Purpose of review This article describes the use of biomarkers in expanding our understanding of chronic non-AIDS comorbidities among persons living with HIV (PLWH) receiving antiretroviral therapy (ART). Recent findings We review current evidence that biomarkers of chronic immune activation and inflammation associate with a broad spectrum of end-organ diseases in PLWH. We discuss how ART may impact inflammation associated with HIV infection and the degree to which inflammation persists despite effective suppression of viral replication in plasma. We then discuss the limitations of the current literature, which lacks evidence of causality and disproportionately involves a few protein biomarkers that are unable to disentangle complex and overlapping biological pathways. Summary Premature end-organ disease among PLWH has been repeatedly associated with higher levels of blood biomarkers reflecting inflammation and immune activation, which, despite viral suppression and CD4+ T-cell increases after ART treatment, remain elevated relative to uninfected persons. There remain important unanswered questions with implications for the development of anti-inflammatory treatment strategies aimed at mitigating excess risk for end-organ comorbidities among PLWH.

Background Heart failure is a prominent cardiovascular disease (CVD) manifestation in sub-Sarahan Africa. Myocardial fibrosis is a central feature of heart failure that we aimed to characterize among persons with human immunodeficiency virus (PWH) in South Africa. Methods Cardiovascular magnetic resonance (CMR) imaging was performed among PWH with viral suppression and uninfected controls, both free of known CVD. Plasma levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) were measured. Comparisons by human immunodeficiency virus (HIV) status were made using linear and logistic regression, adjusted for age, sex, and hypertension. Results One hundred thirty-four PWH and 95 uninfected persons completed CMR imaging; age was 50 and 49 years, with 63% and 67% female, respectively. Compared with controls, PWH had greater myocardial fibrosis by extracellular volume fraction ([ECV] absolute difference, 1.2%; 95% confidence interval [CI], 0.1–2.3). In subgroup analyses, the effect of HIV status on ECV was more prominent among women. Women (vs controls) were also more likely to have elevated NT-proBNP levels (>125 pg/mL; odds ratio, 2.4; 95% CI, 1.0–6.0). Among all PWH, an elevated NT-proBNP level was associated with higher ECV (3.4% higher; 95% CI, 1.3–5.5). Conclusions Human immunodeficiency virus disease may contribute to myocardial fibrosis, with an effect more prominent among women. Research is needed to understand heart failure risk among PWH within sub-Saharan Africa.

Background Coagulation activity among persons with HIV is associated with end-organ disease risk, but the pathogenesis is not well characterized. We tested a hypothesis that hypercoagulation contributes to disease risk, in part, via upregulation of inflammation. Methods Treatment effects of edoxaban (30 mg), a direct factor Xa inhibitor, vs placebo were investigated in a randomized, double-blind crossover trial among participants with HIV and viral suppression and D-dimer levels ≥100 ng/mL. During each 4-month crossover period, blood measures of coagulation, inflammation, and immune activation were assessed. Analyses of change on edoxaban vs change on placebo used linear mixed models. Results Forty-four participants were randomized, and 40 completed at least 1 visit during each study period. The mean age was 49 years, and the CD4+ count was 739 cells/mm3. Edoxaban treatment led to declines in D-dimer (44%) and thrombin-antithrombin complex (26%) but did not lower inflammatory or immune activation measures. More bruising or bleeding events occurred during edoxaban (n = 28) than during placebo or no drug periods (n = 15). Conclusions The direct factor Xa inhibitor edoxaban led to a substantial reduction in coagulation but no effect on inflammation or immune activation. These results do not support that hypercoagulation contributes to ongoing inflammation during chronic antiretroviral therapy–treated HIV disease.

We estimated small arterial elasticity and used linear regression to evaluate its association with inflammatory biomarkers among antiretroviral therapy–naïve, HIV-positive patients with high CD4+ counts. After adjustment, high-sensitivity C-reactive protein and interleukin-6 were inversely associated with small arterial elasticity. These data suggest that systemic inflammation may contribute to vascular dysfunction even in very early HIV disease.

Introduction: HIV-associated inflammation contributes to higher CVD risk among persons living with HIV (PLWH). Heart failure (HF) is a prominent CVD manifestation in sub-Saharan Africa where HIV prevalence is high. Systolic dysfunction is a well-known complication of untreated, advanced HIV disease, but it is unknown if ongoing inflammation contributes to myocardial dysfunction during antiretroviral therapy (ART). We evaluated myocardial function via cardiac magnetic resonance (CMR) and studied associations with inflammatory biomarkers among ART-treated PLWH residing in Khayelitsha township near Cape Town, South Africa. Methods: CMR images were ascertained via a large bore 3T Siemens Skyra MRI scanner using standardized protocols. Biomarkers were measured from stored plasma using immunoassays and were log 2 -transformed for analyses. Linear regression was used to evaluate cross-sectional associations between CMR parameters and biomarker concentrations, adjusted for age, sex, current smoking, and hypertension. Results: Among 133 ART-treated PLWH without known CVD, 64% (85) were female, 99% (132) were Black African, 29% (39) were smokers, 92% (123) had undetectable HIV viral load, mean (SD) age was 50 (9) years, and current and nadir CD4+ count were 535 (270) and 271 (213) cells/μL, respectively. Higher TNFR1, TNF-α, and IFN-γ were associated with lower left ventricular ejection fraction (p=0.03, 0.05, and 0.03, respectively) and systolic global circumferential strain (p=0.01, 0.04, and 0.02) ( Table ). Higher TNFR1 was also associated with lower diastolic strain rate in circumferential (p=0.02), longitudinal (p=0.05), and radial (p=0.01) planes. Conclusion: These data suggest inflammation may contribute to lower myocardial function among ART-treated PLWH prior to development of clinical HF. The magnitude of this effect was modest, but potential long-term effects on myocardial tissue remodeling and subsequent HF risk warrant further investigation among a growing ART-treated population in South Africa.