Saturday, April 11, 2020

Look after your lysosomes: Hydroxychloroquine

This fascinating:

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Forty two patients were enrolled. Sixteen were not given or refused hydroxychloroquine and none of these were admitted to the ITU, none walked out of the hospital and none were nauseated enough to withdraw from the trial.

Of the 26 patients given hydroxychloroquine three were subsequently excluded from the study because they were admitted to the ITU. Oops. One died (not one of those admitted to the ITU). One walked out of the hospital and never came back. Another was too nauseated on the drug to continue in the study.

Exclude these six patients and in the remaining 20 patients hydroxychloroquine was reported as successful at clearing the virus on nasopharyngeal swabbing.

You have to wonder if the poor patient who actually died while taking hydroxychloroquine ended up with high pH lysosomes which leaked enough cysteine to extract the FeS clusters from the nearby complex I FeS chains. Or simply died of pneumonia before he/she could be admitted to the ITU. We'll never know. I hope the patients "lost" in to the ITU made a full recovery.

Perhaps the patients who accepted hydroxychloroquine were simply iller in the first place and were so more willing to accept an experimental drug. I do hope so but I feel that the initial data on hydroxychloroquine are not looking too promising.


Edit: On the plus side there might be an effect if given early. However only time and trials will tell if there really is an effect or whether Turkey happens to have done several other things correctly in addition to using hydroxychloroquine. At least they are not reporting toxicity. End edit.


Dr. Rob said...

Peter, I suspect by the time people are hospitalised, the (ROS) fires are raging, fuelled by the extra oxygen, and a bucketful of hydroxychloroquine won’t be enough to put them out.

The antithrombotic, anti-inflammatory/anti-complement properties may have more potential in the early course of the infection - we are currently doing a study in general practice to find out.

There is another defensive player involved here which needs to be highlighted

NRF2 - is a master regulator of various antioxidants anti-inflammatory cytokines, and Heme oxidase 1 (HO1)

It is linked to hypoxia, HIF-1, ROS, ACE2, haemoglobin, ER stress and lysosomes.

The “crosstalk” just keeps getting louder!

Frunobulax said...

I posted this in another place a while ago. The german virologist Drosten said in his podcast that this study is observational twaddle, and I fully agree.

The fatal flaw -- apart from excluding those 6 patients -- is that they measured virus concentration in the throat and not in the lungs. Apparently the virus concentration in the throat goes down after a week (post becoming symptomatic IIRC) independently of the severity of the symptoms. The viral load in the lungs is the important factor, if it is high then the patient will become severely affected. Bottom line, it’s wasted effort because they measured the wrong thing.

He also says the control group was younger and brought in from another hospital, and the results look as if the treatment group could be simply a day or two further into the disease, which would explain the difference. They chose to measure 6 days after inclusion, right at the time where viral load drops in the throat.

Bottom line: We don’t gain any knowledge from this study, except perhaps that the effectiveness is very limited at best (after all 4 patients died or went to intensive care).

Archie Robertson said...

The patient who died during this trial was 84 years old.
Bilan du Pr Raoult au 30 mars
The headline here is "The summation of Prof Raoult's work as at 30th March: 1291 patients treated, only 1 died, aged 84".

Prof. Raoult's latest study was reported on 9th April and covered 1061 patients. No cardiac toxicity was observed. 91.7% were cured within 10 days. 5 patients died, all aged between 74 and 95. 16 are still ill.
Abstract here.

As for control groups, there is a small one called "the population of the rest of the world not receiving this treatment". The average throughout the world is a 21% death rate.
Prof Raoult's latest study showed a death rate of 0.5% to date, with a further 16 in hospital. Even if all of the latter die, that is a death rate of 2% at worst.

What Prof. Raoult is trying to achieve is for GPs to be allowed to prescribe this protocol freely. Off-label use of hydroxychloroquine was banned by the French health minister on 23rd March, thus limiting the protocol to hospitals only.
HCQ was available over the counter until 15th January 2020, when it was reclassified as prescription-only.

karl said...

