orwin said 2 months ago:

Yes, obviously in case of hyperinflammation doctor are giving immunosuppressing drugs, HCQ or other depending on the stocks (and of course the patient history and other drugs given prior). They are very capable people in most cases, urgentists are often very knowledgable, and reanimation doctors are probably the best at interfering/preventing coktail effect. They are not available in all cases, but they try to be there for the most important ones.

No one, no scientist is saying with certainty that HCQ does not work at all. However, the maxim is primum non nocere. Are HCQ effects important enough to use it in every case when you can do otherwise? Well, according to the last Raoult study on 80 mild cases, no. 3 hospitalisation, 1 death for 80 cases is around the same result as German/S.K. mild cases who are given no treatment at all (a bit superior, even, but n=80 is clearly not enough).

Maybe HCQ reduce contagiosity. In this case, is HCQ more efficient than interferon? I know that i would prefer interferon as my liver and kidneys can take more hit than my heart atm (i already have a medication that cause tachycardia when i overdose it a little + some minor heart issues). Is HCQ more efficient than rinovir? this particular article seems to say that it's not but why should i trust this article more than Raoult and some French articles? Should i take everything (interferon, rinovir, HCQ, CQ) and hope for the best? Or, since i can afford to as i live in a rich country, should i wait the different study results?