AbstractIntroductionThe uptake of Paxlovid in individuals infected with COVID-19 has been significantly limited by concerns around the Paxlovid rebound phenomenon despite the scarcity of evidence around its epidemiology. The purpose of this study was to prospectively compare the epidemiology of Paxlovid rebound in treated and untreated participants with acute COVID-19 infectionMethodsWe designed a decentralized, digital, prospective observational study in which participants who tested positive for COVID-19 using eMed Test-to-Treat telehealth kits and were clinically eligible for Paxlovid were recruited to be evaluated for viral and symptom clearance, as well as rebound. Participants were assigned to a Paxlovid or control group based on their decision to take Paxlovid. Following initial diagnosis based on a telehealth proctored test both groups were provided 12 telehealth proctored rapid antigen home tests and asked to test on a regular frequent schedule for 16 days and answer symptom surveys. Viral rebound based on test results and COVID-19 symptom rebound based on patient reported symptoms were evaluated.ResultsViral rebound incidence was 14.2% in the Paxlovid group (n=127) and 9.3% in the control group (n=43). COVID-19 symptom rebound incidence was higher in the Paxlovid group (18.9%) compared to the control group (7.0%). There were no notable differences in viral rebound by age, gender, pre-existing conditions, or major symptom groups during the acute phase or at the 1-month interval.ConclusionThis preliminary report of our prospective study suggests that rebound after clearance of test positivity or symptom resolution is higher than previously reported. However, we observed a similar rate of rebound in both in the Paxlovid and control groups. Large studies with diverse participants and extended follow-up are needed to better understand the rebound phenomena.