Accepted for/Published in: Interactive Journal of Medical Research
Date Submitted: Jul 21, 2025
Date Accepted: Mar 31, 2026
Coronavirus Disease 2019 Rebound in Nirmatrelvir Plus Ritonavir Treatment and Control Groups: A Prospective Cohort Study
ABSTRACT
Background:
Observation of COVID-19 rebound after Nirmatrelvir Plus Ritonavir (NPR) has driven important questions surrounding one of the only direct acting antiviral treatments for COVID-19.
Objective:
The objective of this study was to examine the epidemiology of COVID-19 rebound among COVID-19 positive outpatients in the United States who independently decided whether or not to take NPR.
Methods:
This prospective, decentralized observational cohort study recruited from August 2022 through December 2023 and provided frequent proctored COVID-19 rapid antigen tests and self-report symptom surveys for 15 days. The primary outcomes were incidence of viral and symptom rebound. Secondary outcomes included time to initial viral and symptom clearance, rebound conditional on initial clearance, and symptom frequency.
Results:
Of 917 consented participants, 669 were eligible for inclusion in analyses (n=443 NPR, n=226 control group) with mean (standard deviation) age of 46.1 (12.9) years, 62.6% female, and 49.2% with at least one preexisting condition. Overall, 15-day cumulative incidence was higher in the NPR than control group for both viral (15.8% vs 5.3%) and symptom (16.5% vs 8.4%) rebound. Time to initial viral and symptom clearance was similar between groups, and among those who experienced clearance by Day 15, the probability of viral rebound (NPR: 19.1% (95%CI: 15.1, 24.0) vs control: 7% (95%CI: 4.0, 12.6), P<.001) and of symptom rebound (NPR: 47.7% (95%CI: 36.1%, 60.8%) vs control: 16.9% (95%CI: 10.9, 25.7), P<.001) was higher in the NPR than control group.
Conclusions:
This study demonstrates that while COVID-19 rebound occurs in both NPR treated and untreated outpatients, the incidence is higher in the NPR group.
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