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Proof-of-Concept Phase 2a Trial of VH4524184: An Emerging Third-Generation Integrase Strand Transfer Inhibitor With an Enhanced Resistance Profile

Year: 2026

Type: article

Study designs: Randomized Controlled Trial, Clinical Trial

Abstract: BACKGROUND: VH4524184 (VH-184) is an emerging third-generation integrase strand transfer inhibitor (INSTI) with an enhanced in vitro resistance profile compared with second-generation INSTIs being developed as a long-acting antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1). We present data from a proof-of-concept phase 2a trial of VH-184 in people with HIV-1. METHODS: This randomized, double-blind, placebo-controlled trial evaluated oral VH-184 monotherapy in adults naive to ART with HIV-1 RNA ≥ 3000 copies/mL. Participants received oral VH-184 10, 50, or 300 mg or placebo on days 1 (baseline), 4, and 7. On day 10, participants initiated standard-of-care ART. The primary endpoint was maximum change from baseline in plasma HIV-1 RNA through day 10. Secondary endpoints included safety, tolerability, exposure-response relationship, CD4+ cell effects, and treatment-emergent resistance. RESULTS: Of 22 participants enrolled (VH-184, n = 19; placebo, n = 3), 86% were male, 68% were White, and median age was 32 years. Mean maximum change from baseline through day 10 in HIV-1 RNA was -1.17, -2.15, and -2.31 log10 copies/mL for VH-184 10, 50, and 300 mg, respectively. No adverse events (AEs) leading to withdrawal, treatment-emergent serious AEs, or deaths occurred. There were no clinically relevant changes in safety laboratory parameters, electrocardiograms, or vital signs. No VH-184 genotypic or phenotypic resistance was detected through day 10. CONCLUSIONS: Monotherapy with VH-184 demonstrated rapid and potent antiviral activity and a favorable safety and tolerability profile. The established exposure-response model and efficacy and safety results support further development of VH-184 as the core agent in complete ART regimens for HIV-1 (ClinicalTrials.gov, NCT06214052).

Source: Clinical Infectious Diseases

DOI: 10.1093/cid/ciag357