Substance use patterns and contexts: impact on epigenetic age and prevention strategies in an HIV clinical care cohort

About This Grant

Drug use is highly prevalent among people with HIV (PWH) and drug use behaviors including overdose rates, drugs used, and patterns of sexualized drug use (SDU) continue to evolve. Many PWH, particularly PWH who use drugs (PWHD) experience high rates of comorbidities at ages younger than those without HIV. Treatment options such as long-acting injectable ART and use of glucagon-like peptide 1 receptor agonists (GLP-1RA) are expanding but their impact among PWHD is unknown. Understanding and addressing these evolving behaviors, increasingly common comorbidities, and expanding treatment options among PWHD remains a crucial gap. This proposal leverages the comprehensive clinical data, specimens, and rich patient reported outcomes data of the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort. CNICS focuses on validation and adjudication for cardiovascular disease (CVD) and other key HIV- and aging-related comorbidities. Extensive genetic data are available on >12,000 PWH and will be expanded with additional genome-wide genotype and methylation data. CNICS is an ideal environment to better understand SDU and other drug use among PWHD. We propose to: Aim 1a. Examine SDU and other evolving drug use patterns and treatments among PWHD. We will determine access, role, impact and uptake of drug treatment options. We will examine gaps in Naloxone access and changes in overdose rates. We will examine the impact of new and understudied potential treatments such as GLP-1 receptor agonists (GLP-1RA) on drug use. Aim 1b. Evaluate prevention approaches focusing on new tools to prevent HIV and STI transmission such as doxyPEP among PWHD. Aim 1c. Examine the HIV care continuum among PWHD focusing on recent changes in care such as long-acting injectable ART. Aim 2. Determine consequences of SDU and other drug use on clinical outcomes. We will examine CVD, liver and kidney disease, diabetes, mortality, health-related quality of life and other HIV-related outcomes to better understand the role of specific drugs and drug-related behaviors. Aim 3. Examine motivations and mechanisms for SDU among PWHD to identify opportunities for potential interventions. Aim 4. Identify the role of genetic and epigenetic predictors of drug use behaviors in HIV-associated outcomes and beneficial response to inflammatory GLP-1RA. Aim 4a. Determine the effects of changes in drug use behavior on epigenetic aging, status, HIV viral load, frailty, multimorbidity and cognitive decline in PWHD. Substance use may accelerate aging, including epigenetic aging, among PWHD and this may be reflected with broad biological changes in PWH. Aim 4b. We will estimate the impact of GLP-1RA usage on epigenetic aging, drug use, risk of clinical outcomes, and chronic inflammation in PWH. We will address critical questions on the interactions between drug use patterns, genetic predisposition, HIV, and long-term consequences of HIV that are increasingly seen with the aging of PWH in the US. We will generate new knowledge at the intersection of HIV and drug use to inform future research, interventions and clinical care.