Covid-19: What’s next for hydroxychloroquine?

Scientists across the world became interested in the drugs hydroxychloroquine and chloroquine after an in vitro study (done in a lab) in China in February 2020 showed promising results in combating Covid-19. The drug, which has anti-inflammatory and anti-viral properties, also showed promising signs in animal studies and in some small clinical studies done early in the Covid-19 pandemic.

Soon, the rush was on and countries like Australia and the US began stockpiling the drug previously best known as a treatment for malaria. 

Hydroxychloroquine has, however, to date not been proven effective to treat Covid-19 in humans, especially in placebo-controlled, randomised controlled clinical trials, considered the gold standard for medical evidence. 

While low-dose chloroquine has an extensive safety track record of long-term use for malaria prevention and treatment of auto-immune disorders like lupus, higher doses of chloroquine and hydroxychloroquine can be toxic and, among others, cause heart problems. Hydroxychloroquine is a less toxic version of its close cousin chloroquine. 

Major blow for hydroxychloroquine 

A major blow for hydroxychloroquine came on 5 June 2020 when British scientists stopped the hydroxychloroquine arm of the Recovery trial. The Recovery trial is a multi-arm randomised controlled trial that is comparing several potential treatments for Covid-19.

In the trial, a total of 1,542 patients were randomised to hydroxychloroquine and compared with 3,132 patients randomised to usual care alone. There was no significant difference between the two groups in terms of deaths or in other key indicators such as how long patients stayed in hospital.

The researchers said the drug does not work as a treatment for infected patients and it should not be used to treat patients with Covid-19 in hospitals. 

The findings have not yet been published in a medical journal. 

WHO trial to continue testing hydroxychloroquine 

Responding to the findings, the World Health Organisation (WHO) said on 5 June 2020 that the Recovery results would not change its plan to test hydroxychloroquine as part of its Solidarity trial. Similar to Recovery, Solidarity is a multi-arm randomised control trial comparing a number of different experimental treatments for Covid-19.  South Africa is one of over 70 countries participating in the Solidarity trial. (Spotlight previously reported on the Solidarity trial here.)

Dr Jeremy Nel, co-principal investigator of the Solidarity trial in South Africa, confirmed that it is going ahead with the hydroxychloroquine arm of the trial. In South Africa, the trial is being conducted in 14 hospitals in most of South Africa’s provinces. According to Nel, recruitment of patients hospitalised with Covid-19 at these healthcare facilities will soon begin.

“Chloroquine can block SARS-CoV-2 from replicating, by a number of different mechanisms including stopping the virus from entering the cell and stopping new virus from being produced by the cell,” says Nel.

Nel, head of the Infectious Diseases Division at Helen Joseph Hospital, University of the Witwatersrand, said the WHO is supplying the drug and has given the assurance that it has sufficient availability. 

Another setback 

Another disappointment for the drug’s use came on 4 June 2020 with the publication in the New England Journal of Medicine of findings from an eagerly awaited trial that tested the use of hydroxychloroquine to prevent Covid-19.

Researchers at the University of Minnesota in the US found hydroxychloroquine did not prevent people, who’d been exposed to others with Covid-19, from developing the disease. A total of 821 people were enrolled in this first double-blind randomised, placebo-controlled trial of hydroxychloroquine as a form of prevention. They were either living in the same household as someone with Covid-19 or were healthcare workers who had been exposed to someone with Covid-19 who had not worn adequate protection.

That trial did, however, have some shortcomings and some researchers remain hopeful of a role for hydroxychloroquine or chloroquine in the prevention of Covid-19.

SA participation in prevention trial 

Researchers in South Africa are taking part in a large international trial exploring the use of low-dose chloroquine as a form of Covid-19 prevention. The trial, called Crown Coronation, is expected to recruit healthy frontline healthcare workers soon. 

National co-principal investigator, Professor Bruce Biccard, makes an important distinction saying that it was a prophylaxis trial unlike the Recovery trial, which was a treatment trial.

“There is good evidence that chloroquine should have good antiviral properties, and there is nothing to suggest that it can’t be used for prophylaxis,” said Biccard, who is based in the department of anaesthesia and perioperative medicine at Cape Town’s Groote Schuur Hospital.

