HIV disease is associated with increased biomarkers of endothelial dysfunction despite viral suppression on long-term antiretroviral therapy in Botswana

Abstract

SummaryBackgroundUntreated HIV infection is associated with increased biomarkers of endothelial dysfunction. However, the predictors and degree of endothelial dysfunction among virally suppressed HIV–infected adults on long–term antiretroviral therapy (ART) have not been well studied in sub– Saharan Africa (SSA). MethodsWe enrolled 112 HIV–infected adults with virological suppression on long–term ART and 84 HIV–uninfected controls in Botswana. We measured plasma levels of markers of endothelial injury [soluble vascular adhesion molecule 1 (VCAM–1), intercellular adhesion molecule 1 (ICAM–1) and E–selectin] and plasma levels of biomarkers of inflammation [interleukin 6 (IL–6)] and monocyte activation (sCD163). Baseline traditional cardiovascular disease (CVD) risk factors and bilateral common carotid intima–media thickness (cIMT) were also available for all participants. We assessed whether HIV status (despite virological suppression on ART) was associated with biomarkers of endothelial dysfunction after controlling for traditional CVD risk factors in linear regression models. We additionally assessed the association between IL–6, sCD163 and cIMT with endothelial dysfunction in separate multivariate linear regression models, controlling for cIMT, among virally suppressed HIV–infected participants only.ResultsIn multivariate analysis, HIV infection was significantly associated with increased VCAM–1 (p < 0.01) and ICAM–1 (p = 0.03) but not E–selectin (p = 0.74) levels. Within the HIV–positive group, higher sCD163 levels were associated with decreased ICAM–1 and E–selectin (p < 0.01 and p = 0.01, respectively) but not VCAM–1 (p = 0.13) levels. IL–6 was not associated with any of the biomarkers of endothelial dysfunction.ConclusionHIV disease was associated with biomarkers of endothelial dysfunction among virally suppressed adults in Botswana on long–term ART after controlling for traditional CVD risk factors. Future work should explore the clinical impact of persistent endothelial dysfunction following longterm HIV viral suppression on the risk of CVD clinical endpoints among HIV–infected patients in this setting.

Endothelial Dysfunction Is Related to Monocyte Activation in Antiretroviral-Treated People With HIV and HIV-Negative Adults in Kenya

“…Our study is the largest to evaluate endothelial activation among PWH on ART and HIV-negative adults in Africa. It builds upon prior work from Kenya [ 43 ], Botswana [ 40 ], South Africa [ 22 ], and the United States and Europe that reported persistent endothelial activation markers in the ART era [ 44–47 ]. However, our findings are in contrast to a US-based study that demonstrated normalization of these markers after 12 months of ART [ 18 ].…”

“…Compared with Europe/US-based studies, the few studies looking at the association between immune activation and endothelial dysfunction conducted in African countries have been relatively small, have not directly evaluated the contribution of risk due to metabolic abnormalities vs HIV-associated inflammation/immune activation, and have not compared people with HIV with HIV-negative individuals. This comparison may be particularly relevant in developing countries, where all adults regardless of HIV status are at risk for inflammation and immune activation due to chronic exposure to bacterial and parasitic infections [ 40 ]. For these reasons, we believe that understanding these complex relationships in the presence of these exposures will be essential to understanding the pathophysiology of CVD in this setting.…”

Immune Activation, Inflammation, and Non-AIDS Co-Morbidities in HIV-Infected Patients under Long-Term ART

“…Recently, it has been shown by Grund et al that IL-6 and D-Dimer are independently associated with non-AIDS co-morbidities in PLWH, suggesting that treatment aiming to decrease these biomarkers may help to reduce morbidity and mortality in PLWH under ART [37]. It has also been shown that intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and D-dimer, markers of CVDs [38,39,40], and monocyte chemotactic protein osteopontin (OPN), related to the risk of dementia, are elevated in PLWH [41].…”

Good Fences Make Good Neighbors: Human Immunodeficiency Virus and Vascular Disease

“…The most commonly measured biomarkers included IL-6 [29, 53, 56, 97–108], highly sensitive CRP [7, 28, 98, 99, 101–104, 106, 108, 109] and D-dimer levels [7, 28, 98, 99, 101–104, 106, 108, 109]. In addition, a number of studies measured markers of endothelial adhesion or activation, or both, including soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1 [7, 15, 17, 50, 97, 106–108, 110–112], monocyte activation (sCD163, sCD14, or changes in monocyte phenotype) [15, 28, 29, 50, 56, 96, 97, 100, 107–114], and platelet activation (expression of s- and p-selectin) [30, 33, 115]. Limitations exist in many studies examining biomarkers for CVD outcomes.…”