Background

Nirmatrelvir-ritonavir is recommended for persons at risk for severe coronavirus disease 2019 (COVID-19) but remains underutilized. Information on which eligible groups are likely to benefit from treatment is needed.

Methods

We conducted a target trial emulation study in the Veterans Health Administration comparing nirmatrelvir–ritonavir treated versus matched untreated veterans at risk for severe COVID-19 who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from April 2022 through March 2023. We measured incidence of any hospitalization or all-cause mortality at 30 days. Outcomes were measured for the entire cohort, as well as among subgroups defined by 30-day risk of death or hospitalization, estimated using an ensemble risk prediction model.

Results

Participants were 87% male with median age 66 years and 16% unvaccinated. Compared with matched untreated participants, those treated with nirmatrelvir-ritonavir (n = 24 205) had a lower 30-day risk for hospitalization (1.80% vs 2.30%; risk difference [RD], −0.50% points [95% confidence interval {CI}: −.69 to −.35]) and death (0.11% vs 0.30%; RD, −0.20 [95% CI: −.24 to −.13]). The greatest reductions in combined hospitalization or death were observed in the highest risk quartile (RD −2.85 [95% CI: −3.94 to −1.76]), immunocompromised persons (RD −1.91 [95% CI: −3.09 to −.74]), and persons aged ≥75 years (RD −1.16 [95% CI: −1.73 to −.59]). No reductions were observed in the 2 lowest risk quartiles or persons younger than 65 years.

Conclusions

Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death in older veterans, those at highest predicted risk for severe outcomes, and immunocompromised groups. Benefit was not observed in younger veterans or groups at lower predicted risk for hospitalization and death.