The N of 26-6 = 20 is not high enough to learn much of anything.

I don't get the hysteria - and the message. There is some idea that they are "saving lives" - and perhaps a few will get exposed at lower levels - later with some less lethal strain - but the virus will continue to infect people until enough of the population has resistance and the 'gain' of the virus goes below 1. There is no secret that they mainly wanted to "flatten the curve" - but the area under the curve still is what it is. Having pockets of people with out immunity may not be that good of an idea.

My hunch is most everyone will get exposed eventually - and so what is amazingly absent is is what people can do to reduce their death rate. People can lower their BG in a single day - lower their circulating PUFA in a similar time frame - yet - the silence is deafening.

My hunch is if BG is normal (postprandials below 110 ) virus replication is slowed - and I would think it would increase survival rates. If circulating PUFA is reduced - again I would think it would increase survival rates. Could be limiting NSADs might help as well. Should people stop their statins?

In the mean time - I see a very frightened public when I go out - the fear - the stress level is palpable - they have seriously frightened people - stress is a real risk factor for coronary events - how many will die? The economic downturn will end up killing people in the third world. ( someone should have told them the the precautionary principal forbids it's own use - seems few are aware of the risk of unintended consequences?)

I don't think what is going on is rational - BUT - what ever happens they will claim success. This intervention is what it is - ( a runaway positive feedback loop of group-think - irrational virtue signaling - political point scoring ) but at what cost? At whose expense?

LA_Bob said...

I suspect it more likely hydroxychloroquine will become acceptable as treatment than blood sugar control (and healthy innate immunity) via carb restriction will.

Frunobulax said...

@Bob There is no proof that carb restriction helps against corona. The low carb community is buzzing there, but a theory needs more than a correlation. Certainly interesting from a sociology standpoint, a massive self-conditioning without any hard facts because we like the warm, fuzzy feeling of being protected. Well, we don't know s^%@. After all only a third of the fatalities were diabetic, only half had hypertension, but this sounds as if a sizable part of the victims had no metS. And we do know that 75% of the population over 65 has metS.

@Archie Death rate can be off by any factor, depending on the percentage of infections detected. If you test only dead people, the fatality rate is 100%. Here in Germany we test a lot and have officially less than 2% death rate, but stats imply that we may have diagnosed only 1/4th of the patients, pushing the death rate to about 0.5%. So the results from Dr. Raoult would be right in line with that.

We're all hoping for an efficient treatment. But on the other hand "Primum non nocere" has to be observed. I have yet to see any convincing evidence that hydroxychloroquine does more than causing side effects.

@Karl SARS-1 vanished without infecting everybody. The same will happen to Corona if we push R0 (new infections per case) below 1.

Passthecream said...

Karl, the socio-cultural and financial damage is already immense. Some of that will be levelling ... ... However it seems obvious to me that flattening out and smearing the curve over time not only relieves the burden on health care (to some extent) but increases the odds of understanding this virus and evolving treatments which will lower the depth and duration of infection which should in turn reduce the transmission rate, thus reducing the total area under the curve.

Nothing is going to quickly solve any of the problems related to a different herd, the herd of elephants in the room, such as massive overpopulation, pollution, environmental destruction, financial and political corruption, religious lunacy - it is a big herd and no immunity in sight for it.

Gyan said...

Didn't the Italians report 88 percent of fatalities having pre-existing conditions?
And of the remaining 12 percent, some would be very old and many could be having diabetes in situ, for instance.
I mean hyperinsulinemia is not regarded as a condition, is it but the low-carb community does regard it as essential to metS.

Frunobulax said...

@Gyan, to validate a theory you have to look at the black swans :)
You will always find data supporting a theory. The trick is to find data contradicting it. If you can't, your theory is sound. If you can, well, no more theory.

