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 was conducted from August 2022 through December 2023 and included frequent proctored COVID-19 rapid antigen tests and self-report symptom surveys for 15 days. The primary outcome was the incidence of viral and symptom rebound. Secondary outcomes included time to initial viral and symptom clearance, rebound probability among patients who cleared by day 15, and symptom frequency. Results Of 917 consenting participants, 669 (73%) were eligible for inclusion in the analysis (n=443, 66% in the NPR group; n=226, 34% in the control group). The mean age was 46.1 (SD 12.9) years, 62.6% (n=419) of participants were female, and 49.2% (n=329) had at least one preexisting condition. Overall, 15-day cumulative incidence was higher in the NPR group than the control group for both viral (70/443, 15.8% vs 12/226, 5.3%) and symptom (73/443, 16.5% vs 19/226, 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 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 group than the 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.
Kueper et al. (2026) studied this question.