Association between SARS-CoV-2 viral kinetics and clinical score evolution in hospitalized patients

Abstract

The role of antiviral treatment in coronavirus disease 2019 hospitalized patients is controversial. To address this question, we analyzed simultaneously nasopharyngeal viral load and the National Early Warning Score 2 (NEWS-2) using an effect compartment model to relate viral dynamics and the evolution of clinical severity. The model is applied to 664 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020-000936-23) randomly assigned to either standard of care (SoC) or SoC + remdesivir. Then we use the model to simulate the impact of antiviral treatments on the time to clinical improvement, defined by a NEWS-2 score lower than 3 (in patients with NEWS-2 <7 at hospitalization) or 5 (in patients with NEWS-2 ≥7 at hospitalization), distinguishing between patients with low or high viral load at hospitalization. The model can fit well the different observed patients trajectories, showing that clinical evolution is associated with viral dynamics, albeit with large interindividual variability. Remdesivir antiviral activity was 22% and 78% in patients with low or high viral loads, respectively, which is not sufficient to generate a meaningful effect on NEWS-2. However, simulations predicted that antiviral activity greater than 99% could reduce by 2 days the time to clinical improvement in patients with high viral load, irrespective of the NEWS-2 score at hospitalization, whereas no meaningful effect was predicted in patients with low viral loads. Our results demonstrate that time to clinical improvement is associated with time to viral clearance and that highly effective antiviral drugs could hasten clinical improvement in hospitalized patients with high viral loads.

FIGURE 1

Model‐based individual fits. Patients represented here are the patients with six viral load data points admitted within the first week of symptom onset. Circles represent detectable viral load, and triangles represent data below the limit of quantification. Orange: individual predictions of nasopharyngeal viral kinetics. Gray: individual predictions of National Early Warning Score 2 (NEWS‐2). Solid lines: patients receiving standard of care (SoC) only. Dashed lines: patients receiving remdesivir + SoC.

FIGURE 2

Predicted impact of antiviral treatment on the time to clinical improvement according to clinical status and viral load at admission. Top row: patients with low clinical risk of deterioration (NEWS‐2 <7) with low (a) or high viral load (b) at admission. Bottom row: patients with high risk of clinical deterioration (NEWS‐2 ≥7) with low (c) or high viral load (d) at admission. Time to clinical improvement was calculated as the time to achieve NEWS‐2 <3 or NEW‐2 <5 in patients with low and high risks of clinical deterioration, respectively, and a cutoff of 3.5 log₁₀ copies/10⁴ cells was used to define low and high viral loads. Treatment was assumed to be initiated on admission, with efficacy of 0% (no treatment, blue), 80% (green), 90% (yellow), 99% (orange), or 99.9% (red). The solid black line represents the median time to clinical improvement with a treatment efficacy of 99.9%, and the broken black line represents the median time to clinical improvement without treatment.