Effectiveness of Antiviral Therapy in Highly-Transmissible Variants of SARS-CoV-2: A Modeling and Simulation Study

Abstract

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 R₀, 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 R₀, 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.

Keywords: COVID–19; SARS–CoV-2 variants; mathematical disease modeling; molnupiravir; paxlovid; pharmacometrics; variants of concern (VOCs); viral kinetic modelling.

FIGURE 1

Simulated viral load profiles by change in within-host infectivity (R₀). Wild type SARS-CoV-2 strain (black), less transmissible (blue), highly transmissible (orange to red) variants. Limit of quantification (Ct = 35) is displayed as a dotted line.

FIGURE 2

Relative treatment effect in different VOCs compared to natural (untreated) course: relative changes of total viral load as area under the viral load curve (AUC) (A) and relative virus permanence time (time above serological positivity threshold) (B). Wild type SARS-CoV-2 strain (black), less transmissible (blue), highly transmissible (orange to red) variants.