What Are the Latest COVID-19 Treatment Recommendations?

Pharmacy Times Health Systems Edition, January 2021, Volume 10, Issue 1

SAP Partners | Health System / Oncology | <b>Society of Infectious Diseases Pharmacists</b>

Guidelines, updated in nearly real time, recommend use of remdesivir, dexamethasone.

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, several antivirals and other medications with antiviral properties have been explored as potential treatment options for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Information about the efficacy and safety of medications used to treat COVID-19 continues to evolve, which has helped provide clarity on the most optimized therapy and establish current guideline recommendations. Many of the agents used early in the pandemic, such as hydroxychloroquine or lopinavir/ritonavir, have been largely abandoned due to lack of efficacy data and/or excessive risk for toxicities. The medical community has identified an evidence-based and guideline-supported treatment approach for patients with COVID-19 that continues to evolve based on rapidly emerging data.

Both the Infectious Diseases Society of America (IDSA) and the National Institutes of Health (NIH) published practice guidelines that have undergone several updates. These guidelines recommend the use of remdesivir (Veklury) as first-line antiviral therapy in patients hospitalized with severe disease.1,2 Recommended remdesivir dosing for adults is a 200-mg loading dose, followed by 100 mg every 24 hours, for a total of 5 days (10 days may be considered for patients with slow response). Dexamethasone, a common corticosteroid, is recommended to be given in combination with remdesivir for patients requiring oxygen supplementation at a daily dose of 6 mg for 10 days. Both treatments can be discontinued if the patient is well enough for discharge prior to completion of the intended course.

The United States Food and Drug Administration (FDA) approved remdesivir on October 22, 2020, for the treatment of COVID-19 in hospitalized patients 12 years or older and weighing 40 kg or more. For younger pediatric patients, remdesivir is still available under emergency use authorization (EUA). Efficacy data from several clinical trials helped support FDA approval and current guideline recommendations. The ACTT-1 trial (NCT04280705) results showed that remdesivir shortened recovery time by 5 days, and in a subgroup analysis the results showed a mortality benefit in patients requiring supplemental oxygen but not mechanical ventilation.3

Conversely, recent preliminary data from the SOLIDARITY trial found that remdesivir showed no benefit in mortality, need for mechanical ventilation, or time to hospital discharge compared with standard of care.4 A peer-reviewed publication of the SOLIDARITY trial is pending. Another trial (NCT04292730) evaluating the use of remdesivir in the setting of moderate COVID-19 (patients with pulmonary infiltrates on chest imaging and oxygen saturation greater than 94%) concluded that 5 days of remdesivir was associated with higher odds of a better clinical status compared with standard of care. However, the clinical implications of this are unclear.5 Finally, the guidelinerecommended duration for remdesivir of 5 days is based on the SIMPLE-Severe Trial (NCT04292899), which determined that a 5-day course offered similar clinical benefit to a 10-day course, based on day 14 clinical status.6

Although remdesivir has not consistently demonstrated a mortality benefit, the use of dexamethasone and other corticosteroids has shown a reduction in mortality among patients with COVID-19 requiring oxygen supplementation. Initial efficacy data for corticosteroids in COVID-19 was first reported from the RECOVERY trial (NCT04381936), in which patients receiving dexamethasone had a lower incidence of death compared with standard of care if on mechanical ventilation or receiving oxygen supplementation without mechanical ventilation.7 Following this study, several other trials and data from a meta-analysis have been published supporting the role of corticosteroids in the management of COVID-19 among patients requiring mechanical ventilation or oxygen supplementation.8,9

The FDA recently granted emergency use authorization approval to baricitinib, a nonselective Janus kinase inhibitor that prevents dysregulated production of proinflammatory cytokines, to be given in combination with remdesivir in hospitalized patients 2 years and older requiring extracorporeal membrane oxygenation, mechanical ventilation, or supplemental oxygen.10 Data from phase III clinical trial ACTT-2 (NCT04401579) showed that the combination of baricitinib and remdesivir was associated with a reduction in median time to recovery (8 days) compared with remdesivir alone (7 days). Patients receiving baricitinib with remdesivir had a lower mortality rate (23% vs 28%) and were less likely to require invasive or noninvasive ventilation and more likely to have a better clinical status by day 15. The recommended dosing of baricitinib is 4 mg once daily for patients 9 years and older or 2 mg once daily for patients aged 2 to 8 years. However, dosage adjustments are required based on absolute lymphocyte count, absolute neutrophil count, hepatic function, and renal function. The recommended duration is 14 days or until hospital discharge. IDSA and NIH guidelines have not been updated yet to provide recommendations regarding the addition of baricitinib to remdesivir. Limited information is available on the use of baricitinib in combination with systemic corticosteroids for the management of COVID-19. Therefore, its role in therapy in the setting where patients are given dexamethasone is uncertain.

The FDA also recently granted EUA approval to 2 monoclonal antibody treatments: bamlanivimab and the combined antibody cocktail casirivimab with imdemivab.11,12 Both are recommended for nonhospitalized adult and pediatric patients 12 years and older weighting at least 40 kg who have mild to moderate COVID-19 and are at high risk for progressing to severe disease in the outpatient setting. Interim data from phase II clinical trials have shown that the use of these monoclonal antibodies was associated with reduced emergency department (ED) visits compared with a placebo.12,13 Among high-risk patients, bamlanivimab reduced ED visits and hospitalizations by 7%, and casirivimab/imdevimab reduced this outcome by 6%. Bamlanivimab is given as a single 700-mg intravenous (IV) dose and casirivimab/imdevimab as a single 2400-mg IV dose. Both should be administered within 10 days of COVID-19 symptom onset. IDSA and NIH guidelines have recommended against the use of monoclonal antibodies as the standard of care. However, note that if use is considered, the antibodies should be reserved for patients at the greatest risk for clinical progression or poor outcomes.

Other therapies still under investigation include antithrombotic therapy, convalescent plasma, and other immune modulators, such as anakinra, sarilumab (Kevzara), and tocilizumab. There are several ongoing clinical trials to further investigate the therapies’ role in the management of COVID-19. For some of these options, clinical data are conflicting and/or insufficient to determine their role in the management of COVID-19.

In the early days of the COVID-19 pandemic in the United States, treatment regimens with limited, if any, clinical data to support use were being implemented, and no evidence-based consensus guidelines were available to guide therapeutic decision-making. However, there is now more concrete guidance on the optimal treatment approach because more data are becoming available. Although COVID-19 treatment recommendations will continue to evolve, an unprecedented point has been reached where guidelines are updated in nearly real time to endorse best evidence-based medicine.

NATASHA N. PETTIT, PHARMD, BCIDP, BCPS, is an infectious diseases clinical/ pharmacy specialist at the University of Chicago Medicine in Illinois.

REFERENCES

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