The COVID-19 pandemic and its disastrous global effects need no introduction. At the time of writing, there have been 13.3 million confirmed cases and 580 thousand deaths from the disease worldwide (WHO, 2020a). Besides these harrowing statistics, the virus has also resulted in the largest global recession since the Great Depression, caused widespread supply shortages, and upheaved billions’ daily lives. Scientists and world leaders realized that SARS-CoV-2 could wreak havoc early into the disease’s spread. Therefore, researchers have been tirelessly looking for possible treatments for months, starting as early as January 2020 (e.g. Wang et al., 2020). This is especially because the development of a vaccine could take years. With the pandemic looming over all our lives, it is important to stay informed about their progress with these treatments, and the outlook for future research.
While there are currently no government-endorsed COVID-19 treatments, scientists have been testing drugs previously shown to be effective against similar viruses, hoping to find one that could be used to fend off this strain of coronavirus. There are many such medicines being put through research trials; however, this article will focus on the two that seem most promising as a precursor to a real weapon against the pandemic: remdesivir and dexamethasone.
Remdesivir is a broad-spectrum antiviral produced by Gilead Sciences in 2009, originally designed to treat hepatitis C (Stephens, 2020). However, it was proven to be effective against other pathogens such as the ebola virus in 2016. When researchers treated ebola-infected rhesus monkeys with remdesivir, the virus was unable to replicate inside of the hosts’ cells, leading to 100% recovery rates for the subjects (Warren et al., 2016). This was a profound success. The drug has also been used to treat other viruses in the research setting, including the Marburg virus, measles, and even coronaviruses (Ko et al., 2020; Sheahan et al., 2017). Furthermore, remdesivir has saved lives in the African ebola epidemics, proving that it’s administration to humans is safe, with minimal side effects (Cao et al., 2020).
Remdesivir stops the spread of coronaviruses by the following mechanism. After remdesivir is injected into a patient’s bloodstream, it enters cells through passive diffusion, and the body metabolizes the drug into GS-441524, which is similar in structure to a DNA or RNA sequence (Agostini et al., 2018). This activates its antiviral capabilities. In a normal coronavirus life cycle, the virus infiltrates a hosts’ cell and latches part of its RNA genome onto one of the millions of ribosomes floating in the cell’s cytoplasm. Then, it commadeers the ribosome, using its protein-constructing capacities to create an RNA-to-RNA-polymerase (RdRp) capable of copying the virus’ entire genome (Jean et al., 2020). The RdRp protein then works to mass produce the entirety of the virus’ genetic code, spreading the infection. Remdesivir throws a wrench in this process: because GS-441524 is structurally similar to RNA, RdRp mistakes it for a genetic building block, and incorporates it into the new viral RNA (Ko et al., 2020). This renders any newly created RNA as useless, stopping the spread of the virus. Furthermore, remdesivir also inhibits viral exoribonuclease, specialized RNA “proofreaders” that would otherwise reverse the drug’s interference (Agostini et al., 2018). Importantly, remdesivir only targets viral polymerases, leaving the host cells’ natural machinery to continue functioning as intended (McKee et al., 2020).
Due to its ability to treat similar viruses, and its established safety profile, remdesivir was quickly identified as a prominent candidate for SARS-CoV-2 treatment. One of the first studies to investigate this possibility was performed in Hubei, China in February and March of this year. In a randomised, double-blind, placebo-controlled, multicentre trial, 237 SARS-Cov-2-infected patients were studied. 158 were administered an initial 200 mg and nine subsequent 100 mg daily infusions of remdesivir, while 79 were administered a placebo; afterwards, scientists could not find significant benefits or detriments to the patients due to the drug (Wang et al., 2020). However, the study was interrupted before the intended 453 subjects could be studied, as the steady stream of patients from Wuhan ran dry in March; thus, other researchers endeavored for a conclusive resolution on remdesivir and COVID-19. Another research study followed the same remdesivir administration methods as Wang et al., but cast a much wider net of 1063 participants. Those patients given remdesivir recovered in a median of 11 days, compared to 15 days with placebo; mortality rates were 7.1% with remdesivir and 11.9% with placebo (Beigel et al., 2020). While this is the first direct evidence that remdesivir could treat SARS-CoV-2, researchers acknowledged that it was not a coronavirus panacea, due to the relatively high mortality rate (7.1%). In another, international study, remdesivir was given on a compassionate-use basis (to patients with no other viable treatment options) to 53 participants. The subjects’ mortality rate was 13%, while 68% of subjects saw improvement in blood-oxygen levels after 10 days of treatment, indicating that the drug is partially effective against the virus (Grein et al., 2020).
