Evolution of viral variants in remdesivir‐treated and untreated SARS‐CoV‐2‐infected pediatrics patients
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Abstract
Detailed information on intrahost viral evolution in SARS‐CoV‐2 with and without treatment is limited. Sequential viral loads and deep sequencing of SARS‐CoV‐2 from the upper respiratory tract of nine hospitalized children, three of whom were treated with remdesivir, revealed that remdesivir treatment suppressed viral load in one patient but not in a second infected with an identical strain without any evidence of drug resistance found. Reduced levels of subgenomic RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication. Haplotype reconstruction uncovered persistent SARS‐CoV‐2 variant genotypes in four patients. These likely arose from within‐host evolution, although superinfection cannot be excluded in one case. Although our dataset is small, observed sample‐to‐sample heterogeneity in variant frequencies across four of nine patients suggests the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalization could compromise the penetration of remdesivir into the lung, limiting the drugs in vivo efficacy, as has been observed in other lung infections.
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SciScore for 10.1101/2020.11.18.20230599: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Duplicated reads were removed using Picard (61). Picardsuggested: (Picard, RRID:SCR_006525)The mapping quality was checked using Qualimap and the consensus whole genome sequence was generated using QUASR (63,64). Qualimapsuggested: (QualiMap, RRID:SCR_001209)Consensus sequences were aligned using MAFFT (65). MAFFTsuggested: (MAFFT, RRID:SCR_011811)Phylogenetic Analysis: Maximum Likelihood tree of the alignment was constructed using RAxML (67), with the GTR model and 1000 … SciScore for 10.1101/2020.11.18.20230599: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Duplicated reads were removed using Picard (61). Picardsuggested: (Picard, RRID:SCR_006525)The mapping quality was checked using Qualimap and the consensus whole genome sequence was generated using QUASR (63,64). Qualimapsuggested: (QualiMap, RRID:SCR_001209)Consensus sequences were aligned using MAFFT (65). MAFFTsuggested: (MAFFT, RRID:SCR_011811)Phylogenetic Analysis: Maximum Likelihood tree of the alignment was constructed using RAxML (67), with the GTR model and 1000 bootstrap replicates. RAxMLsuggested: (RAxML, RRID:SCR_006086)Analysis and figure generation: Analysis was completed in R 3.6.1 using Rstudio 1.2 (68,69). Rstudiosuggested: (RStudio, RRID:SCR_000432)In general data was processed using dplyr (v0.8.3), figures were generated using ggplot2 (v3.3.1), both part of the tidyverse family of packages (v1.2.1) (70). ggplot2suggested: (ggplot2, RRID:SCR_014601)Minority Variant Calling: Minority allele variants had to have a frequency of above 2% and with a minimum of 4 supporting reads identified at sites with a read depth of ≥ 5 using VarScan (71) VarScansuggested: (VARSCAN, RRID:SCR_006849)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:A major caveat to our findings is that our cohort is paediatric, for which both the clinical picture and outcome of SARS-CoV-2 infections are known to differ from adults. Notwithstanding, similar patterns of clinical and virological response to remdesivir have been described in adults (3,10,46,59). Moreover, both clinical and viral sequence data from the use of repurposed drugs to treat other severe RNA viral infections has shown similarities in adults and children (12,50,55). Larger studies using deep clinical and viral profiling of multiple samples from adult patients treated with remdesivir alone and in combination would provide better insight. In summary, we show that treatment with remdesivir is capable of reducing SARS-CoV-2 viral and subgenomic RNA in vivo and demonstrate that the latter, in particular, needs further investigation as a potential biomarker for monitoring antiviral therapy. Our data suggest that heterogeneous response to remdesivir is likely in many cases to be due to non-viral factors including, potentially, inadequate dosing and duration of treatment. The patterns of SARS-CoV-2 within–host genetic heterogeneity uncovered by deep sequencing may be most parsimoniously explained by viral compartmentalisation within lung-tissue, a factor that is already known to impede drug penetration in patients with other lung infections. This may compound inherently poor remdesivir tissue penetration and rapid clearance of active metabolites in those with normal renal ...
Results from TrialIdentifier: No clinical trial numbers were referenced.
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.
- No protocol registration statement was detected.
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