Real-world effectiveness of nirmatrelvir-ritonavir and molnupiravir in non-hospitalised adults with Covid-19: a population-based, retrospective cohort study 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-hospitalised 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-hospitalised adults with confirmed SARS-CoV-2 infection between Jan-2022-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 hospitalisation 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 immunised by previous infection or vaccination. In the nirmatrelvir-ritonavir analysis, the estimated risk of hospitalisation 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--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--0.08). The number needed to treat to prevent hospitalisation 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 hospitalisation 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, -0.08-0.49). 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--0.06).

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