Chicago Investigator-led Active Concepts


Low bone mass and sarcopenia as risk factors for skeletal fractures

Lead Investigator: Ryan Ross, PhD

Skeletal fractures are associated with considerable economic costs, impaired quality of life and surprisingly high mortality rates in the elderly. People living with HIV (PLWH) are at an elevated fracture risk when compared to uninfected controls. The factors that contribute to skeletal fractures are varied and the most commonly employed clinical tool, bone mineral density (BMD) measured by dual energy x-ray absorptiometry (DXA), only accounts for about half of the risk for skeletal fractures. Osteosarcopenia is an emerging gerontological syndrome that has been linked to increased fracture risk in uninfected populations. The co-occurrence of both osteoporosis (low bone mass) and sarcopenia (low muscle mass and function) increases the risk of fracture when compared to either osteoporosis or sarcopenia alone. The contribution of both low bone mass and poor muscle function to fracture risk has not been established in PLWH. Therefore, the current concept proposes to leverage existing muscle mass and function data within the MWCCS, combined with BMD data from the BOSS and MSK sub-studies within MACS and WIHS, respectively, to investigate whether the combination of both bone and muscle factors improve the prediction of skeletal fractures in PLWH.


Bone and fat measures in Chicago MWCCS midlife women with and without HIV

Lead Investigator: Ryan Ross, PhD

Effective antiretrovirals have significantly improved the lifespan of people living with HIV (PLWH). As the population of PLWH ages, there is a growing concern for age-related comorbidities, including osteoporosis and osteoporotic fractures. In women living with HIV, this risk is potentiated by the menopause transition, which is a well-established driver of bone loss. In 2012, a WIHS musculoskeletal (“MSK”) sub study was initiated at select sites including Chicago, to determine factors affecting bone loss. Since that time, the antiretroviral landscape has shifted from drugs known to contribute to bone loss to less bone toxic compounds that may increase fat accumulation. The current study will evaluate bone health in a cohort of midlife Chicago MWCCS women living with HIV (WLWH) and demographically similar women living without HIV to determine whether the prevalence and correlates of osteopenia & osteoporosis in WLWH has changed with more recent, less bone toxic antiretrovirals. We will also examine whether bone health (osteopenia/osteoporosis) as measured by both DXA and Ultrascan predicts frailty, falls, and fractures. Additionally, we aim to: a) evaluate the potential contribution of bone-derived hormones to changes in body composition (measured via DXA and InBody); and b) evaluate the utility of a portable and rapid quantitative ultrasound instrument (Ultrascan) to measure bone mineral density of the distal ulna as a screening tool and/or in lieu of conventional DXA.



Musculoskeletal pain in Chicago MWCCS women

Lead Investigator: Ryan Ross, PhD

Musculoskeletal (MSK) pain is a common age-related complaint. MSK pain is associated with loss of physical function, decreased quality of life, sleep disruption, and increased symptoms of depression. Several studies have suggested increased MSK pain prevalence in people living with HIV (PLWH) with greater rates among women but lack uninfected comparison populations and limited data on pain specificity or severity. The current proposal seeks to overcome these limitations by evaluating MSK pain in women within the Chicago Cook County CRS. Data obtained will help determine the burden of MSK pain in women living with HIV compared to HIV-uninfected women and identify factors associated with increased MSK pain severity by anatomical location.

Sleep/circadian disruption and kynurenine pathway activation: a comorbidity risk for midlife men and women living with HIV?

Lead Investigator: Audrey French, MD

The objective of this supplement application is to investigate targeted kynurenine (KYN) pathway metabolites as molecular mechanisms by which objectively measured habitual sleep and circadian disruption increase risk for HIV-associated cardiometabolic disease and to determine whether these relationships differ by biological sex and HIV disease status. We will measure targeted KYN pathway metabolites in stored plasma (n=1100) from well characterized MACS/WIHS Combined Cohort Study (MWCCS) men and women who already have habitual sleep measures collected, validated, and systematically scored via one week continuous wrist actigraphy (Philips Respironics Actiwatch Spectrum Plus). There will be no MWCCS participant and field staff burden for this supplement. No study to date has examined KYN pathway activation as a mechanism linking sleep and circadian disruption to HIV-related and inflammatory mediated comorbidities such as cardiometabolic disease in a mixed sex sample nor has this been accomplished with representation across all HIV disease status groups (well and poorly controlled HIV with comparison to uninfected controls). Results will provide novel insights into biological sex and HIV disease status differences in the mechanistic relationships between sleep and circadian disruption, KYN pathway activation, and HIV-associated cardiometabolic disease and provide a strong foundation upon which to test targeted sleep and circadian interventions to reduce risk for HIV-associated comorbidities in men and women aging with HIV.


