INTRODUCTION
In December 2019, a severe illness emerged in Wuhan, China and quickly progressed to a worldwide pandemic [1]. The cause of the illness was identified as a novel coronavirus, which was designated severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [2]. The illness caused by SARS-CoV-2 became known as coronavirus disease 2019 (COVID-19). In response to the global threat imposed by COVID-19, a worldwide effort was launched to identify therapeutics. Early evidence was primarily observational; however, randomized trials soon were reported, including large multicenter trials coordinated by the World Health Organization (WHO), United States’ National Institutes of Health (NIH), United Kingdom's National Institute of Health Research, and France's National Institute of Health and Medical Research (INSERM). This review summarizes the current body of evidence on therapeutics and provides a pragmatic approach to applying the evidence at the bedside.Â
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Box 1: no caption available
ANTIVIRAL THERAPY
Viral replication begins prior to the onset of symptoms and is believed to continue for roughly 10 days after the onset of symptoms, although the duration may be longer among patients who are immunosuppressed or have severe illness (Fig. 1) [3,4]. Theoretically, early intervention with antiviral therapy may disrupt viral replication and mitigate the duration and severity of the illness.
FIGURE 1: Viral replication begins prior to the onset of symptoms and continues for roughly 10 days after the onset of symptoms, although the duration may be longer among patients who are immunosuppressed or have severe illness. A systemic proinflammatory response may commence within 10 days of the onset of symptoms and can be progressive, causing the patient to become severely ill.
Remdesivir is an antiviral agent that inhibits viral replication by terminating RNA transcription. It is the only antiviral agent that has demonstrated beneficial effects in COVID-19 clinical trials to-date. However, more than 300 clinical trials are in-progress, evaluating various antiviral agents. Lopinavir–ritonavir [5,6,7▪], darunavir/cobicistat [8], and hydroxychloroquine [7▪,9–11] are antiviral agents that have proven to be ineffective.
Remdesivir has been studied in four major multicenter randomized trials: The Adaptive COVID-19 Treatment Trial (ACTT-1) sponsored by the NIH [12â–ª], Solidarity Trial sponsored by the WHO [7â–ª], SIMPLE Trial funded by Gilead Sciences [13], and an unnamed trial from Wuhan, China funded by the Chinese Academy of Medical Sciences [14â–ª]. It is also an arm of the DISCOVERY Trial sponsored by INSERM, which in ongoing.
The Adaptive Coronavirus Disease 2019 Treatment Trial-1
ACTT-1 randomly assigned 1062 hospitalized adults in the United States with laboratory-confirmed SARS infection and evidence of pulmonary disease [e.g., infiltrates on imaging, oxygen saturation 94% or less on room air, supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)] to receive either remdesivir or placebo for 10 days or until discharge or death. Patients whose transaminases were more than five-times above the upper limit of normal or who had an estimated glomerular filtration rate less than 30 ml/min were excluded [12â–ª].
Remdesivir reduced time to recovery [median time to recovery 10 vs. 15 days, recovery ratio 1.29, 95% confidence interval (CI) 1.12–1.49] and mortality by day 15 (6.7 vs. 11.9%, hazard ratio 0.55, 95% CI 0.36–0.83), although the mortality effect diminished by day 29 (11.4 vs. 15.2%, hazard ratio 0.73, 95% CI 0.52–1.03). It is noteworthy that patients with mild illness appeared to benefit more than patients with severe illness according to subgroup analyses. Specifically, patients receiving supplemental oxygen had more rapid recovery (recovery ratio 1.45, 95% CI 1.18–1.79), whereas there was no effect on time to recovery among patients receiving high-flow supplemental oxygen or noninvasive mechanical ventilation (recovery ratio 1.09, 95% CI 0.76–1.57) or among patients receiving invasive mechanical ventilation or ECMO (recovery ratio 0.98, 95% CI 0.70–1.36). Remdesivir was not associated with more adverse events [12▪].
The SOLIDARITY trial
The SOLIDARITY trial has been published in a prepeer review format only [7â–ª]. The open-label trial in 30 countries randomly assigned 11 266 adults who were hospitalized with COVID-19 to receive no study drug (n = 4088), remdesivir (n = 2750), hydroxychloroquine (n = 954), lopinavir/ritonavir (n = 1411), lopinavir/ritonavir and interferon (n = 651), or interferon alone (n = 1412). The proportion of patients whose diagnosis was laboratory-confirmed was not reported. Patients were not enrolled if the treating physician considered the study drug to be contraindicated or transfer was likely in the next 72 h [7â–ª].
