Doctors on the Front Lines Are Testing New Therapies to Treat COVID-19
Researchers are racing to figure out which treatments might work
Researchers have been working furiously to identify medications and treatments to combat the novel coronavirus that causes COVID-19.
As scientists have better understood the virus, treatments have improved, leading to significantly better survival rates even for hospitalized patients. In one not yet peer-reviewed study of a New York City healthcare system looking at almost 4,700 hospitalizations, researchers found that the chance of dying while hospitalized fell from just over 25 percent near the start of the pandemic in March to 7.6 percent by late June. Significantly improved survival rates were also shown in a similar study from England.
Scientists attribute some of the improvements to therapeutics now being used and to the fact that more of the infections have been in younger people, who are less prone to serious side effects. Doctors have also identified some relatively simple measures that help, such as putting sick patients on their bellies or sides to open their lungs, making more invasive treatment less needed.
Some of the improvement probably also stems from behavioral changes, such as wearing masks. The authors of the New York study write that wearing a mask not only offers some protection in people getting or spreading the disease but also likely decreases the viral load among people who are exposed, lessening the chances of severe illness.
Some new drugs and treatments may also help. On Oct. 22, the Food and Drug Administration approved the antiviral drug remdesivir (under the brand name Veklury) to treat COVID-19, making it the first treatment for the coronavirus to receive full FDA approval. Remdesivir had previously received an emergency use authorization (EUA) allowing use in certain cases.
Despite the approval, there are still questions about just how effective remdesivir is—one recent large study from the World Health Organization found no improved survival rate for patients on remdesivir.
The FDA has also authorized emergency use of other treatments, such as convalescent blood plasma, an antibody-rich fluid donated by people who have survived a previous COVID-19 infection. Still, experts say more research is needed to know whether plasma is effective.
“While the data to date show some positive signals that convalescent plasma can be helpful in treating individuals with COVID-19, especially if given early in the trajectory of disease, we lack the randomized controlled trial data we need to better understand its utility in COVID-19 treatment,” Thomas File, MD, the president of the Infectious Diseases Society of America (IDSA), said in a statement in August when plasma was authorized.
That authorization was not the first time the rapidly evolving information on COVID-19 has led to confusion and conflicting advice.
The Basics of Hospital Care
Most people who contract COVID-19 can be treated at home and start to feel better after a week or so, but about one-fifth of patients experience worsening symptoms, such as difficulty breathing, according to the Centers for Disease Control and Prevention. It’s people with these more severe cases who may need to be treated in the hospital.
Care in the hospital is aimed at supporting patients as their body fights off the virus, Goepfert says. That entails supplemental oxygen to help people breathe, intravenous fluids if they are dehydrated, and antibiotics to treat secondary bacterial infections, such as pneumonia. If patients receiving oxygen still aren’t able to get enough of it into their bloodstream, doctors may put them on a ventilator to help them breathe while their body fights the infection.
Though COVID-19 remains a dangerous disease, improvements in hospital care are probably responsible for some improvements in survival rates. Putting patients in a prone position to open up their lungs may reduce the chances that they need to be put on a ventilator.
As doctors have better understood the virus, they’ve been quicker to recognize warning signs of rapid deterioration. And social distancing measures have helped prevent hospital systems from being stretched beyond their capacity, according to some researchers, though overwhelmed hospital systems remain a risk as case counts rise.
Remdesivir, originally developed by drugmaker Gilead Sciences to combat Ebola, is the first treatment for COVID-19 to receive full FDA approval.
“Today’s approval is supported by data from multiple clinical trials that the agency has rigorously assessed and represents an important scientific milestone in the COVID-19 pandemic,” FDA commissioner Stephen Hahn, MD, said in a statement.
The intravenous antiviral first appeared to help reduce the severity of COVID-19 in a study, sponsored by Gilead, of 53 hospitalized patients. But the study was small and did not directly compare those who got the drug with those who didn’t.
Results from an National Institute of Allergy and Infectious Diseases (NIAID) trial of 1,063 patients, published May 22 in the New England Journal of Medicine, found that those hospitalized with COVID-19 who received remdesivir recovered enough to be discharged or resume normal activities in 11 days, vs. 15 days in those who received a placebo.
Anthony Fauci, MD, director of NIAID, discussing the results in late April, said the mortality rate in the study, at 8 percent for those taking remdesivir compared with 11 percent for people on a placebo, “trended toward being better” but wasn’t statistically important. “The data need to be further analyzed,” he said.
A study in The Lancet around the same day had different findings. It found that of 237 patients with serious COVID-19, those given remdesivir did not recover faster or clear the virus more quickly than those given a placebo. The researchers wrote that they expected other, ongoing trials of remdesivir to “confirm or refute” their findings.
