As of October 2021, neither established agents (e.g., hydroxychloroquine) nor experimental drugs have lived up to their initial promise as antiviral treatment against SARS-CoV-2 infection. While vaccines are being globally deployed, variants of concern (VOCs) are emerging with the potential for vaccine escape. VOCs are characterized by a higher within-host transmissibility, and this may alter their susceptibility to antiviral treatment. Here we describe a model to understand the effect of changes in within-host reproduction number R 0 , as proxy for transmissibility, of VOCs on the effectiveness of antiviral therapy with molnupiravir through modeling and simulation. Molnupiravir (EIDD-2801 or MK 4482) is an orally bioavailable antiviral drug inhibiting viral replication through lethal mutagenesis, ultimately leading to viral extinction. We simulated 800 mg molnupiravir treatment every 12 h for 5 days, with treatment initiated at different time points before and after infection. Modeled viral mutations range from 1.25 to 2-fold greater transmissibility than wild type, but also include putative co-adapted variants with lower transmissibility (0.75-fold). Antiviral efficacy was correlated with R 0 , making highly transmissible VOCs more sensitive to antiviral therapy. Total viral load was reduced by up to 70% in highly transmissible variants compared to 30% in wild type if treatment was started in the first 1–3 days post inoculation. Less transmissible variants appear less susceptible. Our findings suggest there may be a role for pre- or post-exposure prophylactic antiviral treatment in areas with presence of highly transmissible SARS-CoV-2 variants. Furthermore, clinical trials with borderline efficacious results should consider identifying VOCs and examine their impact in post-hoc analysis.
【저자키워드】 molnupiravir, variants of concern (VOCs), Paxlovid, Pharmacometrics, COVID–19, SARS–CoV-2 variants, mathematical disease modeling, viral kinetic modelling, 【초록키워드】 Treatment, antiviral therapy, Efficacy, Vaccine, clinical trial, Hydroxychloroquine, VoC, SARS-COV-2 infection, susceptibility, variant, Infection, variants of concern, Antiviral treatment, Prophylactic, antiviral drug, Transmissibility, SARS-CoV-2 variants, Viral load, VOCs, Reproduction number, Effectiveness, EIDD-2801, wild type, Mutagenesis, post-hoc analysis, while, greater transmissibility, viral mutation, inhibiting viral replication, Alter, susceptible, post inoculation, initial, include, characterized, less, changes in, correlated, initiated, different time point, was reduced, Total, experimental drug, transmissible variant, 【제목키워드】 Simulation, modeling,