Remdesivir was administered for 10 days or until discharge or death. Among all patients, remdesivir had no effect on 28-day in-hospital mortality [12.5 vs. 12.7%, relative risk (RR) 0.95, 95% CI 0.81–1.11]. Patients with mild respiratory dysfunction (i.e., supplemental oxygen) might have benefited from remdesivir therapy as there was a trend toward decreased 28-day in-hospital mortality (RR 0.87, 95% CI 0.71–1.04), but the subgroup had too few events to either confirm or exclude the effect. In contrast, in patients with no respiratory dysfunction (i.e., no supplemental oxygen) remdesivir had no effect on mortality (RR 0.85, 95% CI 0.38–1.88) and in patients with severe respiratory dysfunction (i.e., mechanical ventilation) there was a trend toward harm (RR 1.27, 95% CI 0.99–1.62). Remdesivir had no effect on progression to mechanical ventilation or length of hospitalization [7▪].
The SIMPLE trial
The SIMPLE trial was an open-label trial in 105 hospitals in the United States, Europe, and Asia that randomly assigned 596 adults who had laboratory-confirmed COVID-19 and evidence of pulmonary disease (e.g., infiltrates on imaging and oxygen saturation >94% on room air) to receive remdesivir for 5 days (n = 199), remdesivir for 10 days (n = 197), or no drug (n = 200). Patients whose transaminases were more than five-times above the upper limit of normal or who had an estimated glomerular filtration rate less than 50 ml/min were excluded [13].
On day 11 of the trial, patients who received remdesivir for 5 days were more likely to have a better clinical status across an ordinal scale compared with patients who received no drug [odds ratio (OR) 1.65, 95% 1.09–2.48], but patients who received remdesivir for 10 days had the same clinical status across an ordinal scale compared with patients who received no drug. There were no differences in mortality. Nausea, hypokalemia, and headache were more common among patients who received remdesivir, although adverse events in general were not more common [13].
The Wuhan trial
A double-blind, multicenter trial in China randomly assigned 237 hospitalized adults with laboratory-confirmed SARS infection, evidence of pulmonary disease (e.g., infiltrates on imaging, oxygen saturation 94% or less on room air, or a PaO2/FiO2 < 300), and symptoms for fewer than 12 days to receive either remdesivir or placebo for 10 days or until discharge or death. Patients were excluded if they were pregnant or breast feeding, were receiving dialysis, might be transferred within 72 h, or had any of the following: hepatic cirrhosis, transaminases more than five-times above the upper limit of normal, an estimated glomerular filtration rate less than 30 ml/min were excluded. The trial was terminated early due to poor enrollment as the outbreak subsided [14â–ª].
Among patients who received remdesivir within 10 days of symptom onset, there was a trend toward faster time to clinical improvement (18 vs. 23 days, hazard ratio 1.52, 95% CI 0.95–2.43), although there were too few patients to confirm or exclude the effect. All other outcomes were unchanged with remdesivir therapy including time to clinical improvement among all patients, 28-day mortality, SARS-CoV-2 viral load, and adverse events. Subgroup analyses based upon severity of illness were too small to be informative [14▪].
IMMUNE-BASED THERAPIES
A systemic proinflammatory response may commence within 10 days of the onset of symptoms and can be progressive, causing the patient to become severely ill (Fig. 1). It has been proposed that anti-inflammatory therapies may mitigate the proinflammatory response and improve outcomes. Among the interventions that have been studied are systemic corticosteroids (e.g., dexamethasone), anti-SARS-CoV-2 antibodies, convalescent plasma, and interleukin inhibitors.
Dexamethasone
The effects of systemic corticosteroids in COVID-19 are best illustrated by a meta-analysis sponsored by the WHO. The meta-analysis aggregated data from seven randomized trials conducted in 12 countries. It included 1703 critically ill patients with COVID-19, among which 678 patients received a systemic corticosteroid (dexamethasone, hydrocortisone, or methylprednisolone) and 1025 patients received either placebo or no systemic corticosteroid. The trials used different definitions of critical illness, ranging from supplemental oxygen more than 10 l/min to mechanical ventilation [15▪▪].
Systemic corticosteroids reduced mortality (32.7 vs. 41.5%, OR 0.66, 95% 0.53–0.82). The mortality benefit was seen among the 1559 patients who were mechanically ventilated (30 vs. 38%, OR 0.69, 95% CI 0.55–0.86), as well as the 144 patients who were not mechanically ventilated (23 vs. 42%, OR 0.41, 95% CI 0.19–0.88). Adverse events were not increased among those who received systemic corticosteroids [15▪▪].
