The hydroxychloroquine conundrum

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A pharmacist displays the drug hydroxychloroquine. Photo by: George Frey / Reuters

MANILA — The World Health Organization’s decision to stop the hydroxychloroquine arm of a large-scale clinical trial, and the U.S. Food and Drug Administration’s revocation of the drug’s emergency use authorization has cast doubts over the drug’s potential to treat COVID-19 patients. But experts are divided on whether more research is required to rule out the efficacy of the drug.

Some have long been convinced the drug also known as HCQ bears no benefits in treating COVID-19, or if it does it will likely be small. For those stakeholders, the decisions taken by WHO and U.S. FDA are welcome, if not long overdue. But others argue not all aspects of the drug’s benefits have been ruled out to date — for example, on how beneficial the drug is as a prophylaxis.

Some researchers believe that there is still equipoise  — the absence of a definitive answer to the question of whether the drug works or not  — leading to continued trials in the search for that answer.

But so far, by nature of their design and size, studies have created a mixed picture of the drug’s efficacy. Some had a small population size and had raised design issues, while others had shown limitations.

For example, a large-scale randomized trial that tested hydroxychloroquine for post-exposure prophylaxis found no significant statistical difference between those who received the drug and those who didn’t, but that study wasn’t able to confirm whether COVID-19 was present in several of its participants because of the limited availability of diagnostic testing.

Dr. Tom Frieden, president and CEO of Resolve to Save Lives and former director of the U.S. Centers for Disease Control and Prevention, said that results of trials to date show that it is “unlikely that this drug will have a substantial benefit reducing death rates of patients with severe disease.”

However, he also said the potential role of hydroxychloroquine in preventing infection or severe disease when given prior to infection has yet to be studied rigorously.

“As a scientist and a doctor, I'd say simply, there's no evidence that it works. It has not been proven not to work for prevention. It has not been shown to be effective in several large studies, which suggests that it's not going to be a dramatic benefit to people on it, but we don't know for sure. So it's important that those studies continue and that we find out what the result is,” he told Devex.

“A randomized, blinded, placebo controlled trial is needed to fully understand whether this medication combination is useful or not for outpatients with COVID.”

— Dr. Davey Smith, professor of medicine, University of California San Diego

Others are more skeptical.

“Everyone's free to do whatever they choose to do and focus on,” said Dr. Katherine Seley-Radtke, professor of chemistry and biochemistry at the University of Maryland, Baltimore County, and president-elect of the International Society for Antiviral Research. She added that since the trials are focusing on different cohorts, then perhaps “we'll learn something more or it may just support the fact that there really is no clinical benefit.”

The jury is still out

The decisions made by WHO and U.S. FDA, needless to say, have yet to turn the lights completely off on hydroxychloroquine. Several research leads have told Devex they are forging ahead with their trials, both for the potential of the drug to prevent and treat COVID-19 and halt disease progression. 

Dr. Steven Tong, an infectious disease expert with Australia’s Doherty Institute, said they are continuing to include hydroxychloroquine in the Australasian COVID-19 Trial, or ACOT, which compares the effectiveness of hydroxychloroquine and lopinavir or ritonavir alone or as a combination in treating hospitalized COVID-19 patients.

While he said U.S. FDA should not have issued emergency use authorization for hydroxychloroquine in the first place, ASCOT will not be stopped based on these recent decisions.

“The main decision point will come when other trials publish their full results and we can then make an informed decision on whether to continue. We don’t want to be basing major decisions on press releases,” he told Devex over email, adding that their trial is designed to allow dropping of specific treatments while continuing to investigate others.

Meanwhile, researchers behind a large-scale study that proposes to evaluate the efficacy of drug interventions — the initial treatment being hydroxychloroquine — in community settings for high-risk individuals aged 50 and above, are monitoring outcomes of other randomized controlled trials, and regulatory agency decisions.

Similar to ASCOT, this study allows for drug interventions to be added and removed based on their own data analysis and external trials. The study is still awaiting ethical approval.

“As international studies are progressing, it is possible that we will have sufficient data about the efficacy (or lack of efficacy) of hydroxychloroquine before we are ready to actually start randomising patients to this drug. If that is the case, we would delete this drug from the platform and move on to other interventions (yet to be decided),” Dr. Guy Marks, professor of respiratory medicine at the Woolcock Institute of Medical Research and research lead, wrote to Devex.

