Coronavirus news has been dominated by two big topics—epidemiology and vaccines. We hear less frequently about drugs used to treat the viral infection or its life-threatening sequelae. As coronavirus infections rise globally, treatments will increasingly focus on lessening the impact of the illness in the acute stage, and mitigating long-term adverse health effects. Toward this end, drug developers are examining both development-stage and already-approved medicines.
Coronavirus treatments correspond to the stage and severity of the disease. Asymptomatic and mild cases require no special treatment, or at most supportive care (e.g. analgesics for headache). Serious cases, including hospitalized patients and those in intensive care, are treated with approved drugs off-label, or medicines available through Emergency Use Authorizations (EUAs).
Many developed countries, including China, Japan, and the U.S., issue EUAs, but only a handful of drugs have received EAUs for coronavirus. Dozens of other antibiotics, antivirals, anti-inflammatory agents, and cytokines are used off-label to treat deadly symptoms or the coronavirus infection itself. And, as you read this, hundreds more are undergoing preclinical and clinical testing.
Critical Stages Dictate Treatment
According to the U.S. Centers for Disease Control and Prevention (CDC), choice of COVID-19 treatment depends on the stage of illness.
A search for "asymptomatic + coronavirus" at clinicaltrials.gov, the world's leading clearinghouse for clinical studies, shows 144 trials examining treatments for infected but asymptomatic patients.
Removing the term "asymptomatic" from the search yields 10 times as many studies conducted in almost every country on every continent. For example the website lists 76 Chinese and 17 Japanese studies.
Early in the course of symptomatic infection, when the goal is to prevent serious illness, physicians might prescribe one of two antibody treatments, bamlanivimab or Regeneron's casirivimab/imdevimab combination, to patients at risk for disease progression. At-risk patients may also receive the antiviral remdesivir. This is the point in the disease where treatment is dictated by the need to manage tissue-damaging immune or inflammatory responses.
The paradigm shifts noticeably for hospitalized patients requiring oxygen. Patients in this category receive remdesivir and the steroidal anti-inflammatory drug dexamethasone, either alone or in combination. Dexamethasone has a long history of safe, effective use but its administration is not without side effects, most notably dose-related changes in glucose tolerance, irritability, and appetite.
Physicians also prescribe dozens of drugs not on the CDC's list to manage coronavirus infection, including antivirals, immune-based therapies, anti-inflammatory drugs (including steroids), antimicrobials, and extracorporeal oxygenation. Immune-based coronavirus treatments include immunoglobulins and mesenchymal stem cells, dexamethasone and other corticosteroids, and JAK inhibitors, plus interferons and interleukins 1 and 6.
The UK Randomized Evaluation of COVID-19 Therapy (RECOVERY) clinical project, while by no means comprehensive, is representative of the current state of COVID-19 disease management. RECOVERY is examining just a handful of medicines: low-dose dexamethasone (now only recruiting children), the oral anti-inflammatory colchicine, the injected anti-inflammatory tocilizumab, convalescent plasma-containing coronavirus neutralizing antibodies, Regeneron’s antibody cocktail, and aspirin as a blood-thinner.
In addition to disease stage, prescribers must be aware of special patient populations—those with noteworthy preexisting conditions, who may be at additional risk due to either their health status or because of potential drug interactions.
Special populations include children, pregnant women, cancer patients, organ transplant recipients, patients undergoing cell-based therapies, and carriers of HIV. Exacerbation of side effects is one potential harm in these under-studied populations. Patients already burdened with another illness—the so-called "comorbidities" that put many coronavirus patients at risk—are most likely taking other medicines, raising issues of direct drug interactions and overlapping toxicities.
Drug companies and regulators normally go slowly when evaluating a new treatment. The economic, social, and health effects of the current global pandemic do not afford stakeholders luxuries like 12-year development times to obtain even EUAs, much less full approval. EUAs require many fewer study subjects than a Phase 2 or Phase 3 study. Clinical reports are therefore almost invariably mixed.
Ivermectin, the anti-parasitic drug used for both prevention and treatment of COVID-19, is an example. Some ivermectin studies show improvements, including survival benefits, while others do not. Ivermectin continues to be investigated for preventing COVID-19 infection.
Failures like ivermectin have not discouraged drug developers. Baricitinib, an oral Janus kinase (JAK) inhibitor, is under evaluation for preventing the cellular immune activation and inflammation that is common among coronavirus patients. Baricitinib was originally approved to treat rheumatoid arthritis but on November 19, 2020, FDA issued its developer an EUA for use with remdesivir in hospitalized patients requiring oxygen.
Adjunctive therapies are widely used in coronavirus patients to manage or prevent secondary complications. Since infection is frequently accompanied by a prothrombotic state and thromboembolic disease, several anticoagulant and antiplatelet agents are under investigation both as treatments and preventives. Adjunctive therapy may include oral vitamin supplementation or intravenous vitamin C.
Although vaccines to prevent coronavirus infection are receiving most of the publicity, an industry has evolved around treating the acute symptomatic stages of infection, primarily in hospitalized patients and those in intensive care. Guiding these treatments are large-scale studies like RECOVERY in the UK and other efforts focusing on drugs with the most promise.
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