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Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir against mortality, hospitalization, and in-hospital outcomes among community-dwelling, ambulatory COVID-19 patients during the BA.2.2 wave in Hong Kong: an observational study

Background Evidence evaluating real-world effectiveness of oral antivirals against Omicron variants is lacking. Methods An unselected, territory-wide cohort of all initially non-hospitalized patients with an officially registered diagnosis of SARS-CoV-2 infection between 26th February and 3rd May 2022 during the Omicron BA.2.2 wave in Hong Kong, was identified. We undertook a retrospective cohort design as primary analysis, and case-control design as sensitivity analysis. Outpatient oral antiviral users were matched with controls using 1:10 propensity-score matching. Study outcomes were mortality, COVID-19-related hospitalization, composite outcome of in-hospital disease progression (in-hospital mortality, invasive mechanical ventilation, or intensive care unit admission) and its individual outcomes. Hazard ratios (HR) were estimated by Cox regression, and odds ratios in oral antiviral users compared with non-users by logistic regression. Subgroup analyses evaluated the associations by vaccination status and age. Findings Among 1,072,004 non-hospitalized COVID-19 patients, 5,257 and 5,663 were initiated molnupiravir and nirmatrelvir/ritonavir in the community setting with a median follow-up of 42 and 38 days, respectively. Molnupiravir use was associated with lower risks of mortality (HR=0.61, 95%CI=0.46-0.82, p<0.001) and in-hospital composite outcome (HR=0.64, 95%CI=0.50-0.83, p<0.001) than non-use, while that of hospitalization was comparable to controls (HR=1.06, 95%CI=0.97-1.16, p=0.191). Nirmatrelvir/ritonavir use was associated with lower risks of mortality (HR=0.25, 95%CI=0.13-0.47, p<0.001), hospitalization (HR=0.69, 95%CI=0.60-0.79, p<0.001), and in-hospital outcome (HR=0.47, 95%CI=0.31-0.71, p<0.001) than non-use. Similar protective effects of nirmatrelvir/ritonavir were observed across vaccination status (fully vaccinated versus otherwise) and age (dichotomized at 65 years), whereas those for molnupiravir were less consistent. Findings from case-control analysis broadly confirmed those of primary analysis. Interpretation Amid the Omicron BA.2.2 wave, early initiation of oral antivirals among non-institutionalised COVID-19 patients was associated with reduced risks of mortality and in-hospital outcomes. Nirmatrelvir/ritonavir use was associated with greater and more consistent protection than molnupiravir. Funding Health and Medical Research Fund, Food and Health Bureau