A unifying model to explain high nirmatrelvir therapeutic efficacy against SARS-CoV-2, despite low post-exposure prophylaxis efficacy and frequent viral rebound

Abstract

In a pivotal trial, a 5-day course of oral ritonavir-boosted nirmatrelvir decreased hospitalization and death by 89.1% and reduced nasal viral load by 0.87 log relative to placebo when given early during symptomatic infection to high-risk individuals. Yet, more frequent viral and symptomatic rebound has been observed in community cohorts relative to the clinical trial, and ritonavir-boosted nirmatrelvir failed to achieve efficacy in a post-exposure prophylaxis trial. We developed a mathematical model capturing viral-immune dynamics and nirmatrelvir pharmacokinetics that recapitulated viral loads from the clinical trial. Our results demonstrate that nirmatrelvir IC50 (50% inhibitory concentrations) estimates from in vitro assays are approximately 60-fold lower than the plasma concentration required to reduce viral infection by 50% in humans and that a maximally potent agent would reduce the viral load by approximately 2.5 logs relative to placebo at 5 days. The model produces frequent viral rebound trajectories and identifies that earlier treatment initiation and shorter treatment duration are key predictors of rebound. Extension of early symptomatic treatment duration to 10 days and post-exposure prophylaxis to 15 days, rather than increasing dose or dosing frequency, is predicted to significantly lower the incidence of viral rebound.