Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2
drug discovery/repurposing therapeutics virology
Authors: Williamson et al. Link to paper: https://www.biorxiv.org/content/10.1101/2020.04.15.043166v1
Journal/ Pre-Print: bioRxiv
Key Words: Remdesivir
1. Remdesivir treatment reduced the clinical scores, viral loads (mildly and significant) and the lung damage in SARS-CoV-2-infected rhesus macaques compared to vehicle-treated animals.
2. Remdesivir rapidly (12 h) reduces viral shedding but not RNA loads in the lungs of treated macaques compared to controls. Suggesting that the treatment should be initiated as soon as clinically possible.
3. Remdesivir treatment fails to prevent shedding of infective viral particles in nose, and throat swabs, suggesting it has limited capacity to prevent spread of the disease.
Two groups of six rhesus macaques were infected by SARS-CoV-2 and one group was treated with remdesivir and the other one with vehicle. Remdesivir significantly reduced viral shedding (i.e. infectious virus), but not viral RNA levels (loads) in BAL of treated animals. Remdesivir treatment significantly reduced the clinical score, the presence of gross lung lesions and the lung weight to body weight ratio in the treated animals compared to control. Deep sequencing of the RNA dependent RNA polymerase gene of virus isolated at day 7 pi showed no resistance-conferring mutations.
IMPACT FOR SARS-COV2/COVID19 RESEARCH EFFORTS
Treat of SARS-CoV2/COVID19 positive individuals
Remdesivir treatment cause a quick decay of virus shedding (day 1) and a rapid recovery of treated animals, implicating that remdesivir treatment should be initiated as soon as clinically possible. Remdesivir fails at controlling virus replication and shedding in the upper respiratory tract, therefore treated patients should be considered infectious despite improvement of clinical condition.
In vivo study (rhesus macaques)
STRENGTHS AND LIMITATIONS OF THE PAPER
Novelty: First study to show remdesivir efficacy in a rhesus macaque SARS-CoV-2 model
Standing in the field: In agreement with other publications where remdesivir inhibits SARS-CoV-2 in vitro.
Appropriate statistics: Only one independent experiment. Statistics seems appropriate. They are using parametric testing despite quite a small sample size; they have not mentioned any comments on the data distribution.
Viral model used: SARS-CoV-2 strain nCoV-WA1-2020
Translatability: As the efficacy of remdesivir treatment in SARS-CoV patients is currently being assessed, this study can provide guidance in the administration and clinical management. Firstly, the acute nature of SARS-CoV-2 in rhesus macaques forced the authors to administer remdesivir as soon as 12 hours post-inoculation, close to the peak of virus replication. Therefore, they mentioned that the timing of remdesivir treatment might be crucial and suggested that treatment in COVID-19 patients should be initiated as early as possible. Secondly, the authors emphasized that the clinical improvement did not lead to a reduction in virus shedding which might be crucial in the clinical management of COVID-19 patients.
Main limitations: 1.) The authors administered remdesivir 12 hours post inoculation. Such timing is impossible to be achieved in the clinic; this problem in translatability is acknowledged by the authors as well.
2.) The authors did not assess the pharmacokinetics of remdesivir in the upper respiratory tract and therefore correlating the lack of effect with tissue concentrations is not possible.
· Very exciting and the full trial is still on-going.