The RECOVERY trial was the largest trial in the meta-analysis, contributing 1007 (60%) critically ill patients. The trial provides insights into the effects of systemic corticosteroids in COVID-19 patients with varying severities of illness. The open-label trial enrolled 6425 hospitalized adults with suspected or confirmed COVID-19 and compared systemic dexamethasone (n = 2104) to no systemic corticosteroids (n = 4321). Among all patients, dexamethasone reduced 28-day mortality (22.9 vs. 25.7%, adjusted RR 0.83, 95% CI 0.75–0.93). Subgroup analyses indicate that only patients who required respiratory support had reduced mortality, with the magnitude of benefit correlating with the severity of illness; that is, patients on mechanical ventilation received greater benefit (29.3 vs. 41.4%, RR 0.64, 95% CI 0.51–0.81) than patients on supplemental oxygen (23.3 vs. 26.2%, RR 0.82, 95% CI 0.72–0.94), who received greater benefit than patients not on supplemental oxygen (17.8 vs. 14%, RR 1.19, 95% CI 0.91–1.55) [16▪].
Antisevere acute respiratory syndrome coronavirus-2 antibodies
Bamlanivimab is a neutralizing IgG1 mAb directed at the spike protein of SARS-CoV-2. It is designed to block viral attachment and entry into human cells. A multicenter, double-blind phase 2 trial conducted in the United States randomly assigned 467 outpatients with mild-to-moderate COVID-19 symptoms to receive either a single dose of intravenous bamlanivimab (n = 317) or placebo (n = 150) [17].
The medications were administered a median of 4 days after the onset of symptoms At day 29, the percentage of patients hospitalized with COVID-19 was lower among those who received bamlanivimab than placebo (1.6 vs. 6.3%, RR 0.26, 95% CI 0.09–0.75). In addition, patients who received bamlanivimab had a better symptom score from day 2 through day 11, although most patients had recovered by the latter. No serious side effects occurred in those who received bamlanivimab [17].
Although promising, phase 3 clinical trials of bamlanivimab are still required to confirm efficacy. Numerous randomized trials evaluating other anti-SARS-CoV-2 antibodies are also in progress.
Convalescent plasma
Patients who have recovered from COVID-19 have antibodies against SARS-CoV-2 in their plasma. These antibodies might suppress the virus and alter the immune response, potentially minimizing the severity or duration of the illness.
The largest body of evidence is a case series (i.e., no control group) of more than 70 000 patients who obtained convalescent plasma as part of a United States Food and Drug Administration's Expanded Access Program. Comparison of patients who received plasma with high titers of neutralizing antibodies to those who received plasma with low titers suggests convalescent plasma may be beneficial. In a comparison of 4330 patients who received convalescent plasma, there was no difference in 7-day mortality. However, subgroup analyses suggested a potential 7-day mortality benefit among patients who were not mechanically ventilated (11 vs. 14%, P = 0.03), but no mortality benefit among patients who were mechanically ventilated [18]. In a comparison of 3082 patients that has been published in a prepeer review format only, 7-day mortality among patients who received low-, medium-, and high-titer plasma was 13.7, 11.6, and 8.9% (P = 0.05), respectively, and 30-day mortality among patients who received low-titer, medium-titer, and high-titer plasma was 29.6, 27.4, and 22.3% (P = 0.02), respectively [19].
Several open-label, randomized trials of convalescent serum have been conducted and published in a prepeer review format, but all have flaws that limit their usefulness for clinical decision-making. The ConCOVID Trial was conducted in 14 hospitals in the Netherlands and randomly assigned 86 hospitalized patients with COVID-19 to either receive (n = 43) or not receive (n = 43) convalescent plasma. The trial was terminated early when it was found that the baseline titer of neutralizing antibodies in the patients who were slated to receive the infusion was similar to the titer of neutralizing antibodies in the plasma to be infused [20]. The PLACID trial was conducted in 39 hospitals in India and randomly assigned 464 hospitalized COVID-19 patients with hypoxemia to either receive (n = 235) or not receive (n = 229) convalescent plasma. Patients with critical illness, defined as a PaO2/FiO2 less than 200 mmHg or shock, were excluded. The trial found no difference in 28-day mortality (14.5 vs. 13.6%) or progression to severe disease (7.2 vs. 7.4%). However, the plasma infusions were not tested and, therefore, it is impossible to know whether they had low titers of neutralizing antibodies [21].
Interleukin inhibitors
It is hypothesized that SARS-CoV-2 invokes a systemic inflammatory response that may elicit acute respiratory distress syndrome (ARDS), multisystem organ failure, and death in some patients. IL-1 and IL-6 are inflammatory cytokines that increase in SARS-CoV-2 infection and, therefore, are potential therapeutic targets for blocking progression to severe illness and death [22].
