Selected Acute Safety Events Following the Use of Nirmatrelvir/Ritonavir or Molnupiravir for COVID-19: A Nationwide Cohort Study in South Korea

There had been concerns about the acute complications during or shortly after coronavirus disease 2019 (COVID-19) treatment with nirmatrelvir/ritonavir (NMVr) and molnupiravir (MOL). This study aimed to compare the risks of selected acute safety events in patients treated with or without NMVr or MOL using the COVID-19 oral treatment safety assessment data, constructed through the linkage of nationwide databases: National COVID-19 registry, Real-time Prescription Surveillance, and National Health Insurance data. We identified all adults diagnosed with COVID-19 between January and November 2022, and then constructed two cohorts by matching up to four patients without antiviral treatment records to NMVr or MOL users using propensity score matching. Outcomes of interest were incident-selected cardiac (i.e., atrial fibrillation, other arrhythmia, bradycardia), neurological (i.e., seizure, neuropathy, encephalomyelitis), and miscellaneous (i.e., acute pancreatitis, acute liver injury, dysgeusia) events. A total of 739,935 NMVr users were matched with 2,951,690 comparators and 150,431 MOL users with 759,521 comparators. NMVr users were at lower risk for developing selected cardiac events (hazard ratio 0.74 [95% CI 0.65–0.87] for atrial fibrillation, 0.81 [0.65–0.99] for other arrhythmia, and 0.82 [0.70–0.96] for bradycardia) and dysgeusia (0.58 [0.45–0.74]). For MOL users, the risk was lower for atrial fibrillation (0.72 [0.53–0.96]) and dysgeusia (0.34 [0.18–0.65]). Overall, there were no increased risks of acute complications during and shortly after treatment with oral COVID-19 antivirals. Rather, the findings underscore their effectiveness in attenuating the risk of potential acute sequelae of COVID-19.