Resistance Analyses in Heavily Treatment-Experienced People With HIV Treated With the Novel HIV Capsid Inhibitor Lenacapavir After 2 Years

作者：Nicolas Margot, Vamshi Jogiraju, Nina Pennetzdorfer, Vidula Naik, Laurie A. VanderVeen, John Ling, Renu Singh, Hadas Dvory‐Sobol, Onyema Ogbuagu, Sorana Segal-Maurer, Jean‐Michel Molina, Martin S. Rhee, Christian Callebaut · 发表于：The Journal of Infectious Diseases · 年份：2025 · DOI：10.1093/infdis/jiaf050 · 被引用次数：33 · 研究领域：HIV Research and Treatment、HIV/AIDS drug development and treatment、Biological Research and Disease Studies

BACKGROUND: Lenacapavir is a highly potent first-in-class inhibitor of HIV-1 capsid that was approved for the treatment of heavily treatment-experienced people with HIV-1 harboring multidrug-resistant virus, and it is used in combination with an optimized background regimen (OBR). Resistance analyses conducted after 2 years of lenacapavir treatment in the phase 2/3 CAPELLA study are described. METHODS: CAPELLA enrollment consisted of viremic cases of heavily treatment-experienced people with HIV-1 and resistance to ≥2 drugs per class in at least 3 of the 4 main drug classes. Postbaseline resistance in participants experiencing virologic failure was evaluated by resistance assays (HIV-1 capsid, protease, reverse transcriptase, and integrase genotypic/phenotypic tests). Adherence to OBR was assessed by plasma drug measurement via liquid chromatography-tandem mass spectrometry. RESULTS: After 2 years, lenacapavir + OBR treatment led to HIV-1 RNA suppression in 82% of participants (missing = excluded). Treatment-emergent capsid resistance occurred in 19% (14/72) of participants, including capsid mutations M66I, Q67H/K/N, K70H/N/R/S, and/or N74D/H/K, which were all associated with functional lenacapavir monotherapy. Seven participants with lenacapavir resistance reattained HIV-1 RNA <50 copies/mL upon OBR resumption or change while maintaining lenacapavir treatment. CONCLUSIONS: Emergence of lenacapavir resistance after 2 years in CAPELLA was a consequence of functional lenacapavi...