Abstract
Purpose: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19).
Methods: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable.
Results: We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (- 1 to 15), 0 (- 1 to 9) and-1 (- 1 to 7), respectively, compared to 6 (- 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively).
Conclusion: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.
Trial registration: ClinicalTrials.gov NCT02735707 .
Keywords: Adaptive platform trial; COVID-19; Hydroxychloroquine; Intensive care; Lopinavir-ritonavir; Pandemic; Pneumonia.
【저자키워드】 COVID-19, pandemic, Hydroxychloroquine, intensive care, Pneumonia, Adaptive platform trial, Lopinavir-ritonavir, 【초록키워드】 coronavirus disease, antiviral therapy, Coronavirus disease 2019, Efficacy, Bayesian, Hydroxychloroquine, intensive care, hospital, Lopinavir, Ritonavir, combination therapy, Intervention, outcome, Probability, Randomized, survival, Critically ill, Patient, group, threshold, platform, critically ill patients, in-hospital mortality, Ordinal Scale, Adaptive platform trial, Lopinavir-ritonavir, primary endpoint, credible interval, Critically ill patient, Logistic, adjusted odds ratio, control group, posterior probability, treatment effects, organ support, cumulative, organ, reduced, median, expressed, reached, receive, treatment effect, with COVID-19, worsened, yielding, 【제목키워드】 Randomized controlled trial, Hydroxychloroquine, Lopinavir-ritonavir, Critically ill patient, REMAP-CAP,