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Observational Study
. 2023 Jul 5;77(1):25-31.
doi: 10.1093/cid/ciad102.

The Coronavirus Disease 2019 Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences in Participants Treated With Nirmatrelvir Plus Ritonavir Versus Untreated Controls

Jay A Pandit  1 , Jennifer M Radin  1 , Danielle C Chiang  1 , Emily G Spencer  1 , Jeff B Pawelek  1 , Mira Diwan  1 , Leila Roumani  2 , Michael J Mina  2
Affiliations
Observational Study

The Coronavirus Disease 2019 Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences in Participants Treated With Nirmatrelvir Plus Ritonavir Versus Untreated Controls

Jay A Pandit et al. Clin Infect Dis. .

Abstract

Background: The uptake of nirmatrelvir plus ritonavir (NPR) in patients with coronavirus disease 2019 (COVID-19) has been limited by concerns around the rebound phenomenon despite the scarcity of evidence around its epidemiology. The purpose of this study was to prospectively compare the epidemiology of rebound in NPR-treated and untreated participants with acute COVID-19 infection.

Methods: We designed a prospective, observational study in which participants who tested positive for COVID-19 and were clinically eligible for NPR were recruited to be evaluated for either viral or symptom clearance and rebound. Participants were assigned to the treatment or control group based on their decision to take NPR. Following initial diagnosis, both groups were provided 12 rapid antigen tests and asked to test on a regular 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.

Results: Viral rebound incidence was 14.2% in the NPR treatment group (n = 127) and 9.3% in the control group (n = 43). Symptom rebound incidence was higher in the treatment group (18.9%) compared to controls (7.0%). There were no notable differences in viral rebound by age, gender, preexisting conditions, or major symptom groups during the acute phase or at the 1-month interval.

Conclusions: This preliminary report suggests that rebound after clearance of test positivity or symptom resolution is higher than previously reported. However, notably we observed a similar rate of rebound in both the NPR treatment and control groups. Large studies with diverse participants and extended follow-up are needed to better understand the rebound phenomena.

Keywords: COVID-19; COVID-19 rebound; nirmatrelvir plus ritonavir; symptom rebound; viral rebound.

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Conflict of interest statement

Potential conflicts of interest. M. J. M. is Chief Science Officer of eMed (stock or stock options reported), on the board of directors for Quantum-SI, a protein sequencing company (stock or stock reported), on the scientific advisory board for ImmuneID, a phage display company, and serves on the medical advisory board for 4 Catalyzer. Additionally, M. J. M. reports receipt of consulting fees as a Medical/Science Advisor for Detect, Inc., a Medical Advisor for Quantum SI, a Public Health/Medical Advisor for LivePerson, and a Public Health Consultant for LiquiNano Tech. JBP reports an unpaid position as a Board Member at the San Diego Spine Foundation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Study design. After consent, participants were asked to take a COVID-19 rapid antigen test and a symptom survey on day 2, day 5, day 7, day 9, day 11, day 13, and day 15. Participants were then given an end of 16-day period survey, followed by a long COVID symptom survey at the 1-, 3-, and 6-month periods. Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 2.
Figure 2.
Survival curves comparing NPR treatment and control groups. Comparisons of (A) first positive test to first antigen negative test; (B) symptom start to first report of no symptoms; (C) symptom start to first antigen negative test. Horizontal axes are in days. Abbreviation: NPR, nirmatrelvir plus ritonavir.
Figure 3.
Figure 3.
Survival curves between NPR treatment and control groups (A). Time from negative test to viral rebound (testing positive) grouped by NPR treatment. Only includes participants with event (tested negative after initial positives) from Figure 2A. (B) Time from no symptoms to symptom rebound grouped by NPR treatment. Only includes participants with event (reported no symptoms after initially having symptoms) from Figure 2B. Horizontal axes are in days. Abbreviation: NPR, nirmatrelvir plus ritonavir.
See this image and copyright information in PMC

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