Coronavirus Frontlines is a special series where we are sharing the perspective of experts at the forefront of combating the COVID-19 pandemic.
As the COVID-19 pandemic continues to affect communities throughout the world, the search for effective drugs remains a priority. We’ve heard a lot about two potential treatments, hydroxychloroquine (HCQ) and remdesivir (RDV), both of which are being tested in clinical trials. But what do we know about these compounds and how well they work?
The short answer is that both drugs were developed to fight other diseases, not COVID-19 specifically. There’s data that suggests that either may have some value in treating the disease, but it’s best not to get our hopes up until larger studies have been completed.
What we know about Hydroxychloroquine
HCQ is a derivative of chloroquine, and was approved in 1955 as an antimalarial treatment in the United States. More recently, HCQ has been used to treat rheumatoid arthritis and lupus, two autoimmune diseases characterized by a damaging inflammatory response.
HCQ’s ability to modulate the inflammatory response is one reason why it’s caught the eye of researchers. Inflammation is the body’s natural response to invasion by bacteria, viruses, or other substances. It’s caused by your immune system “attacking” and destroying infected cells or the foreign bodies directly. But sometimes that response can get out of control. In autoimmune disorders, the body mistakenly attacks itself. In COVID-19, the inflammatory response can be so great that it causes severe damage to the lungs, which is why patients with severe cases often need ventilators.
Surprisingly, how HCQ works to diminish the inflammatory response is not fully understood. Current research suggests that it interferes with the normal functioning of two Toll-like receptors, which are “signaling” proteins that your immune system uses to regulate inflammation. This interference may be why HCQ can work to reduce it.
Because HCQ has been used for over half a century, its side effects have been well-documented. Most notably, use, especially long-term use, has been associated with an increased risk of retinopathy, or damage to the retina. Some recent studies have also indicated that it may cause toxic side effects in patients taking other common drugs, such as metformin.
What we know about remdesivir
Remdesivir (RDV) was designed by the pharmaceutical company Gilead as a possible treatment for hepatitis C virus and respiratory syncytial virus. Some studies have shown that RDV may also inhibit other viruses that possess an RNA genome, including those that cause Ebola, SARS and MERS. Right now, it looks like RDV is effective because it looks very similar to a chemical that viruses need to reproduce. But when the virus errantly uses RDV, the replication stops. (If you’re interested, scientists from Gilead and the University of Alberta more completely described how RDV works in this study).
When it comes to the safety of RDV, the data are less clear. In limited human trials, elevated liver enzymes were reported, but a full assessment of its side effects have not been determined.
So, what do we know about these drugs and SARS-CoV-2?
Several groups of researchers have investigated the in vitro efficacy of these two compounds. In these experiments, scientists examined if the compounds can interfere with the virus’s ability to infect cells growing in the laboratory. Briefly, susceptible mammalian cells are grown in a Petri dish. These cells then are treated with various, defined concentrations of the compounds under investigation and then challenged with a defined amount of virus. After a specified period of time, the extent of viral replication is quantified. They then determine the percentage of cells that became infected, or measure the amount of virus that was produced. Those numbers are then compared to cells where the drug wasn’t introduced, which gives the researchers an idea of how potentially effective the drug might be.
In one recently published study, researchers used this approach to evaluate the in vitro effectiveness of several potential COVID-19 treatments, including chloroquine and remdesivir. The results were encouraging. A low concentration of CQ inhibited the virus by 90%. The results for RDV were even better – a 90% inhibition of the virus was achieved with an even lower concentration of this drug.
But cells are not the same as people.
How well these drugs work in people with COVID-19 is still being investigated. Here’s what we do know. On March 5, 2020, investigators reported in The New England Journal of Medicine that the first person confirmed to have COVID-19 in the United States was treated with RDV. Treatment began on the 7th day that the individual was in the hospital and 11 days after he first reported symptoms. A day later, he began showing signs of improvement. The RDV treatment may have led to this improvement - or perhaps his condition would have improved without RDV.
Researchers in France investigated the efficacy of hydroxychloroquine for treating people with COVID-19 in a single-arm protocol. In this study, individuals with the COVID-19 virus in one setting were treated with HCQ (and, in some cases, also the antibiotic azithromycin). Researchers measured the amount of virus in swabs taken from these individuals and a from group of individuals who did not receive HCQ. Over a period of six days, there was a greater decrease in the amount of virus from the individuals who received HCQ. However, the groups were not randomized. Individuals who did not receive HCQ were at various medical facilities and not necessarily like the individuals in the HCQ group.
The results are intriguing. But it’s important to note that scientists have expressed concerns about this study. Indeed, since the publication of these results, the group that publishes the journal it appeared in issued a statement that it did not meet the society’s “expected standard” for research.
The gold standard of a drug trial is a placebo-controlled, randomized, double-blind study. One group of participants should receive the investigational drug and one group should receive a placebo. The individuals in each arm of the study should be randomized; the demographics of both groups should be similar. Finally, the participants should not know if they are receiving the investigational drug or a placebo and the healthcare workers should not know which they are administering. Only under these conditions can we conclusively determine the effectiveness of a potential treatment.
Currently, several human trials of this type are underway. Soon, data from these studies will tell us much about the efficacy of hydroxychloroquine, remdesivir, and other potential SARS-CoV-2 treatments. But it won’t be until then that we can definitively assess whether these drugs will be useful against COVID-19.
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