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Prominent politicians in the USA have been calling for the use of both Chloroquine and Hydroxychloroquine in the management of Covid-19.

Day after day, the salesman turned president has encouraged coronavirus patients to try hydroxychloroquine with all of the enthusiasm of a real estate developer. The passing reference he makes to the possible dangers is usually overwhelmed by the full-throated endorsement. “What do you have to lose?” he asked five times on Sunday.

The USA trade advisor Dr Peter Navarro also claims special expertise

Navarro told CNN that studies including one published in the last few days involving Wuhan, China prove hydroxychloroquine can help coronavirus patients recover. Navarro said the Wuhan study was one of the first randomized in a control group.

The trade adviser also claimed his PhD in economics qualified him to have such debates with health experts like Fauci.

“Doctors disagree about things all the time,” he said. “My qualifications in terms of looking at the science is that I’m a social scientist. I have a PhD, and I understand how to read statistical studies.”

Although generally safe when used in the treatment of malaria and rheumatoid arthritis, sle, these conditions are dramatically different from the scenario of sick hypoxic covid-19 patients who may also be suffering from myocardial injury from the virus.

What are the early trials telling us?

https://www.nytimes.com/2020/04/06/us/politics/coronavirus-trump-malaria-drug.html

https://www.theguardian.com/us-news/2020/apr/06/peter-navarro-fauci-hydroxychloroquine

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We now have some data from randomized studies that provide some indications of safety considerations when using Hydroxychloroquine/Chloroquine in the management of Covid-19. The first study (non-peer reviewed) from Renmin Hospital of Wuhan University

Main methods: From February 4 to February 28, 2020, 62 patients suffering from COVID-19 were diagnosed and admitted to Renmin Hospital of Wuhan University. All participants were randomized in a parallel-group trial, 31 patients were assigned to receive an additional 5-day HCQ (400 mg/d) treatment, Time to clinical recovery (TTCR), clinical characteristics, and radiological results were assessed at baseline and 5 days after treatment to evaluate the effect of HCQ

So, these were 62 patients half of whom were only given 5 days of 400 mg of Hydroxychloroquine, which is a standard dose used in the management of rheumatic disease at approximately 5 mg/Kg, 400 mg/d (200 mg/bid) between days 1 and 5.

It's important to note the inclusion criteria here in particular

  1. SaO2/SPO2 ratio > 93% or PaO2/FIO2 ratio > 300 mmHg under the condition in the hospital room (mild illness);

So, these were mildly affected patients who would have been expected to have a good outcome. Average age was 44.7 years (sd 15.3 years) with approximately even split in gender, so again a group expected to do well. Excluded were:

  1. Severe and critical illness patients

among other criteria.

Although this was an efficacy study, there were minor side effects noted in the treatment arm

Notably, a total of 4 of the 62 patients progressed to severe illness, all of which occurred in the control group not receiving HCQ treatment. For adverse effects, it should be noted that there were two patients with mild adverse reactions in the HCQ treatment group, one patient developed a rash, and one patient experienced a headache, none severe side effects appeared among them.

The next large study we have is from Brazilian Hospital Hospital e Pronto-Socorro Delphina Rinaldi Abdel Aziz and is a

double-blinded, randomized clinical trial addressing different dosages of Chloroquine for the treatment of severe patients with COVID-19 in the absence of a control group using placebo.

The inclusion criteria included

Hospitalized patients aged 18 years or older at the time of inclusion, with respiratory rate higher than 24 rpm AND/OR heart rate higher than 125 bpm (in the absence of fever) AND/OR peripheral oxygen saturation lower than 90% in ambient air AND/OR shock (defined as mean arterial pressure lower than 65 mmHg, with the need for vasopressors medicines or oliguria or a lower level of consciousness) were included.

So, these were very sick patients. Their age was slightly higher at average of 51.1 years (sd 13.9)

Annoyingly there is no placebo controlled arm due to "ethical" considerations, and we note that this study is very different from the Wuhan study in that it looks at severe patients.

The high dose arm intended to give 12 g of Chloroquine over 12 days (Wuhan used 2 g over 5 days), and their low dose arm used 2.7 g over 5 days. Both arms also used ceftriaxone and azithromycin as well, and their preliminary data used 81 patients from a predefined population size of 440.

Given the toxicity of hydroxychloroquine/chloroquine at high dose with Qtc prolongation, and theoretically compounded with the co-administration of azithromycin, not unexpectedly Qtc prolongation was observed:

Regarding cardiotoxicity and QTc over time, the variation in the QTc as compared to the baseline ECG increased more on days 2 and 3 in the high dose CQ arm, with both arms (low and high CQ) showing more similar QTc variations in the last three days of follow-up (Figure 2). Two patients in the high dose CQ arm evolved with ventricular tachycardia before death. This severe type of arrythmia is usually facilitated when QTc is prolonged.

