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Antiretroviral therapy (ART) durability, time to modification or cessation, has declined. The study objective was to determine whether kidney dysfunction is contributing to reduced durability.This retrospective follow-up study of CNICS evaluated treatment-naive PLWH initiating ART between 2007 and 2014. Regimen modification was defined as cessation/modification of any part of the 3-drug ART regimen. We evaluated the role of kidney dysfunction in initial regimen modification as both a mediator and effect measure modifier. Associations of the variables with the ART modification were examined using univariable and multivariable Cox proportional hazard models.Of 4515 PLWH included in the analysis, 1967 modified their ART. Of those receiving TDF-based ART (n = 3888), 1580 (41%) modified their regimen compared with 387 (62%) receiving other regimens. Overall, the median eGFR decreased by 5 mL/min/1.73 m2 (quartiles: first = −16, third = 0) from baseline to follow-up. Of the 128 patients with low baseline eGFR (<60 mL/min/1.73 m2), the final eGFR remained low in 73% while it increased to above 60 mL/min/1.73 m2 in 27%. Of the 4387 with normal baseline eGFR, only 135 (3%) had a final eGFR <60 mL/min/1.73 m2. Those with low eGFR at the baseline and/or final visits were more likely to modify ART than others (hazards ratio = 1.75, 95% confidence interval: 1.39 to 2.19, P < 0.001). Relative to other regimens, TDF-based ART was less likely to be modified when accounting for numerous clinical and demographic traits.For patients in our study initiated on ART, including TDF-based ART, in the last decade, kidney dysfunction is not a major factor leading to regimen modification.