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

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.