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Ask the Expert: Are antiviral drugs available to treat COVID-19 infections? :

August 19, 2020

Editor’s note:Ask the Expert is a column that provides pediatricians with information on pressing topics related to COVID-19. Email your questions

Development of an antiviral drug is more challenging than development of an antibiotic agent because antibiotics generally are directed against a metabolic pathway that is unique to bacteria and not shared with eukaryotic cells.

Antibiotics such as penicillin, for example, inhibit specific enzymes (penicillin-binding proteins) that are essential for the synthesis of the bacterial cell wall (peptidoglycan). The rigid peptidoglycan enables bacteria to remain intact in the face of osmotic pressure. Penicillin prevents proper cross-linking of peptidoglycan during the last stages of bacterial cell wall synthesis. Lack of peptidoglycan results in lysis of the bacterium and impaired replication. Since peptidoglycan is not found in human cells, penicillin is selectively toxic for bacteria.

Viruses are obligate intracellular organisms that replicate largely by cannibalizing a host cell’s metabolic pathways using the same enzymes present in an uninfected host cell. An antiviral drug that interferes with viral replication is likely to interfere with an essential cell function, resulting in unacceptable toxicity. An example of a successful antiviral drug is oseltamivir, which is active against most influenza viruses because it binds to and inactivates a unique enzyme on a viral protein (neuraminidase). Oseltamivir has little activity against neuraminidase activity found in uninfected human cells, so toxicity for an uninfected cell is limited.


Remdesivir is an investigational antiviral drug that inactivates a specific viral enzyme (RNA-dependent RNA polymerase) that is unique to certain RNA viruses, including SARS-CoV-2, the coronavirus that causes COVID-19.

Coronaviruses contain an RNA molecule that carries the genetic information of the virus. In order for a coronavirus to replicate and cause disease, the viral polymerase makes multiple copies of the viral RNA, and these copies are incorporated in progeny viral particles. Inhibition of this enzyme causes little toxicity in humans because uninfected human cells have limited (RNA-dependent RNA) polymerase activity.

On May 1, remdesivir received emergency use authorization (EUA) for hospitalized adult or pediatric patients with proven or suspected severe COVID-19 infection. Severe disease is defined as a patient with an oxygen saturation ≤94% while breathing room air or a requirement for supplemental oxygen, mechanical ventilation or extracorporeal membrane oxygenation.

The safety, effectiveness and pharmacokinetics of remdesivir have not been assessed in pediatric patients. Modeling of pharmacokinetic data from healthy adults was used to derive pediatric doses.

Remdesivir should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus. Little information is available regarding the presence of remdesivir in human milk.

An EUA is different from Food and Drug Administration approval for an investigational drug. An EUA is issued following a declaration by the Secretary of Health and Human Services regarding an emergency situation. This happens when available data indicate a drug may be effective in treatment of a disease; no adequate, approved or alternative treatments are available; and the benefits appear to outweigh potential risks. An EUA remains in effect until data from subsequent experience justifies revision or termination.

At present, remdesivir remains an investigational drug that has not been approved or licensed but is the only antiviral agent with demonstrated benefit in patients infected  with COVID-19.

Remdesivir has been evaluated in two independent trials for the treatment of COVID-19 pneumonia in adults. Remdesivir is the preferred antiviral option for patients meeting eligibility requirements.


On March 28, an EUA was issued for oral chloroquine phosphate and hydroxychloroquine sulfate for treatment of COVID-19 infections in hospitalized adolescents and adults. This EUA was based on reports from China, Italy and France suggesting patients who received these medications with or without azithromycin had more rapid reduction in COVID-19 viral load than patients who did not receive these drugs. A reduction in viral load sometimes is used as a surrogate for antiviral activity.

Recommendations for use of these anti-malarial and rheumatologic drugs were included in guidelines from some countries impacted by COVID-19, including Korea and China. The Infectious Diseases Society of America and the Centers for Disease Control and Prevention did not make a recommendation for or against use of these drugs. When the EUA was issued for chloroquine and hydroxychloroquine use in COVID-19 patients, it appeared these drugs might provide benefit and that the benefit appeared to outweigh the risks of an adverse reaction.

This EUA was revoked on June 15 when results from a randomized clinical trial in hospitalized patients demonstrated that chloroquine and hydroxychloroquine were unlikely to be effective for treatment of COVID-19. Results did not demonstrate reduced mortality, hospital length of stay or need for mechanical ventilation. In vitro data suggested the recommended dosing regimens were unlikely to result in sufficient intracellular concentrations to inhibit the growth of SARS-CoV-2. Cardiac adverse events were reported, particularly prolongation of QT intervals when administered concurrently with azithromycin. Fatal cases of methemoglobinemia occurred. As these data became available, it was determined that the EUA was no longer justified and it was revoked.

Protease inhibitors

HIV protease inhibitors such as lopinavir/ritonavir are not recommended for treatment of COVID-19 infections (except in a clinical trial) because of the absence of data showing benefit in a clinical trial.

Convalescent plasma

Insufficient data are available to recommend convalescent plasma for treatment of COVID-19 infections. It is theorized that plasma from recovered patients may contain antibodies that will suppress viral replication or modify the immune response. Thousands of patients have received convalescent plasma through expanded access treatment trials.

At this time, clear evidence of benefit is not available, and uncommon severe adverse reactions have been reported, including death. Variability in SARS-CoV-2 antibody concentrations in convalescent plasma likely have an impact on the efficacy of plasma products. Currently, standards for screening donor plasma for neutralizing antibody concentrations have not been established.

Potential therapies that are not recommended at this time include baloxavir, nitazoxanide, estrogen products, interferons, ribavirin, niclosamide, famotidine and ivermectin.

A future column will address the status of dexamethasone and other immune modulators, mesenchymal stem cells and immune-based therapy for management of patients with COVID-19 infections.

Dr. Meissner is professor of pediatrics at Floating Hospital for Children, Tufts Medical Center. He also is an ex officio member of the AAP Committee on Infectious Diseases and associate editor of the AAP Visual Red Book.

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