Few drugs have received as much recent publicity as the antimalarial drugs chloroquine and hydroxychloroquine. French researchers leaked their promising preliminary study on treating people with COVID-19 with these drugs. Then, Donald Trump announced that he was taking hydroxychloroquine preventively, and then the news was awash with stories of side-effects in studies of these drugs and WHO’s recommendation to stop treatment trials. The Danish researcher behind an ongoing trial of hydroxychloroquine regrets that the excessively high doses of these drugs administered in the published observational studies now threaten other potentially promising attempts to save people’s lives.
Although a vaccine for COVID-19 has not yet been developed, the first types of medicine that could potentially treat people with the disease have already emerged. To get the medicine into use as soon as possible, researchers have focused on existing drugs that could be effective. There have been many suggestions, but one of the most widely reported has been the antimalarial drugs chloroquine and hydroxychloroquine, after researchers suggested them as a possible treatment and then numerous trials were initiated worldwide.
An uncontrolled observational study showed serious side-effects, and this was emphasized so much that public authorities stopped randomized controlled trials worldwide. Since then, extraordinary safety assessments of the randomized controlled trials found that these drugs are safe and found no replication in the adverse side-effects reported in the observational study. Since then, the much-discussed observational study turned out to be have questionable data quality, and the authors and The Lancet have now retracted the article.
“Fortunately, our study found no serious side-effects. However, some studies have used chloroquine or hydroxychloroquine doses 3–4 times higher than the recommended dose, so having no side-effects in these trials would actually be surprising. We had also initiated a trial in which patients were to be treated with normal hydroxychloroquine doses and did not find any side-effects. The public authorities paused all studies with chloroquine and hydroxychloroquine in Denmark, including ours” explains Jens-Ulrik Stæhr Jensen, Clinical Research Associate Professor, Department of Clinical Medicine, Herlev and Gentofte Hospital.
"Now we have been allowed to start again, and we must assess over the coming months how much damage this whole controversy has caused, since many patients have probably rightly become somewhat confused and insecure. This may make recruiting trial participants difficult, so the article published in The Lancet and the reactions it triggered may delay the development of a potentially effective treatment for COVID-19."
Effective cocktail
Although multiple trials include hydroxychloroquine or chloroquine in the intervention, the ongoing project is the only trial currently recruiting worldwide to test the specific combination of hydroxychloroquine and the antibiotic azithromycin versus placebo. The aim of the trial is to investigate whether people who are acutely hospitalized and have tested positive for COVID-19 can benefit from treatment with hydroxychloroquine and azithromycin.
“The purpose is to find an effective treatment that can reduce hospitalization and intensive care and thus potentially reduce mortality. Both hydroxychloroquine and azithromycin have been approved for treating people with other diseases, and in laboratory experiments, hydroxychloroquine has been shown to inhibit the transmission of viruses and reduce the overreactive immune response some patients have,” says Jens-Ulrik Stæhr Jensen.
Chloroquine has been used as an antimalarial drug since 1934 and the slightly modified hydroxychloroquine since 1955. Azithromycin has also been used since it was approved as an antibiotic in 1988. Combined, the drugs are believed to have multiple effects in COVID-19.
“Hydroxychloroquine appears to affect the pH within the body’s cells, which has been shown to suppress coronaviruses in laboratory experiments, since viral replication is pH dependent. Many people with COVID-19 have bacterial superinfections, and azithromycin has been shown to be very effective in treating and preventing bacterial infections, especially among people with chronic obstructive pulmonary disease, asthma and bronchiectasis,” says Jens-Ulrik Stæhr Jensen.
The unexpected suddenly happened
In addition, azithromycin suppresses the immune response, so it reacts less strongly to viral infections by dampening the effect of cytokines, such as interleukin-6. These are important in fighting infections, but in COVID-19 they create such a strong immune response that patients almost drown. Finally, theories indicate that azithromycin may inhibit the enzyme furin, which appears to be necessary for the virus to attach its spike protein to the cells and invade.
“This seems to be a potent cocktail for fighting COVID-19 in theory, so we have received approval and funding to test the treatment on people to see whether the laboratory results can be confirmed in clinical practice. We are optimistic, since these drugs appear to both prevent viruses from invading and suppress the immune response to the virus attack,” explains Jens-Ulrik Stæhr Jensen.
The researchers were busy with their preliminary studies, including the usual study of drug safety. They did not immediately find any side-effects and had not expected any, since these drugs have been used safely for decades. They were therefore surprised by the events and the publicity that unfolded in May 2020.
“Of course, Donald Trump had started taking hydroxychloroquine preventively, and if there is anything that can bring people together in Europe, it is disagreeing with Trump, but this was nothing compared with the reaction to the article in The Lancet,” says Jens-Ulrik Stæhr Jensen.
Almost catastrophic
The study in The Lancet reviewed data from hundreds of hospitals in which patients had been given chloroquine and hydroxychloroquine, and the first problem arose from the fact that about one quarter of the studies had apparently used extreme doses of the drugs.
“You can compare this with taking paracetamol/acetaminophen: harmless in normal doses, but if you take 3–4 times the recommended dose, it can suddenly be fatal. Some of the patients in the study published in The Lancet received 3–4 times the recommended dose of chloroquine, and this had side-effects on the heart. In fact, I would have been surprised if the patients did not have the side-effects at such high doses,” says Jens-Ulrik Stæhr Jensen.
Although a parallel study in The New England Journal of Medicine showed no serious side-effects, WHO responded promptly to the article in The Lancet and recommended that studies be suspended worldwide until these effects were studied.
“This was nearly catastrophic at many levels. After all, we may seem to be merely delaying some clinical trials, but in a situation like the COVID-19 pandemic, this is serious because it may potentially cost people’s lives if it turns out that this treatment can actually help,” says Jens-Ulrik Stæhr Jensen.
The damage may already be severe
Jens-Ulrik Stæhr Jensen considers the effects on the scientific community to be equally serious. Although new medicines should always be introduced based on the precautionary principle, the article in The Lancet is problematic in many ways.
“I am mystified as to why the editor of The Lancet did not require stratification or at least some adjustment for doses. All the data for the study in The Lancet came from a company called Surgisphere that may have falsified the data. Finally, WHO’s response to recommend stopping all studies based on such suspect findings is deeply problematic,” explains Jens-Ulrik Stæhr Jensen.
After 180 international researchers protested against the study in The Lancet, the journal launched an investigation and the authors retracted their article. But the damage may already be severe.
“The story of hydroxychloroquine being potentially dangerous is already out there. We recently got permission to resume our study, but we strongly risk that both doctors and patients will stop participating, so our study and many other studies are in danger of having to end, thus losing a potential effective treatment for COVID-19. However, we will keep fighting to conclude our trial with the full number of patients, to inform patients and doctors worldwide as to whether this treatment is effective or not,” says Jens-Ulrik Stæhr Jensen.
The article "Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A Structured Summary of a Study Protocol for a Randomised Controlled Trial" was published in Trials.The Novo Nordisk Foundation awarded Jens-Ulrik Stæhr Jensen a grant of DKK 2,162,642 under its emergency coronavirus initiative programme to mitigate the impact of the COVID-19 pandemic for the project Proactive Protection of Inpatients with COVID-19 Lung Disease – Pro-Lung-COVID Trial. In 2020, the Foundation also awarded Jens-Ulrik Stæhr Jensen a grant for the project Understanding and Managing Chronic Obstructive Lung Disease via Time-updated Biomarker Strategies, Comorbidity Control via Microbiome Analysis. "Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis" was published in the Lancet and later retracted .
