Though preclinical studies indicate that HIV medications harm hearing and magnify the risk of ototoxic hearing loss, there has been no investigation of the impact of these drugs, and their resulting mitochondrial damage, on hearing in people taking these medications for the management or prevention of HIV. As such, there is a critical need for knowledge of the effects of HIV and antiretroviral therapy (ART) on mitochondrial DNA (mtDNA) in humans and the relationship between these mitochondrial mutations and auditory status. My long-term career goal is to become a VA Career Scientist dedicated to preventing or alleviating the impacts of auditory impairment in Veterans through studies that combine hearing loss epidemiology, mechanisms and modeling. My immediate goals for this proposed CDA are to gain specific training in statistical modeling, genetics, and human auditory physiology that will enable me to forecast ototoxic-acquired hearing loss in individual-patients and minimize the auditory dysfunction resulting from these exposures. An additional goal for this CDA is to generate publications and pilot data to support a VA Merit Review and/or NIH R01 award. My overall objective for this proposed CDA research is to identify genetic and clinical markers of patients who are at high risk for antiretroviral-induced hearing loss and effective alternatives to reduce and prevent that damage. The central hypothesis is that specific ART drugs cause auditory dysfunction and mtDNA damage. The rationale for the proposed research is that once ART drugs causing these mutations have been identified, treatment recommendations can be modified to reduce and prevent ototoxic hearing loss for people taking antiretroviral medications. To test my central hypothesis, the research team will pursue two specific aims: 1) Classify risk for mutations of mtDNA by ART exposure regimen; and 2) [Estimate ART-related risk for auditory dysfunction] among patients exposed to ART. For this first aim, [we will use data available from the Million Veteran Program (MVP) create a] cohort of patients receiving ART: 1) for the management of HIV and 2) for pre-exposure prophylaxis (PrEP) to prevent HIV infection. [Using clinical and genetic information available in the MVP data core,] the research team will identify relationships between different ART combinations and three mtDNA mutations that have been associated with increased ototoxicity. For the second aim, a predictive machine learning model will be created for antiretroviral-induced ototoxicity. This model will be trained and tested on data from a cross-sectional cohort to identify key predictors of auditory dysfunction. This model-driven approach has the advantage of detecting changes in auditory performance with greater accuracy and speed than traditional hearing screening approaches and can be used to forecast hearing loss due to a hypothetical exposure before the exposure occurs. Additionally, access to this large national cohort ...