Paxlovid (nirmatrelvir/ritonavir) effectiveness against hospitalization and death in N3C: A target trial emulation study

Abstract

Importance: COVID-19 has placed a monumental burden on the health care system globally. Although no longer a public health emergency, there is still a pressing need for effective treatments to prevent hospitalization and death. Paxlovid (nirmatrelvir/ritonavir) is a promising and potentially effective antiviral that has received emergency use authorization by the U.S. FDA. Objective: Determine real world effectiveness of Paxlovid nationwide and investigate disparities between treated and untreated eligible patients. Design/Setting/Participants: Population-based cohort study emulating a target trial, using inverse probability weighted models to balance treated and untreated groups on baseline confounders. Participants were patients with a SARS-CoV-2 positive test or diagnosis (index) date between December 2021 and February 2023 selected from the National COVID Cohort Collaborative (N3C) database who were eligible for Paxlovid treatment. Namely, adults with at least one risk factor for severe COVID-19 illness, no contraindicated medical conditions, not using one or more strictly contraindicated medications, and not hospitalized within three days of index. From this cohort we identified patients who were treated with Paxlovid within 5 days of positive test or diagnosis (n = 98,060) and patients who either did not receive Paxlovid or were treated outside the 5-day window (n = 913,079 never treated; n = 1,771 treated after 5 days). Exposures: Treatment with Paxlovid within 5 days of positive COVID-19 test or diagnosis. Main Outcomes and Measures: Hospitalization and death in the 28 days following COVID-19 index date. Results: A total of 1,012,910 COVID-19 positive patients at risk for severe COVID-19 were included, 9.7% of whom were treated with Paxlovid. Uptake varied widely by geographic region and timing, with top adoption areas near 50% and bottom near 0%. Adoption increased rapidly after EUA, reaching steady state by 6/2022. Participants who were treated with Paxlovid had a 26% (RR, 0.742; 95% CI, 0.689-0.812) reduction in hospitalization risk and 73% (RR, 0.269, 95% CI, 0.179-0.370) reduction in mortality risk in the 28 days following COVID-19 index date. Conclusions/Relevance: Paxlovid is effective in preventing hospitalization and death in at-risk COVID-19 patients. These results were robust to a large number of sensitivity considerations.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This research was supported in part by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The U.S. National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) gave ethical approval for this work. The N3C data transfer to NCATS is performed under a Johns Hopkins University Reliance Protocol #IRB00249128 or individual site agreements with the NIH. Use of N3C data for this study does not involve human subjects (45 CFR 46.102) as determined by the NIH Office of IRB Operations.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

The analyses described in this publication were conducted with data or tools accessed through the NCATS N3C Data Enclave https://covid.cd2h.org and N3C Attribution & Publication Policy v1.2-2020-08-25b supported by NCATS U24 TR002306, and Axle Informatics Subcontract: NCATS-P00438-B. This research was possible because of the patients whose information is included within the data and the organizations (https://ncats.nih.gov/n3c/resources/data-contribution/data-transfer-agreement-signatories) and scientists who have contributed to the on-going development of this community resource11. Enclave data is protected, and can be accessed for COVID-related research by those with an approved protocol and data use request from an institutional review board. Data access is governed under the authority of the National Institutes of Health; more information on accessing the data can be found at https://covid.cd2h.org/for-researchers. The N3C Data Enclave is available for public use. To access data used within this manuscript, institutions must have a signed Data Use Agreement executed with the U.S. National Center for Advancing Translational Sciences (NCATS) and their investigators must complete mandatory training and must submit a Data Use Request (DUR) to N3C. To request N3C data access, researchers must follow instructions at https://covid.cd2h.org/onboarding. Code is available to those with valid login credentials for the N3C Data Enclave, which can be accessed at: https://www.palantir.com/platforms/foundry/. It was written for use in the enclave on the Palantir Foundry platform, where the analysis can be reproduced by researchers. It can be exported for review upon request.

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