Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial

Abstract

Background: The antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial.

Objectives: To estimate the effect of remdesivir in blocking viral replication.

Methods: We analysed nasopharyngeal normalized viral loads from 665 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020-000936-23), randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in blocking viral replication. Additional analyses were conducted stratified on time of treatment initiation (≤7 or >7 days since symptom onset) or viral load at randomization (< or ≥3.5 log10 copies/104 cells).

Results: In our model, remdesivir reduced viral production by infected cells by 2-fold on average (95% CI: 1.5-3.2-fold). Model-based simulations predict that remdesivir reduced time to viral clearance by 0.7 days compared with SoC, with large inter-individual variabilities (IQR: 0.0-1.3 days). Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average (95% CI: 2.8-25-fold) and the median time to viral clearance by 2.4 days (IQR: 0.9-4.5 days).

Conclusions: Remdesivir halved viral production, leading to a median reduction of 0.7 days in the time to viral clearance compared with SoC. The efficacy was larger in patients with high viral load at randomization.

Figure 1.

Nasopharyngeal normalized viral load data in 665 patients from DisCoVeRy trial analysed in the present study. (a) SARS-CoV-2 nasopharyngeal viral load according to the time since randomization. (b and c) SARS-CoV-2 nasopharyngeal viral load according to the time since randomization in patients (N = 184) with ≥3.5 log₁₀ copies/10⁴ cells (b) and patients (N = 236) with <3.5 log₁₀ copies/10⁴ cells (c). Data are presented as means (95% CI). Red lines, patients receiving remdesivir + SoC; green lines, patients receiving SoC only. Tables below show the number of samples available at each time.

Figure 2.

Model-based individual fits for τ = 3. Patients represented here are the patients with seven data points collected within one week of symptom onset. Circles represent detectable viral load, triangles represent data below the limit of quantification. Results obtained by using the individual predictions of the model τ = 3. Red lines and symbols, patients receiving remdesivir + SoC; green lines and symbols, patients receiving SoC only.

Figure 3.

Viral dynamics predicted by the model. (a) Median predicted nasopharyngeal viral dynamics according to the time since symptom onset. (b) Cumulative incidence of the predicted time to viral clearance. Red line, patients receiving remdesivir + SoC; green lines, patients receiving SoC only. Results obtained by sampling 5000 individuals in the estimated parameter distributions.

Figure 4.

Viral dynamics predicted by the model in the subpopulation of viral load at admission ≥3.5 log₁₀ copies/10⁴ cells. (a) Median predicted nasopharyngeal viral dynamics according to the time since symptom onset. (b) Cumulative incidence of the predicted time to viral clearance. Red lines, patients receiving remdesivir + SoC; green lines patients receiving SoC only. Results obtained by sampling 5000 individuals in the estimated parameter distributions.