Real-world effectiveness of nirmatrelvir/ritonavir against COVID-19 hospitalisations and severe COVID-19 in community-dwelling elderly Singaporeans during Omicron BA.2, BA.4/5 and XBB transmission

OBJECTIVES: Real-world data on continued effectiveness of nirmatrelvir/ritonavir against hospitalisation and severe COVID-19 in the context of widespread booster mRNA vaccine uptake and more immune-evasive Omicron subvariants is lacking. We conducted a retrospective cohort study in adult Singaporeans aged ≥60 years presenting to primary care with SARS-CoV-2 infection, during waves of Omicron BA.2/4/5/XBB transmission. METHODS: Binary logistic regression was used to estimate the effect of treatment (receiving nirmatrelvir/ritonavir) on outcomes (hospitalisation, severe COVID-19). Additional sensitivity analyses, including inverse-probability-of-treatment-weighting-adujsted analysis (IPTW) and adjustment using overlap weights, were performed to account for observed differences in baseline characteristics among treated/untreated cohorts. RESULTS: We included 3959 nirmatrelvir/ritonavir recipients and 139,379 untreated controls. Almost 95% received ≥3 doses of mRNA vaccines; 5.4% had preceding infection. Overall 26.5% of infections occurred during the Omicron XBB period and 1.7% were hospitalised. On multivariable logistic regression, receipt of nirmatrelvir/ritonavir was independently associated with lower odds of hospitalisation (adjusted-odds-ratio, aOR=0.65, 95%CI=0.50-0.85). Consistent estimates were obtained after IPTW adjustment (aOR for hospitalisation=0.60, 95%CI=0.48-0.75) and adjustment using overlap weights (aOR for hospitalisation=0.64, 95%CI=0.51-0.79). While receipt of nirmatrelvir/ritonavir was associated with lower odds of severe COVID-19, it was not statistically significant. CONCLUSION: Outpatient usage of nirmatrelvir/ritonavir was independently associated with reduced odds of hospitalisation amongst boosted older community-dwelling Singaporeans during successive waves of Omicron transmission, including Omicron XBB; however, it did not significantly reduce the already low risk of severe COVID-19 in a highly vaccinated population.