Abstract
The prevalence of age-related comorbidities is increased in people living with HIV, even in those well-controlled on combination antiretroviral therapy (ART). Persistent immune activation and inflammation may play pivotal roles in the pathogenesis; however, the burden of morbidities in the older HIV infected population may be exacerbated and driven by distinct mechanisms. In a cross sectional study of 45 HIV-infected participants 60 years or older, we examined the relationships between 14 immunomodulatory and inflammatory factors and the Veterans Aging Cohort Study (VACS) Index, a metric of multimorbidity and mortality comprised of age, CD4 count, hemoglobin, Fibrosis-4 [FIB-4], and estimated glomerular filtration rate [eGFR], by linear regression analysis. All participants were virally suppressed (<50 HIV RNA copies/mL), on ART, and primarily Caucasian (86.7%), and male (91.1%). Plasma levels of monocyte/macrophage-associated (neopterin, IP-10, sCD163, sCD14, and MCP-1) and glycan-binding immunomodulatory factors (galectin (Gal)-1, Gal-3, and Gal-9) were assessed, as well as inflammatory biomarkers previously linked to the VACS Index (i.e., CRP, cystatin C, TNF-α, TNFRI, IL-6, and D-dimer) for comparison. In regression analysis, higher VACS index scores were associated with higher levels of neopterin, cystatin C, TNFRI, and Gal-9 (all p < 0.05), potentially driven by correlations found with individual VACS components, including age, CD4 count, FIB-4, and eGFR. Gal-9, cystatin C, and TNFRI directly correlated with the extent of multimorbidity. Multiple correlations among markers were observed, suggesting an interplay of overlapping, but distinct, pathways. Collectively, in addition to cystatin C and TNFRI, both galectin-9 and neopterin, independently emerged as novel fluid markers of the VACS Index and burden of comorbidity and may further guide in understanding pathogenic mechanisms of age-related disorders in older HIV-infected individuals on suppressive ART.
Highlights
In the current era of effective suppressive combination antiretroviral therapy (ART) regimens people aging with HIV (PAWH) have an increased risk for and earlier onset of age-related comorbidities including cardiovascular, kidney, liver, bone, and neurologic disease [1, 2]
Several of these factors are elevated in the plasma of untreated people living with HIV and, to a lesser degree, those on ART [27,28,29]. Many of these factors are shown to be involved in modulating metabolism and inflammation, directly involved in HIV replication, and linked to comorbidities in the general population [30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52]. We investigated these immunomodulatory factors in addition to biomarkers traditionally associated with the Veterans Aging Cohort Study (VACS) Index in a cohort of older adults living with HIV with long-term viral suppression to better understand the relationship between aging, HIV, and inflammation
Recent comorbid conditions of cohort participants were assessed (Table 2), showing 14% were obese defined by a BMI >30, three had coronary disease, almost half (49%) had hyperlipidemia/hypercholesterolemia, more than half (58%) had hypertension, 22% had diabetes mellitus, one individual had liver disease, 22% had chronic obstructive pulmonary disease (COPD), three previously experienced kidney failure, and one individual had cancer
Summary
In the current era of effective suppressive combination antiretroviral therapy (ART) regimens people aging with HIV (PAWH) have an increased risk for and earlier onset of age-related comorbidities including cardiovascular, kidney, liver, bone, and neurologic disease [1, 2]. Half of the population living with HIV in the United States is older than 50 years of age and non-AIDS-defined events and agerelated comorbidities are the leading cause of mortality in the ART era [3,4,5]. This demographic shift in the HIVinfected population further complicates the clinical care and management of PAWH, as the increased burden of multimorbidity, frailty, geriatric syndromes, and polypharmacy become the norm [6, 7]. Evaluating soluble mediators with these clinical index scores and discovering novel correlations can provide a deeper understanding of the interplay between biological function and outcomes of morbidity and mortality in PAWH [26]
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