Mineral Metabolism and Osteosarcopenia in People Living with HIV (PLWH)

Lead Investigator: Ryan Ross, PhD

Osteosarcopenia is an emerging gerontological syndrome that describes the co-emergence of osteoporosis, or low bone mineral density, and sarcopenia, or loss of muscle mass and strength. Osteosarcopenia increases the risk of falls, fractures, and mortality. HIV increases the risk of both osteoporosis and sarcopenia and yet few studies have investigated the emergence of osteosarcopenia in people living with HIV. Further, several proposed risk factors for both osteoporosis and sarcopenia have been reported to be influenced by HIV-serostatus. For example, vitamin D deficiency is a driver of both muscle weakness and bone loss and the prevalence of vitamin D deficiency is high in people living with HIV. Similarly, fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphate metabolism has recently been associated with frailty in a cohort including people living with HIV. Vitamin D is a critical mediator of calcium metabolism, while FGF23 controls phosphate metabolism, therefore, the current study will investigate the influence of calcium and phosphate metabolism on osteosarcopenia in women living with HIV. We will utilize measures of muscle function (grip strength and gait speed) currently assessed at the Chicago Cook County (Cook) clinical research site (CRS) and new bone mineral density (BMD) measures obtained as part of this proposal. We will determine whether muscle function and BMD are associated and whether this association varies as a function of HIV-serostatus. Finally, we will determine whether markers of calcium or phosphate metabolism influence these associations.

Sex differences in bone-fat crosstalk

Lead Investigator: Ryan Ross, PhD

As HIV has become a chronic disease, there is a growing concern about risk of age-related comorbidities. Two such comorbidities that occur at a higher prevalence in antiretroviral (ARV) treated people living with HIV (PLWH) include osteoporosis or loss of bone and lipodystrophy or body fat redistribution. Bone and fat tissues are linked by a dynamic hormonal crosstalk that affects the physiology of both organ systems. We have recently demonstrated that the bone-derived hormone, undercarboxylated osteocalcin (ucOCN), is associated with fat gain in postmenopausal women living with HIV using samples from the Musculoskeletal (MSK) sub-study collected within the WIHS cohort. We have since confirmed the association between ucOCN and body fat in a smaller subset of men and women initiating tenofovir disoproxil fumarate (TDF)-based treatment and reported an association between the fat-derived hormone, leptin, and bone mass. The current proposal seeks to further investigate the bone-fat connection using samples from the MSK sub-study and the Bone Strength Sub-study (BOSS) within the MACS cohort. Utilizing banked plasma samples from these two sub-studies, we will measure the circulating levels of fat-derived hormones, leptin, adiponectin, and lipocalin-2, and bone-derived hormones, ucOCN and sclerostin (already collected from the MSK sub-study) to determine (1) whether fat-derived hormones are associated with bone mass and (2) whether the bone-fat hormonal link differs by sex. The current proposal will support future NIH grant applications and further our understanding of bone-fat crosstalk in people living with HIV. If successful, the proposal will help to establish the mechanisms driving bone and fat-related pathologies in PLWH and potentially identify novel treatment targets.

The effects of antiretrovirals on bone-fat hormonal crosstalk

Lead Investigator: Ryan Ross, PhD

The widespread use of combination antiretroviral therapy (cART) has significantly increased the lifespan of people living with HIV (PLWH). As HIV has become a chronic disease, there is a growing concern about risk of other health conditions we refer to as comorbidities. Two such comorbidities that occur at a higher prevalence in cART treated PLWH include osteoporosis or loss of bone and metabolic syndrome, a condition characterized by increased abdominal fat accumulation, insulin resistance, and elevated triglycerides. Interestingly, while new cART treatments appear to be better for bone, they appear worse for metabolic syndrome, yet the reasons for this remain unknown. Our goal is to determine the mechanisms contributing to these conditions in cART treated PLWH in order to find less harmful treatment options. We will test whether hormones controlled by bone and fat change with cART treatment and whether these hormones influence bone loss and metabolic syndrome. We will use stored serum samples from WIHS participants that have switched to integrase inhibitors, which do not cause bone loss, but appear to lead to metabolic syndrome. Additionally, we will investigate more current cART regimens by including a cohort of women switching onto a combination of bictegravir, emtricitabine, and tenofovir alafenamide (Biktarvy, or BIC/FTC/TAF).

Prevalence and correlates of poor sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI) in MWCCS

Lead Investigator: Kathleen Weber, MS

HIV infection can directly and indirectly lead to poor sleep quality. Disturbances in sleep have been associated with systemic inflammation and worsening of many medical and mental health problems including mood and anxiety disorders, cognitive dysfunction, and cardiometabolic conditions. Individuals living with HIV are also at higher risk for these same conditions that may cause poor sleep. We are trying to understand sleep quality and the extent that sleep disturbances occur in WIHS women and whether this is influenced by HIV and other factors. We will examine the association between measures of sleep quality, mental health, cognition, and markers of cardiovascular and metabolic disease risk. We plan to start by using an easy to administer but well validated self-report questionnaire called the Pittsburgh Sleep Quality Index or PSQI. 


