This post was co-written by Glen Pyle and Dr. Ryan Marino.

 

An international research effort is underway to solve the global pandemic. A vaccine for COVID-19 is months if not a year away and would not help those already infected. Current treatments largely consist of providing supportive care and allowing the body’s immune defenses to defeat the virus.

Research SOLIDARITY

The main effort to identify an effective treatment for COVID-19 is the global clinical trial called SOLIDARITY. The World Health Organization started SOLIDARITY to test four potential COVID-19 therapies: chloroquine or hydroxychloroquine; remdesivir; lopinavir and ritonavir; and a combination of lopinavir-ritonavir and interferon-beta.

Chloroquine & Hydroxychloroquine

Unpublished anecdotes suggest that the antimalarial agents hydroxychloroquine has both preventative and therapeutic effects on COVID-19; however, no evidence to support this claim has emerged. A small clinical trial from France reported some benefits of hydroxychloroquine treatment, but there are numerous problems with the study. In the treatment group 5 patients died, were transferred to the ICU, or could not tolerate the intervention, and were removed from analysis. Excluding 20% of patients because of negative outcomes presents a serious concern for the validity of the study.

More recently, preliminary results from a Chinese study of 62 moderately ill COVID-19 patients found minor benefit with 5 days of hydroxychloroquine treatment. However, concerns about patient recruitment and the clinical impact of the treatment cast doubt on the reliability of the study. By contrast, other small studies from China and France found no benefit of hydroxychloroquine treatment of COVID-19 patients. In total, studies fail to show any benefit to COVID-19 patients with hydroxychloroquine treatment.

Anecdotal evidence shows Hydroxycloroquine could be beneficial for COVID-19, but there is concern about its toxicity. Recent scientific studies show the drug has minimal or no beneficial effects on COVID-19 patients.

Lopinavir-Ritonavir

Lopinavir-ritonavir is an anti-viral medication used to treat HIV infection. Results from the LOTUS China study found no effect of treatment on clinical outcomes or viral load in 99 patients hospitalized with COVID-19. While these results were disappointing, a few observations provide incentive for further investigation. ICU time was reduced with treatment, and treatment was beneficial when started within 12 days of COVID-19 symptoms.

Remdesivir

Remdesivir, which was used for the treatment of Ebola virus, is a broad anti-coronavirus therapy. Ultimately its treatment for Ebola infections was unsuccessful, but the safety of the drug is generally established. There are conflicting media reports about studies that are examining the effectiveness of remdesvir. Recent statements by Dr. Anthony Fauci noted a faster recovery time and decrease in mortality in COVID-19 patients treated with remdesvir. However, the clinical trial supervised by the National Institute of Allergy and Infectious Diseases (NIAID), has not been peer-reviewed and the data have not been released. The only peer-reviewed study found some positive effects of the drug on 61 severely ill COVID-19 patients, but like many other studies examining novel treatments, there were significant limitations including the lack of a placebo control group.

Remdesivir is an antiviral drug that interferes with ability of SARS-CoV-2 to replicate inside human cells

ACE2

Outside of the SOLIDARITY trial, research is underway to discover new and novel treatments to reduce SARS-CoV-2 infection. Coronaviruses like SARS-CoV-2 use a protein called ACE2 to infect cells. Treatment with synthetic ACE2 may act as a decoy for SARS-CoV-2 and prevent infection. Pilot trials of synthetic ACE2 treatment for COVID-19 patients are currently underway.

The Fine Line of Risk-Reward

One significant concern about some proposed treatments is their cardiovascular side effects. Up to 40% of COVID19 patients have cardiovascular disease and their outcomes are worse: mortality rates for these patients are 50% higher than those with chronic respiratory conditions. The additional strain of treatments that stress the cardiovascular system could cause severe illness or death.

A study from Brazil found chloroquine treatment of COVID-19 patients was cardiotoxic and linked to a higher mortality rate. While these results are concerning, they have not been peer-reviewed and the study has a number of issues including the high dose used. Earlier studies showed chloroquine can cause heart failure. Chloroquine and hydroxychloroquine interfere with the metabolism of “beta-blockers” which are a class of drugs commonly used to treat patients with heart disease. Both hydroxychloroquine and chloroquine increase the risk of arrhythmias, including potentially fatal ventricular arrhythmias.

The risk posed by hydroxychloroquine has been hotly contested. Proponents argue that its widespread prescription for malaria, lupus, and rheumatoid arthritis equates to drug safety. While regular use of hydroxychloroquine for these conditions is not in question, many of these treatments are in countries without active drug safety surveillance systems, which limits confidence. In fact, the narrow safety margin and resulting toxicity are well-documented. Dosing required to effectively treat COVID-19 has not been determined and in some studies were not reported. The daily dose of 600 mg in one study is much higher than the amounts typically used for other conditions, further raising concern. Given the known risk for cardiovascular disease patients and the number of COVID-19 patients with cardiovascular disease, widespread treatment with hydroxychloroquine could cause real harm.

Short-term treatment with lopinavir-ritonavir carries risk for people with cardiovascular disease. Lopinavir-ritonavir interferes with commonly prescribed blood clotting medications including Xarelto, Plavix, and Eliquis. Studies in healthy volunteers showed that the anti-viral medication increased LDL, triglycerides, and total cholesterol after just a few days, as well as increasing insulin resistance. While the short-term effects of lopinavir-ritonavir on blood lipids and insulin are insufficient to cause diabetes or atherosclerosis, the stress these changes place on a body with cardiovascular disease and viral infection increase the risk of a fatal cardiovascular event.

Female medical school professor shows pre-med students a model the human heart.
One significant concern about some proposed treatments is their cardiovascular side effects.

Evidence-Based Decisions

Cardiology organizations like the American College of Cardiology support clinical trials for experimental COVID-19 treatments. Structured clinical trials are necessary to ensure patient safety and effectively measure the impact of treatments. All patients should be pre-screened for cardiovascular disease and risk factors, and a plan for monitoring cardiovascular complications included as a core element of clinical trials. Cardiovascular disease should not be a barrier to treatment: it should be carefully measured against benefits and informed decisions about treatment made based on the data, not an agenda.

The Path Forward

The global threat of COVID-19 requires a concerted effort to solve this monumental health problem. Biomedical and clinical research remain the most promising and effective tools to develop effective therapies. They must be supported and allowed to thoroughly test the benefits of any treatment and weigh them against the risks.


Glen Pyle, PhD

Glen Pyle is a Professor of Biomedical Sciences at the University of Guelph and an Associate Member of the IMPART Investigator Team Canada Network at Dalhousie Medicine.

He is currently a Heart and Stroke Foundation of Canada Senior Career Investigator for Improving the Heart and Brain Health for Women in Canada.

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