Effectiveness of COVID-19 Treatment With Nirmatrelvir-Ritonavir or Molnupiravir Among U.S. Veterans: Target Trial Emulation Studies With One-Month and Six-Month Outcomes
Kristina L Bajema, Kristin Berry, Elani Streja, Nallakkandi Rajeevan, Yuli Li, Pradeep Mutalik, Lei Yan, Francesca Cunningham, Denise M Hynes, Mazhgan Rowneki, Amy Bohnert, Edward J Boyko, Theodore J Iwashyna, Matthew L Maciejewski, Thomas F Osborne, Elizabeth M Viglianti, Mihaela Aslan, Grant D Huang, George N Ioannou, Kristina L Bajema, Kristin Berry, Elani Streja, Nallakkandi Rajeevan, Yuli Li, Pradeep Mutalik, Lei Yan, Francesca Cunningham, Denise M Hynes, Mazhgan Rowneki, Amy Bohnert, Edward J Boyko, Theodore J Iwashyna, Matthew L Maciejewski, Thomas F Osborne, Elizabeth M Viglianti, Mihaela Aslan, Grant D Huang, George N Ioannou
Abstract
Background: Information about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes in the setting of Omicron variant transmission and COVID-19 vaccination is limited.
Objective: To measure the effectiveness of nirmatrelvir-ritonavir and molnupiravir for outpatient treatment of COVID-19.
Design: Three retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir.
Setting: Veterans Health Administration (VHA).
Participants: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022.
Intervention: Nirmatrelvir-ritonavir or molnupiravir pharmacotherapy.
Measurements: Incidence of any hospitalization or all-cause mortality at 30 days and from 31 to 180 days.
Results: Eighty-seven percent of participants were male; the median age was 66 years, and 18% were unvaccinated. Compared with matched untreated control participants, those treated with nirmatrelvir-ritonavir (n = 9607) had lower 30-day risk for hospitalization (22.07 vs. 30.32 per 1000 participants; risk difference [RD], -8.25 [95% CI, -12.27 to -4.23] per 1000 participants) and death (1.25 vs. 5.47 per 1000 participants; RD, -4.22 [CI, -5.45 to -3.00] per 1000 participants). Among persons alive at day 31, reductions were seen in 31- to 180-day incidence of death (hazard ratio, 0.66 [CI, 0.49 to 0.89]) but not hospitalization (subhazard ratio, 0.90 [CI, 0.79 to 1.02]). Molnupiravir-treated participants (n = 3504) had lower 30-day and 31- to 180-day risks for death (3.14 vs. 13.56 per 1000 participants at 30 days; RD, -10.42 [CI, -13.49 to -7.35] per 1000 participants; hazard ratio at 31 to 180 days, 0.67 [CI, 0.48 to 0.95]) but not hospitalization. A difference in 30-day or 31- to 180-day risk for hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants.
Limitation: The date of COVID-19 symptom onset for most veterans was unknown.
Conclusion: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death. Molnupiravir was associated with a benefit for 30-day mortality but not hospitalization. Further reductions in mortality from 31 to 180 days were observed with both antivirals.
Primary funding source: U.S. Department of Veterans Affairs.
Conflict of interest statement
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-3565.
Figures
References
- Fact sheet for healthcare providers: emergency use authorization for Paxlovid™. Accessed at on 2 April 2023.
- Fact sheet for healthcare providers: emergency use authorization for Lagevrio™ (molnupiravir) capsules. Accessed at on 23 February 2022.
- Hammond J, Leister-Tebbe H, Gardner A, et al.; EPIC-HR Investigators. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med. 2022;386:1397-1408. [PMID: ] doi:10.1056/NEJMoa2118542
- Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al.; MOVe-OUT Study Group. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 2022;386:509-520. [PMID: ] doi:10.1056/NEJMoa2116044
- Butler CC, Hobbs FDR, Gbinigie OA, et al.; PANORAMIC Trial Collaborative Group. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet. 2023;401:281-293. [PMID: ] doi:10.1016/S0140-6736(22)02597-1
- Arbel R, Wolff Sagy Y, Hoshen M, et al. Nirmatrelvir use and severe Covid-19 outcomes during the Omicron surge. N Engl J Med. 2022;387:790-798. [PMID: ] doi:10.1056/NEJMoa2204919
- Najjar-Debbiny R, Gronich N, Weber G, et al. Effectiveness of Paxlovid in reducing severe coronavirus disease 2019 and mortality in high-risk patients. Clin Infect Dis. 2023;76:e342-e349. [PMID: ] doi:10.1093/cid/ciac443
- Dryden-Peterson S, Kim A, Kim AY, et al. Nirmatrelvir plus ritonavir for early COVID-19 in a large U.S. health system: a population-based cohort study. Ann Intern Med. 2023;176:77-84. [PMID: ] doi:10.7326/M22-2141
- Aggarwal NR, Molina KC, Beaty LE, et al. Real-world use of nirmatrelvir-ritonavir in outpatients with COVID-19 during the era of Omicron variants including BA.4 and BA.5 in Colorado, USA: a retrospective cohort study. Lancet Infect Dis. 2023; [PMID: ] doi:10.1016/S1473-3099(23)00011-7
