Abstract Background Fostemsavir (FTR), the prodrug of the first-in-class attachment inhibitor temsavir, is indicated in combination with other antiretrovirals (ARVs) for heavily-treatment experienced (HTE) people with multidrug-resistant HIV-1 unable to construct suppressive regimens. After ∼5 years in the phase 3 BRIGHTE study, overall virologic response rate (HIV-1 RNA < 40 c/mL, Snapshot) with FTR + optimized background therapy (OBT) was 45% (120/267) in the Randomized Cohort (RC) and 22% (20/92) in the Non-Randomized Cohort (NRC). We present long-term efficacy of FTR + OBT among subgroups in BRIGHTE. Methods BRIGHTE included HTE adults with HIV-1 (N=371) failing their current ARV regimen (HIV-1 RNA > 400 c/mL) with ≤ 2 fully active and approved ARVs remaining. Participants with 1 or 2 ARVs entered the RC and received open-label FTR + OBT after an 8-day blinded placebo-controlled period; those with 0 ARVs entered the NRC and received open-label FTR + OBT from Day 0. Virologic and immunologic responses were analyzed by baseline (BL) demographics and disease characteristics. Results Of 371 participants (RC, n=272; NRC, n=99), 290 (78%) were male, 166 (45%) were aged ≥ 50 years, and 259 (70%) were White. Virologic response rates were generally comparable among subgroups and consistent with overall response rate (Table 1). Similar efficacy was observed in RC participants with 1 or 2 fully active ARVs in OBT, while both RC and NRC participants with high BL viral loads or low BL CD4+ T-cell counts had lower response rates. Nearly all subgroups demonstrated robust and continuous increases in CD4+ T-cell count from Weeks 96 to 240, with mean change from BL exceeding 200 cells/mm3 in all RC subgroups, including those with BL viral loads ≥ 100,000 c/mL or CD4+ T-cell counts < 20 cells/mm3 (Table 2). Conclusion Virologic response with FTR + OBT in HTE adults with advanced HIV-1 and limited treatment options was durable over ∼5 years, with no major differences among subgroups based on age, sex, race, or geographic region. Robust and continuous CD4+ T-cell increases were also observed, with numerically greater improvements in subgroups with lowest BL CD4+ T-cell counts. These data highlight the role of FTR as a treatment option for HTE people with multidrug-resistant HIV-1 regardless of demographic or disease characteristics. Disclosures Alftan Dyson, PharmD, GSK: Stocks/Bonds|ViiV Healthcare: Employment Judith A. Aberg, MD, Emergent BioSolutions: Institutional research grants|Frontier Technologies: Institutional research grants|Gilead: Institutional research grants|GSK: Advisor/Consultant|GSK: Institutional research grants|Janssen: Institutional research grants|Merck: Advisor/Consultant|Merck: Institutional research grants|Pfizer: Institutional research grants|Regeneron: Institutional research grants|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Institutional research grants Jean-Michel Molina, MD; PhD, Aelix: Advisor/Consultant|Gilead: Advisor/Consultant|Merck: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant Isabel Cassetti, MD, Gilead: Advisor/Consultant|Gilead: Institutional research grants|GSK: Advisor/Consultant|Janssen: Institutional research grants|Merck: Advisor/Consultant|Merck: Institutional research grants|ViiV Healthcare: Institutional research grants Michael Kozal, MD, ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Royalties/Licenses for chapters authored for UpToDate Bo Li, PhD, GSK: Employment|GSK: Stocks/Bonds Manyu Prakash, PhD, GSK: Stocks/Bonds|ViiV Healthcare: Employee Andrew Clark, MD, GSK: Stocks/Bonds|ViiV Healthcare: Employee Allan R. Tenorio, MD, GSK: Stocks/Bonds|ViiV Healthcare: Employee Amy Pierce, BS, GSK: Stocks/Bonds|ViiV Healthcare: Employee Max Lataillade, DO, GSK: Stocks/Bonds|ViiV Healthcare: Employee