SARS-CoV-2 Rebound With and Without Use of COVID-19 Oral Antivirals

Abstract

Early treatment with a first-line therapy (nirmatrelvir/ritonavir [Paxlovid] or remdesivir) or second-line therapy (molnupiravir) prevents hospitalization and death among patients with mild-to-moderate COVID-19 who are at risk for severe disease and is recommended by the National Institutes of Health COVID-19 Treatment Guidelines. On May 25, 2023, the Food and Drug Administration approved nirmatrelvir/ritonavir for treatment of adults at high risk for severe disease. Although antiviral therapies are widely available, they are underutilized, possibly because of reports of SARS-CoV-2 rebound after treatment. To enhance current understanding of rebound, CDC reviewed SARS-CoV-2 rebound studies published during February 1, 2020- November 29, 2023. Overall, seven of 23 studies that met inclusion criteria, one randomized trial and six observational studies, compared rebound for persons who received antiviral treatment with that for persons who did not receive antiviral treatment. In four studies, including the randomized trial, no statistically significant difference in rebound rates was identified among persons receiving treatment and those not receiving treatment. Depending on the definition used, the prevalence of rebound varied. No hospitalizations or deaths were reported among outpatients who experienced rebound, because COVID-19 signs and symptoms were mild. Persons receiving antiviral treatment might be at higher risk for rebound compared with persons not receiving treatment because of host factors or treatment-induced viral suppression early in the course of illness. The potential for rebound should not deter clinicians from prescribing lifesaving antiviral treatments when indicated to prevent morbidity and mortality from COVID-19.

FIGURE 1

Review of SARS-CoV-2 rebound studies based on specific selection criteria^,† — February 1, 2020–November 29, 2023 * Keywords used in search were, “Paxlovid rebound,” “SARS-CoV-2 viral rebound,” “SARS-CoV-2 rebound,” “nirmatrelvir/ritonavir rebound,” “molnupiravir rebound,” “SARS-CoV-2 infection rebound,” “SARS-CoV-2 viral load rebound,” “rebound phenomenon,” “SARS-CoV-2 viral kinetics,” “SARS-CoV-2 virologic rebound,” and “SARS-CoV-2 clinical rebound.” ^† Studies were excluded if they were not related to COVID-19, related to nonrebound aspects of COVID-19, were preprints, editorials, case reports, studies of ancillary medications, or other publications not describing original data or analyses of rebound data.

FIGURE 2

Timing of viral rebound and resolution during SARS-CoV-2 infection among 22 patients^,† — February 1, 2020–November 29, 2023 * Median time to negative test result was defined as day of first negative viral test result (polymerase chain reaction or antigen) after initial positive test result. Viral rebound was defined as the first positive viral test result (polymerase chain reaction or antigen) after a negative test result. Resolution was defined as first negative viral test result after day 1 of viral rebound. ^† Timing and duration of viral rebound generated using data from 22 patients in three studies that used a virologic definition of rebound and had complete data: https://doi.org/10.1093/cid/ciac512, https://doi.org/10.1056/NEJMc2206449, and https://doi.org/10.1016/j.jinf.2022.06.011.