Background
New long-acting antiretroviral therapy (ART) regimens are needed to expand treatment choices for people living with HIV-1. VH4524184 (VH-184) is a 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 agent for the treatment of HIV-1. Here, we present data for VH-184 from a proof-of-concept, phase 2a trial in people living 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 c/mL. In the 10-day monotherapy period, participants received oral VH-184 10, 50, or 300 mg or placebo on Days 1 (baseline), 4, and 7. After monotherapy, 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 relationships, immunologic effects, and treatment-emergent resistance.
Results
Of 22 participants enrolled (VH-184, n=19; placebo, n=3), 86% were assigned male at birth, 68% identified as White, and 59% identified as Hispanic or Latin American; mean age was 34.1 years. Plasma HIV-1 RNA levels declined from baseline through Day 10 with all VH-184 doses (Figure). Mean maximum change from baseline in plasma HIV-1 RNA was −1.17, −2.15, and −2.31 log10 c/mL for VH-184 at 10, 50, and 300 mg, respectively. An exposure-response relationship was observed for plasma HIV-1 RNA decrease. During monotherapy, the only adverse event (AE) reported in >1 participant was vomiting (VH-184, n=2 [11%]). Each drug-related AE was reported in 1 participant. All AEs were grade 1 or 2 in severity. No AEs leading to withdrawal, serious AEs, or deaths were reported during monotherapy or follow-up. There were no clinically relevant changes in clinical laboratory parameters, electrocardiograms, or vital signs. No VH-184 genotypic or phenotypic resistance was detected at Day 10, the end of monotherapy.
Conclusions
VH-184 monotherapy demonstrated rapid and highly potent antiviral activity, with HIV-1 RNA declines of >2 log10 c/mL at the highest doses, and was well tolerated, with a favorable safety and tolerability profile. An exposure-response relationship was established comparable to the maximum effect with other INSTIs. These results support further development of VH-184 as the core agent in a complete long-acting regimen for the treatment of HIV-1.
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