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Third-Generation Integrase Inhibitor Remains Active Against Resistant HIV in Lab
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AIDS 2024, July 22-26, 2024, Munich
Mark Mascolini
VH-184, a third-generation strand transfer HIV integrase inhibitor (INSTI), retained activity against virus resistant to second-generation INSTIs like dolutegravir and cabotegravir in a lab analysis [1]. VH-184 appears not to inhibit or induce the metabolizing enzyme CYP3A4 and thus may not interact with the many antiretrovirals and other drugs in which CYP3A4 does govern metabolism.
ViiV Healthcare researchers in the US and UK designed a first-in-human, double-blind, randomized, placebo-controlled, phase 1 trial to assess the safety, tolerability, pharmacokinetics, and resistance profile of VH-184 [1]. Study participants had to be 18- to 50-year-olds without HIV infection, with a body mass index of 18.5 to 32 kg/m2 and weighing at least 50 kg (110 lb).
In part 1 of the trial 5 cohorts, each with 6 volunteers, received a single ascending dose of VH-184: 10 mg, 50 mg, 150 mg, and 300 mg, and 460 mg, while 15 volunteers got placebo. In part 2 of the trial 12 volunteers got multiple doses of 160 mg once daily, 15 got multiple doses of 480 mg once daily for 14 days with midazolam, a potent inhibitor of CYP3A4, and 6 people got placebo. Part 3 involved 12 volunteers who took 100 mg of VH-184 after fasting, took no drug for at least 15 days, then took 100 mg after eating.
Everyone in every group completed their study. Men made up 91% of part 1 (41 of 45 participants), 96% of part 2 (26 of 27 participants), and 100% of part 3 (12 of 12). Racial and ethnic distributions were 40% white, 47% black, and 33% Hispanic in part 1; 59% white, 26% black, and 37% Hispanic in part 2; and 33% white, 50% black, and 25% Hispanic in part 3. Body mass index averaged 25.8 kg/m2 in part 1, 26.3 kg/m2 in part 2, and 26.4 kg/m2 in part 3.
Twenty-nine of 84 participants (34.5%) reported 44 adverse events during the trial, most of them mild and none serious. Drug-related adverse events occurred in 1 of 6 people taking 10 mg of VH-184 in part 1, 1 of 6 taking 50 mg in part 1, 1 of 6 taking 460 mg in part 1, and in 1 of 6 taking multiple doses of 160 mg once daily in part 2. Drug-related grade 2 to 4 adverse events affected 1 of 6 people taking 50 mg of VH-184 in part 1 and in 1 of 6 people taking 460 mg in part 1. Researchers reported elevated liver chemistry in 1 person each taking 150 mg in part 1, 300 mg in part 1, and 1 person taking 160 mg once daily in part 2.
Geometric mean plasma concentrations of VH-184 rose in a dose-proportional manner after single doses of 10 to 300 mg and did not rise after the 460-mg single dose or 480-mg multiple doses. Geometric mean half-life of the investigational INSTI measured about 24 hours. Observed accumulation of VH-184 varied from 1.3-fold higher after repeat dosing of 480 mg to 1.9-fold higher after repeat dosing of 160 mg. Geometric mean ratio analysis of midazolam and 1-hydroxymidazolam (the drug’s major metabolite) suggested VH-184 would have little impact on the pharmacokinetics of CYP3A inhibitors or inducers.
Taking VH-184 after eating versus after fasting resulted in a 1.5-fold higher maximum concentration and a 1.7- to 1.8-fold higher area under the concentration-time curve. ViiV researchers characterized these findings as “a moderate positive food effect.”
The investigators used genotypic and phenotypic resistance testing to explore VH-184 activity against INSTI-resistant viral isolates of 7 people taking dolutegravir in the SAILING phase 3 trial [4] and 7 taking dolutegravir in the DAWNING phase 3 trial, both of which enrolled INSTI-naive people. In these lab studies VH-184 maintained wild-type antiviral activity against viral isolates with dolutegravir-selected INSTI-related resistance mutations and potent activity against isolates with dolutegravir-selected resistance to dolutegravir and/or cabotegravir.
An ongoing, recruiting phase 2 proof-of-concept trial is evaluating VH-184 in people starting their first antiretroviral regimen [2], and the ongoing, recruiting FTIH study is testing long-acting injectable formulations of VH-184 in people without HIV [3].
References
1. Rogg L, Underwood M, Nanan N, et al. Integrase inhibitor (INSTI) with a unique resistance. AIDS 2024, July 22-26, 2024, Munich. Abstract OAB2603.
2. ClinicalTrials.gov. VH4524184 Proof-of-concept in treatment-naive adults living with HIV. ClinicalTrials.gov ID NCT06214052. https://clinicaltrials.gov/study/NCT06214052
3. ClinicalTrials.gov. First time in human study of long acting VH4524184 formulations. ClinicalTrials.gov ID NCT06310551. https://clinicaltrials.gov/study/NCT06310551
4. Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382:700-8. doi: 10.1016/S0140-6736(13)61221-0. https://pubmed.ncbi.nlm.nih.gov/23830355/
5. Aboud M, Kaplan R, Lombaard J, et al. Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial. Lancet Infect Dis. 2019;19:253-264. doi: 10.1016/S1473-3099(19)30036-2. https://pubmed.ncbi.nlm.nih.gov/30732940/
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