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. 2025 Aug;86(2):202-211.e1.
doi: 10.1053/j.ajkd.2025.02.603. Epub 2025 Apr 7.

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

Marimar Contreras Nieves  1 , Shuchi Anand  2 , I-Chun Thomas  3 , Pascal Geldsetzer  4 , Enrica Fung  2 , Manjula Kurella Tamura  3 , Maria E Montez-Rath  2
Affiliations

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

Marimar Contreras Nieves et al. Am J Kidney Dis. 2025 Aug.

Abstract

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) 15-30mL/min/1.73m2 and COVID-19 between January 2022 and January 2023 cared for in Veterans Health Administration facilities.

Exposure: Treatment with nirmatrelvir-ritonavir, no treatment with nirmatrelvir-ritonavir or molnupiravir, or treatment with molnupiravir.

Outcome: 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 an eGFR of 15-30mL/min/1.73m2 and COVID-19, 117 (2.9%) were treated with nirmatrelvir-ritonavir: mean age, 75.6±12.2 (SD) years and eGFR 24.9±4.0 (SD) 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 (eg, heart failure: risk ratio [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 an eGFR of 15-35mL/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.

Plain-language summary: COVID-19 can cause severe complications in patients with advanced kidney disease, yet nirmatrelvir-ritonavir, one of the first-line antiviral therapies, is not recommended in such patients due to safety concerns. We examined its safety and effectiveness among patients with advanced (stage IV) kidney disease. Using Veterans Health Administration records, we compared patients who received nirmatrelvir-ritonavir with those who were not treated with it nor with molnupiravir (a second-line therapy). We also compared treatment with nirmatrelvir-ritonavir with treatment with molnupiravir. We found that nirmatrelvir-ritonavir was associated with a reduced risk of serious lung problems without any evidence of increased risks of heart, liver, or kidney problems compared with not being treated with nirmatrelvir-ritonavir nor molnupiravir. The effectiveness and safety of nirmatrelvir-ritonavir were similar to that of molnupiravir. This study provides real-world evidence supporting nirmatrelvir-ritonavir use for patients with advanced kidney disease.

Keywords: COVID-19; Chronic kidney disease; Index Words; molnupiravir; nirmatrelvir-ritonavir; pharmacology.

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