As persons living with HIV (PLWH) live longer, approximately 50% will experience HIV-related cognitive dysfunction, which may affect daily activities, contribute to morbidity and mortality, and increase the likelihood of HIV transmission. Alcohol consumption among PLWH may further exacerbate long-term cognitive dysfunction, with the presumed mechanism involving the gut microbiome, microbial translocation, systemic inflammation, and ultimately neuroinflammation. However, there are many gaps in our understanding regarding the specific pathophysiological mechanisms, and a need to offer interventions that are effective and acceptable in helping PLWH to reduce drinking or to protect them against alcohol-related harm. The overarching goal of this P01 is to identify and ultimately implement new/improved, targeted interventions that will improve outcomes related to cognitive and brain dysfunction in persons with HIV who drink alcohol. The proposed P01 activity will extend our current line of research that forms the core of the Southern HIV & Alcohol Research Consortium (SHARC). The specific aims of this P01 are to: 1) improve our understanding of the specific mechanisms that connect the gut microbiome to cognitive and brain health outcomes in persons with HIV; 2) evaluate interventions that are intended to reduce the impact of alcohol on brain and cognitive health in persons with HIV; and 3) connect and extend the research activity from this P01 with the training programs and community engagement activity in the SHARC. Our P01 will utilize two cores that provide infrastructure to two Research Components (RC1, RC2). The two RC will together enroll 200 PLWH with at-risk drinking into clinical trials that share common timepoints and outcome assessments. RC1 will compare two strategies to extend contingency management to 60 days, using breathalyzers and wrist-worn biosensors to monitor drinking. RC2 uses a hybrid trial design to evaluate two biomedical interventions targeting the gut-brain axis. One intervention is a wearable, transcutaneous vagus nerve stimulator that is hypothesized to stimulate the autonomic nervous system, resulting in decreased inflammation and improved cognition. The other intervention is a probiotic supplement intended to improve the gut microbiome in persons with HIV and alcohol consumption. All participants in RC2, and a subset of those in RC1 will have neuroimaging at two timepoints. The Data Science Core will provide data management and analytical support, and will analyze existing data and the data collected from this P01 using a machine learning and AI approach to identify factors associated with intervention success or failure. The Administrative Core will provide scientific leadership, clinical research and recruitment infrastructure, and connection to the outstanding training programs, development opportunities, and community engagement provided by the SHARC. Our community engagement with diverse populations, and collection of acceptability data from clinical trial participants, will facilitate our readiness to scale up the most promising interventions and move towards implementation in the next phase of our research.

This P01 project has public health significance, because brain and cognitive dysfunction are among the most important health issues encountered by persons living with HIV as they age. Our P01 will evaluate three promising interventions that may improve cognitive functioning among persons with HIV who consume alcohol.