Why the most confusing part about Covid-19 may soon have a clearer answer

The disease has taken over our lives, but questions abound about the novel coronavirus.

In an effort to answer Inverse readers’ burning questions, we recently asked what they most want to know about Covid-19. More than a thousand respondents specifically addressed the question: What area do you think is most confusing about treating people with Covid-19?

For the overwhelming majority, 56.7 percent, it boils down to what treatment is best?

It’s difficult to give a definitive answer. Technically, the United States’ Food and Drug Administration has not approved any medicines specifically for the treatment or prevention of Covid-19. But following President Donald Trump’s positive diagnosis, the potential treatment options out there are under increasing scrutiny from experts.

• On Friday, a day after Trump announced he tested positive for Covid-19, his physician Sean Conley reported Trump received a dose of an experimental antibody cocktail developed by the biotech company Regeneron.
• Trump was also given the first infusion of antiviral drug remdesivir as part of a five-day treatment plan.
• On Saturday, Conley told reporters Trump had also received a dose of a common corticosteroid drug dexamethasone.
• Conley had dodged the question of whether the president also received supplemental oxygen.

Trump received what some commentators term the “kitchen sink” of therapeutics. As president, it is perhaps no surprise that he has access to exceptional healthcare and the best treatments available (although some experts say a “multi-pronged” approach of the kind described by Conley is overtreatment).

For now, the Regeneron treatment is only available for people participating in clinical trials, with a “limited product available for compassionate use requests that are approved under certain exceptional circumstances on a case-by-case basis,” a Regeneron spokesperson told The New York Times. That is how the president accessed it. The average American is not so lucky.

Remdesivir and dexamethasone, meanwhile, are readily available and accessible to people with coronavirus. In May, the FDA issued an emergency use authorization for remdesivir to treat severe cases of coronavirus. Dexamethasone is an inexpensive and commonly used steroid. It is frequently prescribed to suppress the body’s immune response from going into overdrive and attacking the body.

Inverse asked readers what confuses them most about the coronavirus pandemic. Over 1,000 people wrote in. Now we’re answering those questions with reporting and expert insight.

These two treatments, experts tell Inverse, appear to be the most promising treatments available — especially in the case of disease so severe that you end up in the hospital. But they also caution that this answer might change, as clinical trials evaluating these treatments and others alter our understanding of this pernicious illness and how it affects different individuals.

Dr. Robert Murphy, executive director of the Institute for Global Health at Northwestern University, puts it bluntly:

“If you end up hospitalized, the drug remdesivir will help. If you get really ill, dexamethasone can help,” Murphy tells Inverse. “Nothing else is approved, but that could change soon, as newer, more potent, therapies are being developed.”

Monoclonal antibody treatments do “look very promising,” notes Murphy. The Regeneron treatment Trump received is a combination of two monoclonal antibodies.

"If you end up hospitalized, the drug remdesivir will help. If you get really ill, dexamethasone can help."

Dr. Krutika Kuppalli, assistant professor of Medicine at the Medical University of South Carolina and one of the physicians called by the U.S. Congress as an expert witness on the coronavirus, agrees that these are the two best treatments currently available.

“They are not what I call ‘slam dunk therapies,’ but they are the two best therapies we have right now,” Kuppalli tells Inverse.

The search for a coronavirus treatment — One of the main players in the search for a Covid-19 treatment is the U.S. government’s Operation Warp Speed, a private-public initiative to produce and distribute a safe and effective Covid-19 vaccine. The FDA also has a Coronavirus Treatment Acceleration Program.

According to the latest update from the FDA, as of August 31, 2020, there are:

• More than 590 drug development programs in planning stages
• More than 310 trials reviewed by the FDA
• 5 Covid-19 treatments authorized for Emergency Use
• 0 Covid-19 treatments FDA-approved

Dr. Mojdeh Heavner is an associate professor at the University of Maryland School of Pharmacy and practices in the medical intensive care unit at the University of Maryland Medical Center. She tells Inverse that, because of evolving data, the way to keep up with “best treatments” for Covid-19 is to follow national and international public health guidelines — not the news cycle. In her own work, she has hewn closely to the recommendations from the National Institutes of Health.

“The danger we saw early on with the pandemic is the poor quality research that was quickly published and gained significant attention,” Heavner says. “The benefit of looking to the NIH guidelines is that the quality of evidence has already been vetted and a recommendation formed based on the consensus of experts.”

