US Pharm. 2022;47(4):HS-1-HS-7.
ABSTRACT: COVID-19 virus prevention strategies and treatments have evolved since the pandemic began in 2019. While many therapies originally recommended for the treatment of COVID-19 have fallen out of favor, remdesivir remains a popular antiviral agent for inpatients with a COVID-19 diagnosis. Monoclonal antibodies have remained a mainstay of prevention throughout the pandemic and have been used in the inpatient setting.
The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in Wuhan City, Hubei Province, China, in December 2019.1 As of January 2022, there have been more than 315 million confirmed cases of COVID-19, with 5.5 million deaths reported to the World Health Organization. Different from both MERS-CoV and SARS-CoV, COVID-19 is the seventh member of the family of coronaviruses that infect humans.1 Genomic sequencing enabled the world to rapidly identify SARS-CoV-2 and allowed for rapid development of diagnostic testing, epidemiologic tracking, and development of both preventative and therapeutic options.2
The number of medical therapies to treat and prevent COVID-19 is expanding and evolving rapidly, including drugs approved by the FDA and those made available under FDA emergency use authorization (EUA). Currently, the only FDA-approved treatment for COVID-19 is remdesivir. In certain emergencies, the FDA can issue an EUA to provide more timely access to critical products (including medications and tests) when there are no adequate, approved, or available alternative options. There are currently 13 active EUAs for the treatment of COVID-19, and there are more than 400 active clinical treatment trials underway. This article aims to summarize major proposed treatment strategies for COVID-19.
Remdesivir, a broad-spectrum antiviral agent, is a prodrug that is metabolized into the active form GS-441524. The active form reduces viral RNA production by acting on viral RNA polymerase.3 Remdesivir was developed by Gilead Sciences in 2017 as a treatment for Ebola virus but has since been used to treat coronaviruses, such as MERS-CoV and SARS-CoV.4 On October 22, 2020, the FDA approved remdesivir for use in adult and pediatric patients (age ³12 years and weighing ³40 kg) for the treatment of COVID-19 requiring hospitalization.
The FDA approval of remdesivir was supported by the agency’s analysis from randomized, controlled trials that included patients hospitalized with mild-to-severe COVID-19.
ACTT-1, a double-blind, placebo-controlled trial conducted by the National Institute of Allergy and Infectious Diseases, randomized 1,062 patients to receive either remdesivir or placebo. Median recovery time was shorter in the remdesivir group compared with placebo (11 vs. 15 days; P <.001).5 Patients who received remdesivir were more likely to have clinical improvement at Day 15 compared with placebo.
Two additional randomized, open-label, multicenter trials sought to compare treatment with remdesivir for 5 days versus 10 days. The first trial found that the odds of a subject’s COVID-19 symptoms improving were statistically significantly higher in the 5-day remdesivir group at Day 11 compared with those receiving only standard of care. The odds of improvement with the 10-day treatment group compared with those receiving only standard of care were numerically favorable but not statistically significantly different.6 The second trial found that the odds of a subject’s COVID-19 symptoms improving were similar for those in the 5-day remdesivir group as those in the 10-day remdesivir group, and there were no statistically significant differences in recovery rates or mortality rates between the two groups.7
Monitoring and Adverse Effects
The most common adverse reactions (incidence ³5%, all grades) observed during treatment with remdesivir were nausea and increases in both ALT and AST.8 Other less-common adverse reactions reported (incidence £2%) included hypersensitivity reactions, generalized seizure, and rash.
Transaminase elevations have been reported in patients receiving remdesivir. Liver-function tests should be performed in all patients prior to receiving remdesivir and repeated routinely during treatment as clinically indicated. Clinicians should consider discontinuation of therapy if ALT levels increase >10 times the upper limit of normal, and therapy should be discontinued if ALT elevation is accompanied by signs or symptoms of liver inflammation.8
Remdesivir Considerations in Special Populations
Renal Insufficiency: The pharmacokinetics of remdesivir have not been evaluated in patients with renal impairment. Clinicians should obtain baseline renal function prior to administration of remdesivir and repeat routinely during treatment as clinically indicated. Remdesivir lyophilized powder contains sulfobutylether beta-cyclodextrin (SBECD).9 This vehicle is renally excreted, and accumulation of SBECD in patients with renal impairment may result in nephrotoxicity.10 However, all formulations of remdesivir contain amounts of SBECD that are below the maximum recommended safety threshold.10
Patients with renal dysfunction were excluded from the majority of clinical trials with estimated glomerular filtration rate (eGFR) cutoffs in the literature ranging from <30 mL/min to <50 mL/min. The FDA product labeling does not recommend use of remdesivir in patients with an eGFR <30 mL/min, as data among individuals with this level of renal impairment are lacking.
