By Vibhu Sharma, MD
Associate Professor of Medicine, University of Colorado, Denver
SYNOPSIS: The WHO Solidarity Trial Consortium found that remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had “little or no effect” on relevant outcomes.
SOURCE: WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, et al. Repurposed antiviral drugs for COVID-19 — Interim WHO Solidarity Trial Results. N Engl J Med 2021;384:497-511.
The Solidarity Trial Consortium sponsored by the World Health Organization (WHO) randomized inpatients with COVID-19 equally among one of the following five drug regimens and the local standard of care: remdesivir (2,750 patients), hydroxychloroquine (954 patients), lopinavir alone (1,411 patients), interferon beta alone (2,063 patients), and lopinavir plus interferon beta (651 patients). The patients were randomized in 405 hospitals and in 30 countries. The trial was open-label, and no placebos were used. The controls were assigned to the local standard of care where the drug that was being randomized was available. The only exception was lopinavir plus interferon beta, where the control group was lopinavir alone. Some institutions had multiple drugs available, and in these institutions, patients assigned to the control group served as controls for each of the drug groups available. Written informed consent was provided by patients or their designees. National monitors were in place to resolve questions about trial strategy or drug adverse effects. One-third of total patients randomized were younger than age 50 years, and 19% were older than age 70 years. One-third were not receiving any oxygen at the time of study entry, and only 8% were mechanically ventilated; the rest received varying amounts of supplemental oxygen. Overall, 62% were male.
The primary outcome was in-hospital mortality for each intervention/control group, in addition to analyses of in-hospital mortality stratified by age and use of mechanical ventilation. Prespecified secondary outcomes included the need for mechanical ventilation among those not requiring support at the start of randomization, duration of mechanical ventilation, and hospital length of stay. All treatments lasted a maximum of 14 days. The results were mostly disappointing, with no drug (or drug combination in the case of lopinavir plus interferon beta) associated with either a reduction in mortality or a favorable outcome with respect to the secondary outcomes. Importantly, none of the trial interventions reduced the need for mechanical ventilation.
COMMENTARY
This ambitious worldwide trial failed to demonstrate any mortality reduction of antiviral therapy (remdesivir, lopinavir, or interferon beta) or treatment with drugs repurposed to treat COVID-19 infection (hydroxychloroquine). The lack of benefit was consistent across age groups and disease severity (i.e., including requirements for oxygen, mechanical ventilation, or extracorporeal membrane oxygenation). The trial consortium also found no impact on the need for mechanical ventilation among those who were not intubated at randomization. The authors performed a meta-analysis of randomized trials for remdesivir (Solidarity [n = 5,451 randomized], the Adaptive COVID-19 Treatment Trial, or ACTT-1 [n = 1,062 patients randomized]) and found no mortality benefit. Similarly, meta-analyses for all trials for hydroxychloroquine and lopinavir, including the Solidarity cohort, showed no mortality benefit.
The European Respiratory Society (ERS) recently published guidelines for the management of hospitalized adults with COVID-19 infection.1 The guidelines were developed by a task force using the GRADE methodology (Grading of Recommendations Assessment, Development, and Evaluation), wherein the quality of evidence is rated from very low to high, and recommendations based on the quality of evidence are rated as strong or weak. With respect to drugs evaluated by the Solidarity consortium reviewed here, the ERS recommends not offering remdesivir to hospitalized patients with COVID-19 infection requiring invasive mechanical ventilation (conditional/weak recommendation, moderate quality of evidence), but it makes no recommendations regarding the use of remdesivir in hospitalized patients not requiring invasive mechanical ventilation. The panel recommends against the use of lopinavir to hospitalized patients with COVID-19 infection (strong recommendation with moderate quality of evidence). The panel also recommends against the use of interferon beta for inpatients with COVID-19 infection (weak recommendation based on very low quality evidence).
A recent randomized controlled trial compared tocilizumab (a monoclonal antibody against the interleukin-6 receptor) to placebo in patients admitted to a hospital with COVID-19 infection and evidence of a hyperinflammatory state (at least one of the following: D-dimer level higher than 1,000 ng/milliliter, ferritin level higher than 500 ng/milliliter, C-reactive protein [CRP] level higher than 50 mg/liter, or a lactate dehydrogenase [LDH] level higher than 250 U/liter).2 The study found no benefit with respect to preventing intubation or death among inpatients with COVID-19, albeit with wide confidence intervals for efficacy implying the “possibility of some benefit or harm.” A recent propensity-matched analysis assessing the effect of tocilizumab on outcomes in COVID-19 critical illness found a mortality benefit among those patients who received tocilizumab compared with those who did not.3 Accordingly, the ERS guidelines suggest “offering interleukin-6 receptor antagonist monoclonal antibody therapy to hospitalized patients with COVID-19 requiring oxygen or invasive ventilatory support” (weak recommendation/low quality of evidence). Therefore, tocilizumab may be considered for inpatients with COVID-19 infection requiring oxygen or undergoing noninvasive mechanical ventilation who worsen while on dexamethasone after 48 hours AND are receiving high-flow nasal cannula oxygen at > 30 L/minute and FiO2 > 0.4 with CRP ≥ 75 mg/L per institutional guidelines. Among inpatients who are mechanically ventilated or undergoing ECMO, tocilizumab may be considered as adjunctive therapy to dexamethasone for patients without improvement or with worsening respiratory function within 24 hours and accompanying worsening inflammatory markers. Tocilizumab typically is dosed at 8 mg/kg (single intravenous dose) rounded to 400 mg (for 40 kg to 65 kg of body weight), 600 mg (for 66 kg to 90 kg of body weight), and 800 mg (> 90 kg of body weight). Considered contraindications to the use of tocilizumab include the following:
• hospitalization > four days;
• duration of mechanical ventilation > 24 hours;
• active tuberculosis;
• pregnancy or breast-feeding;
• suspected or confirmed viral, fungal, or bacterial infection other than SARS-CoV-2.
Results of the ACTT-2 trial were reported recently.4 Baricitinib is an oral Janus kinase 1 (JAK-1) and JAK-2 inhibitor and was hypothesized to modulate the immune response to the virus by inhibiting the signaling pathway of cytokines that are upregulated in COVID-19 infection. Baricitinib and remdesivir were compared to remdesivir alone. Hospitalized adults with COVID-19 infection receiving either high-flow oxygen or noninvasive ventilation were randomized. “Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status.” There was no difference with respect to 28-day mortality rates. A minimal incremental benefit of baricitinib alone over dexamethasone alone is likely. Institution-specific guidelines may recommend the combination in the defined population studied in the trial. Anti-spike neutralizing monoclonal antibodies have been approved for use in outpatients with COVID-19 infection, but none have been approved for hospitalized patients with more severe disease.
The landscape of drug therapy for severe COVID-19 infection has evolved since the start of the pandemic. Unfortunately, only a single therapy (dexamethasone) has clearly been shown to affect mortality in the setting of severe COVID-19 infection. Multiple clinical trials are ongoing.
REFERENCES
- Chalmers JD, Crichton ML, Goeminne PC, et al. Management of hospitalised adults with coronavirus disease 2019 (COVID-19): A European Respiratory Society living guideline. Eur Respir J 2021;57:2100048.
- Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med 2020;383:2333-2344.
- Rajendram P, Sacha GL, Mehkri O, et al. Tocilizumab in coronavirus disease 2019-related critical illness: A propensity matched analysis. Crit Care Explor 2021;3:e0327.
- Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med 2021;384:795-807.
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