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 during the Omicron surge is limited. We sought to determine the effectiveness of nirmatrelvir-ritonavir and molnupiravir for the outpatient treatment of COVID-19.

Methods: We conducted three retrospective target trial emulation studies comparing matched patient cohorts who received nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir in the Veterans Health Administration (VHA). Participants were Veterans in VHA care at risk for severe COVID-19 who tested positive for SARS-CoV-2 in the outpatient setting during January and February 2022. Primary outcomes included all-cause 30-day hospitalization or death and 31-180-day incidence of acute or long-term care admission, death, or post-COVID-19 conditions. For 30-day outcomes, we calculated unadjusted risk rates, risk differences, and risk ratios. For 31-180-day outcomes, we used unadjusted time-to-event analyses.

Results: Participants were 90% male with median age 67 years and 26% unvaccinated. Compared to matched untreated controls, nirmatrelvir-ritonavir-treated participants (N=1,587) had a lower 30-day risk of hospitalization (27.10/1000 versus 41.06/1000, risk difference [RD] - 13.97, 95% CI -23.85 to -4.09) and death (3.15/1000 versus 14.86/1000, RD -11.71, 95% CI - 16.07 to -7.35). Among persons who were alive at day 31, further significant reductions in 31-180-day incidence of hospitalization (sub-hazard ratio 1.07, 95% CI 0.83 to 1.37) or death (hazard ratio 0.61, 95% CI 0.35 to 1.08) were not observed. Molnupiravir-treated participants aged ≥65 years (n=543) had a lower combined 30-day risk of hospitalization or death (55.25/1000 versus 82.35/1000, RD -27.10, 95% CI -50.63 to -3.58). A statistically significant difference in 30-day or 31-180-day risk of hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. Incidence of most post-COVID conditions was similar across comparison groups.

Conclusions: Nirmatrelvir-ritonavir was highly effective in preventing 30-day hospitalization and death. Short-term benefit from molnupiravir was observed in older groups. Significant reductions in adverse outcomes from 31-180 days were not observed with either antiviral.

Figure 1.

Matching strategy for A. target trials 1 and 2 (nirmatrelvir versus no treatment and molnupiravir versus no treatment) and B. target trial 3 (nirmatrelvir versus molnupiravir).

Figure 2.

Criteria for the identification of eligible study participants for the emulation of three target trials comparing the effectiveness of A. nirmatrelvir-ritonavir versus no treatment, B. molnupiravir versus no treatment, and C. nirmatrelvir-ritonavir versus molnupiravir. *Excludes persons receiving COVID-19 antiviral agents (nirmatrelvir-ritonavir or molnupiravir) outside of an expected treatment window, allowing for small discrepancies in test-positive and treatment dates. Also excludes persons who received other outpatient COVID-19 treatments (nirmatrelvir-ritonavir, molnupiravir, sotrovimab, remdesivir) on or prior to the antiviral treatment date. ^†See Supplemental Methods. ^‡See Supplemental Table 4. ^§Documented within 1 week prior to positive SARS-CoV-2 test date. ^‖Match eligible numbers presented here include persons who received nirmatrelvir-ritonavir, molnupiravir, sotrovimab, or remdesivir between January-February 2022. See Supplemental Table 9 for additional exclusions for any treatments received on or prior to the matched index date.

Figure 3.

Kaplan-Meier curves comparing Veterans treated with nirmatrelvir-ritonavir versus their matched untreated counterparts (trial 1), molnupiravir versus their matched untreated counterparts (trial 2), and nirmatrelvir-ritonavir versus molnupiravir (trial 3) showing cumulative incidence (%) with 95% confidence intervals of any hospitalization or all-cause death, any hospitalization, and all-cause death through day 30 after the index date.

Figure 4.

Kaplan-Meier curves comparing Veterans treated with nirmatrelvir-ritonavir versus their matched untreated counterparts (trial 1), molnupiravir versus their matched untreated counterparts (trial 2), and nirmatrelvir-ritonavir versus molnupiravir (trial 3) showing cumulative incidence (%) with 95% confidence intervals of any acute or long-term care admission or all-cause death, any acute or long-term care admission, and all-cause death 31–180 days after the index date among match groups alive at day 31.