Treatment Research Investigating Depression Effects on Neuroimmune Targets (TRIDENT)

项目摘要 自疫情早期以来，心理神经免疫学研究证实，有一种双- 抑郁症与HIV发病的方向性关系。在艾滋病毒携带者(PWH)中，大量 胃肠道损伤发生在急性艾滋病毒感染期间，这是导致 肠道微生物群失调(即生物失调)和炎性微生物产物转移到 外围。即使在那些接受有效的抗逆转录病毒治疗(ART)的人中，这些病理生理 肠道的改变导致持续的免疫失调，这部分解释了抑郁风险的放大 以及威尔斯亲王医院的其他神经精神障碍。一个重要的差距是，之前没有关于PWH的临床研究 接受有效的抗逆转录病毒治疗已经检查了微生物群、胃肠道之间的功能联系 肠道、免疫系统和脑--微生物组-肠道-脑(MGB)轴。治疗研究调查 抑郁症对神经免疫靶点的影响(三叉戟)是一项随机对照试验，利用 循证认知行为疗法治疗依从性抑郁症(CBT-AD) 降低抑郁如何改变脑内MGB轴通路的实验探索 威尔斯亲王医院。三叉戟将招募120名抑郁的PWH服用基于整合酶链转移抑制物(INSTI)的 病毒载量检测不到的抗逆转录病毒疗法。三叉戟将有一个短暂的磨合期(即等待期 在随机化之前)，其中潜在符合条件的参与者将被要求完成基线心理社会 评估，提供生物样品，并参加单独的基线fMRI评估。总共120个 完成磨合期的参与者将被随机分为：1)CBT-AD(n=60)； 2)等待列表控制(WLC)条件(n=60)。随机化后，CBT-AD参与者将立即 在4个月内接受最多12次个人会议。WLC参与者将有机会获得 CBT-AD治疗后延迟6个月。在意向治疗期间，在2个月时进行随访评估 和4个月(即，在CBT-AD交付期间和之后)将表征 微生物组，与HIV致病相关的可溶性免疫标志物，以及用于测量 逆境保守转录反应(CTRA)。这些人将被视为可能的调解人 与CBT-AD相关的改善主要结果-静息状态的激活和连接 负价系统在6个月时(通过功能磁共振评估)。随机化六个月后，WLC参与者 将交叉并有机会获得CBT-AD，所有参与者(CBT-AD和WLC)都将 在10个月内完成最终的后续评估。三叉戟将产生特殊的影响，通过提供 用实验模型加深我们对抑郁减轻如何改变脑内MGB轴的理解 威尔斯亲王医院。三叉戟将包括MGB轴上的多层次、高维数据，以催化新一代 PWH中抑郁症及其神经行为底物的药物和行为治疗研究进展。

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.