REMDESIVIR
standard therapy in 389 patients. 55 Patients had COVID-19 pneumonia and were not intubated. Results showed that tocilizumab reduced the rate of mechanical ventilation or death (12.0% versus 19.3%). More recently, the RECOVERY platform trial assessed tocilizumab plus standard care versus standard care alone in patients hospitalized with COVID-19 with various degrees of hypoxia. Per preliminary data, patients assigned to tocilizumab (n=2022) were more likely to be discharged from the hospital alive within 28 days (54% vs. 47%). 56 Among patients in the tocilizumab group there were 596 (29%) deaths compared to 694 (33%) in the standard care group. Although these recent studies hint at the potential for IL-6 inhibitors, and particularly tocilizumab, to reduce duration of ICU stay and hospitalization, there is a more modest trend reduction in mortality. The RECOVERY platform trial results are encouraging in light of the large sample size, but it is not yet clear how these findings will impact current guidelines. Another attempt at using immunemodulation for treatment of SARS-CoV-2 was with Baricitinib in combination with remdesivir. Baricitinib is an orally administered, selective inhibitor of Janus kinase (JAK)-1 and 2. Interestingly, baricitinib was identified as a SARS-CoV-2 therapeutic candidate based on artificial intelligence algorithms. Baricitinib inhibits the intracellular signaling pathway of cytokines known to be elevated in severe Covid-19, including IL-2, IL-6, IL-10, interferon-γ, and granulocyte– macrophage colony-stimulating factor, it reduces SARS- CoV-2 cellular entry and infectivity, and it also improves lymphocyte counts in patients with COVID-19. ACTT-2 trial was a randomized, double-blind, placebo-controlled trial designed to evaluate remdesivir and baricitinib versus remdesivir and placebo. 57 Patients who required supplemental oxygen and received combination treatment with baricitinib plus remdesivir recovered a median of one day faster than patients who received remdesivir and placebo. Patients receiving noninvasive ventilation or high- flow oxygen had a median time to recovery of 10 days in the baricitinib arm versus 18 days in the control arm. The study was not sufficiently powered to assess for a difference in mortality. Baricitinib plus remdesivir was shown to be superior to remdesivir alone in reducing recovery time and has received an EUA for use in SARS-CoV-2. 58
Originally developed to treat hepatitis C and respiratory syncytial virus, and then later repurposed and studied to treat Ebola virus and Middle East respiratory syndrome (MERS-CoV), 47 remdesivir has been studied in several studies for SARS-CoV-2. The drug inhibits viral RNA-dependent, RNA polymerase and was found to have in vitro inhibitory activity against SARS-CoV-2. 48 Remdesivir was subsequently evaluated in the Adaptive Covid-19 Treatment Trial (ACTT-1), which was a randomized, double-blind, placebo-controlled trial to evaluate remdesivir for treatment of Covid19. 49 All participants were hospitalized, and stratification occurred based on disease severity. Those who received remdesivir had a median recovery time of 10 days, as compared with 15 days among those who received placebo. No statistically significant difference in mortality was noted. Subsequently, remdesivir has gained FDA approval for the purpose of treating SARS-CoV-2. 50 Another trial that evaluated its efficacy has been the WHO Solidarity Trial, which was a large, open-label, randomized trial to evaluate the effect of remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a in patients hospitalized with COVID-19. The authors concluded that the agents studied—including remdesivir—had little or no effect on hospitalized patients with Covid-19 based on outcomes in overall mortality, initiation of ventilation, and duration of hospital stay. 35 This has caused theWHO to issue a conditional recommendation against the use of remdesivir due to lack of evidence of efficacy. 51 Remdesivir does however remain part of NIH recommendations for SARS-CoV-2 management in the appropriate clinical context. 52
IMMUNOMODULATORY AGENTS
Consistent with the host inflammatory response discussed above, the phenomenon of “cytokine storm” is suspected to play a large role in pathogenesis of SARS-CoV-2, 53 and therapeutic agents targeting cytokine pathways have also been studied. Anti-IL-6 receptor monoclonal antibodies (e.g., tocilizumab, sarilumab) have been investigated in hopes of using them to modulate the immune response in COVID-19. Early studies did not demonstrate significant efficacy, although more recent studies may show some benefit. The COVACTA trial was adouble-blind, randomized trial toevaluate tocilizumab plus standard therapy versus placebo plus standard therapy in 452 patients with severe Covid-19 pneumonia. 54 Results have not yet been published with peer review, but reportedly no difference in mortality was seen at 28 days; however, median time to hospital discharge and duration of ICU stay were 8 and 5.8 days shorter, respectively, in patients randomized to tocilizumab. The EMPACTA trial evaluated tocilizumab plus standard therapy versus placebo plus
STEROIDS
The RECOVERY platform trial was a randomized, controlled, open-label platform trial which sought to evaluate the efficacy of hydroxychloroquine, lopinavir-ritonair, azithromycin, and dexamethasone. The dexamethasone arm of the trial was significant for demonstrating a mortality benefit in patient requiring noninvasive oxygen support and invasive mechanical ventilation. 59 Patients on dexamethasone and mechanical ventilation were 20
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