“We’ve come a long way with therapeutics,” she notes. Heavner highlights dexamethasone and remdesivir as two success stories. But she has “learned to never say never and never say always” when it comes to what the ‘right’ therapeutic is. She’s been surprised in the past by therapies panning out when she didn’t think they would, and vice versa.

What does dexamethasone do?

Future therapies aside, the treatments we do have are still questionable. Dr. Bryan McVerry, an associate professor of medicine at the University of Pittsburgh, notes it is difficult to answer the question of what drug is best. But in general, the best treatments for Covid-19 are “supportive in nature,” he explains.

“There is good evidence that for patients with more severe disease, that is patients requiring oxygen or intensive care support, a short course of relatively low dose corticosteroids is beneficial,” he tells Inverse.

“As such, hospitalized patients requiring oxygen or intensive care should be prescribed corticosteroids,” he adds. McVerry and his colleagues announced in September that corticosteroids, a class of drugs that lower inflammation and modulate the immune response, appear to improve the odds of survival in very sick patients.

Dexamethasone is a corticosteroid. It is similar to a hormone produced by the body’s own adrenal glands. It comes in either tablet form or as a drinkable solution, and is already used to treat various common ailments, including arthritis, intestinal disorders, and asthma.

A handful of papers conclude, both peer-reviewed and not, argue it's also effective in reducing mortality from Covid-19 (though there is concern it is less helpful for Black patients with severe cases, on average). In July, scientists published results from the RECOVERY trial, a large-scale clinical trial of various potential coronavirus treatments. In the trial, more than 6,000 people were given 6 milligrams of dexamethasone daily for up to 10 days. The results suggest the treatment resulted in lower mortality rates at 28 days, but the most marked difference was in the most severe of cases.

“This benefit was specifically seen in patients who were receiving oxygen therapy at the time of randomization, with even more benefit seen in patients who needed the ventilator,” Heavner says. Heavner was not involved in the study.

“Importantly, the benefit was not seen in patients who were not sick enough to receive oxygen therapy,” she notes.

The NIH recommends dexamethasone only be administered to coronavirus patients receiving supplemental oxygen, or who are on a ventilator. This recommendation is part of the reason some doctors felt concerned when they learned the president received dexamethasone.

“Generally you start dexamethasone when you’re starting to worry that they’re heading down the wrong path,” Dr. Rochelle Walensky, chief of infectious diseases at Massachusetts General Hospital, told CNN. “Either he progressed or people are like, well, let’s just throw the kitchen sink at him.”

What does remdesivir do?

Remdesivir is an intravenous medication — meaning it’s administered via IV drip — made by Gilead Sciences (the company is working on an inhaler version). Originally developed to treat Ebola, it’s an antiviral drug that targets RNA transcription and reduces the virus’ ability to reproduce.

In April, Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, said remdesivir could set a new “standard of care” for the coronavirus. That was in response to a study that found the median recovery time for people taking the drug to be 11 days. Study participants who were given a placebo recovered in an average of 15 days — the preliminary results hint people on remdesivir have a 31 percent faster recovery time.

The trial “established the role of remdesivir for Covid-19,” Heavner says. But again, some people may benefit from this treatment more than others.

“The patient population with the greatest benefit observed was those who were sick enough to require oxygen therapy but not needing the ventilator,” she says. “To me, this makes sense that it would be most beneficial to start an antiviral early in patients already showing some burden from the disease.”

In August, researchers also found that a 5-day course of the drug benefited people hospitalized with moderate cases of Covid-19. But McVerry notes that in comparison to corticosteroids, the data supporting antiviral treatment with remdesevir are less clear.

Who benefits, what dose is best, and whether there is an additional benefit to be had by combined therapies remains obscure.

“That being said, the current recommendation is to treat inpatients with Covid-19 pneumonia with a five-day course of remdesivir,” McVerry says. Notably, that was Trump’s treatment plan.

Matthias Götte is a professor and virologist at the University of Alberta and an expert in the study of antiviral drugs. Since the pandemic began, he and his team have discovered two mechanisms of action by the drug against SARS-CoV-2, the virus that causes Covid-19. Both make it more difficult for the virus to replicate.

Götte originally studied remdesivir “before the world knew about Covid-19,” back when it was only associated with Ebola and other coronaviruses.

