A major international study, published in the journal The Lancet, has concluded hydroxychloroquine or chloroquine treatment for COVID-19 is not safe or effective. The large-scale observational analysis encompassed nearly 100,000 subjects, finding the drug treatment potentially increases risk of mortality and cardiovascular events. In light of the study the World Health Organization has paused its trialing of the drug for COVID-19 treatment.

In the fog of a fast-moving global pandemic, as doctors across the world experiment with unproven treatments, hydroxychloroquine became one of the early contenders for a useful COVID-19 therapy. Approved for well over half a century as an anti-malarial treatment, hydroxychloroquine and the chemically similar chloroquine, have also been used to treat rheumatoid arthritis and lupus.

In the very early stages of the viral outbreak, doctors in China experimented with a number of different pre-existing drugs in the hopes that something could be repurposed to prevent infection, or at least improve patient outcomes. Hydroxychloroquine was one of those drugs, and initial anecdotal successes led to a wave of subsequent experimental uses as the novel coronavirus quickly spread across the globe.

Rigorous, randomized clinical trials are certainly underway, investigating the true efficacy of this experimental treatment for COVID-19. However, clinical research is a slow process, and in the meantime doctors across the world have already been treating patients with hydroxychloroquine.

A new Lancet study has gathered thousands of cases together to present the first comprehensive observational review of hydroxychloroquine’s efficacy in treating COVID-19. Data was analyzed from 671 hospitals spanning six continents, including 14,888 patients treated with some form of either hydroxychloroquine or chloroquine, matched against 81,144 COVID-19 patients included as a control.

Four different treatment variations were included in the study: chloroquine alone, hydroxychloroquine alone, chloroquine with a macrolide or hydroxychloroquine with a macrolide. Two specific outcomes were studied: overall mortality and occurrence of a cardiovascular event known as ventricular arrhythmia.

The study found all four treatment groups showed higher rates of overall mortality and ventricular arrhythmia, compared to patients not receiving the experimental therapy. Even after accounting for variables such as age, weight and pre-existing conditions, the drug treatment groups still displayed higher rates of mortality.

“This is the first large scale study to find statistically robust evidence that treatment with chloroquine or hydroxychloroquine does not benefit patients with COVID-19,” says lead author on the study Mandeep Mehra, from Brigham and Women’s Hospital in Boston. “Instead, our findings suggest it may be associated with an increased risk of serious heart problems and increased risk of death.”

The study is of course not the final word on hydroxychloroquine for treating COVID-19. It is observational, and cannot infer causality. It also does not examine whether hydroxychloroquine can function as a preventative agent against viral infection, or whether it may be effective in highly specific treatment scenarios. The research did, however, only include patients who commenced one of the four drug regimes within 48 hours of initial COVID-19 diagnosis. Patients at more advanced stages of the disease, or receiving other experimental antiviral treatments, were excluded from the large cohort.

The ultimate conclusion presented by the study is hydroxychloroquine, chloroquine and other combination treatments should not be administered outside of clinical trial contexts until further evidence can establish any potential benefit.

Stephan Evans, from the London School of Hygiene and Tropical Medicine, suggests although this study is observational it does offer good evidence examining potential benefits and harms from hydroxychloroquine or chloroquine. He points out, no definitive answer will be clear until larger clinical trials deliver results.

“A definitive answer still awaits the results of the randomized trials, but it is clear that the drugs should not be given for treatment of Covid-19 other than in the context of a randomized trial,” says Evans. “It might even be said that to go on giving them other than in a trial is unethical, given this evidence that is not yet contradicted by other available evidence.”

Whether or not the large volume of clinical trials currently underway investigating this very treatment should even continue is another question entirely. The Director-General of the World Health Organization revealed in a recent statement it has temporarily paused the hydroxychloroquine arm of its large global trials testing several potential drugs to treat COVID-19.

This decision was made after the Executive Group managing the international research, dubbed the Solidarity Trial, reviewed the current data, including this new Lancet study. A Data Safety Monitoring Board will now closely examine all available data on hydroxychloroquine and chloroquine to establish whether these treatment arms of the trial will resume.

The new study was published in the journal The Lancet.

Sources: Brigham and Women’s Hospital, The Lancet via Eurekalert