In the agency’s announcement, the FDA also cited two randomized controlled trials that found no significant difference between a five-day or a ten-day course of remdesivir. One of those studies found a significant improvement in symptoms between patients who received remdesivir and patients who did not, according to the FDA.
Remdesivir appears to be safe. And it has been recommended for some hospitalized patients with disease severe enough to require supplemental oxygen in treatment guidelines from the IDSA and the National Institutes of Health (NIH). But there are still questions about how much it reduces mortality.
The recent WHO study tested the drugs remdesivir, hydroxychloroquine, lopinavir, and interferon, either alone or combined with other drugs, on a study population of 11,266. Investigators concluded that none of the drugs seemed to reduce the risk of dying or the chance that a patient would need to be put on a ventilator.
In addition, studies using remdesivir are underway in people with milder symptoms. Like the antiviral drugs used against the flu (such as Tamiflu), remdesivir may work better if given soon after patients first develop symptoms, Goepfert says.
Other Experimental Drugs
With doctors sometimes trying multiple drugs in seriously ill patients, when people recover it’s hard to know what—if anything—helped. Or whether a drug caused harm. That’s why clinical trials are so important, Goepfert says.
Here are some of the therapies researchers are currently investigating.
Blood Plasma From Recovered Patients
This experimental therapy, called convalescent plasma, collects blood plasma from people who have recovered from COVID-19 and injects it into people fighting the disease. The idea is that survivors’ blood, which contains antibodies against the virus, may help recipients who are ill recover faster or may prevent the disease in those at high risk, such as frontline medical workers and those living with a COVID-19 patient.
Dating back to the late 19th century, the venerable treatment is a “great idea,” says Gregory Poland, MD, an infectious disease expert and director of the Mayo Clinic’s Vaccine Research Group in Rochester, Minn. “It has worked in many other infections, and therefore, there is reason to suspect it may be helpful.”
Early data from research in China was promising. A national initiative to investigate the therapy is still seeking plasma donors in the U.S. (Read more about how to help.) And in April, the FDA expanded the use of convalescent plasma to make it available to some patients with severe disease outside of clinical trials.
Then, in August, the agency authorized convalescent plasma for emergency use. Some researchers, including Frank Harrell, PhD, a professor of biostatistics at Vanderbilt University School of Medicine in Nashville, Tenn., have expressed concern that the benefits of plasma were overstated when the EUA was announced. The authorization was largely based on data collected from 35,322 patients who received plasma through the FDA’s expanded access program.
A study from the Mayo Clinic analyzing that data, which has not yet been peer-reviewed, indicated that patients who received plasma with high levels of antibodies were more likely to survive than patients who received plasma with low levels of antibodies. The study also found that patients who received plasma within the first three days after being diagnosed fared better than patients who received plasma on or after day four after diagnosis.
The body of evidence seems to indicate that plasma is safe, but it is not yet sufficient to say that we know that plasma works, says Shmuel Shoham, MD, an associate professor of medicine and associate director of the Transplant and Oncology Infectious Diseases Center at the Johns Hopkins University School of Medicine in Baltimore.
“What we don’t have are the randomized controlled trials, which are the gold standard to bring it home,” he says. Such trials involve a control group that does not receive the plasma treatment, something the Mayo Clinic study did not include. (Shoham, who is a fellow of the IDSA, is involved with two randomized control trials of plasma that are still trying to recruit patients.)
Even if additional data suggests that convalescent plasma is effective, it still is not a cure or even a scalable treatment—it’s just a stopgap measure, Poland says. The immunity conferred generally lasts only a few weeks. And because plasma from one patient treats only two or three others, it’s not practical for widespread use. “As a crowdsourced product, there could be problems with supply,” Shoham says. The IDSA still recommends that plasma be used only in the context of a clinical trial.
Monoclonal antibodies are created in a lab, based on the antibodies in blood plasma that researchers think are most crucial to fighting off an infection with the coronavirus. Theoretically, if these antibodies are given to a person quickly enough, they may be able fight off an infection before it becomes severe and potentially even prevent disease in the first place, according to Adarsh Bhimraj, MD, an infectious disease physician with the Cleveland Clinic who is on the panel that develops treatment guidelines for the IDSA.
But while there’s a long history of using monoclonal antibodies to treat certain diseases, Bhimraj says we don’t yet have enough data to say whether the monoclonal antibodies being developed for COVID-19 prevent illness.
