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

Verena Schöning,Felix Hammann,Carlos Chaccour,Charlotte Kern

doi:10.3389/fphar.2022.816429

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.

Highlights

With almost 2 years into the COVID-19 pandemic caused by SARS-CoV-2 there have been abundant drug repurposing efforts
While the study is in silico and not based on in vivo data, the results suggest that patients infected with a VOC are likely to experience shorter, but stronger exposures to virions with higher peak loads
Treatment of SARS-CoV-2 infections achieved the greatest effect on total viral load and peak load, independently from the antiviral treatment studied, as previously noted (Goncalves et al, 2020; Kim et al, 2020; Kern et al, 2021)

Summary

Introduction

With almost 2 years into the COVID-19 pandemic caused by SARS-CoV-2 there have been abundant drug repurposing efforts. There are indications that immunity acquired during the natural course of a SARS-CoV-2 infection is reduced (Andreano et al, 2021). Most notorious amongst these variants of concern (VOCs) are five lineages, termed Alpha through Delta and Omicron (lineages B.1.1.7, B.1.351, P.1, B.1.617.2, and B.1.1.529, respectively). While they were first detected in late 2020 through November 2021, they are assumed to have been circulating for much longer (Rambaut et al, 2020; Tegally et al, 2020; Faria et al, 2021). A hallmark feature of those VOCs is their high transmissibility, in part caused by mutations such as N501Y in the spike protein, resulting in greater affinity for the ACE2 receptor (Baric, 2020)

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