Treatment Research Investigating Depression Effects on Neuroimmune Targets (TRIDENT)

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Project Summary Since the early days of the epidemic, psychoneuroimmunology research established that there is a bi- directional relationship between depression and HIV pathogenesis. Among people with HIV (PWH), substantial damage to the gastrointestinal tract occurs during acute HIV infection, which is partially responsible for dysregulation of the gut microbiome (i.e., dysbiosis) and translocation of inflammatory microbial products into the periphery. Even among those receiving effective anti-retroviral therapy (ART), these pathophysiologic alterations in the gut drive persistent immune dysregulation that partially explains amplified risk for depression and other neuropsychiatric disorders in PWH. An important gap is that no prior clinical research in PWH receiving effective ART has examined the functional connections between the microbiome, gastrointestinal tract, immune system, and the brain – the microbiome-gut-brain (MGB) axis. Treatment Research Investigating Depression Effects on Neuroimmune Targets (TRIDENT) is a randomized controlled trial that leverages an evidence-based Cognitive-Behavioral Therapy for Adherence and Depression (CBT-AD) treatment as an experimental probe to advance our understanding of how decreasing depression alters MGB axis pathways in PWH. TRIDENT will enroll 120 depressed PWH taking an integrase strand transfer inhibitor (INSTI)-based ART regimen who have an undetectable viral load. TRIDENT will have a brief run-in period (i.e., waiting period prior to randomization) where potentially eligible participants will be asked to complete a baseline psychosocial assessment, provide biospecimens, and attend a separate baseline fMRI assessment. A total of 120 participants who complete the run-in period will be randomized to receive either: 1) CBT-AD (n = 60); or 2) a wait-list control (WLC) condition (n = 60). Immediately following randomization, CBT-AD participants will receive up to 12 individual sessions over 4 months. WLC participants will have the opportunity to receive the CBT-AD treatment after a 6-month delay. During the intent-to-treat period, follow-up assessments at 2 months and 4 months (i.e., during and immediately following the delivery of CBT-AD) will characterize changes in the microbiome, soluble immune markers relevant to HIV pathogenesis, and leukocyte signaling to measure the conserved transcriptional response to adversity (CTRA). These will be examined as plausible mediators of CBT-AD related improvements in the primary outcome – resting state activation and connectivity of the negative valence system at 6 months (assessed via fMRI). Six months after randomization, WLC participants will crossover and have the opportunity to receive CBT-AD, and all participants (both CBT-AD and WLC) will complete a final follow-up assessment at 10 months. TRIDENT will have an exceptional impact by providing an experimental model to advance our understanding of how decreasing depression changes the MGB axis in PWH. TRIDENT will include multi-level, high dimensional data on the MGB axis to catalyze a new generation of pharmacologic and behavioral treatments for depression and its neurobehavioral substrates in PWH.