A unifying model to explain high nirmatrelvir therapeutic efficacy, low post-exposure prophylaxis efficacy, and frequent viral rebound

Abstract

AbstractIn a pivotal trial, a 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic infection, decreased hospitalization and death by 89.1% and reduced nasal viral load by 0.87 log relative to placebo in high-risk individuals. Yet, ritonavir-boosted nirmatrelvir failed as post-exposure prophylaxis in a follow-up trial, and frequent viral rebound has been observed in the community. We developed a mathematical model capturing viral-immune dynamics and nirmatrelvir pharmacokinetics that recapitulated viral loads from this and another clinical trial. Our results suggest that nirmatrelvir’sin vivopotency is significantly lower thanin vitroassays predict. A maximally potent agent would reduce the viral load by approximately 3.5 logs relative to placebo at 5 days. The model identifies that earlier initiation and shorter treatment duration are key predictors of post-treatment rebound. Extension of early symptomatic treatment 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.