{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:58:22Z","timestamp":1790812702537,"version":"4.1.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010877","name":"ViiV Healthcare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010877","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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\u2013460\u2005mg; part 1), multiple ascending doses (160\u2013480\u2005mg) for 14 days with concomitant midazolam (480\u2005mg cohort; part 2), and as a single dose (100\u2005mg) 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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\u2013300\u2005mg, 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\u2005mg, 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\u2013resistant pseudotyped viruses.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These data support the safety and further development of VH-184 as a third-generation INSTI with long-acting potential for HIV-1 treatment.<\/jats:p>\n                  <jats:p>Clinical Trials Registration. NCT05631704.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciaf135","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T04:30:44Z","timestamp":1742704244000},"page":"510-520","source":"Crossref","is-referenced-by-count":5,"title":["Phase 1 Evaluation of VH4524184, a Third-Generation Integrase Strand Transfer Inhibitor With an Enhanced Resistance Profile"],"prefix":"10.1093","volume":"81","author":[{"given":"Luise","family":"Rogg","sequence":"first","affiliation":[{"name":"ViiV Healthcare , Durham, North Carolina ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Underwood","sequence":"additional","affiliation":[{"name":"ViiV Healthcare , Durham, North Carolina ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Hanan","sequence":"additional","affiliation":[{"name":"GSK , Collegeville, Pennsylvania 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