Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial

Intensive Care Med. 2021 Aug;47(8):867-886. doi: 10.1007/s00134-021-06448-5. Epub 2021 Jul 12.

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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Antiviral Agents / therapeutic use
  • Bayes Theorem
  • COVID-19* / drug therapy
  • Critical Illness
  • Drug Combinations
  • Humans
  • Hydroxychloroquine / therapeutic use
  • Lopinavir / therapeutic use
  • Ritonavir* / therapeutic use
  • SARS-CoV-2

Substances

  • Antiviral Agents
  • Drug Combinations
  • Lopinavir
  • Hydroxychloroquine
  • Ritonavir

Supplementary concepts

  • COVID-19 drug treatment

Associated data

  • ClinicalTrials.gov/NCT02735707