Effectiveness of COVID-19 Treatment With Nirmatrelvir-Ritonavir or Molnupiravir Among US Veterans: Target Trial Emulation Studies With One-Month and Six-Month Outcomes

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. Ann Intern Med. doi:10.7326/M22-3565 Annals.org For author, article, and disclosure information, see end of text. This article was published at Annals.org on 6 June 2023.