“The primary outcome of the trial is preventing infection, but we are also looking at severity of infection. So either you don’t get infected or you get infected with a milder form of Covid-19,” he said.

Internationally, the trial will recruit 30,000 volunteers, half of whom will be in Africa (Zambia, Zimbabwe and possibly Cameroon) with most healthcare workers enrolling in South Africa.

He pointed out that a low dose of chloroquine will be given – 500mg twice weekly and that there was no indication that low doses of chloroquine were harmful.

According to the National Department of Health, by 6 June 2020, 2,528 healthcare workers had already been infected and 23 died in South Africa’s public and private health sectors. The ability to provide healthcare services is impacted by healthcare workers becoming infected, as is already being witnessed in the Western Cape. The province currently accounts for just over 65% of all infections in the country. 

“We don’t have enough healthcare workers. Many are sick and this makes delivering a service really difficult. If we can decrease the rate of infection or decrease the severity of the disease, frontline healthcare workers can recover sooner and return to work sooner,” Biccard said.

“We are trying to recruit at a very high rate and hopefully to get a signal of benefit early. We want to make an impact during this pandemic, which will be around for a while. But even if we don’t manage to impact this pandemic, then we will impact the next one because these coronavirus epidemics seem to come every few years,” he said. 

Controversial study muddies the waters 

Controversy over the use of hydroxychloroquine intensified two weeks ago when The Lancet medical journal published a study that showed hydroxychloroquine was not effective in treating hospitalised patients with Covid-19 and that patients who got the drug were dying at higher rates and experiencing more heart-related complications than other infected patients.

The large observational study analysed data from 15,000 patients with Covid-19 who received the drug alone or in combination with antibiotics and comparing this data with 81,000 controls who did not receive the drug. 

The WHO responded by temporarily suspending the hydroxychloroquine arm of its Solidarity trial. It resumed its trials last week after the study was retracted on 4 June 2020 by its authors who could not vouch for its data.

The withdrawal of the study followed a statement to The Lancet from 150 clinicians who were concerned about the reliability of the data used in the study. An investigation by British media group, The Guardian found serious flaws in the data and raised concerns about the reliability of the analytics company Surgisphere and its CEO who was a co-author of the study. It was revealed that the company had also provided data for a New England Journal of Medicine study which has also since been retracted.

Peter Horby, professor of emerging infectious diseases and global health at the University of Oxford, who was a chief investigator in the Recovery trial, was quoted in The Guardian, pointing out that the retracted Lancet study was not a randomised controlled trial, but an observational study – comparing patients in hospitals who had been treated with the drug with others who had not. “One of the key lessons we should learn historically is that making treatment decisions based on observational data is not the way forward,” he said. 

Since the retraction of studies in two leading international medical journals, some researchers are concerned that perceptions of the potential benefits of hydroxychloroquine and chloroquine for Covid-19 have become negative and this could affect recruitment to future trials.  

Commenting on the retracted Lancet study, Nel said, “It’s unfortunate in that it has cast what appears to be an unjustified pall over the drug.” He hopes that this will not affect recruitment for the Solidarity trial.

Professor Linda-Gail Bekker, who is on the Crown Coronation trial committee, said the study had a significant impact. “It has a knock-on effect” in that it “makes people nervous”.

She said the team had been negotiating with the South African Health Products Regulatory Authority and their ethics committee when the article was published. “We had to make it clear that our dose was a tenth of the dose quoted in the Lancet paper. It made us have to work harder to convince people. When doing a prophylaxis trial in healthy healthcare workers, you have to be sure that it won’t do more harm than good,” she said. 

Bekker, who is the deputy director of the Desmond Tutu HIV Centre at the University of Cape Town, said that the regulatory authorities in the UK did temporarily hold back consent for the arm of the trial in that country.

The two journals will have to work hard at regaining credibility, she said.

“The pressure to get data out and to rapid peer review may have been the issue. These instruments of medical literature are incredibly powerful and with this comes huge accountability and when this is missing, they can become instruments of harm rather than good. It’s hard to find a balance, but we cannot compromise quality for speed,” she said. DM/MC

 Adele Baleta is an independent science writer, media consultant and facilitator.

*This article was produced by Spotlight – health journalism in the public interest. Sign up for our newsletter.