Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multi-Drug Resistant HIV-1: Week 104 Results of a Phase 2/3 Trial

Abstract Background 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 living 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.