According to the disease control agency, while the country has logged a total of 53477 COVID-19 positive cases, it has also successfully discharged 41017 patients of the rampaging virus.
But, a new meta-analysis of published studies into the drug hydroxychloroquine shows that it does not lower mortality in coronavirus patients.
Sadly, using it combined with the antibiotic azithromycin is associated with a 27% increased mortality.
The study is published in Clinical Microbiology and Infection, the official journal of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).
This is unfolding as researchers at the University of Alberta are preparing to launch clinical trials of a drug used to cure a deadly disease caused by a coronavirus in cats that they expect will also be effective as a treatment for humans against COVID-19.
“In just two months, our results have shown that the drug is effective at inhibiting viral replication in cells with SARS-CoV-2,” said Joanne Lemieux, a professor of biochemistry in the Faculty of Medicine & Dentistry.
“This drug is very likely to work in humans, so we’re encouraged that it will be an effective antiviral treatment for COVID-19 patients.”
The drug is a protease inhibitor that interferes with the virus’s ability to replicate, thus ending an infection. Proteases are key to many body functions and are common targets for drugs to treat everything from high blood pressure to cancer and HIV.
First studied by U of A chemist John Vederas and biochemist Michael James following the 2003 outbreak of severe acute respiratory syndrome (SARS), the protease inhibitor was further developed by veterinary researchers who showed it cures a disease that is fatal in cats.
The work to test the drug against the coronavirus that causes COVID-19 was a co-operative effort between four U of A laboratories, run by Lemieux, Vederas, biochemistry professor Howard Young and the founding director of the Li Ka Shing Institute of Virology, Lorne Tyrrell. Some of the experiments were carried out by the Stanford Synchrotron Radiation Lightsource Structural Molecular Biology program.
Their findings were published today in the peer-reviewed journal Nature Communications after first being posted on BioRxIV, a research website.
“There’s a rule with COVID research that all results need to be made public immediately”, Lemieux said, which is why they were posted before being peer-reviewed.
She said interest in the work is high, with the paper being accessed thousands of times as soon as it was posted.
Lemieux explained that Vederas synthesized the compounds, and Tyrrell tested them against the SARS-CoV-2 virus in test tubes and in human cell lines. The Young and Lemieux groups then revealed the crystal structure of the drug as it binds with the protein.
“We determined the three-dimensional shape of the protease with the drug in the active site pocket, showing the mechanism of inhibition”, she said. “This will allow us to develop even more effective drugs.”
Lemieux said she will continue to test modifications of the inhibitor to make it an even better fit inside the virus.
But she said the current drug shows enough antiviral action against SARS-CoV-2 to proceed immediately to clinical trials.
“Typically for a drug to go into clinical trials, it has to be confirmed in the lab and then tested in animal models”, Lemieux said. “Because this drug has already been used to treat cats with coronavirus, and it’s effective with little to no toxicity, it’s already passed those stages and this allows us to move forward.”
“Because of the strong data that we and others have gathered we’re pursuing clinical trials for this drug as an antiviral for COVID-19.”
The researchers have established a collaboration with Anivive Life Sciences, a veterinary medicine company that is developing the drug for cats, to produce the quality and quantity of drug needed for human clinical trials. Lemieux said it will likely be tested in Alberta in combination with other promising antivirals such as remdesivir, the first treatment approved for conditional use in some countries including the United States and Canada.
In the meantime, the meta-analysis shows that ‘’hydroxychloroquine alone is not effective for the treatment of COVID-19 patients and that the combination of hydroxychloroquine and azithromycin increases the risk of mortality’’, say the authors who include Thibault Fiolet, Center for Research in Epidemiology and Population Health, INSERM, Institut Gustave Roussy and Paris-Sud 11 University/Paris-Saclay University, Paris, France.
“These data support current clinical recommendations such as those of the US National Institutes of Health (NIH) which do not recommend the use of hydroxychloroquine alone or in combination with azithromycin for COVID-19 patients.”
Chloroquine is used to prevent and treat malaria, while hydroxychloroquine is a less toxic metabolite of chloroquine and is used to treat rheumatic diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and Sjogren’s syndrome.
Hydroxychloroquine, in particular, has received extensive media coverage since the outbreak of the SARS-CoV-2 pandemic as a potential treatment for COVID-19. Azithromycin is used to treat a wide range of bacterial infections but has also been promoted as a potential treatment for COVID-19 due to its alleged antiviral or anti-inflammatory properties.
In this new analysis, the authors searched for studies that assessed chloroquine or hydroxychloroquine with or without the antibiotic azithromycin.
The authors found 29 articles that met their criteria, all except one of which were conducted on hospitalised patients and evaluated the effects of hydroxychloroquine with or without azithromycin.
Among the 29 articles, three were randomised controlled trials, one was a non-randomised trial and 25 were observational studies, including 11 with a ‘critical’ risk of bias and 14 with a ‘serious or moderate’ risk of bias.
After excluding studies with a critical risk of bias, the meta-analysis included 11,932 patients in the hydroxychloroquine group, 8,081 in the hydroxychloroquine with azithromycin group and 12,930 in the control group (who received neither drug).
The results showed that hydroxychloroquine was not associated with mortality, either in all trials combined, or in separate analyses of randomised controlled trials or observational studies. The relative risk of death for use of hydroxychloroquine was 17% lower than controls for all studies combined, but 9% higher in randomised controlled trials. In both cases, these results were not statistically significant.
However, the combination of hydroxychloroquine and azithromycin in patients with COVID-19 was associated with a statistically significant 27% increase in mortality compared with controls. The authors say:
“These results confirm the preliminary findings of several observational studies which have shown that the combination of hydroxychloroquine and azithromycin might increase the risk of acute, life-threatening cardiovascular events.”
The authors discuss limitations of their work which include the differing levels of COVID-19 disease severity across patients and also the actual definition of severity. Furthermore, most of the studies included were observational studies (not designed to find a causal relationship).
Finally, this meta-analysis did not include results from the European DisCoVeRy trial and the WHO Solidarity trial that are not yet published or communicated (but both have already discontinued their hydroxychloroquine arms).
The authors conclude: “There is already a great number of studies that have evaluated hydroxychloroquine alone or in combination and it seems unlikely at this stage that any efficacy will ever emerge.
‘’Our results suggest that there is no need for further studies evaluating these molecules, and the European DisCoveRy and WHO international Solidarity clinical trials have already discontinued treatment arms using hydroxychloroquine.”
