Politics aside, hydroxychloroquine could (maybe) help fight COVID-19

Editor’s note: On June 4, 2020, three of the authors on a May 22 Lancet paper cited in this story retracted their paper. The study found that taking hydroxychloroquine or chloroquine for COVID-19 raised the risk of death. Reports that the study might be based on faulty data provided by a company founded by coauthor Sapan Desai prompted the editors of the Lancet to issue an expression of concern about the study on June 3. Citing confidentiality, that company, Chicago-based Surgisphere Corp., declined to provide the data for an independent review, according to the retraction notice. “Based on this development, we can no longer vouch for the veracity of the primary data sources,” the other authors write.

President Donald Trump’s announcement that he is taking the drug hydroxychloroquine as a precaution against the coronavirus has once again thrown a decades-old antimalarial drug into the headlines.

There’s currently not enough data to say whether the drug can protect people from catching COVID-19 or from getting very ill if they do get infected with the virus. Studies of its use in treating very sick patients have shown mixed results and, in some cases, have led to dangerous side effects.

But now, with the president touting hydroxychloroquine even as scientists issue cautions about its use, the drug has found itself at the center of political divides, to the possible detriment of figuring out whether it works.

Nevertheless, researchers are busy testing hydroxychloroquine and a related drug called chloroquine to see if they can either prevent infection or keep illness from worsening. Nearly 200 clinical trials are under way or planned around the world to test the drugs, either alone or in combination with other medications. That includes at least 28 trials examining whether either drug can protect healthcare workers and others at high risk of getting COVID-19.

Here’s what scientists know about the drugs and their potential.

Why do researchers think chloroquine or hydroxychloroquine may prevent coronavirus infections?

Both are antimalarial drugs that also have well-known antiviral activity against many viruses, including SARS and MERS. At least they work against those viruses in lab dishes.

In lab tests, hydroxychloroquine can also stop SARS-CoV-2, the coronavirus that causes COVID-19, from infecting cells and decreases replication of viruses that do get inside cells, researchers report March 18 in Cell Reports. A February 4 report in Cell Research found that chloroquine also inhibits the virus.

The drugs are thought to block viruses from entering cells by changing the pH, or acidity, of cellular compartments called lysosomes. That “creates a less friendly environment for the virus, so it might be more difficult for the virus to get into human cells in the first place,” says Michael Avidan, an anesthesiologist at Washington University School of Medicine in St. Louis. Avidan is involved in a clinical trial testing whether chloroquine can protect healthcare workers from infection or from developing serious disease.

In addition, hydroxychloroquine and chloroquine disrupt interactions between some of SARS-CoV-2’s proteins with proteins called sigma receptors in human cells, researchers report April 30 in Nature. Interrupting those protein interactions may make it difficult for the virus to replicate, says study coauthor Adolfo Garcia-Sastre, a microbiologist who directs the Global Health and Emerging Pathogens Institute of Icahn School of Medicine at Mount Sinai in New York City. 

Together, those antiviral capabilities make the drugs attractive for use against the coronavirus. But there’s another important reason chloroquine and hydroxychloroquine were some of the first drugs pressed into action: They’re available. Doctors have been prescribing the drugs, already approved by the U.S. Food and Drug Administration, for decades and they’re generally safe, although there are some serious side effects.

“Time is of the essence,” says Adam Spivak, an infectious-disease doctor at the University of Utah in Salt Lake City. “When you have a drug that you understand and can safely administer that’s on the shelf, that’s the drug you reach for first.”

Hydroxychloroquine is better tolerated by most people, so is the one researchers are testing more often.

But isn’t taking hydroxychloroquine or chloroquine dangerous?

It can be for some people, such as those prone to heart problems, or when taken in combination with other drugs that can alter heart rhythms.

While hydroxychloroquine latches on sigma receptors proteins that are used by the virus, it can also bind to other proteins in the heart, Garcia-Sastre said in a news conference May 15. “It may not be the best drug that we can use right now to inhibit viral replication in people because of this.” Some other drugs also interrupt the coronavirus’s interactions with sigma receptors, but don’t bind to the heart proteins, which may make them safer alternatives to hydroxychloroquine, Garcia-Sastre said (SN: 4/30/20).

In trials with very sick people, hydroxychloroquine has caused sometimes fatal heart-rhythm problems. People with existing heart problems, those with low potassium levels or low oxygen levels in their blood are especially vulnerable to these serious side effects, says Raymond Woosley, a pharmacologist the University of Arizona in Phoenix.

The largest study to date, published May 22 in the Lancet, found that the drugs raised the risk of death for hospitalized COVID-19 patients. The findings are based on data from more than 96,000 coronavirus patients in 671 hospitals on six continents. Of those, nearly 15,000 received either chloroquine or hydroxychloroquine, either alone or in combination with a type of antibiotic called macrolides — usually azithromycin.

The researchers accounted for risk factors, including age, obesity, sex, underlying diseases, smoking and the severity of COVID-19 at the start of treatment. Among people taking hydroxychloroquine alone, 18 percent died; 16.4 percent of those taking chloroquine alone died; and combining either drug with a macrolide was associated with even higher numbers of deaths. In comparison, only 9.3 percent of people taking neither drug died.  The drugs were also associated with heart rhythm irregularities.

