Is HCQ testing ethical given its side effects and (lack of) evidence?

[kadu-vido]

As a drug for malaria prophylaxis, the recommended HCQ dosage is 400mg weekly, starting two weeks prior to exposure and ending for weeks after. When used in lupus or rheumatoid arthritis treatment, the recommended daily dose is between 200mg and 400mg. Daily usage above 5mg/kg body mass/day is discouraged due to increased risk of retinopathy, especially in older or obese patients (who are at higher risk of developing covid19 in the first place). Moreover, nearly 50% of patients report gastrointestinal side effects to HCQ.

Didier Raoult proposes 600mg daily, which is between 1.5 and 2 times the recommended daily dosage when applied to chronic disease treatment. Besides, given current spread of the disease, it's unlikely that the treatment could have clear start and end dates, as is the case when applied to malaria prophylaxis (which requires a dose 10 times smaller).

The only hard evidence presented so far is a trial with 42 patients, out of which 16 were the control group, and from the 26 remaining, 2 quit the study due to the side effects, 3 were moved to the ICU (presumably after having a decline in their condition) and 1 died. That's nearly 25% of the test group, yet the report concludes 100% effectiveness of the treatment, with p<0.001 somehow.

Considering how thin the actual published evidence is, is it not irresponsible to encourage testing of prophylactic use of HCQ? Especially at doses known to be dangerous?

[GabrielSGoncalves]

Hi Kadu,

First of all, I really appreciate your opinion.

I think that one of the main questions about testing HCQ prophylactically is the dosage.

1) Is the dosage used to prevent Malaria (400mg per week) enough to protect from an infection? 2) If not, if the patient following the treatment gets infected, does he have a better outcome in terms of not needing ICU or death?

From these questions we can expand many more, and try to develop a strategy.

As I mentioned on my article, although Raoult's paper has some inconsistencies, he has expanded his cohort and the results are good. You can follow their numbers on the link: https://www.mediterranee-infection.com/covid-19/

I've been following some news and reports that many groups are already treating patients using HCQ and Azithromycin. I'll be posting the links tomorrow and updating it daily.

Going back to your concern about HCQ side effects, which dose would you propose for a trial to test HCQ prophylactically against Covid-19?

Once again I appreciate your words and look forward for your answer,

[kadu-vido]

The linked website contains, presumably, a screen capture of a dashboard, which is hardly data. It is unsupported by any explanation of the methodology, clinical condition of patients before the start of the trial, sizes of control and test groups, details on the data or data manipulation done. My technical French in this subject is admittedly lacking, so I could be missing some important link, however no efforts were made to make any details obvious to the public accessing the website. Thus, these data can hardly be called "results", let alone good ones.

The only information I obtained from the website is that he is combining HCQ to Azithromycin, both of which can lengthen QTc. Combining multiple drugs with this effect lead to a higher risk of torsades de pointes, arrhythmia and, ultimately, sudden cardiac arrest. These effects are particularly pronounced in older individuals, as well as those with history of heart disease, high blood pressure. This is yet another risk presented by the proposed treatment that is much greater for the population at risk from the Covid19.

There are other, less documented possible risks associated with HCQ, including motor diseases like dyskinesia and tremors, and psychiatric ones like psychosis, heightened risk of suicide. All of these, as well as the aforementioned retinopathy, could be extremely worrying for health professionals, especially the psychiatric ones -- given the increased mental, physical and emotional strain already put on them by the crisis.

Taking into account all the listed risks associated with HCQ, the relative lack of scientific evidence supporting its use, and given the relatively high dosage that the only in vivo published experiment required, I would not pursue it as a prophylactic measure against Covid19. The effort and money of such a trial would be, in my opinion, more adequately applied to hastening research of a vaccine against the virus, which is a much safer and definitive alternative.

