Tesamorelin as an Adjunct to Exercise for Improving Physical Function in HIV (TRIUMPH)

Project Summary/Abstract With the advent of modern antiretroviral therapy, life expectancy in people with HIV (PWH) now approaches that of the general population. Nonetheless, PWH continue to experience earlier onset and accelerated progression of complications of aging, including impaired physical function and frailty, which in turn may predispose to

morbidity, mortality, and reduced quality of life. While exercise is the mainstay of therapy to prevent and to treat these conditions, we have shown that PWH display a limited clinical and biologic response to exercise as compared to uninfected controls. We have further found that long-term adherence to exercise among PWH is

limited, even following a supervised exercise intervention. Based on these observations, novel pharmacologic strategies are critically needed to slow or reverse progression of impaired physical function and frailty in HIV with

the potential for broader translation to other high-risk groups. In the proposed clinical trial, we will test for the first time the novel hypothesis that tesamorelin as an adjunct to exercise (the current standard of care) will ameliorate impaired physical function and frailty in PWH. Tesamorelin is a growth hormone (GH)-releasing hormone

analogue that is FDA-approved to reduce visceral fat accumulation in PWH with the pivotal Phase III trials led by our team. Unlike recombinant human GH which leads to non-physiologic, sustained elevations in GH levels, tesamorelin augments physiologic, pulsatile GH secretion while keeping feedback inhibition intact. Tesamorelin

has a proven track record of safety and efficacy in PWH, having been used clinically for >10-years. As key Preliminary Data, we have shown that tesamorelin mitigates multiple metabolic features of frailty by increasing muscle mass, reducing muscle fat, and improving mitochondrial function. In the proposed study, a total of 100

community-dwelling older adults (age 50-80-years) with HIV, ≥1 feature of frailty, and excess abdominal adiposity will be randomized to tesamorelin or identical placebo in combination with a home-based exercise intervention for 24 weeks. In a subsequent 24-week extension phase, participants will be monitored off study drug and

supervised exercise to determine the extent to which changes in study endpoints are sustained following treatment cessation. Outcomes will include measures of physical function (primary endpoint: repeated chair stand time), muscle mass, exercise adherence and self-efficacy, and quality of life (Aim 1). Biologic effects of

tesamorelin on muscle quality, including muscle fat and mitochondrial function, also will be assessed (Aim 2). This proposal leverages the complementary expertise of its investigative team in HIV-associated frailty (Multi-PI Dr. Erlandson, University of Colorado), GH biology (Multi-PI Dr. Fourman, Massachusetts General Hospital),

exercise physiology, advanced imaging, mitochondrial phenotyping, and biostatistics. If our hypothesis is proven correct, tesamorelin will become the first function-promoting therapy in HIV, which may have key implications for other high-risk populations. Furthermore, by studying short-term and sustained effects of tesamorelin on physical

function, we will be poised to identify a treatment schedule that minimizes polypharmacy and cost.