Safety and Effectiveness of Nirmatrelvir-Ritonavir in Patients With Advanced Kidney Dysfunction and COVID-19.

RATIONALE & OBJECTIVE Nirmatrelvir-ritonavir prevents COVID-19 hospitalization among high-risk adults, but safety concerns limit its use in advanced kidney dysfunction. This study examined safety and effectiveness outcomes from its off-label use in patients with advanced kidney dysfunction. STUDY DESIGN Retrospective matched cohort study. SETTING & PARTICIPANTS Patients with estimated glomerular filtration rate (eGFR) 15-30 mL/min/1.73m2 and COVID-19 between January 2022 and January 2023 cared for in Veterans Health Administration facilities. EXPOSURES Treatment with nirmatrelvir-ritonavir, no treatment with nirmatrelvir-ritonavir or molnupiravir, or treatment with molnupiravir. OUTCOMES Incidence of cardiac events, stroke, acute kidney injury, liver injury, hypertension, and infection-related death, respiratory failure, pneumonia, severe infection, and hospitalization within 30-60 days of diagnosis with COVID-19. ANALYTICAL APPROACH Logistic regression for propensity matching, standardized mean differences for assessment of covariate balance, and conditional logistic regression for estimation of relative risk ratios comparing exposures for each outcome. RESULTS Among 4,020 patients with eGFR 15-30 mL/min/1.73m2 and COVID-19, 117 (2.9%) were treated with nirmatrelvir-ritonavir (mean age 75.6 [SD 12.2] years and eGFR 24.9 [SD 4.0] mL/min/1.73m2). Compared with no treatment with either nirmatrelvir-ritonavir or molnupiravir, treatment with nirmatrelvir-ritonavir was not detectably associated with different risks of cardiovascular events (e.g., heart failure (RR 1.0 [95% CI, 0.7-1.2]), liver injury (RR 1.2 [95% CI, 0.7-1.7]), or acute kidney injury (RR 1.0 [95% CI, 0.8-1.2]), but was associated with a lower risk of acute respiratory failure (RR 0.5 [95% CI, 0.2-0.7]) and pneumonia (RR 0.6 [95% CI, 0.3-0.8]). Compared with treatment with molnupiravir, treatment with nirmatrelvir-ritonavir was not detectably associated with different risks of cardiovascular events, acute respiratory failure, or pneumonia, but was associated with a higher risk of acute kidney injury. Sensitivity analyses among patients with eGFR 15-35 ml/min/1.73m2 yielded similar findings. LIMITATIONS Retrospective analysis, predominantly men in the study cohort. CONCLUSIONS Nirmatrelvir-ritonavir use in the setting of advanced kidney dysfunction was associated with a reduced risk of acute respiratory failure and pneumonia, and no detectable differences in non-respiratory adverse outcomes compared with no treatment with either nirmatrelvir-ritonavir or molnupiravir.