Assessment of metformin for restoration of immune homeostasis in HIV+ and HIV- individuals with a history of injection drug use - Project Summary The combined opioid and stimulant use epidemic is an escalating public health emergency with numerous biological and psychological drivers and consequences, which are amplified in people with HIV (PWH) and other marginalized groups. We and others have described significant immune alterations in PWH and individuals that inject opioids and/or stimulants including increased systemic inflammation and lymphocyte dysregulation, including among B cells. This heighted inflammatory state and distorted B cell function likely contribute to increased risk and severity of infections and inflammatory co-morbidities including cardiovascular, kidney, liver, and autoimmune diseases. Although anti-retroviral therapy (ART) suppresses HIV, its ability to restore immune homeostasis is incomplete, resulting in accelerated immunological aging and associated co-morbidities; subsequently development of adjunctive interventions to mitigate these complications is ongoing. Active substance use, intoxication, and related behaviors associated with injection drug use can impact HIV viral dynamics and immune competency. Among people who inject drugs (PWID) that do not have HIV, there is a high risk for acquiring HIV, clear indications of reduced effectiveness of HIV vaccines, and altered viral dynamics in the acute stage of HIV infection; these unique factors highlight the challenges of HIV vaccine development for PWID. There is an unmet need for interventions that can restore immune homeostasis in PWID in order to improve responses to pathogens and minimize inflammatory-related co-morbidities. Metformin (MTF), the most widely prescribed drug for type 2 diabetes (T2D), may be such an intervention. Animal and human studies have demonstrated MTFs ability to reduce inflammation and enhance vaccine responses. Our central hypothesis is that MTF can mitigate the inflammation and immune dysregulation that is prevalent in PWID including among PWH, restoring immune homeostasis and responsiveness. This will be addressed through a placebo controlled, randomized clinical trial of MTF in PWH and non-PWH with a history of recent injection drug use including opioids and stimulants. Assessment of Hepatitis A/B and pneumococcal vaccine responses during this trial will allow examination of adaptive responses to pathogens of concern within these populations and serve as a surrogate for assessing their potential response to a future HIV vaccine. Vaccine outcomes will provide a metric to complement the integrated behavioral and high-resolution functional analysis of systemic and mucosal inflammation and immunity, providing mechanistic insights relevant to HIV prevention and pathogenesis. Our hypothesis will be addressed through the following aims: 1) determine the ability of MTF to mitigate inflammation and improve vaccine response in PWID, 2) determine the ability of MTF to normalize B cell phenotype and function in PWID, and 3) determine the influence of MTF on mucosal inflammation and immunity.