- Wong CKH, Au ICH, Lau KTK, et al. Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the Omicron wave in Hong Kong: an observational study. Lancet. 2022;400:1213-1222. [PMID: ] doi:10.1016/S0140-6736(22)01586-0
- Yip TC, Lui GC, Lai MS, et al. Impact of the use of oral antiviral agents on the risk of hospitalization in community coronavirus disease 2019 patients (COVID-19). Clin Infect Dis. 2023;76:e26-e33. [PMID: ] doi:10.1093/cid/ciac687
- Xie Y, Bowe B, Al-Aly Z. Molnupiravir and risk of hospital admission or death in adults with Covid-19: emulation of a randomized target trial using electronic health records. BMJ. 2023;380:e072705. [PMID: ] doi:10.1136/bmj-2022-072705
- Hernán MA, Robins JM. Using big data to emulate a target trial when a randomized trial is not available. Am J Epidemiol. 2016;183:758-764. [PMID: ] doi:10.1093/aje/kwv254
- Dickerman BA, Gerlovin H, Madenci AL, et al. Comparative effectiveness of BNT162b2 and mRNA-1273 vaccines in U.S. veterans. N Engl J Med. 2022;386:105-115. [PMID: ] doi:10.1056/NEJMoa2115463
- Ioannou GN, Locke ER, O'Hare AM, et al. COVID-19 vaccination effectiveness against infection or death in a national U.S. health care system: a target trial emulation study. Ann Intern Med. 2022;175:352-361. [PMID: ] doi:10.7326/M21-3256
- Ioannou GN, Locke ER, Green PK, et al. Comparison of Moderna versus Pfizer-BioNTech COVID-19 vaccine outcomes: a target trial emulation study in the U.S. Veterans Affairs Healthcare System. EClinicalMedicine. 2022;45:101326. [PMID: ] doi:10.1016/j.eclinm.2022.101326
- U.S. Department of Veterans Affairs. Veterans Health Administration. Accessed at on 1 March 2022.
- Labrecque JA, Swanson SA. Target trial emulation: teaching epidemiology and beyond. Eur J Epidemiol. 2017;32:473-475. [PMID: ] doi:10.1007/s10654-017-0293-4
- Centers for Disease Control and Prevention. Underlying Medical Conditions Associated with Higher Risk for Severe COVID-19: Information for Healthcare Professionals. Updated 9 February 2023. Accessed at on 10 May 2022.
- U.S. Food and Drug Administration. PAXLOVID Patient Eligibility Screening Checklist Tool for Prescribers. Accessed at on 27 September 2022.
- National Academies of Sciences, Engineering, and Medicine. Facilities Staffing Requirements for the Veterans Health Administration—Resource Planning and Methodology for the Future: Interim Report. National Academies Pr; 2019. doi:10.17226/25455
- Randall M, Stern A, Su Y. Five Ethical Risks to Consider Before Filling Missing Race and Ethnicity Data: Workshop Findings on the Ethics of Data Imputation and Related Methods. Urban Institute; March 2021. Accessed at on 20 November 2022.
- Osborne TF, Veigulis ZP, Arreola DM, et al. Automated EHR score to predict COVID-19 outcomes at US Department of Veterans Affairs. PLoS One. 2020;15:e0236554. [PMID: ] doi:10.1371/journal.pone.0236554
- Rosenbaum P, Rubin D. Reducing bias in observational studies using subclassification on the propensity score. J Am Stat Assoc. 1984;79:516-524. doi:10.1080/01621459.1984.10478078
- VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-Value. Ann Intern Med. 2017;167:268-274. [PMID: ] doi:10.7326/M16-2607
- Mathur MB, Ding P, Riddell CA, et al. Web site and R package for computing E-values. Epidemiology. 2018;29:e45-e7. [PMID: ] doi:10.1097/EDE.0000000000000864
- StataCorp. 11: Language syntax. Accessed at on 20 November 2022.
- Austin PC, Cafri G. Variance estimation when using propensity-score matching with replacement with survival or time-to-event outcomes. Stat Med. 2020;39:1623-1640. [PMID: ] doi:10.1002/sim.8502
- Adjei S, Hong K, Molinari NM, et al. Mortality risk among patients hospitalized primarily for COVID-19 during the Omicron and Delta variant pandemic periods - United States, April 2020–June 2022. MMWR Morb Mortal Wkly Rep. 2022;71:1182-1189. [PMID: ] doi:10.15585/mmwr.mm7137a4
- Ioannou GN, Locke E, Green P, et al. Risk factors for hospitalization, mechanical ventilation, or death among 10 131 US veterans with SARS-CoV-2 infection. JAMA Netw Open. 2020;3:e2022310. [PMID: ] doi:10.1001/jamanetworkopen.2020.22310
- Centers for Disease Control and Prevention. Risk for COVID-19 Infection, Hospitalization, and Death By Age Group. Updated 25 April 2023. Accessed at on 11 November 2022.
- Lewnard JA, McLaughlin JM, Malden D, et al. Effectiveness of nirmatrelvir–ritonavir against hospital admission or death: a cohort study in a large US healthcare system [preprint]. medRxiv. 2023. [PMID: ] doi:10.1101/2022.10.02.22280623
- National Institutes of Health. Therapeutic Management of Nonhospitalized Adults With COVID-19. Updated 20 April 2023. Accessed at on 21 March 2023.
Source: PubMed