We propose a comprehensive investigation into the biological factors influencing antiretroviral therapy (ART) adherence and subsequent treatment outcomes among people who inject drugs (PWID). The AIDS Linked to the Intravenous Experience (ALIVE) Cohort, a large (N>5000) prospective community-based cohort of PWID with available GWAS data ascertained for illicit drug use over 3 decades, provides an ideal platform to examine the interplay between ART adherence, individual level factors (demographic, sociobehavioral and genetic) and HIV-related outcomes. This sample is >90% African-American addressing a common race/ethnicity shortcoming in genomics research. In a systematic fashion, we propose to move from large-scale epidemiologic data to examining the underlying cellular mechanisms of differential ART response. In Aim 1, we will perform high-resolution mass spectrometry (HRMS) of stored bio-specimens to biologically define ART adherence and illicit drug use in the cohort and perform an informed-GWAS approach (iGWAS) of impulse control in relation to ART adherence, controlling for illicit drug use. We will also conduct prospective assessment of delayed discounting to examine the impact of impulsivity on ART adherence, illicit drug use and HIV-related outcomes. In Aim 2, among HRMS- confirmed ART-adherent subjects we will investigate the relationship between ART-pharmacogenomic factors and HIV-related outcomes (CD4 recovery, viral load). In Aim 3, we will sort homogenous sets of naïve and memory CD4+ cells from adherent ALIVE subjects, who vary on CD4 recovery, for multi-level –omics assessment (genetic, epigenetic, gene expression). In Aim 4, in a sample of non-adherent HIV+ PWID, we will carry forward the biomarkers identified in Aims 1-3 to explore if pharmacogenomics risk stratification predicts treatment outcomes to long-acting injectable antiretroviral (LAARV) treatment. This work is novel and innovative for several reasons. While prior work has been done on ART pharmacogenomics, ALIVE is uniquely positioned to investigate a largely African American sample of PWID. We will apply novel HRMS methods on >3,200 stored plasma samples to construct amongst the largest cohort database with biologically-defined ART adherence and illicit drug use measures. We will examine CD4 cell- specific genomic differences in subjects with differential CD4 recovery. Lastly, we will perform a pharmacogenomically-informed, first-in-population trial of injectable LAARV in a non-adherent PWID population. In addition to evaluating feasibility, acceptability and safety of this novel treatment, we will explore if a pharmacogenomics risk score derived from our earlier work can predict ART responses.