Dr. Davey Smith, protocol chair of the National Institute of Allergy and Infectious Diseases-sponsored trial that aims to evaluate the efficacy of hydroxychloroquine in combination with the antibiotic azithromycin in preventing hospitalization and death for outpatients with COVID-19, told Devex last week that no study to date has evaluated the usefulness of these drugs’ combination for non-hospitalized persons with COVID-19.

Most, he said, have only investigated hydroxychloroquine’s use for hospitalized patients with very late stage disease, and many of them were designed in a way that could harbor inherent biases.

“Many of those studies were observational only and not randomized prospective controlled trials, thus with likely inherent biases. Thus, equipoise remains for this question. A randomized, blinded, placebo controlled trial is needed to fully understand whether this medication combination is useful or not for outpatients with COVID,” he said.

A clinical trial led by the University of the Philippines in Manila that aims to look at the efficacy of the drug as a prophylaxis in preventing COVID-19 infection will proceed, said Dr. Belen Dofitas, the trial’s principal investigator.

They are not yet recruiting patients for the trial, but Dofitas said the trial received technical and ethics review board approval. It also has a different target population from WHO’s Solidarity Trial.

“[The] PEP COVID trial will include only exposed [health care workers] who do not have COVID yet while the Solidarity trial included hospitalized COVID cases,” she told Devex over email.

“The main decision point will come when other trials publish their full results and we can then make an informed decision on whether to continue.

— Dr. Steven Tong, infectious disease expert, Doherty Institute

A study in Pakistan that looks at the efficacy of hydroxychloroquine when given in various doses as a preexposure prophylaxis in health care personnel will also continue, according to principal investigator Dr. Fibhaa Syed.

“Our trial is looking at HCQ in preexposure prophylaxis, not as a treatment option,” she said.

A potential consequence

There are concerns however that WHO’s decision to end its trial on hydroxychloroquine may affect recruitment for ongoing trials on the drug.

Dofitas surmises that it “may create doubts in the minds of HCWs [health care workers] about HCQ's efficacy and safety as a post-exposure prophylaxis.”

Smith, who is also head of the Division of Infectious Diseases at the University of California San Diego’s Center for AIDS Research, shared similar thoughts.

“Given all the mixed messages in the news, I think enrollment will be hard,” he said.

On June 20, NIAID said it will stop enrolment and close the trial, noting the U.S. FDA decision could further dampen enthusiasm for enrolment in studies evaluating the drugs hydroxychloroquine and azithromycin. The trial has only enrolled 20 patients since launching in May.

Two other trial leads told Devex they had withdrawn their study plans or are no longer recruiting new participants due to dwindling numbers of COVID-19 cases in their areas. Their decisions were made prior to the WHO announcement.

A study in Slovenia that aimed to investigate the therapeutic potential of the combined medication of hydroxychloroquine and bromhexine in hospitalized COVID-19 patients has not even gone onto recruitment stage as no more patients are being admitted to their intensive care unit.

A study in Alberta, Canada, that aims to investigate whether the drug reduces chances of COVID-19 progression to severe disease is continuing its follow up of enrolled patients, but no longer enrolling new ones due to the small number of cases there.

The hydroxychloroquine journey

WHO clarified that its decision to stop the hydroxychloroquine arm of its Solidarity Trial is not a policy recommendation, and therefore does not affect other clinical trials focused on the drug.

U.S. FDA also clarified that clinical trials studying both hydroxychloroquine and chloroquine, of CQ, drugs for the treatment and prevention of COVID-19 can continue. However, it no longer recommends using either drugs for the treatment of hospitalized patients with COVID-19 outside clinical trials, “after determining that it is unlikely that CQ and HCQ may be effective in treating COVID-19” and due to ongoing reports of serious side effects of the drugs. The agency said it has determined that “the known and potential benefits of CQ and HCQ do not outweigh the known and potential risks for its authorized uses.”

Their decisions follow the publication of the RECOVERY Trial in early June, and the now infamous large observation study published by The Lancet in May that has since been retracted after three of the study’s authors said they “can no longer vouch for the veracity of the primary data sources.”