There was also evidence of myocardial injury in both arms

Occurrence of myocarditis (defined as CKMB higher than 2x the upper normal limit), which may be a final complication of severe sepsis or a lesion triggered by the virus itself, was seen in 2/24 (8.3%) patients (1 patient/arm). No echocardiogram was performed.

By day 6, 4 of the low dose arm had died, and 7 of the high dose arm. Ventricular tachycardia was observed in 2 of the high dose arm deaths at total dose of 7.2 g of Chloroquine. However, more patients with heart disease were randomized to the high dose arm, and there were 5 people over age 75 in the high dose arm, and none in the low dose.

Given the appearance of a cardiotoxicity signal as well as excess deaths, enrollment in the high dose arm was ceased and all patients were moved to the low dose arm. However, there is no comparator arm going forwards.

Their table 3 also has a mistake in that they state 4/41 died in the High Dose arm, and 7/40 in the low dose which is not what the conclusions state.

Update: 16 April 2020

A review has just been pre-published looking at the safety of Hydroxychloroqine in combination with other drugs that points to the possible lethality of combination of hydroxychloroquine with azithromycin.

Results: Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included. No excess risk of SAEs was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. SCCS confirmed these findings. However, when azithromycin was added to hydroxychloroquine, we observed an increased risk of 30-day cardiovascular mortality (CalHR2.19 [1.22-3.94]), chest pain/angina (CalHR 1.15 [95% CI 1.05-1.26]), and heart failure (CalHR 1.22 [95% CI 1.02-1.45]) Conclusions: Short-term hydroxychloroquine treatment is safe, but addition of azithromycin may induce heart failure and cardiovascular mortality, potentially due to synergistic effects on QT length. We call for caution if such combination is to be used in the management of Covid-19.

Update: 22 April 2020

A VA review looked at 386 VA patients treated with Hydroxychloroquine with or without Azithromycin vs with neither until 11th April 2020

performed a retrospective analysis of data from patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation.

And there appeared to be worse outcomes for those on HC

RESULTS: A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively

A weakness of the study was that it was retrospective review of outcomes.

Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study https://www.medrxiv.org/content/10.1101/2020.04.08.20054551v1

https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3.full.pdf

https://www.medrxiv.org/content/10.1101/2020.04.07.20056424v1.full.pdf

https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1

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  • Interestingly the large meta-analysis by US researches (the last paper in your post) doesn't mention ECG changes as an adverse event. (According to the latter Fr paper, their national guidelines say to discontinue HCQ if ECG changes are detected.) Only things like chest pain etc. were considered AEs in the US analysis. Also it doesn't seem to have looked at discontinuations of HCQ to see for what reason they were. I'm curious to see if they'll get it published like that. – Fizz Apr 18 at 16:13
  • Also the corresponding author of that US study works for Janssen, which happens to be a major manufacturer of HCQ (and have published research on it before.) The fact that the paper only covers [major] side effects but not efficacy is also a bit of a question mark for me. – Fizz Apr 18 at 16:26
  • According to CNN, Trump stopped touting [H]CQ after the VA study came out. For anyone else reading this, my Apr 18 comments refer to the Apr 16 update. – Fizz Apr 25 at 16:14
  • Also, there's a scandal in the US now that one of their [more obscure] agency heads was fired, supposedly fired because he resisted [H]CQ. nytimes.com/2020/04/22/us/politics/… – Fizz Apr 25 at 17:41
  • Just wondering if this new study published 1 August 2020 changes things. The conclusion is “Hydroxychloroquine provided a 66% hazard ratio reduction, and hydroxychloroquine + azithromycin 71% compared to neither treatment”. Is this study a game changer or am I missing something? ijidonline.com/article/S1201-9712(20)30534-8/fulltext – Petras Jul 31 at 12:37
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And June news: that large study was withdrawn. And there are some real questions if their data was real!

May 23 news (AFP) of a large study found no benefits and an increased risk of dying from treatment of Covid-19 with hydroxychloroquine and chloroquine:

A study of nearly 100,000 coronavirus patients has shown no benefit in treating them with anti-viral drugs hydroxychloroquine and chloroquine and even increased the likelihood of them dying in hospital.

Chloroquine is an anti-malarial. Both drugs can produce potentially serious side effects, particularly heart arrhythmia.

And neither drug benefitted patients hospitalised with COVID-19, according to a study published on Friday in The Lancet.