2 weeks ago I would have agreed. Today I'm no longer sure. No doubt metabolic syndrome damages health, so you are at higher risk. But is it the primary cause? I'd say that we have not enough data to tell either way. Obviously any pre-existing condition will reduce your chance of survival for any infection. I just don't know that it's specifically tied to metabolic syndrome.

Corona has something that is different from most other diseases. For almost all other diseases, young children are considered a risk group. Not corona. Why? I have no clue.

(Starting arbitrary theory. Just for the heck of it.)
Assume that COVID-19 kills people that have some condition that is typical for old age, but does happen in younger people too. Something not related to metS. Think low stomach acid, or whatever. Now pick a random sample of age 70+ people (typical corona victims). Choose the bottom third, health wise. How many will have diagnosed diabetes? I'd say north of 30%, perhaps even 50%. How many will have any chronic disease? 90%? More?

If it were metabolic syndrome, we'd have a ton of victims in the middle age group, 40-60. They certainly have plenty of diabetes cases ( But those people hardly die from Corona. Hell, we have many diabetic children, but they don't die from Corona, almost never. (thank god)

No proof either way. But for me, enough doubts to question the assumption.

Dr. Rob said...

It is a Non-Linear thermodynamic systems problem.

There is nothing more fundamental to life than energy, consequently the body has developed systems to protect that energy.

Stresses on the system consume energy.

These stresses come from the environment, both inside and outside the body.

The people dying already have very stressful environments and this virus is a direct attack upon their energy supplies. The effects will be non linear.

For example; obesity:

The view that obesity is due to the overconsumption of energy (food) is linear thinking. A systems view would see it as an energy consuming stress which initially triggers a response from the immune system (inflammation) and then elicits an energy protective tactic of Leptin resistance and insulin resistance.

So obesity is actually due to your body’s response to a loss of energy - it attempts to store more and more and makes it more difficult for you to use it. Some people can get really obese because they have insulin sensitivity whereas others develop insulin resistance when they are not even overweight by today’s standards (TOFI) - hence it is non-linear.

This is the paradigm shift in thinking needed to understand the root cause of the problem.

Archie Robertson said...

@Frunobulax, you said, "Death rate can be off by any factor, depending on the percentage of infections detected. If you test only dead people, the fatality rate is 100%. Here in Germany we test a lot and have officially less than 2% death rate, but stats imply that we may have diagnosed only 1/4th of the patients, pushing the death rate to about 0.5%. So the results from Dr. Raoult would be right in line with that."

I certainly agree that frequency of testing is a significant factor in all statistical reasoning. But using hard endpoints should give us more reliable figures.
So, for France, according to Worldometers, there are 40,223 closed cases at the time of writing. 26,391 patients (66%) have recovered or been discharged, which could provide one endpoint, and 13,832 (34%) have died, which gives us the other endpoint.

Since France is a country with universal healthcare and highly-centralised diagnosis and treatment guidelines, those national statistics give us the outcome of "conventional" treatment. Applying those statistics to a group of 1061 patients, to match those in Prof. Raoult's latest study, we would expect 700 recoveries and 361 deaths. In Prof. Raoult's study, there were 5 deaths and 1040 recoveries, with 16 still sick.

So we might expect that conventional treatment for the IHU group would have resulted in an additional 356 deaths. Any medication giving those kinds of outcomes (0.5% mortality versus 34%) would be hailed as a lifesaver.

"I have yet to see any convincing evidence that hydroxychloroquine does more than causing side effects."
The major side effects are nausea and cardiac complications. Nausea can usually be overcome with basic medication, while from the Abstract of the second study, "No cardiac toxicity was observed". This may be unfair, as the IHU study selection criteria include electrocardiograms, but I think you may agree that this study satisfies your objection.