Observational studies evaluating the use of remdesivir in hospitalized patients with COVID-19 found no significant difference in the incidence of acute kidney injury between patients with a creatinine clearance >30 mL/min versus <30 mL/min.11,12 These observational data, coupled with the limited duration of treatment and relatively low concentrations of SBECD vehicles, suggest that remdesivir can be used in patients with a creatinine clearance <30 mL/min if the benefits outweigh the risks.
Pregnancy: Clinical trials that evaluated the safety and efficacy of remdesivir for the treatment of COVID-19 excluded pregnant patients. Among 86 pregnant patients who received compassionate-use remdesivir, recovery rates were high (89%), with low incidence of serious adverse events (16%).13 Most adverse events reported were related to pregnancy and underlying disease. Remdesivir should be considered as a treatment option in pregnant patients if benefits outweigh the risks.
Pediatric Patients: Data on the safety and efficacy of remdesivir in hospitalized patients aged younger than 12 years or weighing <40 kg are limited, as these populations were excluded in clinical trials. The FDA has authorized an EUA for remdesivir in hospitalized pediatric patients weighing 3.5 kg to <40 kg or aged younger than 12 years and weighing >3.5 kg. The limited data available from the compassionate-use program suggest that remdesivir was well tolerated in pediatric patients meeting the EUA criteria. Data on young infants and neonates are limited.14-16 The CARAVAN clinical trial is currently evaluating the safety, tolerability, and pharmacokinetics of remdesivir in patients aged 0 days to 18 years.
As proven therapies for COVID-19 are limited, the mainstay of therapy for COVID-19 patients remains supportive care. This includes a wide range of therapies and inpatient support with corticosteroids, monoclonal antibodies, and anticoagulation.
Many randomized, controlled trials have shown the benefit of corticosteroids in the treatment of COVID-19 by improving clinical outcomes and reducing mortality in hospitalized patients requiring supplemental oxygen.17 The anti-inflammatory properties of corticosteroids reduce host inflammatory response and exudative fluid in the lung tissue and prevent further diffuse alveolar damage, thereby improving hypoxia and minimizing the risk of respiratory failure.18 There are no data available to support corticosteroid use in patients with COVID-19 who are not hospitalized.
Clinical Evidence: The RECOVERY trial was an open-label, multicenter trial that randomly assigned 6,425 patients to receive oral or IV dexamethasone (at a dose of 6 mg daily) for up to 10 days or to usual care alone. Twenty-eight-day mortality was lower in the dexamethasone group compared with standard of care for patients who were mechanically ventilated (29.3% vs. 41.4%; 95% CI 0.51-0.81) and patients on supplemental oxygen (23.3% vs. 26.2%; 95% CI 0.72-0.94). There was no difference in 28-day mortality between groups for patients not on any respiratory support (17.8% vs. 14.0%; 95% CI 0.91-1.55).
Systemic corticosteroids other than dexamethasone, including hydrocortisone and methylprednisolone, have been studied for the treatment of COVID-19; however, several trials evaluating the use of alternative corticosteroids were stopped early due to under enrollment following the release of the RECOVERY trial results.19-22 Evidence to support the use of other corticosteroids for the treatment of COVID-19 is not as robust as the available evidence for dexamethasone.
Recommendations for Alternative Corticosteroids: Based on available evidence, the National Institutes of Health (NIH) currently recommends that alternative corticosteroids such as prednisone, methylprednisolone, and hydrocortisone can be used if dexamethasone is not available. When using alternative corticosteroids, the total daily dosage should be equivalent to 6 mg of dexamethasone (IV or oral), which is 40 mg of prednisone, 32 mg of methylprednisolone, or 160 mg of hydrocortisone. It is important to note that half-life, duration of action, and frequency of administration vary among corticosteroids.