“The landscape of therapeutics is very complex and rapidly evolving,” Götte tells Inverse. “Nobody knows whether or not this is the best antiviral or not. We just don’t have another comparison at this point.”

Remdesivir is promising, but scientists don’t fully know why and how it works, Götte says. He hopes future trials establish how the virus responds to the drug — and clearly demonstrate that remdesivir reduce its viral load. But the nature of the disease means it is not easy to test for that, he explains. You can use blood samples to measure viral load for illness like HIV and hepatitis C, but blood tests for Covid-19 aren’t reliable.

"The landscape of therapeutics is very complex and rapidly evolving."

It is also unclear why it doesn’t work for certain individuals. “The human body is another layer of complexity, and there could be reservoirs of the virus that the drug just doesn’t reach,” he speculates.

There are ongoing trials to see if other therapeutics could augment the effect of remdesivir, something that experts tell Inverse is needed. Remdesivir can help some patients; it’s possible that combined with another class of compounds, the antiviral effect can be stronger.

In August, NIH scientists launched the Adaptive Covid-19 Treatment Trial, a randomized, controlled clinical trial to evaluate the safety and efficacy of remdesivir combined with the immunomodulator interferon beta-1a. This is a medication approved in the U.S. and abroad for the treatment of multiple sclerosis. It has both antiviral and anti-inflammatory properties. Preliminary results from the study are expected this fall.

“We are all anxiously awaiting this data,” Götte says.

Update: On 10/22 the FDA approved remdesivir as a treatment for coronavirus. It was previously available through emergency use authorization. It is the first and only fully approved treatment for the novel coronavirus in the US. This announcement comes a week after the release of a preprint version of a World Health Organization mega-study, which found remdesivir did not increase a patient's chance of survival in severe cases. The drug is sold under the brand name Veklury.

What comes next — Unlike vaccines, the approval process for new treatments for Covid-19 appears to be “rather slow,” Murphy says.

“This should be a priority,” he says. “Ideally, you would want to test and treat everyone so you limit the extent of the patient’s illness and decrease their infectious rate to others.”

But there is also a danger of treatments reaching the public before they are completely vetted. McVerry notes that “we simply do not have answers at this time” regarding all the options because of ongoing trials, and it’s best to wait for good quality, peer-reviewed science.

Hydroxychloroquine is an example of how communication about a potential treatment can be badly mishandled, Kuppalli says.

“It should never have been touted as ‘this is a drug that’s going to save everybody,’” she says. “I was one of the people who voiced initial concerns over that study because it was small, and there were problems with the data. But, we had the person in the White House that blew it up into a big deal. It goes to show you how politicized the outbreak has become.”

“There are still a lot of myths out there” regarding what treatments work and what doesn’t, she says. There are still people who believe herbal medications can cure you, or disinfectants, she adds. As the country gets closer to the election, Kuppali worries there is a risk of politicizing the data and pushing out a therapeutic that’s not completely ready.

"For me as a person who’s worked on infectious disease outbreaks, who’s worked on healthcare security, who’s on the front lines of this and seeing it, it’s very disheartening."

“I feel like I’ve been saying the same thing for months now, but we need to let the scientific data lead how we respond,” Kuppalli says. We spoke the day after the first 2020 presidential debates. She was exhausted from two straight weeks of inpatient services, sometimes caring for 30 people at a time. Watching the debates, it seemed the candidates just didn’t understand what was going on, she says.

“For me as a person who’s worked on infectious disease outbreaks, who’s worked on healthcare security, who’s on the front lines of this and seeing it, it’s very disheartening,” she says.

“I see what it’s not just doing to people in my profession, but what it’s doing to patients. It feels a little bit raw at times.”

For some experts, a therapy available to treat people with coronavirus that actually prevents hospitalization is the holy grail. This is what’s really missing right now, Götte says: a drug, ideally an easy-to-take pill, that can be prescribed to patients early on in the course of their disease.

That is one of the most intriguing aspects of the Regeneron treatment Trump received, Heaver says. The 275 patients included in the preliminary report evaluating its effectiveness were not hospitalized, and other unpublished data indicate it may reduce viral load and improve symptoms when compared to a placebo.

“My heart aches for patients who have been hospitalized with Covid-19, and especially those who have ended up needing a stay in the intensive care unit,” Heavner says. “The long term battles faced by these patients and their families is what I hope we can someday avoid with therapies.”