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Background: We evaluated long-term trajectories of circulating hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) in persons with and without hepatitis B surface antigen (HBsAg) loss during tenofovir therapy in the Swiss HIV Cohort Study., Methods: We included 29 persons with HIV with HBsAg loss and 29 matched persons with HIV without HBsAg loss. We compared HBV RNA and HBcrAg decline and assessed the cumulative proportions with undetectable HBV RNA and HBcrAg levels during tenofovir therapy using Kaplan-Meier estimates., Results: HBsAg loss occurred after a median of 4 years (IQR, 1-8). All participants with HBsAg loss achieved suppressed HBV DNA and undetectable HBV RNA preceding undetectable quantitative HBsAg levels, whereas 79% achieved negative HBcrAg. In comparison, 79% of participants without HBsAg loss achieved undetectable HBV-RNA and 48% negative HBcrAg. After 2 years of tenofovir therapy, an HBV RNA decline ≥1 log10 copies/mL had 100% sensitivity and 36.4% specificity for HBsAg loss, whereas an HBcrAg decline ≥1 log10 U/mL had 91.0% sensitivity and 64.5% specificity., Conclusions: HBV RNA suppression preceded undetectable quantitative HBsAg levels and had high sensitivity but low specificity for HBsAg loss during tenofovir therapy in persons with HIV. HBcrAg remained detectable in approximately 20% of persons with HBsAg loss and 50% of persons without HBsAg loss., Competing Interests: Potential conflicts of interest. L. B. reports support for travel and conference participation from the CROI Foundation and the SAFE-ID Foundation. A. B. has received speaker honoraria from Gilead unrelated to this work. M.-L. P. reported support for the present article from the CirB-RNA-RHU program paid to her institution. B. T. has received honoraria for lectures from Gilead Sciences France, Hopital Vall D’Hebron, and the Belgian Association for the Study of the Liver and payment for expert testimony and travel support from the International Hepatology Education Program. L. S.-V. has received honoraria for consulting from Gilead paid to her institution and unrelated to this work. F. S.-R. reports no potential conflicts. C. S. received speaker honoraria and travel support from Gilead and a grant from Roche Diagnostics paid to her institution and unrelated to this work. C. B. has received advisory board membership fees from Gilead paid to his institution. J. K. R. has received honoraria for consulting or speaking at educational events from Boehringer, Gilead, Merck, Janssen, and ViiV. H. F. G. has received unrestricted research grants from Gilead Sciences; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences, Merck, Johnson & Johnson, Janssen, GSK, Novartis, and ViiV Healthcare; and grants from the Swiss National Science Foundation, the Bill & Melinda Gates Foundation, the Yvonne Jacob Foundation, Gilead, ViiV, and the National Institutes of Health. A. C. reported unrestricted educational grants from ViiV, Gilead, and MSD and industry-sponsored clinical trials at her HIV unit. M. C.'s institution received research grants from Gilead, MSD, and ViiV and financial compensation for expert opinion given to Gilead, MSD, and ViiV. H. H. H. received grant support from Moderna paid to his institution and honoraria for consulting or speaking at educational events from AICuris, Allovir, Moderna, VeraTx, Roche, Takeda, Biotest, and Gilead. P.S.'s institution has received travel grants and congress/advisory fees from Gilead and ViiV unrelated to this work. The institution of E. B. received grants from MSD; consulting fees from Moderna; speaker fees from Pfizer AG Switzerland; and payments for the participation of E. B. to advisory boards or travel grants from Gilead Sciences, ViiV Healthcare, MSD, Pfizer AG Switzerland, Moderna, Astra Zeneca, Eli Lilly, and Abbvie. M. L. has received lecture and presentation fees from Abbvie and Gilead and coverage and reimbursement of travel expenses from Abbvie, Gilead, Inventiva, Madrigal, and MSD. G. W. received unrestricted research grants from Gilead Sciences and Roche Diagnostics and lecture/advisory board membership fees from Gilead Sciences, MSD, and ViiV Healthcare, all paid to his institution. F. Z. has received speaker fees from Gilead; consulting fees from Aligos, Assembly, Blue Jay, and GSK; and research grants through INSERM from Assembly, Beam, Blue Jay, and Janssen. A. R. reports support to his institution for advisory boards and/or travel grants from MSD, Gilead Sciences, Pfizer, and Moderna and an investigator-initiated trial grant from Gilead Sciences. All remuneration went to his home institution and not to A. R. personally, and all remuneration was provided outside the submitted work. 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)