And June news: that large study was withdrawn.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:
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.)
