Real-world effectiveness of nirmatrelvir-ritonavir and molnupiravir in non-hospitalized adults with COVID-19: a population-based, retrospective cohort study

OBJECTIVES: The real-world effectiveness of the oral antivirals nirmatrelvir-ritonavir and molnupiravir against the SARS-CoV-2 Omicron variant remains uncertain. We aimed to estimate their effectiveness in non-hospitalized adults with COVID-19.

METHODS: This retrospective cohort study used data from the Municipal Department for Public Health Services of Vienna, Austria, to identify non-hospitalized adults with confirmed SARS-CoV-2 infection between January 2022 and May 2023. Nirmatrelvir-ritonavir users were compared with untreated controls and molnupiravir users with untreated controls by calculating adjusted risk differences (aRDs) using a covariate-adjusted logistic regression model with inverse probability weighting. Outcomes were hospitalization and all-cause death within 28 days.

RESULTS: We identified 113 399 eligible cases (90 481 untreated controls, 12 166 nirmatrelvir-ritonavir users, and 10 752 molnupiravir users). Over 96% of the patients were immunized by previous infection or vaccination. In the nirmatrelvir-ritonavir analysis, the estimated risk of hospitalization was 0.57% (95% CI, 0.35-0.78) in nirmatrelvir-ritonavir users and 1.09% (95% CI, 0.86-1.32) in untreated controls (aRD, -0.53%; 95% CI, -0.77 to -0.28). The estimated risk of death was 0.0% (95% CI, 0.0-0.0) in nirmatrelvir-ritonavir users and 0.13% (95% CI, 0.08-0.18) in untreated controls (aRD, -0.13%, 95% CI, -0.18 to -0.08). The number needed to treat to prevent hospitalization and death was 190 (95% CI, 130-356) and 792 (95% CI, 571-1289), respectively. These statistically significant aRDs were restricted to the subgroup of patients ≥60 years. In the molnupiravir analysis, the estimated risk of hospitalization was 1.36% (95% CI, 0.95-1.77) in molnupiravir users and 1.16% (95% CI, 0.93-1.39) in untreated controls (aRD, 0.2%; 95% CI, -0.08 to 0.49). The estimated risk of death was 0.12% (95% CI, 0.01-0.23) in molnupiravir users and 0.14% (95% CI, 0.06-0.21) in untreated controls (aRD, -0.01%; 95% CI, -0.08 to -0.06).

DISCUSSION: Among outpatients aged ≥60 years with COVID-19 in an Omicron-dominated era, treatment with nirmatrelvir-ritonavir was associated with a lower risk of hospitalization and all-cause death within 28 days, albeit with wide CIs and high numbers needed to treat. This finding was not observed in molnupiravir users and younger nirmatrelvir-ritonavir users.