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.

Visual Abstract.. 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

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. This article summarizes 3 retrospective target trial emulation studies that sought to measure the effectiveness of nirmatrelvir–ritonavir and molnupiravir for outpatient treatment of COVID-19.

Figure 1.. Identification of eligible veterans in the emulation of 3 target trials comparing the effectiveness of nirmatrelvir–ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir–ritonavir versus molnupiravir.

VHA = Veterans Health Administration. * Includes all persons not hospitalized within 7 days before through the day following the date they tested positive for SARS-CoV-2 and treated persons not hospitalized on or before receipt of nirmatrelvir–ritonavir or molnupiravir. † Nirmatrelvir–ritonavir, molnupiravir, any anti–SARS-CoV-2 monoclonal antibodies, or remdesivir. ‡ See the Supplement Methods. § See Supplement Table 4. ‖ Documented within 1 week before the date of a SARS-CoV-2 test with a positive result. ¶ Numbers eligible for matching include persons who received nirmatrelvir–ritonavir, molnupiravir, bebtelovimab, sotrovimab, or remdesivir between January and July 2022.

Figure 2.. Cumulative 30-day incidence of hospitalization or death among outpatient veterans testing positive for SARS-CoV-2, by study group.

The figure shows comparisons of nirmatrelvir–ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir–ritonavir versus molnupiravir. Shaded areas indicate 95% CIs.

Appendix Figure.. Forest plots for subgroup analyses in target trials of nirmatrelvir–ritonavir versus no treatment and molnupiravir versus no treatment with respect to 30-day death or hospitalization.

Matched control participants not belonging to the subgroup of interest were dropped, and the remaining control participants were reweighted. Incidence is expressed as events per 1000 persons. Subgroup analyses for treatment ≤5 days after symptom onset include 1720 (nirmatrelvir–ritonavir vs. no treatment) and 848 (molnupiravir vs. no treatment) participants.

Figure 3.. Cumulative 31- to 180-day incidence of hospitalization or death among outpatient veterans testing positive for SARS-CoV-2, by study group.

The figure shows comparisons of nirmatrelvir–ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir–ritonavir versus molnupiravir. Incidence was calculated among veterans who were alive at day 31. Shaded areas indicate 95% CIs.