On account of this evidence that remdesivir can indeed treat COVID-19, the European Union authorized the drug for use in its borders on July 3, and it has been approved for limited use in the United States (Veklury EPAR, 2020). However, there are concerns for the widespread use of the antiviral. Though side effects are limited, remdesivir is certainly not a cure for SARS-CoV-2, and further research must be performed to confirm its positive effects. Moreover, some researchers indicate that delivery by intravenous therapy alone is not adequate for recovery, and that inhalation of the drug is necessary (Sun, 2020). At the very least, health professionals can use remdesivir to fast-track the recovery of COVID-19 victims already on the road to rehabilitation, and as a stepping stone for research into a more efficacious coronavirus antidote.
Another burgeoning treatment for SARS-CoV-2 is dexamethasone, a corticosteroid used to treat a wide variety of illnesses, from arthritis, to severe allergic reactions, to tuberculosis. It is valued for its anti-inflammatory and immunosuppressive properties, and because it has relatively few side effects. One of COVID-19’s most dangerous manifestations is severe inflammation in the respiratory and associated circulatory system. This inflammation can lead to many life-threatening complications, including cytokine storms, acute respiratory distress syndrome (ARDS), and pneumonia. Therefore, scientists inferred that anti-inflammatory drugs, such as certain steroids, could be utilized to mitigate these symptoms of the virus, leading to a decreased death rate and rapid recovery.
The first studies to investigate such a link researched the effects of many steroids on COVID-19 patients, hoping to find one that is especially powerful. Some of these studies indicate that steroids were effective at treating patients, with medicated subjects recovering faster than those given placebo (Kolilekas et al., 2020; Fadel et al., 2020), while others’ results were inconclusive (So et al., 2020; Yuan et al., 2020). Additionally, a meta-analysis was performed on research examining the efficacy of corticosteroids in relation to COVID-19, encompassing 15 studies and 1,520 patients. Results from this analysis indicate that corticosteroids lead to an increased mortality rate for the average COVID-19 victim; however, the drug may have a positive effect on patients with severe conditions who require corticosteroid treatment to survive (Yang et al., 2020).
Thus, the influence of general corticosteroids on SARS-CoV-2 is uncertain; unfortunately, research concerning specifically dexamethasone is also unclear. Dexamethasone works by mimicking chemicals produced by the adrenal glands, such as cortisol, to suppress the body’s immune system responses and inflammation. For example, the drug obstructs the migration of neutrophils, impedes proliferation of lymphocytes, causes capillary membranes to become less permeable, increases levels of surfactant in the lungs, etc. (Johnson et al., 2020). This reduced immune response leads to less inflammation, helping to resist the onset of ARDS, pneumonia, and other deadly complications (Theoharides & Conti, 2020).
The prime research study in support of dexamethasone’s healing capabilities was performed by the Randomised Evaluation of COVID-19 Therapy (RECOVERY) Trial. 2,104 infected patients were administered 6 mg of dexamethasone daily, while 4,321 patients received standard care. 21.6% of patients treated with the anti-inflammatory drug died after 28 days, compared to 24.6% of patients who received usual care (Horby et al., 2020). Encouragingly, among patients receiving invasive mechanical ventilation, those treated with dexamethasone saw a 28.7% decrease in mortality rate, while patients requiring oxygen (without ventilation) saw a 14.0% decrease in mortality rate (Horby et al., 2020). This further supports the idea that dexamethasone is helpful for those with more severe cases of COVID-19.
Very limited research currently exists on dexamethasone and SARS-CoV-2, and much of their relationship is currently left to speculation. The World Health Organization states that dexamethasone can improve severe cases of the virus, but maintains that the drug should only be used in patients in critical condition and under close scrutiny (WHO, 2020b). Only certain aspects of the immune response to COVID-19, such as cytokine storms, contribute to harmful inflammation, while other aspects of the response, such as B and T Cell proliferation, serve just to combat the virus (Theoharides & Conti, 2020). Because use of dexamethasone also inhibits these helpful immune responses, it weakens the body’s abilities to fight the virus itself.
The hunt for viable COVID-19 treatments is of extreme importance to controlling the disease, alleviating strain on hospitals, and preventing further loss of life. Two drugs that currently hold some of the most potential are remdesivir and dexamethasone. Remdesivir interferes with SARS-CoV-2’s ability to replicate inside of hosts’ cells, putting an end to viral proliferation. In contrast, steroidal dexamethasone does not resist the virus directly, but suppresses the body’s immune and inflammatory response, lowering risks of complications such as ARDS and pneumonia. While dexamethasone clearly poses greater health risks than remdesivir, both drugs need to be researched far more extensively to optimize their healing capacities and minimize side effects. However, the COVID-19 pandemic has pushed researchers to scramble for new forms of medical care at record pace, and humanity does not have the time required to exhaustively research drugs such as dexamethasone and remdesivir. For now, researchers must continue to creatively pursue treatments with as efficient and sound research practices as possible.
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Written by Alex Borengasser
Edited by Devanandh Murugesan
Graphics by Tiya Shah