After grappling with the virus SARS-CoV-2 for more than a year, clinics still face the same reality they did months ago: There are no quick and easy fixes for treating COVID-19.
“I’m not surprised that we don’t have a magic bullet,” says the Cleveland Clinic’s Adarsh Bhimraj, one of the lead authors of the Infectious Diseases Society of America’s (IDSA) COVID-19 treatment guidelines. “None of the respiratory viral infections that we’ve known for all these decades and centuries has a magic bullet.”
Advances in treating COVID-19 have come piecemeal, with a combination of medications originally developed to combat other viruses and treatments shown to be safe and effective in treating the disease’s late-stage symptoms, such as steroids used to combat inflation.
But in recent months, clinical trials have pointed to several additional drugs that could join the COVID-19 tool kit. By themselves, each of these treatments confers a modest benefit. Their real power comes from stacking multiple treatments on top of each other—the kind of additive approach that, after years of research, has paid major dividends for other diseases.
“Think about the way people with heart attacks are treated: You have a stent, you have aspirin, you have blood-thinning agents, you have blood pressure treatments, you have statins—each of which is just taking the next chunk off the risk of dying,” says Oxford cardiologist Martin Landray, a co-principal investigator of the United Kingdom’s RECOVERY trial, the largest COVID-19 drug trial in the world.
Expanding the COVID-19 tool kit
For now, only two medications are widely agreed upon to be effective against COVID-19. The first is the expensive antiviral drug remdesivir, which shortens hospital stays by disrupting the virus’s ability to replicate, but it doesn’t seem to reduce the risk of dying from COVID-19. The other, the inexpensive steroid dexamethasone, is the only medication confirmed in clinical trials to reduce the risk of death among severe COVID-19 patients. “Hands-down, people believe steroids are useful,” Bhimraj says.
But researchers might be getting close to finding additional treatments that are safe and effective. Of the dozens of medications that Bhimraj and his fellow IDSA panelists are vetting, a few strike him as possible candidate treatments. One of them is the immune-modulating drug tocilizumab, an antibody currently used to treat rheumatoid arthritis.
Like dexamethasone, tocilizumab works by blunting the overzealous immune response that, in severe COVID-19 cases, can cause damaging inflammation. The two work in different ways, however. Dexamethasone reduces swelling and dials down the body’s inflammatory response. Tocilizumab suppresses a cell receptor that can play a part in frenzied “cytokine storms,” which can lead to damaging inflammation in COVID-19.
Previous trials looked at tocilizumab but didn’t find any benefit of note. But in recent weeks, two large, randomized trials found that the drug lowered the risk of death among hospitalized COVID-19 patients.
In January, the 19-country REMAP-CAP trial announced results from an 803-person test of tocilizumab and the related drug sarilumab. The results showed that critically ill COVID-19 patients who received the drugs were less likely to need a ventilator and survived more often than critically ill patients who didn’t receive the drug.
In the RECOVERY trial, which recruits from 180 sites across the U.K., researchers identified a 4,116-person group of hospitalized COVID-19 patients and randomly gave half tocilizumab and the other half a placebo. For patients on tocilizumab, the relative risk of death from COVID-19 was reduced by about 14 percent and the odds of being discharged from the hospital improved by about 20 percent when compared to patients who didn’t receive the drug.
Bhimraj says that while the results are promising, they will need to be fully vetted. “They're preprints, they're not peer-reviewed, right? So I take those with a pinch of salt,” he says.
Unlike previous trials, which might include dozens or hundreds of people, the RECOVERY trial has recruited more than 37,000 patients across the multiple treatments it’s tested. The trial’s sheer size gives its studies—which included the first clear evidence of dexamethasone’s effectiveness—enough statistical heft to see whether a given drug helps or harms COVID-19 patients. “If you added all the previous trials [of tocilizumab] together, they're substantially smaller,” Landray says.
For now, the U.S. National Institutes of Health (NIH) and the IDSA haven’t recommended tocilizumab as a COVID-19 treatment outside of a clinical trial.
Another drug that has recently shown some promise is baricitinib, a drug normally used to treat rheumatoid arthritis. The NIH recommends administering baricitinib with remdesivir in cases when patients with severe COVID-19 can’t receive steroids such as dexamethasone because of allergies or other medical conditions. On average, adding the drug cuts another day off of patients’ recovery times by curbing runaway immune system responses, versus receiving remdesivir alone, according to a trial published in December in the New England Journal of Medicine.
The treatment guidelines are also changing for convalescent plasma, which is antibody-rich blood plasma taken from COVID-19 survivors and given to patients. On February 4, the U.S. Food and Drug Administration limited authorization of the treatment to plasma containing high levels of antibodies, citing evidence that low-antibody plasma didn’t help. The updated guidance also limits convalescent plasma treatments to hospitalized COVID-19 patients still early in the course of disease.
Other treatments on the horizon?
Ongoing clinical trials continue to screen both well-known and brand-new medications for effectiveness against COVID-19. It’s still too early to know whether these treatments will pan out.
One promising treatment involves blood thinners such as heparin, which could help lower the risk of COVID-19-related blood clots and help keep patients from deteriorating. In a January 22 release, the U.S. National Heart, Lung, and Blood Institute announced that among 1,000 moderately ill patients admitted to hospital during three clinical trials, blood thinners lowered patients’ risk of needing to be put on ventilators. However, the institute stressed that blood thinners didn’t appear to help—and may even harm—COVID-19 patients who were already critically ill, echoing findings released in December.
“This is a compelling example of how critical it is to stratify patients with different severity in clinical trials—what might help one subgroup might be of no benefit, or even harmful, in another,” NIH director Francis Collins wrote in a February 2 blog post about the blood thinner results.
As researchers look at different severities of COVID-19 cases, some are focusing on preventing mild cases from progressing to the hospital at all. The Montreal Heart Institute’s COLCORONA trial, for example, is examining the anti-inflammatory drug colchicine, which is widely used to treat gout and some heart conditions.
In a news release and accompanying preprint released in late January, COLCORONA researchers claimed that among 4,488 participants with mild, at-home COVID-19 cases, colchicine helped cut the combined risk of hospitalization or death by about 21 percent, when compared to patients who didn’t receive the drug.
However, clinicians still view colchicine with healthy skepticism, since the study’s key stat—the 21-percent decline—is based on a small group of people. The trial had a low death and hospitalization rate overall, meaning that any one death or hospitalization could have an outsize effect on the results. Of the 4,488 enrolled patients, only 235 ended up in the hospital or died, including 104 who had been taking colchicine and 131 who didn’t receive the drug.
It’s also unclear whether the drug lowers the risk of death. Of the study’s 4,159 patients with lab-confirmed cases of COVID-19, five in the half receiving colchicine died, versus nine in the half without colchicine.
In February, Quebec’s clinical research institute INESSS said that it was “premature to support the use of colchicine in non-hospitalized persons with a diagnosis of COVID-19," according to the CBC.
In the meantime, other researchers are starting to study whether colchicine can help hospitalized COVID-19 patients with severe illness. Landray says that the RECOVERY trial is expanding to test colchicine as well as aspirin, baricitinib, and the antibody cocktail used to treat U.S. President Donald Trump in late 2020.
Experts stress that in the short term, however, the biggest boon to lowering the COVID-19 death rate won’t come from therapeutics; it’ll come from vaccines, which are ramping up in the U.S. and around the world. All of the currently authorized vaccines are highly effective at preventing life-threatening cases of COVID-19.
“The virus is adapting to us, but luckily, we adapt to it technologically with our brains—and we can adapt to it fairly quickly,” Bhimraj says.