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Background: Viral rebound during antiretroviral treatment (ART) is most often driven by suboptimal adherence in the absence of drug resistance. We assessed the diagnostic performance of point-of-care (POC) tenofovir (TFV) detection in urine for the prediction of viral rebound and drug resistance during ART., Methods: We performed a nested case-control study within the ADVANCE randomized clinical trial (NCT03122262) in Johannesburg, South Africa. Adults with human immunodeficiency virus (HIV) and newly initiating ART were randomized to receive either dolutegravir or efavirenz, tenofovir disoproxil fumarate or alafenamide, and emtricitabine. All participants with rebound ≥200 copies/mL between 24 and 96 weeks of follow-up were selected as cases and matched to controls with virological suppression <50 copies/mL. Rapid POC urine-TFV detection was performed retrospectively., Results: We included 281 samples from 198 participants. Urine-TFV was detectable in 30.7% (70/228) of cases and in 100% (53/53) of controls. Undetectable urine-TFV predicted rebound with a sensitivity of 69% [95% confidence interval {CI}: 63-75] and specificity of 100% [93-100]. In cases with virological failure and sequencing data (n = 42), NRTI drug resistance was detected in 50% (10/20) of cases with detectable urine-TFV versus in 8.3% (2/24) of cases with undetectable urine-TFV. Detectable urine-TFV predicted NRTI resistance (odds ratio [OR] 10.4 [1.8-114.4] P = .005) with a sensitivity of 83% [52-98] and specificity of 69% [50-84]., Conclusions: POC objective adherence testing using a urine-TFV test predicted viral rebound with high specificity. In participants with rebound, urine-TFV testing predicted the selection of drug resistance. Objective adherence testing may be used to rapidly provide insight into adherence, suppression, and drug resistance during ART., Competing Interests: Potential conflicts of interest. S. K. H. was employed by OraSure Technologies Inc and provided technical assistance during the study. OraSure Technologies Inc. was not involved in the design, execution, or analysis of this study. S. K. H. also reports grants from NIMH (Assay development was funded in part through SBIR grants from NIMH); Stock or stock options for OraSure Technologies (RSUs and options as part of general compensation from OraSure). A. M. J. W. received funding for this study through her institution from the Dutch AIDS Fund. A. M. J. W. reports grants or contracts from an Investigator-initiated grant from Gilead global for the study of HIV Integrase resistance (Rosetta) (pending, grant to institution), Health Holland ICD-ICK4HIVCure (paid to institution), and ZonMW (dutch government, paid to institution); consulting fees from Gilead, ViiV/GSK, and Janssen (paid to institution); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Virology Education and the Southern African HIV Clinicians Society (paid to institution). A. M. J. W. Serves as a CEO for the European Society for Antiviral Research (ESAR) (unpaid), as governing Board member European AIDS Clinical Society, Chair of the European AIDS conference 2021 (unpaid, travel expenses paid to Institution), Member of the WHO Resnet (unpaid, travel expenses paid to Institution), Chair of the IAS-USA HIV drug resistance panel (unpaid), and as an Organizing Committee member of the European HIV and Hepatitis Meeting (unpaid, travel expenses paid to Institution). W. D. F. V. received funding for the ADVANCE RCT through his institution from Unitaid, USAID, and SAMRC, and received study drug from ViiV Healthcare and Gilead Sciences. W. D. F. V. also reports funding for his unit from the Bill and Melinda Gates, Foundation, National Institutes for Health, Unitaid, Foundation for Innovative New Diagnostics (FIND) and the Children's Investment Fund Foundation (CIFF), and received drug donations from Merck and J&J Sciences for investigator-led clinical studies. The unit leads investigator-led studies that receive financial support from Merck and ViiV and is involved in commercial drug studies for Merck. The unit performs evaluations of diagnostic devices for multiple biotech companies. W. D. F. V. also receives honoraria for educational talks and advisory board membership for Gilead, ViiV, Mylan, Merck, Adcock-Ingram, Aspen, Abbott, Roche, J&J, Sanofi and Virology Education; participates on DSMB for NIH International; is currently an unpaid board member for Dira Sengwe and was an unpaid board member for SAHCS. None of the ADVANCE RCT funders were involved in the design, execution, or analysis of this study. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)