Argument from authority is a weak debating tactic, but it should be borne in mind that Prof. Raoult is the most highly-ranked expert in the world on communicable diseases, according to the US ranking site Expertscape. Didier Raoult is not only a researcher but still a working doctor; he sees patients in person one day per week, to keep in touch with clinical reality. He is also a compassionate man—perhaps this is why he did not want to condemn 356 additional patients to death just to satisfy the critics baying for a control group.

It should also be borne in mind that as much as 80% of medical practice is not based on randomised controlled trials. Did Frederick Banting conduct RCTs on his diabetic patients?

Dr. Rob said...

I agree Archie, in the current climate faced with worsening covid symptoms I would most definitely want to be taking hydroxychloroquine and azithromycin - because both have mechanisms of action which suggest they should be efficacious. I also, like you, suspect the lack of profit margin to drug companies from these medications is clouding the issue. These companies stand to make far more money from expensive anti-viral and immune - modulating medications.

As the saying goes - Follow the Money!

Frunobulax said...

@Archie, there are 3 effects all driving up "observed" death rate. (1) People not getting adequate care (Italy, possibly New York). (2) People reporting too late to the hospital, which appears to be a thing with Corona. (3) Lack of testing (this is probably the main factor and can be orders of magnitude.) None of these 3 will have happened to patients of Dr. Raoult. Then there's (4), which can go both ways: How do you count? Is a terminal cancer patient with Corona a Corona fatality, if he/she had 4 more weeks to live at most? In Italy, yes. In Germany, no.

If we learn anything from nutrition, then this: It's VERY easy to draw wrong conclusions if your numbers aren't rock solid. And it's equally easy to shift public opinion, at which time the real data gets lost. These numbers games are crapshooting. Let's see a placebo-controlled trial.

I've heard from an ongoing trial in China (I think), testing hydroxychloroquine placebo-controlled, doubly blind, for a few weeks. They have *not* aborted the trial yet. If there was clear evidence for hydroxychloroquine working better than placebo, then they would abort the trial and give hydroxychloroquine to all patients.

Banting was a completely different case. Take 10 obese patients that couldn't lose weight with various diets, all 10 lose weight like crazy following Bantings advise, that's a 100% success rate vs. a 0% rate of conventional care. With hydroxychloroquine, it's hard to find statistical significant evidence at all. Again, there is some weak evidence.

Gyan said...

In US it is reported that 20-30 percent deaths are to under 65. So there are plenty of younger deaths not easily ascribed to general old age.

As metS promotes aging why shouldn't a diet that inhibits metS be recommended.

Cristian said...

Italian vet think he found a treatment based on his experience with cat coronavirus FeCoV. A protocol based on l-asparaginase, heparin and chloroquine.

What do you think abou it?

rjanusonis said...

@Archie, unfortunately, you have been duped by Didier Raoult's press releases - he and his team have a history of academic fraud, so I would be suspicious of any "studies" or recommendations he or his team publish.

karl said...

@Frunobulax who said...
SARS-1 vanished without infecting everybody. The same will happen to Corona if we push R0 (new infections per case) below 1.

This is not SARS - more infectious - once again they are only delaying cases - not preventing. Most everyone will get exposed. I'm not sure the interventions have nearly as much effect as is claimed. I am sure they will claim success - claim to have perfect knowledge - but they are guessing. At what point do the missed cancer screenings kill more than the virus?

So you want to ruin the current generations economic future by continuing this madness for the next year?

A case can be made that keeping children in school (keep them away from the elderly) - so they rapidly develop immunity - would be a much better policy. Once the children have immunity, we are on the way of having enough public(herd)resistance that it dies out.

Telling the public they can lower risks via dietary changes - even if we don't have controlled studies - seems like a lower cost than destroying peoples jobs/futures - for a different intervention that also has no controlled studies.

How many of the young deaths have T2D + combined with a large amount of seed oil in their diet?
I think part of the problem is there is an illusion that the medical community has abilities that the public wishe. It is an illusion that we will have treatments/vaccines in a short time frame. Or that the delay is going to save a huge number of people. This virus is going to play out in a few months time - only after it has finished with us, will they have a safe/tested vaccine.

