Umifenovir. Remdesivir. Favipiravir. Lopinavir. Tocilizumab.
Most of us have never even heard of these drugs, at least until recently. But they are all antiviral agents now being discussed—and in many cases studied or used empirically—to prevent and treat infections caused by the SARS-CoV-2 virus (COVID-19.)
None of these drugs has yet been proven beneficial for moderate to severe COVID-19. There has been considerable excitement about remdesivir recently based on partial anecdotal reports from a large multicenter clinical trial. More complete data and analysis from this trial may be available in the coming months.
In the meantime, all clinicians should have a basic understanding of the life cycle of the coronavirus, how various proposed pharmaceutical treatments may attack different parts of that process, and the known and expected side effects of each drug. Fortunately, the Journal of the American Medical Association just posted a superb article that provides an up-to-date review of these issues.
Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review
Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB
2020 Apr 13 [Epub ahead of print]
The SARS-CoV-2 virus enters the host cell after the viral outer spike protein attaches to the host's angiotensin-converting enzyme 2 (ACE2) receptor on cells in the respiratory tract. Once inside the cell, the virus releases its single RNA strand that codes for proteases, enzymes that cleave long viral polypeptides into functional viral-specific proteins, and polymerases that produce multiple copies of the viral RNA. Each step—viral entry, protease activity, and RNA replication—presents a potential target for drug therapy.
The drugs being discussed and studied as potential therapies for COVID-19 can be classified according to which part of the virus's life cycle they may attack.
Viral Entry Blocker
Chloroquine and hydroxychloroquine: Long used to treat malaria and some chronic inflammatory diseases, these drugs may impede viral entry by altering host cellular receptors. Small studies from China and France suggesting that they may be effective against COVID-19 have major limitations. Larger studies are under way. The authors noted that the therapeutic doses of chloroquine and hydroxychloroquine are generally safe, but they can cause significant adverse effects, including QTc prolongation, hypoglycemia, and central nervous system toxicity. Irreversible retinopathy is sometimes seen with long-term use. The authors recommend that patients being started on these drugs first get a baseline ECG to check for prolonged QTc. They noted that “no significant adverse effects have been reported for chloroquine at the doses and durations proposed for COVID-19.”
Umifenovir (Arbidol): This drug is used in Russia and China to prevent and treat influenza. In vitro data suggest that umifenovir may block the interaction between the viral outer spike protein and the ACE2 receptor, impairing membrane and enter the host cell. No data are available about its role in treating COVID-19 besides small observational studies. Therapeutic doses of umifenovir appear to have little toxicity except from occasional hypersensitivity or allergic reactions. To my knowledge, umifenovir is not being used or studied in the United States.
Viral Protease Inhibitor
Lopinavir/ritonavir (Kaletra): This oral combination is FDA-approved for treating HIV. No published studies demonstrate its effect against SARS-CoV-2, but in vitro evidence has shown antiprotease activity against other novel coronaviruses such as SARS. Significant drug-drug interactions are possible because lopinavir/ritonavir affects multiple enzymes in the cytochrome P450 system as an inhibitor and an inducer. Common adverse effects include gastrointestinal distress, hepatotoxicity with transaminitis, and elevated serum triglyceride levels.
Viral Polymerase Inhibitors
Remdesivir: Remdesivir inhibits viral RNA polymerase, the enzyme that allows the virus to mass-produce copies of its genetic material. The drug has been around since 2009 and has been used to treat Ebola. Remdesivir has in vitro activity against SARS-CoV-2, but so do almost all of the other drugs discussed in the JAMA paper. We are still a long way from knowing if it will ultimately improve clinical outcomes. The drug does seem to be relatively well tolerated, but has been associated with elevated liver enzymes.
Ribavirin: Ribavirin is currently used to treat hepatitis C and some viral hemorrhagic fevers, but its safety profile is distinctly unfavorable. The authors noted that the “high doses used in the SARS trials resulted in hemolytic anemia in more than 60% of patients.” In addition, 75 percent of patients had elevated transaminase levels. Ribavirin is teratogenic, and should not be given to pregnant patients.
Favipiravir: This drug is approved in Japan for treating influenza, where it appears to be well tolerated in the doses used. No good data on adverse effects are available that might be associated with higher doses. Studies are underway in China and Japan.
Tocilizumab (Actemra): Tocilizumab is a human monoclonal antibody against IL-6, an inflammatory interleukin crucial in producing cytokine storm, the out-of-control, runaway immune response associated with rapid deterioration and death in some patients with COVID-19. This drug is FDA-approved to treat rheumatoid arthritis. Adverse effects include increased incidence of respiratory infections, headache, elevated liver enzymes, and gastrointestinal perforation (rarely). Studies evaluating tocilizumab in patients with COVID-19 and severe lower respiratory tract infection are being conducted in China.
As the authors of the paper pointed out, this list was necessarily selective and provisional. Some of the drugs covered may never be used to treat COVID-19 routinely. Some like remdesivir are being used already, although proof of efficacy is not yet available. Some side effects mentioned might end up as unimportant with short-term use of these drugs; other effects might become apparent if higher doses than usual are needed in cases of COVID-19. This is a rapidly evolving area of medical toxicology. Another review of these drugs is worth reading. (J Med Toxicol 2020 Apr 30; https://bit.ly/2WIMeW1.)
Dr. Gussowis a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Follow him on Twitter@poisonreview, and read his past columns athttp://bit.ly/EMN-ToxRounds.