Evaluation of SARS-CoV-2 RNA Rebound After Nirmatrelvir/Ritonavir Treatment in Randomized, Double-Blind, Placebo-Controlled Trials — United States and International Sites, 2021–2022

• Published in: MMWR. Morbidity and mortality weekly report Vol. 72; no. 51; pp. 1365 - 1370
• Main Authors: Harrington, Patrick R., Cong, Jie, Troy, Stephanie B., Rawson, Jonathan M.O., O’Rear, Julian J., Valappil, Thamban Illath, McGarry Connelly, Sarah, Farley, John, Birnkrant, Debra
• Format: Journal Article Newsletter
• Language: English
• Published: United States U.S. Government Printing Office 22.12.2023; U.S. Center for Disease Control; Centers for Disease Control and Prevention
• Subjects: Analysis; Antiviral agents; Antiviral Agents - therapeutic use; Cell culture; Clinical trials; COVID-19; COVID-19 Drug Treatment; Enrollments; Full Report; Health aspects; Hospitalization; Humans; Maryland; Mortality; Peptide Hydrolases; Placebos; Product development; Proteases; Public health; Ribonucleic acid; Ritonavir; Ritonavir - therapeutic use; RNA; RNA, Viral; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Signs and symptoms; Maryland
• ISSN: 0149-2195; 1545-861X; 1545-861X
• DOI: 10.15585/mmwr.mm7251a2

Rebound of SARS-CoV-2 shedding or COVID-19 signs and symptoms has been described after treatment with nirmatrelvir/ritonavir (Paxlovid). The direct association of nirmatrelvir/ritonavir to COVID-19 rebound remains unclear because most reports are based on individual cases or nonrandomized studies. Viral RNA shedding data from two phase 2/3, randomized, double-blind, placebo-controlled clinical trials of nirmatrelvir/ritonavir (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients [EPIC-HR] and Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients [EPIC-SR]) were analyzed to investigate the role of nirmatrelvir/ritonavir treatment in COVID-19 rebound. Rates of rebound of SARS-CoV-2 RNA shedding, identified based on an increase in nasopharyngeal viral RNA levels from day 5 (end-of-treatment) to day 10 or day 14, were similar between nirmatrelvir/ritonavir and placebo recipients. Among subjects with a virologic response through day 5, viral RNA rebound occurred in 6.4%-8.4% of nirmatrelvir/ritonavir recipients and 5.9%-6.5% of placebo recipients across EPIC-HR and the 2021/pre-Omicron and 2022/Omicron enrollment periods of EPIC-SR. Viral RNA rebound after nirmatrelvir/ritonavir treatment was not associated with COVID-19-related hospitalization or death. Data from randomized trials demonstrated that SARS-CoV-2 rebound can occur with or without antiviral treatment, supporting the Food and Drug Administration's determination of safety and efficacy of nirmatrelvir/ritonavir in eligible patients at high risk for severe COVID-19.