Inhibitors of IL-1 signaling include anakinara, canakinumab, and rilonacept. Randomized trials are in-progress to evaluate the efficacy of these agents in COVID-19 but, to date, all relevant data is observational. The Ana-COVID study was a single-center study from France that compared a prospective cohort of 52 COVID-19 patients with pneumonia and hypoxemia who received anakinra to a historical cohort of 44 similar patients who did not receive anakinra. Patients who received anakinra were less likely to be admitted to the ICU for mechanical ventilation or death than patients who did not receive anakinra (hazard ratio 0.22, 95% CI 0.11–0.41), although confidence in the estimate is limited by the observation that many events in the control group occurred within the first 2 days of follow-up [23]. A single-center retrospective cohort study from Italy that compared 29 COVID-19 patients with ARDS and hyperinflammation who received anakinra to 16 similar historical control patients who did not receive anakinra reported a higher 21-day survival rate among those who received anakinra (90 vs. 56%, P < 0.01), but confidence in the estimate is limited because the anakinra group was younger and healthier at baseline [24].
Inhibitors of IL-6 signaling include tocilizumab, siltuximab, sarilumab, and clazakizumab. Tocilizumab is the best studied of the agents, having been evaluated in three randomized, placebo-controlled trials (EMPACTA trial, COVACTA trial [25], and BACC BAY trial [26]), two randomized open-label trials comparing tocilizumab to usual care [27,28], and two observational studies [29,30]. No beneficial outcomes were consistently found across multiple trials, although there were sporadic positive outcomes that were not confirmed by other trials. The large REMAP-CAP trial is in progress with results pending.
AT THE BEDSIDE
The only therapeutics for which there is consistent evidence of efficacy are the antiviral therapy, remdesivir, and the immunomodulator, dexamethasone. Subgroup analyses suggest that remdesivir is more beneficial in hospitalized patients whose severity of illness falls at the lower end of the spectrum, in contrast to dexamethasone, which appears more beneficial in patients whose severity of illness falls at the higher end of the spectrum. As a result, the following approach based upon severity of illness is recommended (Fig. 2):
- Patients who do not require supplemental oxygen – neither remdesivir nor dexamethasone is indicated.
- Patients who require supplemental oxygen but are not mechanically ventilated – both remdesivir and dexamethasone are indicated. Remdesivir use is based upon subgroup analyses from the ACTT-1 and the SOLIDARITY trial, which found a significant improvement in recovery rate and a trend toward lower mortality, respectively. Dexamethasone use is based upon subgroup analyses from the RECOVERY trial, which found a significant reduction in mortality. If time permits, clinicians may want to initiate remdesivir before dexamethasone to avoid the theoretical risk that dexamethasone alone may reduce viral clearance.
- Patients who require mechanical ventilation-dexamethasone alone is indicated. This indication is based upon the RECOVERY trial, in which subgroup analyses demonstrated a large mortality benefit in such patients. In contrast, remdesivir is not indicated since subgroup analyses of such patients in both the ACTT-1 and the SOLIDARITY trial estimated potential harm, although the subgroups were too small to either confirm or exclude a harmful effect.
FIGURE 2: In patients who do not require supplemental oxygen, neither remdesivir nor dexamethasone is indicated. However, in patients who require supplemental oxygen but are not mechanically ventilated, both remdesivir and dexamethasone are indicated. In patients who require mechanical ventilation, dexamethasone alone is indicated.
Notably, the anti-SARS-CoV-2 antibody, bamlanivimab, demonstrated potential efficacy in outpatients in a phase 2 trial. While the results are promising and no therapeutics exist for this population, outcomes for such patients are generally favorable and, therefore, confirmatory evidence from phase 3 clinical trials is necessary before bamlanivimab becomes routine therapy.
CONCLUSION
The body of evidence related to COVID-19 therapeutics continues to evolve and, as a result, management is likely to change with time. The only therapeutics that randomized trials have found to be efficacious are the antiviral therapy, remdesivir, and the immunomodulator, dexamethasone. Early evidence about the anti-SARS-CoV-2 antibody, bamlanivimab, and convalescent plasma is promising, but more definitive data is necessary before either is recommended as routine therapy. Trials evaluating other types of anti-SARS-Cov-2 antibodies and various interleukin inhibitors will be forthcoming. As new evidence is generated and published, the optimal approach to managing patients with COVID-19 should be reconsidered.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
â–ª of special interest
▪▪ of outstanding interest
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