[GabrielSGoncalves]

Hi Kadu,

I understand when you say that the HCQ has side effects. Every drug has side effects, but what really matters is the extent of the protection it may offer to the patient. If HCQ was extremely dangerous, it would not be used to prevent or treat Malaria in adults and kids. We have to weight the benefit against the side effect to make this decision.

I'm not stating that HCQ is the ideal treatment, or that it works. That's why we need data to answer this question.

This randomized trial for HCQ has showed significant results: https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v2

Once again I appreciate your words and I'm sure you are also looking forward for new papers with the trials that are being performed.

[kadu-vido]

Sorry for the late reply, work has kept me busy,

If HCQ was extremely dangerous, it would not be used to prevent or treat Malaria in adults and kids.

What determines whether anything is "dangerous" or not is the dosage, even water can kill if you drink too much of it. As I said before: the only published paper using HCQ for Covid19 prevention uses a dosage 10x higher than the one used for malaria prevention. Morphine is a safe drug, would you take 10x the recommended amount?

Moreover, malaria is geographically confined. You can safely use HCQ as a treatment because you start it before entering a "malaria hot spot", and stop it after leaving. It's not usually consumed by people living in such hot spots (and even if it were, it would be done at one tenth of the dosage). Covid19 is worrying specifically because its not geographically confined.

We have to weight the benefit against the side effect to make this decision.

You've either ignored or missed my previous objections to this poing, so I'll repeat them. The evidence which supports this trial is:

• Raoult's paper with 26 patients (which grossly over-reports the success of the experiment)
• Raoult's larger trial (for which there are no details except his word - I'm sure you understand my skepticism)

As for evidence against this trial, we have three well-documented phenomena:

• HCQ is known to cause blindness and heart disease, this effect is extensively observed in Lupus patients, who take it daily for long periods of time (at one third of the proposed dose for Covid19 prevention), and they have to monitored because of this.
• Raoult's trial combines HCQ to Azithromycin, a drug interaction explicitly counter-indicated, because both lengthen the QT cycle, increasing even further the chances for cardiac problems.
• Side-effects are specially pronounced in older patients, as well as those with high blood pressure, diabetes, or previous cardiac conditions. These are exactly the demographics most affected by Covid19, and who need this prevention the most.

I believe before making a large-scale drug trial, we should be more certain that the drug may cause more good than harm. Currently, there is more evidence of the harm of the proposed treatment than there is of its good. My argument is that, since HCQ is not the last option on the table, and since we need to consider the money, time and effort to be invested in such an experiment, we should prioritise more proven prophylactic methods - like researching a vaccine.

This randomized trial for HCQ has showed significant results

Indeed, for treating Covid19. Citing this paper makes me wonder whether you're more interested in Covid19 prevention or in HCQ usage. This drug, regardless of our intentions, has been converted into an agenda by political forces in Brazil and in the US, which interferes with objectivity. This almost makes me wonder if I am missing out on some HCQ manufacturing company's stocks.

At this point I think you should ask yourself whether your interest lies in contributing to research a prophylactic solution against the virus (in which case I think we could both better invest our time in identifying other significant prophylaxis options and how we can contribute to them) or in pushing forth HCQ for whatever purpose.

[kadu-vido]

By the way, we've long been digressing from the originating question. I have now presented four premises:

1. HCQ has slim evidence of benefit.
2. There's significant evidence of (risk of) harm using it in the proposed dosage/cocktail.
3. There is significant political pressure backing HCQ, due to interests other than healthcare.
4. Laypeople with little access to the information's we're discussing here are being bombarded both by HCQ propaganda (for lack of a better word) and by the risks of Covid19.

I have already argued for 1 and 2, you have given your counterarguments for the first and I think we've reached a stalemate, so let's go back to the matter at hand.

Given these four premises. Do you think it's ethical to test it, knowing that the demographics most likely to take an interest are the ones at the largest risk, and that (as in any human trial) their ability to make an informed decision is limited?

[kadu-vido]

Have you checked out the latest study, with 368 patients in the US? Still not reviewed or published, but worrying nonetheless.