Efficacy of Nirmatrelvir/Ritonavir in High-Risk Adults with Preexisting SARS-CoV-2 Immunity: A Pooled Analysis of Two Randomized Controlled Trials

INTRODUCTION: Nirmatrelvir/ritonavir (NMV/r) is an oral antiviral treatment approved to treat mild-to-moderate COVID-19 among adults at high risk of severe disease. We conducted a pooled analysis of NMV/r efficacy among high-risk participants from two clinical trials who had evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity through vaccination or previous infection. METHODS: Data were pooled from a subset of participants from the Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) trial (high-risk, unvaccinated) who were baseline seropositive for SARS-CoV-2 antibodies and high-risk Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (EPIC-SR) participants who were vaccinated against SARS-CoV-2. In both trials, participants were randomized within 5 days of symptom onset to twice-daily NMV/r 300/100 mg or placebo for 5 days. Endpoints included coronavirus disease 2019 (COVID-19)-related hospitalization or all-cause death through day 28, number of medical visits, time to symptom alleviation, and percentage of participants with severe symptoms. RESULTS: Overall, 1600 participants were included in the pooled analysis (NMV/r, 807 [EPIC-HR, n = 490; EPIC-SR, n = 317]; placebo, 793 [EPIC-HR, n = 479; EPIC-SR, n = 314]). NMV/r significantly reduced COVID-19-related hospitalization or all-cause death by 73.7% compared with placebo (0.5% versus 1.9%, P = 0.0104). Relative to placebo, NMV/r was also associated with fewer medical visits (21 versus 53, P = 0.0076) and a 2-day reduction in time to symptom alleviation (12 versus 14 days, P = 0.0470). Participants treated with NMV/r were less likely to report severe targeted COVID-19 symptoms compared with placebo (22.1% relative reduction on days 2-6 [P = 0.0441]; 46.6% relative reduction on days 7-28 [P = 0.0011]). CONCLUSIONS: NMV/r reduced hospitalization and death, medical visits, time to symptom alleviation, and severe symptoms among high-risk participants with preexisting SARS-CoV-2 immunity. CLINICAL TRIALS REGISTRATION: NCT04960202; NCT05011513.