Looking at the records of 96,000 patients across hundreds of hospitals, they found that administering the drugs actually increased the risk of dying.

They compared outcomes from four groups: those treated with hydroxychloroquine alone, with chloroquine alone, and then two groups given the respective drugs in combination with antibiotics.

There was also a control group of patients not given these treatments.

At the end of the study period around nine per cent of those in the control group had died.

Of those treated with hydroxychloroquine or chloroquine alone, 18 per cent and 16.4 per cent respectively had died.

And those given each drug in combination with antibiotics were even more likely to die: 22.8 per cent with chloroquine and 23.8 per cent with hydroxychloroquine.

The authors estimated that the drugs put patients at up to 45 per cent higher risk of dying from COVID-19 compared with underlying health issues.

Some additional expert commentary on this study on Stat news.

The study is the largest observational study so far on the use of chloroquine and hydroxychloroquine to treat Covid-19; it combined data from 15,000 Covid-19 patients at 671 hospitals on six continents who were treated with the drugs. Those patients were compared to 81,000 patients who had Covid-19 but did not receive the drugs.

Other observational studies have made comparisons in smaller populations. A study of 368 U.S. veterans also showed that the drugs might be potentially harmful. But two different studies each including 1,400 patients treated in New York during the Covid-19 pandemic showed no impact on mortality at all. [...]

Adding more patients helps. But the problem is that, while researchers can control for risk factors that they know about, they can’t rule out that patients getting chloroquine and hydroxychloroquine are dying for reasons they don’t understand that have nothing to do with the drugs.

Still, the results don’t bode well for the malaria drugs as Covid-19 treatments. After controlling for risks such as weight, heart disease, and lung disease, the mortality rate in the control group was 9%. For those who received hydroxychloroquine, it was 18%; when an antibiotic was added, it was more than 20%. That’s not what would be expected if the drugs were highly effective treatments.

(And thankfully, this latter piece of news has a link to the actual study.)


Old (April) answer below

This is a pretty partial answer since several studies (including a NIH one) are ongoing on CQ and HCQ (I'm assuming you'll accept answers about the latter too, as related enough).

The NYT and various medical blogs have reported on a draft paper of Brazilian researchers highlighting that they stopped one (high-dose) arm of their trial. Quoting from the conclusions:

CQ, despite being a safe drug used for more than 70 years for malaria, might be toxic in the dosages recommended by Chinese authorities (high dosage 10g, for 10 days). Our study raises enough red flags to stop the use of such dosage (12g of CQ in total [...]

As for safety details:

One patient developed severe rhabdomyolysis, and causality could be attributed to the virus or to CQ, which is already known to cause myolysis. Regarding cardiotoxicity and QTc over time, the variation in the QTc as compared to the baseline ECG increased more on days 2 and 3 in the high dose CQ arm, with both arms (low and high CQ) showing more similar QTc variations in the last three days of follow-up. Two patients in the high dose CQ arm evolved with ventricular tachycardia before death. This severe type of arrythmia is usually facilitated when QTc is prolonged.

And they did a Kaplan-Meier analysis too:

enter image description here

Time (in days) from randomization to death, in patients treated with each chloroquine dosage. The gray band represents the upper and lower limits of the confidence interval for lethality in hospitalized patients not receiving CQ obtained by the meta-analysis of the studies by Zhou et al. (Lancet, 2020) and Chen et al. (BMJ, 2020) (167/990 = 16.9%; 95% CI 14.5-19.2).

In term of efficacy (which I won't detail here) they've concluded that (up to day 6):

Major presented outcomes were not different between the arms.

It might also be useful to quote a bit more from their related-research section:

Before the CloroCovid-19 trial began, to our knowledge, there were no published reports of robust clinical studies on the safety and/or efficacy of chloroquine (CQ) and/or hydroxychloroquine (HCQ) for the treatment of COVID-19 during the recent 2020 pandemic. [...] We found three non-randomized studies with limited sample sizes in which (1) HCQ use led to a decrease in SARS-Cov-2 detected in respiratory secretions five days after treatment, together with azithromycin (France, 36 patients); (2) HCQ use shortened time to clinical recovery (China, 62 patients); and (3) CQ was superior to control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, and promoting virus-negative conversion and shortening the disease course (China, 100 patients). We found no published studies comparing different dosages of CQ/HCQ and their thorough safety assessment.

There's also a CMAJ review posted a few days before that Brazilian paper came out. It mentions the same studies from China and France, as far as I can tell, and discusses the safety concerns from the general knowledge/perspective of CQ use in malaria etc.