I think they will try very hard to not measure the damage done by the lock-down - lives lost/ruined. Stress kills - I see lots of people with extremely high(irrational) stress over. People with canceled cardiac appointments etc etc etc etc..

There is a little secret I know about life - non of us get out alive. Everything has some amount of risk. The key bit about this that makes it appear to me to be 'a madness of crowds' is when I look at relative risks. There are other health issues that represent a much larger life time risk that are being ignored.

Kahneman's Focusing Illusion:
"Nothing in life is as important as it appears it is when we are thinking about it."

History may not be kind to the people that put these policies in place.

Passthecream said...

Frunobulax, working in schools, 2 of them, which are resolutely being kept open here for any students who wish to attend (R-12), it is the staff who are concerned about being placed in the front line with nothing more than hand sanitiser and reduced class sizes. And of course not just concerned for themselves but for their own families at home. Masks are not allowed on site! That's a whole can of worms but there is little doubt in my mind that they are a useful precaution to some extent IF handled properly. And the effect is possibly non-linear ie 20% reduction by barrier function gives much more than 20% odds reduction. Two people in an interaction both wearing masks gives an even greater effect than that odds reduction squared.

However, this next paper seems plausible to me and changes the scenario dramatically. There are niggles with some of his assertions but the author is upfront with his hypotheses and has attached the Python code with links to the data you would need to test it for yourself.

Passthecream said...

Sorry that was @ Karl not @ Frunobulax.

Passthecream said...

Stretching the ideas a little from that Razavian paper, possibly past breaking point, it could be that the curative effect of eg hcq falls within the gamut of regression to the mean? ie those people are just getting better anyway.

Eric said...

@ Gyan: Do you have a link for the 20-30% of deaths under 65 in the US? How does this compare to other countries with less metS and better health care?

@ Pass and all: I read that article, and yes, it seems plausible at first sight. Do we know how complete testing in Iceland was?
How does he estimate real cases in Sweden for the 80-90 and 90+ groups?

And most importantly, how does this square with the Austrian study of 1000+ randomly selected individuals which showed way below 1% active infections? The Austrian study did not detect immunity, but from his model, one would expect way more active infections than the Austrians found.

Archie Robertson said...

@Frunobulax: I was not talking about William Banting, undertaker and weight loss expert in the 19th century, but Frederick Banting, discoverer of insulin in 1922. However, neither of them conducted any randomised controlled clinical trials.

@rjanusonis: I was not "duped by Didier Raoult's press releases"… I've never read any of them. I have however read his articles and watched video interviews with him—I am bilingual French/English. Certainly the horror stories recounted in the article you linked to bear investigation, though they may not impugn Prof. Raoult's own scientific rigour or capacity to manage such a large institution as well as carrying out research and treating patients.
The thinly-veiled accusation that Sanofi stands to profit by massive HCQ prescription is nonsense: it is giving away 100 million doses of HCQ to 50 countries. Its only profit will be brownie points.


But surely what really matters here is whether Raoult's protocol works, as his research seems to show? Other trials in progress, e.g. the Shanghai study reported on 3rd March, use different dosages of HCQ, and do not combine it with azithromycin. Incidentally, such tactics have been used in many different circumstances to discredit a treatment or intervention, such as "low-carb" diet trials using 150 g/d of carbs, or completely wrong dosages of medications or vitamins. Other uses of HCQ for COVID-19, including that recommended by the French Haute Autorité de Santé, are for patients whose viral loads have already dropped, and have been moved to intensive care to deal with their respiratory failure. This is far too late for HCQ to have any effect, as both Raoult and another virologist I know have pointed out independently.

