A unifying model to explain nirmatrelvir / ritonavir's high efficacy during early treatment and low efficacy as post-exposure prophylaxis, and to predict viral rebound

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by National Institutes of Health (NIH) grants R01AI169427 and R01AI121129. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The data analyzed in this work was previously published by Hay et al. and is available on github at https://github.com/gradlab/SC2-kinetics-immune-history. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data analyzed in this work was previously published by Hay et al. and is available on github at https://github.com/gradlab/SC2-kinetics-immune-history.