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 supportfree
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.
Keywords: Adaptive platform trial, Intensive care, Pneumonia, Pandemic, COVID-19, Lopinavir-ritonavir,
Hydroxychloroquine
