(236) Effectiveness of Molnupiravir and Nirmatrelvir-Ritonavir in Patients Hospitalized with COVID-19: A Target Trial Emulation Study

Publication Number: 569

Background: Real-world effectiveness of COVID-19 oral antivirals for patients hospitalised with COVID-19 remains uncertain, especially in a largely vaccinated population.

Objectives: To examine the effectiveness of molnupiravir and nirmatrelvir-ritonavir in hospitalised COVID-19 patients during the Omicron outbreak.

Methods: Target trial emulation using territory-wide electronic health databases in Hong Kong. Adults hospitalized with COVID-19 (with documented SARS-CoV-2 infection on the same day of admission) from February 26 [molnupiravir] / March 16 [nirmatrelvir-ritonavir] to July 18, 2022 were included. Patients were followed from hospital admission (index date) till the earliest of outcome, death, 28 days post-index, or study end (August 15, 2022). Treatment strategies compared were (i) initiation of molnupiravir or nirmatrelvir-ritonavir within 5 days post-index, versus (ii) no molnupiravir or nirmatrelvir-ritonavir treatment initiation. Separate emulated trials were conducted for each drug. Outcomes were 28-day all-cause mortality, ICU admission and use of ventilatory support. Cloning and censoring approach was applied to minimize immortal time bias. Weighted pooled logistic regression adjusted for baseline covariates (age, sex, Charlson comorbidity index [CCI], number of vaccine doses received) and post-assignment time-varying covariates (CCI, concomitant treatments received) were used to estimate hazard ratio of each outcome associated with treatment.

Results: 16495 and 7119 eligible individuals were included in molnupiravir and nirmatrelvir-ritonavir emulated trials respectively, with median (IQR) age of 75.4 (17.6) and 74.4 (18.3) years, 52.2% and 50.1% male, 56.7% and 66.6% vaccinated. During a median (IQR) follow-up of 28 (0) days, 3214 and 776 deaths, 123 and 33 ICU admissions, 293 and 78 events of ventilatory support occurred. Oral antivirals initiation was associated with lower risk of all-cause mortality [hazard ratio (95% CI): molnupiravir, 0.866 (0.806-0.931); nirmaltrevir-ritonavir, 0.772 (0.662-0.902)], but not for ICU admission [molnupiravir, 1.016 (0.759-1.361); nirmaltrevir-ritonavir, 1.083 (0.581-2.021)] and ventilatory support [molnupiravir, 1.074 (0.889-1.298); nirmaltrevir-ritonavir, 1.031 (0.698-1.523)]. No significant interaction was observed between treatment and number of vaccine doses received, supporting the effectiveness of oral antivirals regardless of vaccination status.

Conclusions: Molnupiravir and nirmatrelvir-ritonavir reduced 28-day all-cause mortality in both vaccinated and unvaccinated patients hospitalised with COVID-19, but no significant risk reduction for ICU admission or ventilatory support was observed.