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Am Fam Physician. 2023;107(4):432-433

Clinical Question

Does symptomatic rebound occur in patients with COVID-19 who are not treated with nirmatrelvir/ritonavir (Paxlovid)?

Bottom Line

Symptomatic recurrences in patients who initially recovered from COVID-19 are common, even without nirmatrelvir/ritonavir treatment, and are generally mild. Some symptoms may represent viral recurrence, and some may represent postinflammatory symptoms or the development of long COVID. Some symptoms may be caused by different infections. (Level of Evidence = 1b)


Nirmatrelvir/ritonavir rebound has been widely reported by patients and in the media. It comprises recurrent symptoms of COVID-19 following a five-day course of nirmatrelvir/ritonavir in someone who initially recovered. Is this causally related to the use of this drug, or is it part of the natural history of SARS-CoV-2 infection? The authors used data from the placebo group in the ACTIV-2 randomized trial that compared several treatments (including nirmatrelvir/ritonavir with placebo) in symptomatic outpatients with COVID-19 for 10 days or less. The current study reports only on symptom recurrence in the placebo group. The 158 participants in the placebo group completed a daily symptom diary for 28 days, tracking 13 symptoms. The participants had a median age of 47 years, 50% were women, 18% self-identified as part of a minority racial group, and 31% were Hispanic. During the 28 days of follow-up, 108 of 158 participants (68%) achieved complete resolution of all symptoms for at least two consecutive days. Of these 108 people, 48 (44%) reported at least one symptom recurring at least one day during the follow-up period. The most common recurrent symptoms were cough (44%), fatigue (35%), and headache (35%). The recurrent symptoms were mild, with no patient reporting severe recurrent symptoms, and only eight of the 48 reporting moderate-severity symptoms for at least one day. The interval between resolution of the initial symptoms and recurrence varied from one day to more than two weeks later, so some of these recurrences may represent a separate viral illness. Approximately one-half recurred in the first week after resolution.

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POEMs (patient-oriented evidence that matters) are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, see Copyright Wiley-Blackwell. Used with permission.

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This series is coordinated by Natasha J. Pyzocha, DO, contributing editor.

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