The retracted Lancet study served as the trigger for a series of suspensions of hydroxychloroquine trials, including that of WHO, and others in the United Kingdom. WHO resumed its hydroxychloroquine trial on June 3, but decided to stop it altogether on June 17.

Meanwhile, the U.K. Medicines and Healthcare Products Regulatory Agency last week halted recruitment of patients in all U.K. clinical trials using hydroxychloroquine to prevent or treat COVID-19 “until further data which justifies their continuation have been provided, and any additional safety measures have been implemented.”

What next?

WHO dropping the hydroxychloroquine arm from its trial comes a day after another potential drug has caught the worldwide spotlight. A U.K. study found that dexamethasone, a steroid, was effective in reducing mortality rates for people on oxygen and those on ventilator support.

“I think what we're going to have to do, if we want to treat this properly, is to use two, three, or possibly more drugs at a time.”

— Dr. Jeffrey Aronson, clinical pharmacologist, University of Oxford

Early to tell whether this will trigger a shift in interest from hydroxychloroquine. Some experts said others will start looking at it. But so far, there are only a handful of studies looking at the efficacy of the drug. Hydroxychloroquine continues to dominate studies on COVID-19 treatments. Interest in the drug, many believe, was largely due to U.S. President Donald Trump’s promotion as a cure against COVID-19.

"In the beginning days of the pandemic, I think people were extremely desperate and they were looking for any possible ... answer that they could find. And so he just sort of was the catalyst to the fire," Seley-Radtke said.

But experts argue that the scientific community should not just be focusing on one medical treatment. Frieden said one of the potential treatment options he’s very interested in is the use of convalescent serum, or blood taken from people who survived from the viral infection and infusing the protective parts to sick patients.

“There are a couple of studies of it. It's hard to harvest enough of it, and it's hard to do the studies, but that's certainly a promising treatment that would be worth exploring further,” he said.

Another potential treatment is using direct-acting antivirals such as remdesivir, originally designed to treat hepatitis C but is more known for being tested against the Ebola virus. Seley-Radtke said the drug hasn’t received the same attention as hydroxychloroquine, but it has shown promise much early on in the pandemic.

But Frieden said the focus shouldn’t be just on treatment interventions alone.

“We need to look not only at things like what medicines worked, but what's the best way to do contact tracing? What's the best way to diagnose someone who is feeling ill? What's the best way to isolate or quarantine? What's the best way to stop spread in hospitals? I think sometimes we're a little bit too reliant on biomedical solutions, and not relying enough on good management,” he said, adding that infectious disease controls globally fail when it only focuses on biomedical treatments.

Dr. Jeffrey Aronson, a clinical pharmacologist at the University of Oxford and president emeritus of the British Pharmacological Society, shared that very few infectious virus diseases can be treated effectively.

“Once you've got the infection, you just have to wait for it to go. There's very little you can do about it, apart from supportive measures,” he said. "Although the recent results with dexamethasone look encouraging for treating severely ill people."

He explained that the SARS-CoV-2 virus is “very clever” and has got “all kinds of mechanisms for protecting itself,” making it difficult to treat the virus with just a single agent.

“I think what we're going to have to do, if we want to treat this properly, is to use two, three, or possibly more drugs at a time,” he said, similar to current treatment for HIV and AIDS.

“You send your troops to storm the back door. You send them around the side to scale the walls. And you batter down the door at the front. You attack it from all quarters. That way you are much more likely to succeed than just attacking from one direction,” he said.

Senior Reporter Lisa Cornish contributed reporting.

Update, June 24, 2020: This article has been updated to reflect that Dr. Katherine Seley-Radtke is professor of chemistry and biochemistry at the University of Maryland, Baltimore County, and president-elect of the International Society for Antiviral Research.

About the author

  • Jenny Lei Ravelo

    Jenny Lei Ravelo is a Devex Senior Reporter based in Manila. She covers global health, with a particular focus on the World Health Organization, and other development and humanitarian aid trends in Asia Pacific. Prior to Devex, she wrote for ABS-CBN, one of the largest broadcasting networks in the Philippines, and was a copy editor for various international scientific journals. She received her journalism degree from the University of Santo Tomas.