Abstract: medRxiv preprint doi: https://doi.org/10.1101/2023.01.20.23284849; this version posted January 22, 2023. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Comparative effectiveness of Paxlovid versus sotrovimab and molnupiravir for preventing severe COVID-19 outcomes in nonhospitalised patients: observational cohort study using the OpenSAFELY platform Bang Zheng1, John Tazare1, Linda Nab2, Amir Mehrkar2, Brian MacKenna2, Ben Goldacre2, Ian J Douglas1, Laurie A Tomlinson1, on behalf of The OpenSAFELY Collaborative 1 London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK 2 The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, OX2 6GG, UK Correspondence to: Laurie A Tomlinson; Email: laurie.tomlinson@lshtm.ac.uk 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2023.01.20.23284849; this version posted January 22, 2023. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Abstract Objective: To compare the effectiveness of Paxlovid vs. sotrovimab and molnupiravir in preventing severe COVID-19 outcomes in non-hospitalised high-risk COVID-19 adult patients. Design: With the approval of NHS England, we conducted a real-world cohort study using the OpenSAFELY-TPP platform. Setting: Patient-level electronic health record data were obtained from 24 million people registered with a general practice in England that uses TPP software. The primary care data were securely linked with data on COVID-19 infection and therapeutics, hospital admission, and death within the OpenSAFELY-TPP platform, covering a period where both Paxlovid and sotrovimab were first-line treatment options in community settings. Participants: Non-hospitalised adult COVID-19 patients at high risk of severe outcomes treated with Paxlovid, sotrovimab or molnupiravir between February 11, 2022 and October 1, 2022. Interventions: Paxlovid, sotrovimab or molnupiravir administered in the community by COVID19 Medicine Delivery Units. Main outcome measure: COVID-19 related hospitalisation or COVID-19 related death within 28 days after treatment initiation. Results: A total of 7683 eligible patients treated with Paxlovid (n=4836) and sotrovimab (n=2847) were included in the main analysis. The mean age was 54.3 (SD=14.9) years; 64% were female, 93% White and 93% had three or more COVID-19 vaccinations. Within 28 days after treatment initiation, 52 (0.68%) COVID-19 related hospitalisations/deaths were observed (33 (0.68%) treated with Paxlovid and 19 (0.67%) with sotrovimab). Cox proportional hazards model stratified by region showed that after adjusting for demographics, high-risk cohort categories, vaccination status, calendar time, body mass index and other comorbidities, treatment with Paxlovid was associated with a similar risk of outcome event as treatment with sotrovimab (HR=1.14, 95% CI: 0.62 to 2.08; P=0.673). Results from propensity score weighted Cox model also showed comparable risks in these two..