Effectiveness and Safety of Lenacapavir-Containing Regimens in Highly Experienced HIV-Infected Patients With Multidrug Resistance: Real-world Results From the French Compassionate Use Program a.

BACKGROUND: Lenacapavir (LEN) with an optimized background regimen (OBR) was evaluated in a French cohort of participants with multidrug-resistant human immunodeficiency virus (HIV) via compassionate use. METHODS: Adults (n = 42) with HIV-1 (PLWH1, n = 33) or HIV-2 (PLWH2, n = 9), receiving at least 1 dose of LEN plus OBR, were prospectively followed between January 2021 and December 2023. The primary endpoint was virological suppression (plasma HIV-1 RNA [VL] <50 copies/mL at week 26 (W26)) or maintenance, using the US Food and Drug Administration Snapshot algorithm. Secondary endpoints included long-term VL, resistance emergence, LEN plasma concentration, and drug safety. RESULTS: At baseline, PLWH1 presented with a median VL of 4.0 log10 copies/mL with 14 of 33 (42%) having VL <50 copies/mL, while PLWH2 had 3.0 log10 copies/mL (with baseline VL <50 copies/mL for 3). By W26, virological suppression was achieved or maintained in 67.0% (95% CI, 48.2%-82.0%) of PLWH1, with a mean CD4+ increase of +86 cells/μL. In PLWH2, virological suppression occurred in only 22.0% (95% CI, 2.8%-60.0%), with CD4+ counts rising by +27 cells/μL. Emergence of LEN resistance was documented in 1 PLWH1 (Q67H) and 3 PLWH2 (all N73D). The median (IQR) LEN plasma concentration was 43 (31&ndashng/mL after 26 weeks of subcutaneous injections. Tolerance was acceptable with 31% reported injection site reactions leading to discontinuation in 2 patients, and no grade 3/4 treatment-related adverse events occurred (2 deaths unrelated to treatment). CONCLUSIONS: LEN plus OBR showed robust efficacy and safety in PLWH1 but limited antiviral activity in PLWH2 due to limited OBR. These findings support LEN as an effective option in highly treatment-experienced PLWH1, while underscoring challenges for PLWH2.