Luise Rogg, Mark Underwood, Nathan Hanan, Jose R Castillo-Mancilla, Lesley Kahl, Fiona Halliday, Gabriela L Ghita, Jerry L Jeffrey, Stuart Byrne, Tsukasa Onodera, Joseph Horton, Martin Gartland
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引用次数: 0
Abstract
Background: Integrase strand transfer inhibitors (INSTIs) have been fundamental to human immunodeficiency virus type 1 (HIV-1) treatment for over 15 years. VH4524184 (VH-184) is a third-generation INSTI with long-acting potential currently in development for HIV-1 treatment.
Methods: This double-blind, randomized, placebo-controlled, phase 1, first-time-in-human (FTIH) study evaluated oral VH-184 in adults without HIV-1 administered as single ascending doses (10-460 mg; part 1), multiple ascending doses (160-480 mg) for 14 days with concomitant midazolam (480 mg cohort; part 2), and as a single dose (100 mg) under fasted/fed conditions (part 3) to assess safety, tolerability, and pharmacokinetics. VH-184 resistance was evaluated in vitro against pseudotyped viruses containing participant-derived integrase sequences from the SAILING and DAWNING studies that conferred reduced susceptibility to second-generation INSTIs.
Results: Eighty-four participants (VH-184, n = 63; placebo, n = 21) were included in the FTIH study. VH-184 demonstrated a good safety and tolerability profile. Dose-proportional increases in exposures were observed after single doses of 10-300 mg, without further increase after 460 mg single or 480 mg multiple doses. Geometric mean half-life was approximately 24 hours. Observed accumulation in exposures ranged from 1.3- to 1.9-fold after repeat VH-184 dosing of 480 and 160 mg, respectively. VH-184 had minimal impact on the pharmacokinetics of CYP3A substrates and exhibited a moderate positive food effect. The in vitro resistance profile of VH-184 was enhanced compared with prior INSTIs, retaining antiviral activity against second-generation INSTI-resistant pseudotyped viruses.
Conclusions: These data support the safety and further development of VH-184 as a third-generation INSTI with long-acting potential for HIV-1 treatment. Clinical Trials Registration. NCT05631704.
期刊介绍：
Clinical Infectious Diseases (CID) is dedicated to publishing original research, reviews, guidelines, and perspectives with the potential to reshape clinical practice, providing clinicians with valuable insights for patient care. CID comprehensively addresses the clinical presentation, diagnosis, treatment, and prevention of a wide spectrum of infectious diseases. The journal places a high priority on the assessment of current and innovative treatments, microbiology, immunology, and policies, ensuring relevance to patient care in its commitment to advancing the field of infectious diseases.
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