Real-world effectiveness of nirmatrelvir-ritonavir against severe outcomes of COVID-19 in Taiwan: A nationwide population-based cohort study

Background Real-world data evaluating the effectiveness of nirmatrelvir-ritonavir across diverse age groups and vaccination statuses remain limited, particularly in East Asian populations. This study evaluates its effectiveness in reducing severe COVID-19 outcomes using a large, comprehensive nationwide healthcare database and to provide new evidence. Methods This retrospective observational cohort study involved outpatient COVID-19 patients diagnosed between January 1, 2022, and December 1, 2022, within Taiwan’s National Health Insurance Research Database (NHIRD). Patients who received nirmatrelvirritonavir were compared with untreated patients. Primary outcomes include COVID-19-related hospitalization, ICU admission, invasive ventilatory support, death, and the composite outcome of hospital admission or death. Results A total of 2,300,131 non-hospitalized patients with confirmed COVID-19 between January 1 and December 1, 2022, including 530,807 patients treated with nirmatrelvirritonavir and 1,769,324 untreated patients. Treatment with nirmatrelvir-ritonavir was associated with a significantly lower risk of COVID-19-related hospitalization (HR 0.32 [95% CI 0.31 to 0.34]), ICU admission (0.41 [0.38 to 0.45]), invasive ventilatory support (0.38 [0.33 to 0.43]), death (0.42 [0.40 to 0.45]), and the composite outcome of hospital admission or death (0.34 [0.33 to 0.35]). Effectiveness was consistent across subgroups stratified by age and vaccination status, with the greatest benefit observed in unvaccinated individuals and those aged ≥65 years with additional risk factors. Conclusions In a large, nationally representative cohort, outpatient use of nirmatrelvir-ritonavir was associated with a significantly lower risk of severe COVID-19-related outcomes, regardless of age or vaccination status. These findings reinforce the clinical value of early antiviral treatment, particularly in aging and unvaccinated populations.