The broad objective guiding our research is to provide critical insights to clinicians and decision makers regarding the value of interventions to diagnose, prevent and reduce progression of physical frailty (PF) in people with HIV (PWH). More than a million persons in the United States live with HIV, a previously fatal infection that has become a highly treatable chronic condition with the use of antiretroviral therapy. The life expectancy of PWH now approaches that of the general population, revealing an earlier than expected and growing prevalence of PF. PF carries substantial individual and societal burden. If unmanaged, it may lead to loss of independence, recurrent falls, fractures, disability, and death. Routine screening and management of PF has not been part of the treatment guidelines, which instead focused on opportunistic infections early in the HIV epidemic, and more recently on HCV co-infection, CVD, and tobacco and other substance use disorder. The challenges in diagnosing and managing PF and its associated conditions in PWH are further exacerbated by the gap between ‘what we know’ and ‘what we do.’ Evidence indicates that pre-frailty and early stages of PF are reversible with timely diagnosis and effective interventions. However, this evidence has not been translated to routine HIV care. Regular frailty assessment is essential to prevent falls, fractures and other consequences, yet most PWH have not been assessed for PF. Evidence also suggests that multimodal interventions including cardiovascular and strength exercise in conjunction with fall prevention, treatment of osteoporosis, and careful medication de-escalation are effective in reducing musculoskeletal manifestations of PF. There are similar benefits for PWH, however this evidence has not been translated into routine HIV care. Guidance on choosing among effective interventions to maximize health benefits for PWH with constrained budgets is lacking. Knowledge of the cost-effectiveness (value) and budgetary impact of these programs would help facilitate translation of research findings into clinical management of PWH. Cost-effectiveness analysis is an important methodology that helps to inform choice among multiple efficacious programs when resources including data, time, and money are limited. We propose to develop a computer simulation model that portrays the natural history and treatment of PF in PWH to narrow the gap between evidence and practice by assessing the value of three major strategies to prevent and attenuate progression of PF in PWH: 1) timely diagnosis of PF; 2) implementation of structured strengthening and cardiovascular fitness improvement exercise programs to reduce falls and fractures and prevent PF incidence and slow its progression; and 3) use of fall prevention programs, including polypharmacy de-escalation, osteoporosis screening and diagnosis and management to reduce falls and fractures.