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

Abstract

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.

FIGURE

SARS-CoV-2 RNA shedding levels for subjects with viral RNA rebound who experienced COVID-19–related hospitalization any time through day 28 in the Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (A) and Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (B) clinical trials, and two subjects with evidence of treatment-emergent nirmatrelvir resistance–associated substitutions detected in the viral main protease gene (C) — United States and international sites, 2021–2022 Abbreviations: EPIC-HR = Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients; EPIC-SR = Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients; M^pro = viral main protease gene. * On study day 10, 23.9% of patient A’s M^pro sequence reads had a T304I substitution, and 23.6% of patient B’s M^pro sequence reads had an E166V substitution.