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'Balancing Act': How Might HCQ Work (or Not) in COVID-19?

— Only clinical trials can prove efficacy of the drug against this virus, experts say

MedpageToday
A close up of a doctor holding a box of hydroxychloroquine tablets

Hydroxychloroquine, the antimalarial also used in the treatment of lupus and rheumatoid arthritis, has gained outsized stature for treating COVID-19 coronavirus due to its army of endorsers, but little is known about how it might work against the virus, experts said.

This drug may have initially received attention due to existing evidence suggesting it might have effectiveness against SARS, Warner Greene, MD, PhD, of the University of California San Francisco, and director of the Center for HIV Cure Research at Gladstone Institutes, told 鶹ý.

He added the drug could potentially block acidification that prevents the spike protein of SARS-CoV-2, the virus that causes COVID-19, from getting into the cytoplasm of a cell.

"Hydroxychloroquine, or chloroquine, can inhibit the attachment of the virus before it engages the ACE2 receptor," Greene said, as SARS-CoV-2 enters the cell by binding to the surface receptor via its spike protein. As the virus moves into deeper parts of the cell, it becomes more and more acidic, he added.

In an email to 鶹ý, Mark Cushman, PharmD, PhD, of Purdue University College of Pharmacy in West Lafayette, Indiana, noted, "the proposed mechanism [of hydroxychloroquine] is supposed to involve downregulation of the immune response (less inflammation) and inhibition of viral replication (the mechanism involves inhibition of viral entry)."

Because the drug would block or interfere with the acidification process, it could theoretically be used not only as treatment, but as prevention.

"If you block acidification of endosomes, then if a healthcare worker would happen to get infected with coronavirus, the theory is the infection would be blocked," Greene said. "But using it prophylactically like that, this is a drug with a lot of toxicity."

The mechanism of action of hydroxychloroquine is the same in other diseases, such as rheumatoid arthritis and lupus, Greene said, where hydroxychloroquine causes "interference with the antigen-processing macrophages."

In malaria itself, its original intended treatment, the drug blocks the acidification of the food vacuoles of the malaria parasite, he added. Chloroquine has been used as malaria prophylaxis, although Greene noted that chloroquine resistance has spread across the world, due to overuse of the drug.

But antimalarials do have some history of being tried for respiratory infections. People were trying quinine-based drugs for viral pneumonia in 1919, experts at the University of Pittsburgh Medical Center (UPMC) said in a press conference.

"Quinine is what's in gin and tonic. It's been used in malaria for hundreds of years," the UPMC experts said.

So, for hydroxychloroquine to work, it has to block this acidification process, and this has to work as well in the virus that causes COVID-19 as it works in other diseases where the drug is approved for treatment. But all of this obviously hinges on how effective the drug is in this particular virus.

"It's not a potent inhibitor of the acidification process. In the lab, we have four, five, six more compounds with more activity than this," Greene said. "It depends on how effective the drug is in terms of changing pH, blocking acidification. It's a balancing act."

This is in addition to concerns experts have previously raised about the lack of clinical trials proving the safety and effectiveness of the drug in patients with this particular virus.

"We need to do a well-controlled clinical trial in COVID-19 patients to establish whether or not hydroxychloroquine is really working," Greene said.

Cushman also noted prior research about the drug's potential cardiotoxicity.

"My major concern about this drug is that it can (rarely) prolong the QT interval, which is associated with arrhythmias and cardiac arrest," he added.

Indeed, several major U.S. medical societies have now issued warnings about using hydroxychloroquine plus the antibiotic azithromycin, due to this risk of sudden cardiac death.

Greene characterized most of the evidence for hydroxychloroquine in COVID-19 as "anecdotal" and added, "it's preposterous someone is pushing an unproven set of drugs in this disease," citing stories about how patients with arthritis have been unable to get their medications because of this interest in the drug to treat COVID-19.