COVID-19 Rebound in Nirmatrelvir Plus Ritonavir Treatment and Control Groups: Prospective Cohort Study.

Cohort studyInteractive journal of medical research· Jun 2026

COVID-19 Rebound in Nirmatrelvir Plus Ritonavir Treatment and Control Groups: Prospective Cohort Study.

Jacqueline K Kueper, Kalyani Kottilil, Giorgio Quer … Michael J Mina

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Infectious DiseaseCohort studyTreatment

COVID-19 viral rebound probability is higher in nirmatrelvir plus ritonavir treated patients.

COVID-19 Rebound in Nirmatrelvir Plus Ritonavir Treatment and Control Groups: Prospective Cohort Study.

Jacqueline K Kueper … Michael J Mina

Interactive journal of medical research · Jun 2026

Background

Observation of COVID-19 rebound after nirmatrelvir plus ritonavir (nirmatrelvir plus ritonavir) has driven important questions surrounding one of the only direct-acting antiviral treatments for COVID-19.

Purpose

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 nirmatrelvir plus ritonavir.

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.

n = 443,

19.1%

Results

19.1%

Viral rebound was 19.1% in treated patients, higher than 7% in controls.

n = 443,

More results

Of 917 consenting participants, 669 (73%) were eligible for inclusion in the analysis (n=443, 66% in the nirmatrelvir plus ritonavir 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.

More results

Overall, 15-day cumulative incidence was higher in the nirmatrelvir plus ritonavir 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.

“

Conclusion

This study demonstrates that while COVID-19 rebound occurs in both nirmatrelvir plus ritonavir-treated and untreated outpatients, the incidence is higher in the nirmatrelvir plus ritonavir group.

COVID-19 Rebound in Nirmatrelvir Plus Ritonavir Treatment and Control Groups: Prospective Cohort Study.

COVID-19 Rebound in Nirmatrelvir Plus Ritonavir Treatment and Control Groups: Prospective Cohort Study.

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