Ogbuagu, OnyemaOnyemaOgbuaguMolina, Jean-MichelJean-MichelMolinaChetchotisakd, PloenchanPloenchanChetchotisakdRamgopal, Moti NMoti NRamgopalSanchez, WilliamWilliamSanchezBrunetta, JasonJasonBrunettaCastelli, FrancescoFrancescoCastelliCrofoot, Gordon EGordon ECrofootCHIEN-CHING HUNGRonot-Bregigeon, SylvieSylvieRonot-BregigeonMargot, Nicolas ANicolas AMargotWang, HuiHuiWangDvory-Sobol, HadasHadasDvory-SobolRhee, Martin SMartin SRheeSegal-Maurer, SoranaSoranaSegal-Maurer2025-05-162025-05-162025-03-17https://scholars.lib.ntu.edu.tw/handle/123456789/729374Background. Lenacapavir is a long-acting human immunodeficiency virus type 1 (HIV-1) capsid inhibitor for treatment of HIV-1 infection. We evaluated the efficacy and safety of lenacapavir in combination with an investigator-selected optimized background regimen (OBR) after 104 weeks in adults with multidrug-resistant HIV-1. Methods. This ongoing, international, Phase 2/3 trial at 42 sites included 72 adults with multidrug-resistant HIV-1. Following a 2-week oral lenacapavir loading phase, participants received subcutaneous lenacapavir every 26 weeks with an OBR. HIV-1 RNA, CD4 cell counts, and adverse events were assessed over 104 weeks. One participant did not enter the extension phase. Results. At Week 104, 44 of 71 participants (62%, 95% confidence interval [CI]: 50; 73) had HIV-1 RNA <50 copies/mL via US Food and Drug Administration (FDA) snapshot algorithm. When missing data (including discontinuations) were excluded, 44 of 54 participants (82%) had HIV-1 RNA <50 copies/mL at Week 104, mean CD4 cell count increased by 122 cells/µL (95% CI: 80; 165), and the proportion of participants with CD4 cell count <200 cells/µL decreased from 64% (46 of 72) at Baseline to 29% (16 of 55). Fourteen participants had treatment-emergent lenacapavir resistance; 7 resuppressed (HIV-1 RNA <50 copies/mL) while maintaining lenacapavir use. There were no Grade 4 or serious treatment-related adverse events. One participant discontinued study drug due to an injection site reaction. Conclusions. Treatment with subcutaneous lenacapavir in combination with an OBR was well tolerated and resulted in a high rate of virological suppression over 104 weeks. Lenacapavir represents an important treatment option in people with multidrug-resistant HIV-1.enHIV-1capsid inhibitorheavily treatment-experiencedlenacapavirsubcutaneousjournal article10.1093/cid/ciae42339206943