Several companies, including Eli Lilly and Regeneron, are testing monoclonal antibodies. (NIAID is also conducting tests.) Both companies have announced what they describe as promising results from early clinical trials and applied for emergency use authorizations for their products, but neither has completed the large scale randomized trials that show products are effective and safe. At this time, neither NIAID or the IDSA has issued guidelines on the use of monoclonal antibodies.
Chloroquine and Hydroxychloroquine
Research shows that, in test tubes, these anti-malarial drugs can block coronaviruses such as the one that causes COVID-19 from invading cells. Scientists at first theorized that the anti-inflammatory effect of the drugs, which makes them useful against arthritis, could reduce the swelling in the lungs that can make it hard for people with COVID-19 to breathe.
Early evidence from experiments in humans with the virus were mixed. Ultimately, larger trials suggested that the potential harms may outweigh any potential benefits. “This drug may not be effective to treat COVID-19,” the FDA concluded in the June 15 letter (PDF) revoking its emergency use authorization.
What’s important to remember, Goepfert says, is that “none of these drugs is innocuous.” Hydroxychloroquine and azithromycin can trigger dangerous irregular heart rhythms, and the drugs may be more dangerous when given together.
Clinical trials are underway to study whether drugs such as sarilumab (Kevzara) and tocilizumab (Actemra), used to treat autoimmune disorders such as rheumatoid arthritis, could help prevent severe complications of COVID-19. Because the drugs help prevent the immune system from attacking healthy cells, researchers theorize that they may help quell the overactive immune response in COVID-19 patients (known as a cytokine storm) that leads to dangerous inflammation and damage to the lungs. But because of uncertainty about its efficacy and the risks of potentially harmful side effects, the IDSA suggests tocilizumab should not be used to treat hospitalized patients at this time.
Studies in test tubes and animals suggest that this HIV drug may work against other types of coronaviruses. But in a recent trial of 199 people with severe COVID-19 infections, those who took Kaletra fared no better than those who didn’t. Researchers hope the drug will work better if given earlier in the course of the illness. The IDSA advises that this combination should also be used only in the context of a clinical trial.
Doctors were cautious about using steroids early in the pandemic, according to the IDSA, because they can suppress an immune response and make it more difficult to fight off an infection. But as it became clear that many of the most dangerous symptoms of COVID-19 emerged because of an overactive immune response—known as a cytokine storm—research began to suggest that an inexpensive steroid called dexamethasone might help in certain severe cases.
A clinical trial involving thousands of patients, published July 17 in the New England Journal of Medicine, found that a 10-day course of dexamethasone significantly reduced deaths in patients on ventilators or on oxygen. There was no evidence of any benefit in patients who were not ventilated or on oxygen, and the study did not look at patients who were not hospitalized.
Based largely on that trial, the IDSA guidelines recommend steroids such as dexamethasone for hospitalized patients with severe COVID-19 but caution against their use in patients who do not require supplemental oxygen, warning that they may cause harm.
“Compared to other drugs that we have seen data for thus far, [dexamethasone] is the one that seems to have the greatest effect on patients, especially those who are critically ill,” says Krutika Kuppalli, MD, an infectious disease physician in the Bay Area and vice chair of the IDSA Global Health Committee. Still, she adds, doctors need more data to better understand potential side effects and long-term outcomes, especially because previous experiments using other steroids to treat COVID-19 have had variable results.
The Real Hope: A Vaccine
The most promising path for returning to prepandemic life is to immunize people to protect them against the virus that causes COVID-19. And researchers have made unprecedented strides toward quickly developing a vaccine.
As of Aug. 25, more than two dozen vaccines were being tested on humans in clinical trials and more than 135 others were in earlier stages of development, according to an analysis by The New York Times.
“Having a variety of approaches is important because this is a completely new pathogen, and we don’t yet know what will work,” says Ruth Karron, MD, director of the Center for Immunization Research at the Johns Hopkins Bloomberg School of Public Health.
If everything goes right, researchers estimate we could have at least one version of the vaccine—if not more—ready in spring 2021, according to Karron, or perhaps earlier. To put that in context, she says, “historically, vaccine development has taken 10 or 20 years.”
However, even after a vaccine goes through all the necessary testing to prove that it’s safe and effective, it still takes time to ramp up a global supply, she says. “We’ll know more by then about who the at-risk groups are and who we should prioritize to get the vaccine.”
Like the flu vaccine, a COVID-19 vaccine is unlikely to provide complete protection against the virus.
“The real goal is to protect against severe disease,” Karron says, so that even if you do get infected, you’ll be more likely to have a mild case and avoid serious complications, such as pneumonia.
—Additional reporting by Lauren F. Friedman and Kevin Loria