Nirmatrelvir plus ritonavir for early COVID-19 and hospitalization in a large US health system

BackgroundIn the EPIC-HR trial, nirmatrelvir plus ritonavir led to an 88% reduction in hospitalization or death among unvaccinated outpatients with early COVID-19. Clinical impact of nirmatrelvir plus ritonavir among vaccinated populations is uncertain. ObjectiveTo assess whether nirmatrelvir plus ritonavir reduces risk of hospitalization among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune evasive SARS-CoV-2 lineages. DesignPopulation-based cohort study analyzed to emulate a clinical trial utilizing two-stage, inverse-probability weighted models to account for anticipated bias in testing and treatment. SettingA large healthcare system providing care for 1.5 million patients in Massachusetts and New Hampshire during Omicron wave (January 1 to May 15, 2022) with staged access and capacity to prescribe nirmatrelvir plus ritonavir. Patients30,322 non-hospitalized adults (87.2% vaccinated) aged 50 and older with COVID-19 and without contraindications to nirmatrelvir plus ritonavir. MeasurementPrimary outcome was hospitalization within 14 days of COVID-19 diagnosis. ResultsDuring the study period, 6036 (19.9%) patients were prescribed nirmatrelvir plus ritonavir and 24,286 (80.1%) patients were not. Patients prescribed nirmatrelvir were more likely to be older, have more comorbidities, and be unvaccinated. Hospitalization occurred in 40 (0.66%) and 232 (0.96%) patients prescribed and not prescribed nirmatrelvir plus ritonavir, respectively. The adjusted risk ratio was 0.55 (95% confidence interval 0.38 to 0.80, p = 0.002). Observed risk reduction was greater among unvaccinated patients and obese patients. LimitationsPotential for residual confounding due to differential access and uptake of COVID-19 vaccines, diagnostics, and treatment. ConclusionsThe overall risk of hospitalization was already low (<1%) following an outpatient diagnosis of COVID-19, but this risk was 45% lower among patients prescribed nirmatrelvir plus ritonavir. FundingNational Institutes of Health (P30 AI060354 and R01 CA236546).