Coronavirus Disease 2019 Rebound in Nirmatrelvir Plus Ritonavir Treatment and Control Groups: A Prospective Cohort Study

Abstract 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. This prospective cohort study to investigate rebound incidence enrolled 917 COVID-19 positive outpatients via a digital proctored test-to-treat solution. Among 669 included in evaluation 493 intended to take NPR and 176 did not. Participants were provided frequent proctored COVID-19 tests and symptom surveys for 15 days. Time to initial viral or symptom clearance was not different between groups. Overall, 15-day viral rebound was three-fold higher in the NPR group (15.2% vs 5.4%, p <0.001) and symptom rebound was double (16.4% vs 8.4%, p <0.01). Among those experiencing initial symptom resolution, rebound after resolution was notably higher in the NPR group (43.8% vs 17.5%). This study demonstrates that while COVID-19 rebound occurs in both NPR treated and untreated outpatients, the incidence is higher in the NPR group.