What is the role of the IL-6 inhibitor tocilizumab (Actemra) in the treatment of coronavirus disease 2019 (COVID-19)?

Updated: Jun 25, 2021
  • Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
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Answer

Interleukin-6 inhibitors 

IL-6 is a pleiotropic proinflammatory cytokine produced by various cell types, including lymphocytes, monocytes, and fibroblasts. SARS-CoV-2 infection induces a dose-dependent production of IL-6 from bronchial epithelial cells. This cascade of events is the rationale for studying IL-6 inhibitors. [172]  

Tocilizumab was issued an EUA on June 24, 2021 for hospitalized adults and pediatric patients (aged 2 years and older) with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). 

The Infectious Disease Society of America guidelines recommend tocilizumab in addition to standard of care (ie, steroids) among hospitalized adults with COVID-19 who have elevated markers of systemic inflammation. [129] The NIH guidelines recommend use of tocilizumab (single IV dose of 8 mg/kg, up to 800 mg) in combination with dexamethasone in recently hospitalized patients who are exhibiting rapid respiratory decompensation caused by COVID-19. [173] These recommendations are based on the paucity of evidence from randomized clinical trials to show certainty of mortality reduction. 

The EMPACTA trial found nonventilated hospitalized patients who received tocilizumab (n = 249) in the first 2 days of ICU admission had a lower risk of progression to mechanical ventilation or death by day 28 compared with those not treated with tocilizumab (n = 128) (12% vs 19.3% respectively). The data cutoff for this study was September 30, 2020. In the 7 days before the trial or during the trial, 200 patients in the tocilizumab group (80.3%) and 112 patients in the placebo group (87.5%) received systemic glucocorticoids and 55.4% and 67.2% of the patients received dexamethasone. Antiviral treatment was administered in 196 (78.7%) and 101 (78.9%), respectively, and 52.6% and 58.6% received remdesivir. However, there was no difference in incidence of death from any cause between the 2 groups. [174]

Results from the REMAP-CAP international adaptive trial evaluated efficacy of tocilizumab 8 mg/kg (n = 353), sarilumab 400 mg (n = 48), or control (n = 402) in critically ill hospitalized adults receiving organ support in intensive care. Hospital mortality at day 21 was 28% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab, and 35.8% (142/397) for control. Of note, corticosteroids became part of the standard of care midway through the trial. Estimates of the treatment effect for patients treated with either tocilizumab or sarilumab and corticosteroids in combination were greater than for any single intervention. [175]  

The RECOVERY trial assessed use of 4,116 hospitalized adults with COVID-19 infection who received either tocilizumab (n = 2,022) compared with standard of care (n = 2,094) in the United Kingdom from April 23, 2020 to January 24, 2021. Among participants, 562 (14%) received invasive mechanical ventilation, 1686 (41%) received non-invasive respiratory support, and 1868 (45%) received no respiratory support other than oxygen. Median C-reactive protein was 143 mg/L and most patients (82% in both treatment groups) were receiving systemic corticosteroids at randomization. The primary outcome of all-cause mortality within 28 days of randomization occurred in 35% of the usual care group compared with 31% of those who received tocilizumab (p = 0.0028). Tocilizumab mortality benefits were clearly seen among those who also received systemic corticosteroids. Patients in the tocilizumab group were more likely to be discharged from the hospital within 28 days (57% vs 50; p < 0.0001). Among those not receiving invasive mechanical ventilation at baseline, patients who received tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 40%; p < 0.0005). [176]   

Conversely, the COVACTA study, 452 with COVID-19 (oxygen saturation, 93% or less) were randomly assigned in a 2:1 ratio to receive 1 dose of tocilizumab or placebo. At day 28, no significant difference was observed for mortality between the tocilizumab group and placebo (19.7% vs 19.4%, respectively). [177]    

An editorial by Rubin et al discusses the discordant results of the RECOVERY and REMAP-CAP trials compared with the COVACTA trial. One significant difference noted is that patients with severe disease, now almost universally receive glucocorticoids. Only a minority of patients in the COVACTA trial were treated with glucocorticoids. Fewer in the group that received tocilizumab (19.4%) than in the group that received placebo (28.5%) also received glucocorticoids. In contrast, 93% and 82% of all patients in REMAP-CAP and the RECOVERY trial, respectively, were receiving glucocorticoid therapy. [180]  

Average wholesale price of tocilizumab is approximately $5000 for an 800-mg dose. Preliminary results for sarilumab have also been reported.


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