Of the Chinese studies, the Wuhan one reported as adverse events (on 31 HCQ-treated patients) only

2 patients with mild adverse reactions in the HCQ treatment group [...] one patient developed a rash, and one patient experienced a headache

but this was with

5-day HCQ (400 mg/d) treatment

There's a much shorter "Breakthrough" (yeah, that's a word from its title) paper on the Chinese studies, which alas covers a lot more of them, but it's pretty contrieved in just annoucing:

A number of subsequent clinical trials [ChiCTR ids list] have been quickly conducted in China to test the efficacy and safety of chloroquine or hydroxychloroquine in the treatment of COVID-19 associated pneumonia in more than 10 hospitals in Wuhan, Jingzhou, Guangzhou, Beijing, Shanghai, Chongqing, and Ningbo

Thus far, results from more than 100 patients have demonstrated that chloroquine phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus negative conversion, and shortening the disease course according to the news briefing. Severe adverse reactions to chloroquine phosphate were not noted in the aforementioned patients.

More annoyingly, it says absolutely nothing about dosage.

And as far as I can tell the French study does not mention any adverse reactions either. The dose administered was 600mg/day.

On the other hand, a BMJ news/review (Apr 1) of this French paper says:

Although Raoult reported the results as positive, he excluded from the analysis six patients in the hydroxychloroquine arm because they had not remained in the study for six days. The reasons for non-completion were that one patient died, three were transferred to the intensive care unit (ICU), and two withdrew. None of the 16 patients in the control group died, withdrew, or needed care in an ICU. [...]

Eight days after his initial study, Raoult posted the results of an uncontrolled observational study of 80 patients. In that study one patient died and one remained in the ICU at the time of the report, putting the case fatality rate at 1.3% or 2.5%, depending on the outcome of the ICU patient. This compares with case fatality rates in Germany and the US of 0.9% and 1.8%, respectively.

Raoult did not respond to requests for an interview by The BMJ.

Another BMJ editorial published a week later is also quite critical of the CQ studies published thus far.

Apparently the protest/questions directed at the French paper have resulted in a official reaction from the journal board (this was mentioned in "quick reactions" the later BMJ piece)

Official Statement from International Society of Antimicrobial Chemotherapy (ISAC)

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial (Gautret P et al. PMID 32205204)

ISAC shares the concerns regarding the above article published recently in the International Journal of Antimicrobial Agents (IJAA). The ISAC Board believes the article does not meet the Society’s expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety.

Despite some suggestions online as to the reliability of the article's peer review process, the process did adhere to the industry's peer review rules. Given his role as Editor in Chief of this journal, Jean-Marc Rolain had no involvement in the peer review of the manuscript and has no access to information regarding its peer review. Full responsibility for the manuscript's peer review process was delegated to an Associate Editor.

Although ISAC recognises it is important to help the scientific community by publishing new data fast, this cannot be at the cost of reducing scientific scrutiny and best practices. Both Editors in Chief of our journals (IJAA and Journal of Global Antimicrobial Resistance) are in full agreement.

Andreas Voss ISAC President

April 3rd-2020

The Lancet noted (on Apr 11) that contra France (and US/FDA), based on current data, the European Medicines Agency is not convinced CQ/HCQ has any role in treating Covid-19.

See also, podcast discussion on Annals of Internal Medicine and Science Translational Medicine blog critical of the 2nd (draft) French study. The latter piece notes that at one point:

Raoult and several of his co-authors were banned from publishing in any ASM (American Society for Microbiology) journals for a year.


A more recent French study (not from the Raoult group) found that HCQ wasn't effective (or more precisely that the effect wasn't statistically significant--although just a preprint it was also covered by CNN on April 15). The study also found some patients had to discontinue HCQ due to ECG changes:

This study included 181 patients with SARS-CoV-2 pneumonia; 84 received HCQ within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group). Initial severity was well balanced between the groups. In the weighted analysis, 20.2% patients in the HCQ group were transferred to the ICU or died within 7 days vs 22.1% in the no-HCQ group (16 vs 21 events, relative risk [RR] 0.91, 95% CI 0.47–1.80). In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13–2.89), and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days (24 vs 23 events, RR 1.14, 95% CI 0.65–2.00). Eight patients receiving HCQ (9.5%) experienced electrocardiogram modifications requiring HCQ discontinuation.

Interpretation: These results do not support the use of HCQ in patients hospitalised for documented SARSCoV-2-positive hypoxic pneumonia.

(The HCQ dose was 600 mg daily.)

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  • 2
    No, SJS is not a mild adverse reaction! Upvoted anyway but SJS is often fatal. – Graham Chiu Apr 14 at 21:31

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