Background: While antiretroviral therapy is successful in conferring peripheral human immunodeficiency virus type 1 (HIV-1) suppression, eradication of HIV-1 reservoirs in the central nervous system (CNS) is an immediate goal in the management of HIV-1 infection. The primary goal of this randomized and placebo-controlled Phase IIb trial is to evaluate the effects of baricitinib versus placebo on HIV-1 CNS persistence markers in a ten-week mechanistic study, with secondary endpoints evaluating the effects on peripheral blood, neuroimaging, and neuropsychological measures. Given the large scope of this two-arm trial, the focus of the present manuscript is to report the study protocol for neuroimaging, a key secondary endpoint of the trial.
Methods: Individuals who are enrolled in the trial will undergo two brain magnetic resonance (MR) scans on a 7 Tesla Siemens TERRA whole-body MR scanner. Baseline MR data are acquired within 7 days prior to the date of randomization and week 10 MR data are acquired during the final week of the study drug or placebo. MR acquisition includes T1-weighted structural MR imaging (MRI), resting state functional MRI, single-voxel MR spectroscopy (MRS), diffusion weighted MRS, diffusion weighted imaging, and arterial spin labeling.
Discussion: The neuroimaging protocol described herein will provide non-invasive metrics of brain health, complementing the primary study outcome focused on HIV-1 levels measured from cerebrospinal fluid. While neuroimaging in the context of HIV-1 is a well-established application, the limited number of studies using ultrahigh field strength (> 3 Tesla) MRI to explore high resolution MR metrics provides strong motivation for this work. We anticipate the direct and localized measures of structure, function, and neuroinflammation will provide insight into the effect of HIV-1 on the brain, as well as related changes if the CNS HIV-1 reservoir is significantly reduced. Given the increasing availability of ultrahigh field strength MR scanners, combined with extensive secondary metrics available for additional exploratory hypotheses including biomarker levels and neuropsychological evaluations, we expect the proposed neuroimaging protocol and the results from the overall trial will contribute added value to the HIV-1 and neuroimaging literature more broadly.
Trial registration: The clinical trial was prospectively registered at ClinicalTrials.gov (NCT05452564) on 06 July 2022.
Keywords: 7 Tesla; Central nervous system; HIV; MRI; Neuroimaging; Neuroinflammation; Ultrahigh field strength.