Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial
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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 (NCT 04315948; 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.
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SciScore for 10.1101/2021.10.19.21265209: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization Distribution of randomization times since symptom onset Fig. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:We acknowledge some important limitations to our study. First a more complete evaluation of remdesivir would involve the analysis of viral dynamics in the lower respiratory tract, as was done in non-human …
SciScore for 10.1101/2021.10.19.21265209: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization Distribution of randomization times since symptom onset Fig. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:We acknowledge some important limitations to our study. First a more complete evaluation of remdesivir would involve the analysis of viral dynamics in the lower respiratory tract, as was done in non-human primates (12, 13). Here, viral loads in lower respiratory tracts were available in a subset of 120 individuals. However, the number of samples were limited and these individuals had a very severe disease (Supplementary table S6.), making it not possible to provide an unbiased and precise estimate of remdesivir. Second, we could not evaluate the association between remdesivir drug concentration and viral decay, which would be important to draw more definitive evidence on remdesivir antiviral activity. Here, drug concentrations were available for only a limited number of patients (N=61), and no significant association between drug concentrations and the time to viral clearance (Supplementary Fig. S6.) could be found. Moreover, given that symptom onset are posterior to the peak viral load (17, 27), a potential bias in the estimation of early viral dynamic parameters cannot be ruled out (see a discussion on that aspect in Néant et al (17)), in particular in hospitalized patients. Finally, the use of adjuvant drugs such as corticosteroids or any immunosuppressive treatment which might promote viral replication, as well as the intrinsic immune competency of each treated individual have not been considered. In conclusion, the use of a within-host model of the infection allowed us t...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04315948 Recruiting Trial of Treatments for COVID-19 in Hospitalized Adults Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
Results from scite Reference Check: We found no unreliable references.
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