Those findings led a group overseeing a clinical trial for COVID-19 treatments for the World Health Organization to temporarily suspend testing of hydroxychloroquine, pending a safety review, WHO director-general Tedros Adhanom Ghebreyesus announced May 25. A committee will review data collected so far in the trial and decide whether to continue testing hydroxychloroquine. Testing for three other drugs in the trial will continue without pause.

Safety concerns about hydroxychloroquine have mainly come from use of the drug in people who are sick in the hospital with COVID-19, says Susanna Naggie, an infectious disease doctor at Duke University School of Medicine. She is leading a clinical trial testing hydroxychloroquine as a prophylactic to protect healthcare workers exposed to COVID-19 patients. Because of reports of harm in very sick COVID-19 patients, “people have kind of forgotten about the decades of safety data that we do have in an ambulatory, healthy population,” she says.

In places where malaria is a problem, people often take the drugs without any serious side effects, says Ira Baeringer, chief operations officer of Rising Pharmaceuticals, a company based in East Brunswick, N.J. that donated hydroxychloroquine and chloroquine for several large clinical trials.

So far, studies looking at hydroxychloroquine use before or early in infection haven’t produced any of the heart rhythm problems seen in studies of seriously ill patients. “When used alone, we’re not seeing major issues,” says Sarah Lofgren, an infectious disease doctor at the University of Minnesota Medical School in Minneapolis, where researchers are testing hydroxychloroquine’s ability to prevent COVID-19. “Out of our thousands of patients, we’re not seeing things people are quite concerned about, particularly the heart arrhythmias.”

Still, researchers are taking precautions when giving the drug to healthy people. People with existing heart problems, kidney disease or who are taking other drugs that may alter heart rhythms aren’t allowed to participate in the trials.

Isn’t there already evidence that hydroxychloroquine doesn’t work against COVID-19?

Yes, and no. Very few rigorous trials of the drug have reported data. Some people were given the drug in studies in which there wasn’t a control group that got placebos, and results from some of those studies have been mixed, with some reporting benefits, others showing no effect, and some indicating that the drugs may even be harmful for some patients. Even the latest data from the large multinational study in the Lancet combined studies that used the drugs in different doses and in different ways that may not be directly comparable.  

Hydroxychloroquine is also used to treat rheumatoid arthritis and lupus. It is effective against those diseases because it helps regulate the immune system’s responses, pushing away from harmful inflammation.

It’s clear that the immune system also plays an important role in COVID-19, Spivak says. So researchers thought that hydroxychloroquine might be able to calm overactive immune reactions that do damage to people with severe cases of COVID-19.

Early evidence from tests of the drug points to hydroxychloroquine having no effect in combatting the disease in seriously ill patients (SN: 4/21/20). The large Lancet study also failed to show any benefit.

But just because the drug didn’t seem to help in late stages of the disease, that doesn’t mean it won’t be effective if given early, perhaps even before people are exposed to the virus, Avidan says.

“If you bring on a star player consistently [only] in the last minute of a game and you’re still losing, you might say, ‘This star player is no good,’” Avidan says. “But that’s not a good use of your star player, because most of the outcome is already established at that very late stage.” Bringing a star in early to play the whole game, he says, may produce a much better outcome.

That’s exactly what researchers are attempting in multiple trials testing the drugs effectiveness as a preventative, or prophylactic, treatment for the coronavirus.

Some of those trials are just wrapping up — including two trials at the University of Minnesota — but aren’t reporting results yet. Others are still under way.

In Utah, Spivak and colleagues have begun testing 40 people of the planned 400 for a trial to determine whether hydroxychloroquine can shorten the duration of virus production in people who have tested positive. “If we get results by February, I’m going to be ecstatic,” Spivak says. “Although, February feels like a century away given all that is going on.”

For now, there’s no evidence that hydroxychloroquine or chloroquine can prevent COVID-19, but there’s also no evidence that they can’t.

So what’s the big deal about the president saying he’s taking hydroxychloroquine?

Doctors and researchers worry that based on the president’s endorsement, people will take the medications without medical supervision and could do harm to themselves. When President Trump first touted hydroxychloroquine in March, internet searches seeking places to buy the drug increased 1,389 percent, researchers report April 29 in JAMA Internal Medicine. Interest in buying the drug peaked again after reports of a fatal poisoning resulting from taking a fish tank treatment containing chloroquine, the researchers found.

“These drugs have been villainized and politicized,” Baeringer says. “That leads to hyperbole on both sides of the debate.”

Some researchers have voiced concern that so many people would take hydroxychloroquine on their own that researchers wouldn’t be able to find enough people not taking the drug to participate in clinical trials. That hasn’t happened, Spivak says. “The public has been appropriately wary of it,” he says. “The pendulum has swung. There was huge interest, then there was a lot of negative press and warnings. We’ve had a lot of local press stories where people came to us said, ‘Hey, wait, you’re still doing that?’ The science follows the pace of the news cycle.”

In Minnesota, enrollment in the studies has both fallen, and risen, with greater media and political attention, Lofgren says. One study recruited volunteers via the internet. Initially there was excitement and quick enrollment, but “as it became a political, partisan medication, our enrollment really dropped down,” she says. “This week we’ve had a bump in enrollment.”

And soon, researchers hope to have data that will say whether the drugs are effective or not.