HIV, Depression, and Insulin Resistance - PROJECT ABSTRACT Diabetes is a key driver of serious non-AIDS events in people with HIV (PWH). Depression potentially contributes to new-onset diabetes in PWH. Collectively, our preliminary data indicate that successful depression treatment with internet cognitive behavioral therapy for depression (iCBT-D) could reduce diabetes risk in PWH by improving gut integrity, reducing monocyte activation, and preventing worsening insulin resistance. In addition, our data suggest that examining the metabolome may elucidate new mechanistic and potentially therapeutic pathways linking successful depression treatment to improved insulin resistance. However, these promising findings are preliminary and require confirmation in a sufficiently powered RCT. Our multidisciplinary group of investigators propose the following Specific Aims: Aim 1: To determine the effects of iCBT-D on insulin resistance in depressed PWH on ART. We hypothesize that iCBT-D, compared to active control, will prevent worsening insulin resistance as measured by HOMA-IR at 24 weeks. In secondary analyses, we will also compare changes in HbA1c and glycated albumin as endpoints more proximal to diabetes diagnosis. Aim 2: To determine the effects of iCBT-D on monocyte activation in depressed PWH on ART. We hypothesize that iCBT-D, compared to active control, will lead to reduced circulating sCD14, sCD163, and CD14+CD16+ intermediate monocyte levels at 24 weeks. In secondary analyses, we will examine the effects of iCBT-D on markers of gut barrier integrity (REG3α) and microbial translocation (16S rDNA and β-D-glucan). Aim 3: To determine the effects of iCBT-D on metabolomic profiles in depressed PWH on ART. We hypothesize that iCBT-D, compared to active control, will result in changes in the circulating metabolome at 24 weeks. We will then perform formal pathway analysis based on differential metabolite profiles to identify novel mechanistic biologic mechanisms to explain the treatment group - HOMA-IR relationship. We will test these hypotheses by conducting a 48-week RCT comparing iCBT-D with an active control comparator group (depression education, depressive symptom monitoring, and current care for depression in the HIV clinics) in 150 depressed PWH on ART. The primary analyses will be performed at the 24-week timepoint with similar secondary analyses performed at the 48-week timepoint to assess duration of response. Given the high prevalence of depression in PWH of up to 40%, depression treatment could have significant and widespread benefits by preventing diabetes in addition to its mental health importance. Thus, this application meets the stated objectives of PAS-24-163, “Priority HIV/AIDS Research within the Mission of NIDDK.”