Raoult's purpose is simply to allow French GPs to prescribe HCQ according to their own clinical judgment. HCQ has been taken by millions upon millions of people over nearly 70 years. Its side effects are well known and mostly easily controlled, and the most serious contra-indication, heart arrhythmia, is predictable from an EKG. The point is to stop patients deteriorating so far that they require transfer to ICU.

karl said...


Interesting bit by Razavian - when this is over and papers are published that show just how little the intervention accomplished - will the public 'get it'? I don't think so - instead I expect there will be a mantra claiming success.

My take is it is quite possible that the intervention is causing net harm. One of the things about the 'precautionary principal' - if you apply it to itself - it precludes it own use. Unintended consequences are a real risk.

My understanding is there is now an antibody test for COVID-19 - It would seen prudent to test - say 300 random people and see what the exposure rate actually is.

LA_Bob said...


US FDA has approved its first antibody test

Might be a lot of unreliable antibody tests available

Antibody testing has reported begun in Los Angeles

Passthecream said...

Karl "My understanding is there is now an antibody test for COVID-19"

Report from the WHO today saying they weren't finding a lot of antibodies, only enough to suggest that the general virus exposure rate was estimated to be about 3%. Isn't it the case though that the type of immune response you get to a virus like this one doesn't usually use antibodies, rather cytokines and such like? Maybe you shouldn't expect to find many antibodies.

Frunobulax said...

High-dose Chloroquine Diphosphate is fairly deadly. Study had to be stopped.

Archie Robertson said...

@Frunobulax: Thank you for this study. It's a classic example of what I mentioned in a previous comment: a trial set up to fail. It is not testing the Raoult protocol in any way. The patients recruited had already developed severe respiratory symptoms. The high-dosage group were older and had more heart disease. Raoult specifies that the La Timone protocol should be implemented as soon as unmistakable symptoms develop, such as fever and loss of taste and smell. The point is to prevent people reaching the acute stage. All patients receiving the La Timone protocol are given EKG tests, thus virtually eliminating the risk of serious cardiac side effects. Once pneumonia has developed, the viral load has already dropped, and HCQ cannot really help.

Archie Robertson said...

An interesting sidelight on hydroxychloroquine is to be found in this article in the Italian newspaper Il Tempo — and the Italians have more experience of COVID-19 than anybody bar the Chinese.
Selected extracts (apologies for Google translation, but my Italian is nonexistent):
"For example, the central mechanism of action of hydroxychloroquine can now be explained and fully understood, and its effectiveness in countering Covid19. What this mechanism consists of is immediately said: the drug by binding permanently with ferriprotoporphyrin (of the Eme group of Hb) removes the substrate from viral proteins and also becomes an important means of prophylaxis. Although there are still no Italian publications on the effectiveness of hydroxychloroquine as a "shield" from the virus, among the directors of the infectious disease wards, the specialists, Primaries and general practitioners contacted during this research, many admitted - sotto voce - to using the drug as a "prophylaxis", that is, to prevent infection. Healthcare professionals who are in close contact with contagious patients take the drug in advance, precisely to decrease the probability of contracting the infection. For now, in support of this "prophylaxis" effect, there is a recent publication, involving 211 people. It was published in the International Journal of Antimicrobial Agents, the official body of the International Society of Antimicrobial Chemotherapy. Of 211 people exposed to Covid19-positive individuals and undergoing hydroxychloroquine prophylaxis, none were infected.

"Finally, further confirmation of this hypothesis is the data collected in the register of the SIR (Italian rheumatology society). To assess the possible correlations between chronic patients and Covid19, SIR interrogated 1,200 rheumatologists throughout Italy to collect statistics on infections. Out of a total of 65,000 chronic patients (Lupus and Rheumatoid Arthritis), who systematically take Plaquenil / hydroxychloroquine, only 20 patients tested positive for the virus. Nobody died, nobody is in intensive care, according to the data collected so far." (emphasis mine)

Do we still need double-blinded placebo-controlled randomised clinical trials?