Patient-engaged approach to addressing depressive symptoms

Lead Investigator: Kathleen Weber, MS

During each WIHS visit, interviewers ask women about specific symptoms related to depression using a validated 20-item screening instrument for depression, the Center for Epidemiologic Studies-Depression (CESD). Depressive symptom burden is high in WIHS. Reports confirm that a CES-D total score of 16 or greater can predict depression even in HIV infected individuals and is associated with poor medication adherence, higher HIV viral load, increased cardiometabolic risk, frailty, and even death. In the past, we have not shared CES-D
scores with women or their providers. We will now do computerized scoring at the WIHS visit so that we can identify women with scores of 16 or greater, highlight significant symptoms, and encourage women to discuss these symptoms with their providers. We will monitor changes in symptoms and symptom management over time.

Neighborhoods, chronic stress, and CVD risk among women with HIV in Chicago WIHS

Lead Investigator: Kathleen Weber, MS

Women living with HIV (WLWH) are reaching older age due to enhancements in antiretroviral medications and improved access and quality of care. Additional chronic diseases often impact women with HIV as they age, such as cardiovascular diseases. To meet the complex needs of women aging with HIV, it is important to understand various factors that contribute to cardiovascular disease risk. The purpose of this study is to examine the relationship between how women with HIV perceive aspects of their neighborhood that may be associated with heart health. Longer term cardiovascular disease will be measured with the Framingham Risk Score. If there is an association between perception of neighborhood environment and the FRS, we will determine whether this varies by cortisol levels in hair, a good biomarker of chronic stress.

The contribution of sleep and circadian disruption to kynurenine pathway activation and cardiometabolic risk in women with HIV

Lead Investigator: Audrey French, MD

It is clear from the medical literature that disrupted or poor sleep patterns are associated with medical problems including heart and other cardiovascular diseases, cognitive dysfunction and depression. People with HIV are at higher risk of these diseases as well. There is some preliminary information that sleep disruption leads to increased co-morbidity risk by leading to inflammation. We are trying to understand the extent of sleep disruption in WIHS women and whether the extent of sleep disruption is affected by HIV status. In addition, we want to look at an inflammatory pathway, called the IDO pathway, to see how it is affected by sleep quality. HIV infection is now a manageable chronic disease for individuals with access to combination antiretroviral therapy (cART), yet immune activation and inflammation persist even with high levels of adherence, low viral levels, and a robust treatment response. Mechanisms underlying this residual immune activation and inflammation despite viral control are incompletely understood but contribute substantially to earlier onset and greater incidence of comorbid disorders. However, the drivers for these inflammatory responses have not been fully elucidated. We will focus this application on defining a role for sleep and circadian disruption in contributing to these inflammatory processes.

Assessment of plasma soluble urokinase plasminogen receptor (suPAR) as a marker of cognitive dysfunction in persons living with HIV

Lead Investigator: Hemil González, MD

The soluble urokinase plasminogen activator receptor (suPAR) is broadly utilized as a clinical biomarker of acute and chronic renal insufficiency. It is expressed in its membrane-bound form (uPAR) by peripheral blood mononuclear cells and resident tissue macrophages. It can be readily found in peripheral blood in its soluble form (suPAR). More recently, suPAR has been studied as a non-specific marker of inflammation and a predictive tool in acutely ill patients with systemic sepsis1. In people living with HIV, it is an independent predictor of acute cardiovascular events despite optimal virologic control and normal CD4+ counts2. The mechanism of this phenomenon is not well characterized. In the CHARTER cohort, among people living with HIV experiencing cognitive dysfunction, suPAR correlated with the presence and severity of cognitive dysfunction compared to controls14. In this study, the investigators found suPAR levels elevated in peripheral blood and CSF. This study was performed only in men, and data on this correlation is lacking in women. We propose undertaking a retrospective study to assess the correlation between suPAR levels and cognitive dysfunction in women participating in the Chicago Cook County site of the MWCCS cohort. The groups will be adequately matched by age, comorbidities, and viremia status. We believe this study will significantly contribute to understanding the role of suPAR as a biomarker in HIV and potentially fill a knowledge gap in the management and treatment of women living with HIV, particularly those belonging to underrepresented minorities.

Cannabis Use by Older Women with HIV

Lead Investigator: Julie Bobitt, PhD

The proportion of persons with HIV who use cannabis is 2–3 times higher than in the general population with prevalence in persons living with HIV ranging from 23%-56% versus 13% in persons living without HIV. A recent study using WIHS data found cannabis use by women with HIV to be around 27%. Another study on older adults with HIV and cannabis use found 32.6% used cannabis. Reported reasons for using cannabis include for HIV-related pain, anxiety, and stress though this data is quantitative and provides little insight into the decision making, patterns of use relative to major life events, and health impacts. Nor compared cannabis use by older women with HIV to those without HIV. Using the socioecological model of health the purpose of this study is to identify and compare the multi-level influences on cannabis use decision-making and health impacts by older women (age 60+) with and without HIV.