Brain-Focused Research on Antiretrovirals and Methamphetamine (Brain-FRAMe) - Methamphetamine (METH) remains a major public health challenge for the clinical management of people with HIV (PWH) and for controlling HIV transmission. METH can increase HIV transcription, alter immune responses, and disrupt immunometabolism and the blood-brain barrier (BBB). These and other processes combine to worsen brain health, including cognition, mood, and impulsivity. Because PWH with active METH use disorder (aMUD) often struggle with medical adherence, some do not achieve durable viral suppression with oral antiretroviral therapy (ART). Advances in long-acting injectable (LAI)-ART and medication-assisted treatment (MAT) for addiction could change this. The combination of LAI-ART and MAT that includes LAI naltrexone could improve the durability of viral suppression and reduce METH use in PWH with aMUD, which creates an opportunity to investigate the brain health effects of these changes. Addressing this requires a multidisciplinary framework. We propose to leverage these advances and integrate methods from implementation science, pharmacology, virology, immunology, and clinical and basic neuroscience to understand how LAI-ART and MAT for aMUD interact to alter brain health and its biological underpinnings. The Brain-Focused Research on Antiretrovirals and Methamphetamine (Brain-FRAMe) program will pursue a single, transformative goal: to improve the clinical care and brain health of PWH with aMUD. The proposed research will be organized into three subgoals: Clinical Implementation, Brain Health Phenotyping, and Biological Mechanisms. Investigators will form four teams that will study the same participants over 52 weeks from different perspectives. The Clinical Implementation Team will deploy and evaluate the implementation of LAI-ART and MAT in PWH with aMUD in a primary care HIV clinic. The Neurobehavioral Phenotyping Team will characterize the neuromedical, neurocognitive, and psychiatric changes that result from LAI-ART and MAT. The Biophenotyping and Pharmacology Team will assess effects of METH and MAT on ART pharmacokinetics as well as changes in the HIV reservoir and proteomic and transcriptomic profiles in blood and CSF. Using biospecimens from the same participants over time, the Basic Science Mechanisms Team will interrogate targeted biological mechanisms that underlie the effects of aMUD, LAI-ART, and MAT, such as BBB integrity, immunometabolism, and immune competence. The robust and reproducible methods used by all teams will generate data that will be analyzed individually and in aggregate by the Data Integration and Analysis Group. The Scientific Program Coordinator and Contact PI will work with the MPIs and program staff to coordinate all aspects of the program, monitor progress, foster communication, curate data and biospecimens, convene advisory boards, and assure synergy and integration. Using these and other innovative methods, Brain-FRAMe will achieve within five years its goal of transforming the clinical care and brain health of this highly vulnerable group of people, which should also reduce new HIV infections in our community.
