Dozens of scientists have raised concerns over a large-scale study of hydroxychloroquine and chloroquine published in the Lancet that led to the World Health Organization suspending clinical trials of the anti-viral drugs as a potential treatment for COVID-19.
Hydroxychloroquine, normally used to treat arthritis, has become one of the most high profile drugs being tested for use against the new coronavirus partly because of endorsements by public figures including US President Donald Trump.
Researchers on Friday stood by the conclusion of their study that treatment with hydroxychloroquine and chloroquine, an anti-malarial, showed no benefit and even increased the likelihood of patients dying in hospital.
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The letter writers, who include James Watson, PhD (Mahidol Oxford Tropical Medicine Research Unit, Thailand), a statistician who first raised concerns about the integrity of the results in a review on Twitter, call for the release of patient data and for the findings to be validated by the World Health Organization (WHO), or at least one other independent institution.
Contacted by TCTMD, one of the Lancet study investigators said that they, too, will conduct an independent review of the data they used for their analysis, which was provided by a private company.
Published May 22, 2020, and reported on by TCTMD along with a wide range of other media outlets, including the New York Times, the Wall Street Journal, and the Washington Post, the study in question focused on 96,032 patients hospitalized with COVID-19 between December 20, 2019, and April 14, 2020, at 671 hospitals on six continents.
On multivariable adjustment, use of chloroquine and hydroxychloroquine with or without a macrolide antibiotic was associated with a 33% to 45% higher risk of in-hospital mortality. The risks of ventricular arrythmia were increased by several orders of magnitude.
The observational study has had a “considerable impact on public health practice and research,” according to the letter writing group, which also noted that the WHO paused the recruitment of patients into the hydroxychloroquine arm of the SOLIDARITY trial the day after the study was published.
Other regulators around the globe have also pressed pause on their studies of hydroxychloroquine in COVID-19.
“The subsequent media headlines have caused considerable concern to participants and patients enrolled in randomized controlled trials seeking to characterize the potential benefits and risks of these drugs in the treatment and prevention of COVID-19 infections,” according to the letter.
“There is uniform agreement that well-conducted randomized controlled trials are needed to inform policies and practices.”
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The observational research, led by Mandeep Mehra of the Brigham and Women’s Hospital in the US, looked at records from 96,000 patients in hundreds of hospitals between December and April and compared those who received treatment with a control group.
The research, published in the Lancet medical journal on May 22, followed numerous smaller studies that suggested hydroxychloroquine is ineffective in treating COVID-19 and might even be more dangerous than doing nothing.
Both drugs can produce potentially serious side effects, particularly heart arrhythmia.
Within days the WHO temporarily suspended use of the drugs in its Solidarity Trial, which has seen hundreds of hospitals across several countries enrol patients to test possible treatments for COVID-19.
“This impact has led many researchers around the world to scrutinise in detail the publication in question,” said the open letter in response to the study, which was signed by a number of prominent scientists and published Thursday.
It added that this scrutiny raised “both methodological and data integrity concerns”.
One of the main concerns was a lack of information about the countries and hospitals that contributed data, which was provided by Chicago-based healthcare data analytics firm Surgisphere.
Other issues highlighted included discrepancies in the data for Australia, where they said there were more deaths recorded in the hospitals covered by the study than official figures for the entire country.
In a statement late Friday the Lancet said it was publishing a correction to amend the discrepancy, which occurred because one hospital had self-designated as being in the Australasia continent, when it should have been in Asia.
“The Lancet encourages scientific debate and will publish responses to the study, along with a response from the authors, in the journal in due course,” it said, adding that the conclusion of the study remained unchanged.
‘Serious doubts’
Mehra also released a statement saying the authors of the study had initiated an academic review of their work, adding that it had been undertaken “in the absence of a large, robust and publicly available dataset on hydroxychloroquine or chloroquine”.
“As articulated in the study, the authors have underscored the importance and value of randomized, clinical trials and articulated that such trials will be necessary before any conclusions can be reached,” he said.
“However, results are not anticipated from such trials until the summer and, given the urgency of the situation, leveraging the available dataset was an intermediary step.”
A spokesman for the WHO said a comprehensive review of the drugs was expected to reach a conclusion in mid-June.
Among the signatories of the letter questioning the research were clinicians, epidemiologists and other researchers from around the world, from Harvard to Imperial College London.
Francois Balloux of University College London, said he believed it was his “duty” to add his name to calls for answers to questions about the study and for greater transparency.
“I have serious doubts about the benefit of CQ/HCQ treatment for #COVID19 infection, and cannot wait for the whole drama to be over,” he said on Twitter.
“Though, I believe ‘research integrity’ cannot be invoked only when a paper doesn’t support our preconceptions.”
