Abstract
Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients.Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients.Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores.Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs.Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients.
Highlights
After more than 1 year of COVID-19 pandemic there are still no solid certainties on the efficacy of the therapies variously proposed
This national retrospective observational study was conceived within the CORIST Project (ClinicalTrials.gov ID: NCT04318418), which is a multicenter study launched in March 2020 [15] and aimed at testing the association of risk factors [16] and therapies with in-hospital COVID-19 mortality [17, 18]
We included in the final analyses 3,451 COVID-19 patients; of these, 1,824 (52.9%, range among hospitals 22.5–64.3%) received neither LPV/r nor DRV/c, 1,148 (33.3%, range 17.7–66.3%) received LPV/r and 479 (13.9%, range 2.2–18.1%) received DRV/c
Summary
After more than 1 year of COVID-19 pandemic there are still no solid certainties on the efficacy of the therapies variously proposed. Lopinavir is a human immunodeficiency virus (HIV) type aspartate protease inhibitor, with an in vitro inhibitory activity against the coronaviruses causing severe acute respiratory syndrome (SARS) [2] and Middle-East respiratory syndrome (MERS) [3]. It is administered in combination with ritonavir to increase its plasma half-life. Both drugs have been shown to be able to bind well to the SARS-CoV 3C-like protease (3CLpro) [4], which is involved in the proteolytic processing of the replicase polyprotein and is crucial for viral replication [5]. Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients
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