Clinical and neurohormonal correlates of plasma TNF-α in a Zambian outpatient cohort

Background Chronic inflammation persists in populations with high HIV and tuberculosis (TB) burden, even during suppressive therapy. Tumor necrosis factor-alpha (TNF-α) is a key mediator, but its correlates beyond infectious status remain unclear in people living with HIV on stable antiretroviral therapy and who are virologically suppressed. We investigated clinical, metabolic, and neurohormonal correlates of TNF-α in a Zambian cohort. Methods This was a cross-sectional study, which included 227 adults recruited from the outpatient medical clinic at Livingstone University Teaching Hospital in the Southern Province of Zambia. Simple and multivariable linear regression analyses were performed to determine independent associations with plasma TNF-α levels. Models were adjusted for HIV serostatus and history of TB. Standardized beta coefficients (β_std) were computed to compare the relative magnitude of associations across predictors measured on different scales. Results Among 227 participants, 64.8% were living with HIV (95.3% on integrase strand transfer inhibitor-based ART) and 14.0% had a history of tuberculosis. In multivariable analysis, the strongest independent associations with TNF-α were observed within the renin-angiotensin-aldosterone system (RAAS): angiotensin II (β = 1.18 per pg/mL, p < 0.001; β_std = 0.51) and aldosterone (β = 0.884 per pg/mL, p < 0.001; β_std = 0.47). Living with HIV serostatus was also independently associated with higher TNF-α (β = 2581.1 pg/mL, p = 0.018; β_std = 0.19), while the history of TB was not. Significant metabolic factors associated with TNF-α levels included VLDL (β = 4397.4 per mmol/L, p = 0.038; β_std = 0.16) and triglycerides (β = 1971.6 per mmol/L, p = 0.034; β_std = 0.17). Inflammatory markers sST2 (β = 104.4 per ng/mL, p < 0.001; β_std = 0.31), IL-17 A (β = 1.137 per pg/mL, p = 0.003; β_std = 0.21), and D-dimer (β = 0.037 per pg/mL, p = 0.001; β_std = 0.22) were independently associated, as was plasma potassium (β = 107.3 per mmol/L, p < 0.001; β_std = 0.46). Renin, IL-6, IL-5, hs-CRP, and left ventricular mass were not associated with TNF-α. Conclusion In this high-burden population, RAAS activation was an independent correlate of TNF-α, exceeding the effect of HIV serostatus. These findings support the hypothesis that RAAS inhibition may have anti-inflammatory effects; however, this remains to be tested in prospective and interventional studies.