The letter was also signed by French researcher Philippe Parola, a colleague of the Marseille-based professor Didier Raoult, whose work has been at the forefront of promoting hydroxychloroquine and has also been subject to criticisms over methodology.
The coronavirus crisis has put enormous strain on the normally sedate system of scientific publication, with an avalanche of research and the process of peer review considerably accelerated.
Uses of hydroxychloroquine and chloroquine in covid-19 (SARS-CoV-2)
The worldwide effects of the SARS-CoV-2 pandemic has been unparalleled and it has prompted the scientific community to consider all possible solutions. Due to covid-19 similarities to SARS-CoV, several researchers have proposed the use of hydroxychloroquine and chloroquine on the novel virus.34–36
Wang et al tested the effect of several Food and Drug Administration-approved antiviral drugs on the virus in vitro. Remdesivir showed post entry blockage of viral infection with an effective concentration at 50% of EC50=0.77 µM and a cytotoxic concentration of 50% of CC50>100 µM. Chloroquine was found to have an effective concentration at 50% of EC50=1.13 µM, a cytotoxic concentration at 50% of CC50>100 µM and an effective concentration at 90% EC90 of 6.90 µM.
Chloroquine showed effectiveness at an entry and post entry level, while remdesivir was only effective at a post entry level. This further suggests the possible prophylactic use of chloroquine on SARS-CoV-2.37
Yao et al also tested the effect of hydroxychloroquine and chloroquine in vitro. They divided the experiment into two phases: treatment study and prophylaxis study. In the treatment study, the EC50 values for chloroquine were 23.90 and 5.47 µM at 24 and 48 hours, respectively, and the EC50 values for hydroxychloroquine were 6.14 and 0.72 µM at 24 and 48 hours, respectively.
In the prophylaxis study, the EC50 values for chloroquine were >100 and 18.01 µM at 24 and 48 hours, respectively, and the EC50 values for hydroxychloroquine were 6.25 and 5.85 µM at 24 and 48 hours, respectively.
They concluded that hydroxychloroquine is more effective in vitro than chloroquine for both prophylaxis and treatment.38
The promising results of the in vitro experiments have led to the creation of multiple clinical trials to further investigate the chloroquine effect on covid-19. Currently, there are two trials with available data.
Gao et al demonstrated the superiority of chloroquine over the control treatment in more than 100 patients regarding inhibition of pneumonia exacerbation, improvement in lung imaging findings, promoting a virus negative conversion and shortening the disease course in more than 10 hospitals in China.39
Gautret et al treated 20 patients with hydroxychloroquine and compared the results with 16 controls in France. They used PCR to measure the viral load on day 3, 4, 5 and 6 of postinclusion. The treatment group had a higher age mean, but no difference in gender was made between the two groups.
Asymptomatic patients and patients with both lower and upper respiratory tract infections were treated. They concluded that hydroxychloroquine was effective in viral load reduction. The results on day 3 indicated that 50% of the hydroxychloroquine-treated patients had a viral load reduction with a p=0.005; on day 4, it showed a 60% reduction with a p=0.04; on day 5, a 65% reduction with a p=0.006; and on day 6, 70% of the patients showed viral load reduction with a p=0.001.
Furthermore, they described the synergistic effect of azithromycin when using it alongside hydroxychloroquine in decreasing the viral load. The dual treatment showed 100% decrease on the viral load with a p<0.001 by day 6, while hydroxychloroquine alone showed a 70% decrease.40
Ongoing studies and guidelines
Several randomised clinical trials regarding antimalarial drug use in covid-19 have been proposed. On the US National Institute of Health’s (NIH) medical library, there are already 143 trials on covid-19 registered from all over the world and 14 of them are specifically about the use of antimalarial drugs on the virus.
These trials aim to demonstrate the effectiveness of hydroxychloroquine and chloroquine in pre-exposure and postexposure prophylaxis and treatment. Table 1 enlists six of these studies, but further information can be found at the NIH web page.41
Moreover, on the Chinese clinical trial entry there are over 500 studies enrolled and 16 of them are about hydroxychloroquine and chloroquine use on covid-19. This information can be found on their web page.42
Multiple institutions worldwide are already using hydroxychloroquine in their treatment guidelines, including the Centers for Disease Control and Prevention (CDC),43 pointing to the relevance of this drug in the current pandemic.
Journal information:The Lancet
30 World Health Organization. Novel coronavirus (2019-nCoV) technical guidance. Available: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance; https://www.who.int/emergencies/diseases/novel-coronavirus-2019 Google Scholar
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37 Wang M , Cao R , Zhang L , et al . Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269–71.doi:10.1038/s41422-020-0282-0 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32020029 CrossRefPubMedGoogle Scholar
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39 Gao J , Tian Z , Yang X . Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020;14:72–3.doi:10.5582/bst.2020.01047 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32074550 CrossRefPubMedGoogle Scholar
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