The spike protein on SARS-CoV-2 is broken into two subunits that mediate invasion and host-cell attachment. Viral entry of SARS-CoV-2 into the host cell occurs through the binding of a spike subunit to the host cell’s angiotensin-converting enzyme 2. Anti–SARS-CoV-2 monoclonal antibodies (mAbs) target this spike protein and have been shown to be effective in treating and preventing COVID-19 infection.23
Postexposure Treatment Options—Bamlanivimab/Etesevimad and Casirivimab/Imdevimab: The FDA authorized an EUA for bamlanivimab/etesevimab and casirivimab/imdevimab to be used as postexposure prophylaxis (PEP) in select individuals meeting certain criteria. However, with the increasing prevalence of the Omicron variant, it is expected that these agents will not be active for PEP of COVID-19, and the NIH advises against their use.9
Inpatient mAb Treatment Options—Tocilizumab and Sarilumab: Tocilizumab and sarilumab are anti–interleukin-6 receptor mAbs. Interleukin-6 is a proinflammatory cytokine that is induced by SARS-CoV in bronchial epithelial cells.24 It is recommended that tocilizumab and sarilumab only be used in combination with dexamethasone or another corticosteroid. They should be used with caution in those not represented in the clinical trials, as their benefits are unknown in other individuals.9 In the RECOVERY and REMAP-CAP trials that studied tocilizumab coadministered with a corticosteroid, mortality benefit was seen in certain patients with severe COVID-19 infection.25,26 These were rapidly deteriorating patients with increased oxygen requirements and a substantial inflammatory response, but researchers found it difficult to determine the patient groups who would benefit most from the agent. Sarilumab is recommended when tocilizumab is unavailable.
As clinicians and researchers have gained a better understanding of COVID-19 and its clinical course, venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, have been recognized as a complication of the disease.27 Expert groups such as the NIH have released guidance concerning the prevention and treatment of VTE in patients without high bleeding risk and who are hospitalized with COVID-19.9 Criteria for increased bleeding risk include platelet count <50 x 109/L, hemoglobin <8 g/dL, need for dual antiplatelet therapy, known bleeding within the past 30 days requiring an emergency room visit or hospitalization, known history of a bleeding disorder, or an inherited bleeding disorder. The following recommendations are based on the current recommendations from the COVID-19 Treatment Guidelines Panel.
Anticoagulation for Patients Not Receiving Intensive Care: COVID-19 patients who are not at ICU level of care but requiring low-flow oxygen, have D-dimer above the upper limit of normal, and have no increased bleeding risk should receive therapeutic-dose heparin. Three open-label, randomized, controlled trials (a large multiplatform trial and the smaller RAPID and HEP-COVID studies) compared therapeutic doses of heparin with prophylactic or intermediate doses in select hospitalized patients who did not require ICU care.28-30 In the therapeutic heparin group, the multiplatform trial showed an increase in organ support–free days but no difference in mortality or length of hospital stay. In the RAPID trial, therapeutic heparin showed a reduction in 28-day mortality (a secondary outcome), and the HEP-COVID trial found that the occurrence of VTE, arterial thromboembolism, or all-cause death at Day 30 was significantly lower in the therapeutic arm.
The current recommendation is that in patients without a VTE who are started on therapeutic-dose heparin should continue for 14 days or until hospital discharge, whichever comes first. If the clinician makes the choice to not use therapeutic-dose heparin, prophylactic-dose heparin (low molecular weight heparin or unfractionated heparin) may be used unless a contraindication exists. The use of therapeutic-dose oral anticoagulants for VTE prophylaxis or prevention of COVID-19 progression in hospitalized patients is not recommended.9
Anticoagulation for Patients Receiving ICU Level of Care: Patients receiving ICU level of care, including those who are receiving high-flow oxygen, should receive prophylactic-dose heparin unless a contraindication exists. Several randomized, controlled trials have evaluated the role of therapeutic doses of heparin in reducing VTE events or mortality in patients hospitalized for COVID-19. In the ICU setting, studies have shown that therapeutic heparin did not reduce mortality but was associated with higher risk of bleeding events.30 In the event that a patient is started on therapeutic-dose heparin while on low-flow oxygen and then transferred to the ICU, anticoagulation should be switched from therapeutic dosing to prophylactic dosing unless a VTE is confirmed.9
Conclusion and Limitations
The worldwide pandemic caused by SARS-CoV-2 has brought forth ever-changing treatment recommendations and therapies. This article is limited by the fast-moving literature on COVID-19 treatment as it is continuously evolving. Clinicians are responsible for remaining current on the latest recommendations as new evidence is published and reviewed. Updated information can be found in the NIH COVID-19 Treatment Guidelines.9 Pharmacists in both the inpatient and community settings can assist providers with COVID-19 prevention and treatment by assessing appropriate use based on available evidence and providing drug monitoring and drug information.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
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