Antiretroviral therapy reduces but does not normalize immune and vascular inflammatory markers in adults with chronic HIV infection in Kenya

Abstract

Introduction: Markers of monocyte/macrophage activation and vascular inflammation are associated with HIV-related cardiovascular diseases (CVD) and mortality. We compared these markers among African people living with HIV (PLWH) and HIV-negative adults, and examined risk factors associated with elevated biomarkers (>75th percentile) in PLWH on antiretroviral therapy (ART). Design: Cross-sectional study. Methods: We measured serum concentrations of a gut integrity biomarker (intestinal-fatty acid binding protein), monocyte/macrophage activation biomarkers (soluble CD14 and CD163), and vascular inflammation biomarkers [soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular adhesion molecule 1 (sVCAM-1)]. We assessed the relationship of these inflammatory parameters with HIV, using logistic regression adjusting for traditional CVD risk factors. Results: Among the 541 participants, median age was 43 years and half were female. Among 275 PLWH, median CD4+ T-cell count and duration of ART use was 509 cells/μl and 8 years, respectively. PLWH had significantly higher prevalence of elevated inflammatory biomarkers compared with HIV-negative individuals even after adjustment for traditional CVD risk factors. Compared with individuals without HIV, the prevalence of elevated biomarkers was highest among persons with detectable viral load and CD4+ T-cell counts 200 cells/μl or less. In a subanalysis among PLWH, nadir CD4+ T-cell count 200 cells/μl or less was associated with elevated soluble CD14 (sCD14); dyslipidemia with elevated sCD14, sICAM-1, and sVCAM-1; and overweight/obesity with reduced sCD14. Longer ART exposure (>4 years) was associated with reduced sVCAM-1 and sICAM-1. Conclusion: HIV and not traditional CVD risk factors is a primary contributor of monocyte/macrophage activation and inflammation despite ART. Anti-inflammatory therapies in addition to ART may be necessary to reduce these immune dysregulations and improve health outcomes of African PLWH.

Deprenyl reduces inflammation during acute SIV infection

“…The specific etiology for these non-AIDS comorbidities varies, but many are associated with chronic inflammation, which is prevalent in ART-treated PLWH, especially in aging populations ( Deeks et al., 2013b ; Negin et al., 2012 ; Pelchen-Matthews et al., 2018 ; Peterson and Baker, 2019 ; Yang et al., 2019 ). While ART suppresses viral replication and reduces systemic inflammation relative to that seen in untreated HIV infection, it does not return inflammation to pre-infection levels ( Sereti et al., 2017 ; Temu et al., 2021 ; Zanni et al., 2016 ). Serum biomarkers of chronic, low-level inflammation, such as C-reactive protein (CRP), D-dimer, IL-1β, IL-6, IL-8, CXCL10, and TNF-α, remain elevated in ART-treated PLWH despite extended viral suppression ( Funderburg, 2014 ; Gay et al., 2011 ; Jennes et al., 2004 ; Keating et al., 2011 ; Regidor et al., 2011 ; Sereti et al., 2017 ; Shive et al., 2012 ; Temu et al., 2021 ; Wada et al., 2015 ; Yao et al., 2013 ).…”

“…While ART suppresses viral replication and reduces systemic inflammation relative to that seen in untreated HIV infection, it does not return inflammation to pre-infection levels ( Sereti et al., 2017 ; Temu et al., 2021 ; Zanni et al., 2016 ). Serum biomarkers of chronic, low-level inflammation, such as C-reactive protein (CRP), D-dimer, IL-1β, IL-6, IL-8, CXCL10, and TNF-α, remain elevated in ART-treated PLWH despite extended viral suppression ( Funderburg, 2014 ; Gay et al., 2011 ; Jennes et al., 2004 ; Keating et al., 2011 ; Regidor et al., 2011 ; Sereti et al., 2017 ; Shive et al., 2012 ; Temu et al., 2021 ; Wada et al., 2015 ; Yao et al., 2013 ). Many of these factors are produced by myeloid cells, such as monocytes and macrophages.…”

Central obesity is a contributor to systemic inflammation and monocyte activation in virally suppressed adults with chronic HIV in Kenya

“…We have previously shown that HIV was associated with greater inflammation and immune activation in our study cohort [ 10 , 16 ]. The present study expands on our data and those from prior studies in the USA and Europe that found greater inflammation and monocyte/macrophage activation among obese PWH [ 12 , 19 – 21 ].…”

“…The cohort was established to assess risk factors for CVD in PWH on long-term ART. Recruitment and study procedures have been described elsewhere [ 10 , 30 , 31 ]. Briefly, the study is composed of a convenience sample of PWH and HIV-negative men and women at least 30 years old enrolled from the Kisumu District Hospital HIV clinic and voluntary HIV testing centres.…”

“…Models were adjusted for demographic characteristics (age and sex), and traditional CVD risk factors (hypertension, hypercholesterolemia and alcohol use status) and further adjusted for BMI. These covariates were selected based on prior work suggesting an association between covariates and the biomarkers [ 10 , 16 , 41 ]. Multivariable models were sequentially adjusted for each of the biomarkers; I-FABP, sCD14 and sCD163, respectively.…”