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As many Americans have now heard, President Trump believes that the drug hydroxychloroquine is a “game changer” in the treatment of COVID-19. His endorsement of the antimalarial medication led to an extraordinary surge of interest in an otherwise obscure, preliminary study by a group of French doctors, which in the three weeks since it was published online has been analyzed, dissected and disputed all over the world — including by the administration’s infectious-disease expert Dr. Anthony Fauci, to whom it fell to explain that a study involving 36 subjects and lasting less than two weeks didn’t prove very much of anything.
But hydroxychloroquine is only one of a large number of drugs under investigation for COVID-19 therapy. As of Tuesday, a database by the National Institutes of Health listed 524 ongoing and proposed clinical trials related to COVID-19, up from 469 the day before, in laboratories and hospitals from the Pentagon to the Kermanshah University of Medical Sciences in Iran. At least 50 of the trials involve hydroxychloroquine (or a related compound, chloroquine) — in subjects of different ages, with different underlying health conditions, different symptoms or no symptoms at all, at a range of dosages, for varying lengths of time, alone or in combination with other drugs and with specified parameters to measure if the drug is doing any good. One of the most ambitious studies, at the University of Oxford, plans to enroll 40,000 participants in what Fauci has described as the gold standard of research studies, a “double-blind, randomized, placebo-controlled trial.” If that doesn’t prove hydroxychloroquine works — or doesn’t work — to treat COVID-19, it’s hard to imagine what will.
It’s always been a bit of a mystery why the coronavirus might be susceptible to hydroxychloroquine, which is a synthetic analogue of quinine, an extract of the bark of the cinchona tree, and has been used for centuries to treat malaria. Malaria is caused by a protozoan that is nothing like a virus, and the chloroquine drugs eventually proved useful in treating autoimmune conditions such as lupus, which also seems to have little in common with COVID-19. Bill Sullivan, a professor at Indiana University School of Medicine, published a lucid explainer here. (Short version: COVID-19 requires a slightly acidic environment to invade and replicate within human cells, and the chloroquine drugs make the cellular interior more alkaline. In case you were wondering, that doesn’t mean you can treat the virus by taking stomach antacids, or drinking quinine water, with or without gin.)
There are, of course, many thousands of drugs in the world, and it isn’t practical to test them all against the coronavirus. But laboratories appear to be ransacking their shelves in search of a workable antidote, preferably one, like hydroxychloroquine, that is already in widespread use and whose side effects are tolerable — or, in Trump’s blunt formulation, that “doesn’t kill you.” (That’s an optimistic assessment; one small study in Brazil was halted recently when subjects on a relatively high dose developed potentially dangerous heart-rhythm anomalies, and CNN notes that “the label for Plaquenil, a brand of hydroxychloroquine, says patients taking the drug have reported ‘life threatening and fatal’ cardiac problems and ‘irreversible’ vision problems.”)
Research is also underway in a wide range of topics. Some of these are:
Anti-inflammatories. This category includes hydroxychloroquine and familiar over-the-counter drugs such as aspirin. That interest reflects a growing conviction that some of the fatalities in COVID-19 aren’t caused by the virus attacking the body directly, but by an overly vigorous response from the body’s immune system, an overreaction that paradoxically damages the lungs and other organs more than the infection itself. Hydroxychloroquine has anti-inflammatory properties, which is why it is used to treat autoimmune conditions. So one goal of the studies is to understand how those two modes of action interact.
Azithromycin. Further complicating the picture, the hydroxychloroquine study Trump likes to cite also used azithromycin, a broad-spectrum antibiotic, to treat COVID-19. By definition, viruses aren’t killed by antibiotics, but could the coronavirus be an exception? Or does azithromycin work on COVID-19 because it also has anti-inflammatory properties? Or because it doesn’t really treat the coronavirus itself, but protects against opportunistic bacterial infections arising in patients already sick with COVID-19? Each of these possibilities has to be investigated by trying the drugs in different combinations, in different patients at different stages of the disease.
Antivirals. There is also considerable interest in an antiviral drug called remdesivir, which was developed to combat Ebola. Other drugs being studied include deferoxamine, which is ordinarily used to clear the body of a toxic buildup of iron, a mineral that viruses require for their replication; favipiravir, which inhibits RNA activity in the flu virus; and levamisole, a deworming agent that has been investigated as an immune-system booster.
Calcium channel blockers. These are drugs commonly used to treat high blood pressure, and that aren’t actually believed to work for COVID-19 at all. Instead, researchers at the National University of Ireland in Galway are investigating a theory that they can substitute for a different class of hypertension drugs, called renin-angiotensin system inhibitors. High blood pressure is considered a risk factor for COVID-19, which might, or might not, simply reflect the fact that hypertension is more common in older adults. But the Galway team is looking into the possibility that renin-angiotensin drugs might affect the ability of the coronavirus to invade cells — in other words, that the risk factor isn’t hypertension per se, but the drugs used to treat it. They hope to test it by taking people off angiotensin medications and giving them calcium channel blockers instead, and after a year seeing how many from each group get sick from COVID-19 — and, to give the full picture, compare it with the number who have strokes or other complications of high blood pressure. (Obviously, no one currently taking drugs for high blood pressure should discontinue them, or change to a different one, or change their dosage, unless their doctor tells them to.)
Miscellaneous ideas. Researchers are also investigating vitamin C, vitamin D and zinc supplements, which support the immune system, and the potential of hyperbaric (high-pressure) oxygen therapy as an alternative to using mechanical ventilators to support respiration. In the U.K., a community-based holistic health group is investigating the use of “herbs, lifestyle and yoga” to bring down fever and alleviate other respiratory symptoms. In Pakistan, researchers at Aga Khan University are looking into different kinds of mouthwash to see if they can reduce the viral load in saliva in order to protect dentists. And research is also underway on a variety of conditions associated with COVID-19, including depression, anxiety and stress resulting from living amid a pandemic, anxiety-induced migraines and frontline physician burnout.
Any of these approaches to the disease might prove helpful, but the breakthrough that could make them all unnecessary is a vaccine. A handful of trials getting underway, in China and elsewhere, are testing experimental vaccines — including an existing tuberculosis vaccine, known as BCG, which is believed to activate the immune system against respiratory disease. More vaccines are under development — but testing a vaccine is a multistep process to determine if it is safe, if it elicits an immune response and if the subjects who receive it are actually protected against the disease. None is likely to be in widespread use before next year.
Still, the concerted international effort to cure COVID-19 should give the world hope that eventually research can move on from studying the coronavirus.
Click here for the latest coronavirus news and updates. According to experts, people over 60 and those who are immunocompromised continue to be the most at risk. If you have questions, please refer to the CDC’s and WHO’s resource guides.