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ObjectivesWe evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and/or ventilatory support. While preliminary results were previously published, we present here the final results, following completion of the data monitoring.MethodsWe conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely.ResultsThe intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147; lopinavir/ritonavir-IFN-β-1a, n=147; hydroxychloroquine, n=150; control, n=149), among whom 421 (71.0%) were male, the median age was 64 years (IQR, 54-71) and 214 (36.1%) had a severe disease. The day 15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.82, (95% confidence interval [CI] 0.54-1.25, P=0.36); lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.05, P=0.08); hydroxychloroquine versus control, aOR 0.94 (95%CI 0.62-1.41, P=0.76). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.ConclusionIn adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.

Despite several clinical studies, the antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. We analyzed nasopharyngeal normalized viral loads collected in the 29 days following randomization from 665 hospitalized patients included in the DisCoVeRy trial, allocated to either standard of care (SoC, N=329) or SoC + remdesivir for 10 days (N=336). We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in reducing viral production. To identify factors associated with viral kinetics, additional analyses were conducted stratified either on time of treatment initiation (≤ or > 7 days since symptom onset) or viral load at randomization (< or ≥ 3.5 log10 copies/104 cells). In our model, remdesivir reduced viral production by 2-fold on average (95%CI: 1.5-3.2). Using the estimated parameter of the model, simulations predict that remdesivir reduces time to viral clearance by 0.7 day compared to SoC, with large inter-individual variabilities (Inter-Quartile Range, IQR: 0.0-1.3 days). Exploratory analyses suggest that remdesivir had a larger impact in patients with a high viral load at randomization, reducing viral production by 5-fold on average (95%CI: 2.8-25), leading to a predicted median reduction in the time to viral clearance of 2.4 days (IQR: 0.9-4.5 days).In summary, our model shows that remdesivir reduces viral production from infected cells by a factor 2, leading to a median reduction of 0.7 days in the time to viral clearance compared to SoC. The efficacy was larger in patients with high level of viral load at treatment initiation.One sentence summaryRemdesivir reduces the time to SARS-CoV-2 clearance by 1 day in hospitalized patients, and up to 3 days in those with high viral load at admission.

INTRODUCTIONPredicting the number of Covid-19 patients in the Intensive Care Units (ICU) could be useful to avoid the breaking point. We attempted to deduce a formula in order to model the number of the ICU patients in France from the official data and patient turnover in the ICU.METHODSThe Covid-19 ICU patient turnover was calculated using a recurrence relation from the internal data provided by Hospices Civils de Lyon. The number of new Covid-19 cases detected daily was modelized to fit with the last known data in France and extrapolated for the coming days using two scenarios following the existing data in China (best scenario) and Italy (worst scenario). The number of daily admissions in ICU was calculated as the sum of 13.7% of the new Covid-19 cases detected on a given day and 7.8% of the average of the total new Covid-19 cases recorded in the last week. Approximately 39.7% of patients admitted to the ICU were non-intubated with an average ICU length of stay of 4 days. Conversely, 60.3% of patients were intubated and for those who died among them (14.44%) the ICU length of stay was of 4 days for 78.3% of them and of 15 days for 21.7% of them. For the intubated patients that were discharged alive, the ICU length of stay was of 6 days for 44.4% of them and of 20 days for 55.6% of them.RESULTSWe predict a peak of 7072 – 8043 patients for the overall French territory.CONCUSIONDespite a simplified mathematical model, the strength of our study is a narrow possible range of predicted total number of ICU patients.