COVID-19 Hydroxychloroquine Studies Flawed, Experts Say

A pharmacy tech pours out pills of hydroxychloroquine at Rock Canyon Pharmacy in Provo, Utah, on May 20, 2020. (George Frey/AFP via Getty Images)

News Analysis

There are many studies on the effectiveness of hydroxychloroquine (HCQ) in treating COVID-19, but only a handful of them adhere to the highest scientific standards. Even those, however, fail to answer some of the most pressing questions.

The debate over HCQ turned into an information tug of war after President Donald Trump endorsed its potential early on. Each side now accuses the other of getting swayed by politics.

Each side has its arguments, but when they’re all put together, it turns out that some of the most crucial questions still haven’t been definitively answered. For example, is there a way to use HCQ to prevent the most at-risk people from dying of COVID-19, if caught early?

HCQ has been used for decades to treat ailments including malaria and lupus. It’s a cheap drug with manageable side effects, such as headaches, dizziness, and an upset stomach. In people with certain heart conditions, it can affect the heart rate, according to the American College of Cardiology, which recommended increased monitoring for at-risk patients.

In theory, HCQ should be helpful in inhibiting COVID-19 by prying open the infected cells to allow zinc, which is naturally present in the human body, to enter the cell and slow the replication of the virus.

Several doctors who have been both vocal and successful in using HCQ to treat hundreds of patients have explained that the point of using the drug is not necessarily to cure a patient or suppress all symptoms. Their argument is that HCQ can slow the virus down and allow the body to build up immunity against it so that the body can get over it on its own.

The main benefit should be to give people most at risk of dying of COVID-19, particularly the elderly, a chance to survive, with manageable symptoms and without a need for hospitalization. HCQ is thus best combined with a zinc dietary supplement and possibly an antibiotic, azithromycin, to prevent secondary bacterial infection, explained Dr. Vladimir Zelenko of Monroe, New York, who’s reported promising results among his patients.

Anecdotal evidence and a dozen studies indicate this is the case.

But none of these studies are both controlled and randomized, which diminishes their value. For a study to match the scientific golden standard, it needs to be conducted on a sufficiently large number of truly random people so the specific makeup of the group (such as its demographics) doesn’t influence the results. The group is then divided in half. One half gets the drug and the other, the control group, gets a placebo. The outcomes for the two groups are then compared.

Yale epidemiology professor Harvey Risch, one of the proponents of HCQ treatment, noted that many drugs have been adopted for use without randomized controlled trials.

But other experts remain unconvinced, pointing to the handful of randomized controlled trials of HCQ that do exist. None of them showed statistically significant benefits in treating COVID-19 with the drug.

Risch and others have criticized what they see as design flaws in these studies.

Some of the studies looked at hospitalized patients in serious conditions. But in those cases, it was already too late for HCQ to help, Risch argued. Others looked at people in early stages of the disease, but most of their participants were people under 50 without serious health issues. These people usually go through COVID-19 without serious complications anyway.

None of the studies used the HCQ-zinc-azithromycin combo that appears to have been the most effective in clinical practice.

Also, some of the studies included only a minority of people who’d actually tested positive for COVID-19. Other participants were included based on symptoms (such as cough, fatigue, headache, or fever) and risk of contact with the virus (such as by sharing workplace with somebody who’d tested positive). The virus that causes COVID-19, SARS-CoV-2, isn’t the only one causing such symptoms, leaving the possibility that some of the people didn’t have COVID-19 to begin with.

Furthermore, the studies used much higher doses of HCQ than what clinicians on the ground seem to recommend.

Zelenko prescribes 200 milligrams (mg) of HCQ every 12 hours for five days.

In contrast, the controlled randomized studies mostly used doses ranging from 1,200 mg to 2,400 mg in the first 24 hours, followed with 600 mg to 1,200 mg daily for the next 4 to 21 days.

This didn’t sit well with Meryl Nass, a physician and chemical toxicity expert.

“The drug is very safe when used correctly, but not a lot more can potentially kill,” she wrote in a June 14 blog post.

She pointed to a 1979 World Health Organization (WHO) review that said a single 1,500 mg dose of chloroquine base is considered toxic and 2,000 mg can be fatal (pdf). Chloroquine has similar potency as HCQ. A 200 mg HCQ pill contains 155 mg of the base drug. That suggests anything above 1,900 mg of HCQ at once can be considered a toxic dose, while a single dose above 2,500 mg could be deadly.

Moreover, it takes about a month for a human body to excrete half the ingested drug, “so the cumulative amount is important,” Nass said.

The 1979 paper notes that a daily base dose of 1,200 mg (about 1,550 mg in pills) “has been tolerated for at least a few days.” But it adds that this dosage “appears to be a limit which should not be exceeded.”

Nass specifically took issue with the United Kingdom’s Recovery trial, which used a 2,000 mg HCQ dose in the first 24 hours and 400 mg every 12 hours for nine more days (pdf). She also criticized the now-halted WHO’s Solidarity trial which proposed to use 1,600 mg in the first 24 hours and then 400 mg twice a day for nine more days, according to the Canadian and Norwegian arms of the trial.

Nass called these dosage regimens “non-therapeutic, toxic, and potentially lethal.”

Neither Nass nor representatives for the Solidarity trials respond to requests for comment.

Peter Horby, contact for the Recovery trial and Oxford professor of Emerging Infectious Diseases and Global Health, responded with the following comment:

“The loading dose and maintenance doses of hydroxychloroquine used in the RECOVERY trial were carefully selected based on knowledge of the absorption and distribution of the drug and the drug concentrations needed to inhibit the SARS-CoV-2 virus. The dose selection was done with a world recognised expert in the pharmacology of antimalarial drugs. ... The doses were designed to achieve the concentrations needed to inhibit the virus as quickly and safely as possible. We looked carefully at data on hydroxychloroquine toxicity. The doses used in RECOVERY are very unlikely to cause toxicity. ... Regarding the long half-life of hydroxychlroquine, the regimen we used is predicted to result in concentrations that are at the upper end of those observed in the treatment of rheumatoid arthritis.”

He referred to two studies, one on clinical pharmacology of HCQ and one on HCQ overdoses, that both indicated that HCQ doses used in the Solidarity and Recovery trials shouldn’t have reached potentially deadly levels. The overdose study estimated the dosages would result in about one in 50,000 risk of death for a 150 lb person and one in 500 risk of death for a 90 lb person. The study noted, however, that the estimates were based on some 300 overdose cases that involved people younger “than in the majority of more seriously ill COVID-19 patients.”

There has been at least one randomized controlled study by the U.S. National Institutes of Health (NIH) that used lower HCQ doses (800 mg on day one, 200 mg for four more days), but it’s been halted without publishing complete results. The NIH stated in a press release that the data indicated HCQ “provided no additional benefit compared to placebo control for the treatment of COVID-19 in hospitalized patients.”

Update: The article has been updated with a response from Peter Horby, contact for the Recovery trial and Oxford professor of Emerging Infectious Diseases and Global Health.