Resistance Analyses in Highly Treatment-Experienced People With Human Immunodeficiency Virus (HIV) Treated With the Novel Capsid HIV Inhibitor Lenacapavir. (9th September 2022)

• Record Type: Journal Article
• Authors: Margot, Nicolas A; Naik, Vidula; VanderVeen, Laurie; Anoshchenko, Olena; Singh, Renu; Dvory-Sobol, Hadas; Rhee, Martin S; Callebaut, Christian
• Is Part Of: Journal of infectious diseases. Volume 226:Number 11(2022)
• Page Start: 1985
• Page End: 1991
• Publication Date: 2022-09-09
• Subjects: HIV -- capsid -- lenacapavir -- monotherapy -- multidrug resistance -- optimized background regimen; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiac364
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract: Background: Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function in clinical development for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) harboring multidrug resistance (MDR) in combination with an optimized background regimen (OBR). Here we describe resistance analyses conducted in the pivotal phase 2/3 CAPELLA study. Methods: CAPELLA enrolled viremic HTE PWH with resistance to ≥3 of 4 of the main antiretroviral (ARV) classes and resistance to ≥2 ARV drugs per class. Baseline resistance analyses used commercial assays (HIV-1 protease, reverse transcriptase, integrase genotypic/phenotypic tests). Postbaseline resistance was evaluated in participants experiencing virologic failure. Results: At baseline, 46% of participants had resistance to the 4 main ARV drug classes, with one-third of participants having exhausted all drugs from ≥3 of the 4 main ARV classes. Treatment with LEN + OBR for 26 weeks led to viral suppression in 81% of participants. Postbaseline resistance mutations to lenacapavir occurred in 8 participants (6 with M66I, 1 with K70H, 1 with Q67H + K70R) who were receiving unintended functional LEN monotherapy at the time of resistance selection. Conclusions: LEN added to OBR led to high efficacy in this HTE patient population with MDR but could select for resistance when used unintentionally as functional monotherapy. Abstract : Addition of lenacapavir to optimized background regimen in persistently viremic highly treatment-experienced people with multidrug-resistant HIV led to 81% viral suppression by week 26. Selection of resistance occurred in 8 participants receiving unintended functional lenacapavir monotherapy.