Increased systemic inflammation is associated with cardiac and vascular dysfunction over the first 12 weeks of antiretroviral therapy among undernourished, HIV-infected adults in Southern Africa

Abstract

Introduction: Persistent systemic inflammation is associated with mortality among undernourished, HIV-infected adults starting antiretroviral therapy (ART) in sub-Saharan Africa, but the etiology of these deaths is not well understood. We hypothesized that greater systemic inflammation is accompanied by cardiovascular dysfunction over the first 12 weeks of ART.

Methods: In a prospective cohort of 33 undernourished (body mass index <18.5 kg/m²) Zambian adults starting ART, we measured C-reactive protein (CRP), tumor necrosis factor-α receptor 1 (TNF-α R1), and soluble CD163 and CD14 at baseline and 12 weeks. An EndoPAT device measured the reactive hyperemia index (LnRHI; a measure of endothelial responsiveness), peripheral augmentation index (AI; a measure of arterial stiffness), and heart rate variability (HRV; a general marker of autonomic tone and cardiovascular health) at the same time points. We assessed paired changes in inflammation and cardiovascular parameters, and relationships independent of time point (adjusted for age, sex, and CD4+ T-cell count) using linear mixed models.

Results: Serum CRP decreased (median change -3.5 mg/l, p=0.02), as did TNF-α R1 (-0.31 ng/ml, p<0.01), over the first 12 weeks of ART. A reduction in TNF-α R1 over 12 weeks was associated with an increase in LnRHI (p=0.03), and a similar inverse relationship was observed for CRP and LnRHI (p=0.07). AI increased in the cohort as a whole over 12 weeks, and a reduction in sCD163 was associated with a rise in the AI score (p=0.04). In the pooled analysis of baseline and 12 week data, high CRP was associated with lower HRV parameters (RMSSD, p=0.01; triangular index, p<0.01), and higher TNF- α R1 accompanied lower HRV (RMSSD, p=0.07; triangular index, p=0.06).

Conclusions: Persistent inflammation was associated with impaired cardiovascular health over the first 12 weeks of HIV treatment among undernourished adults in Africa, suggesting cardiac events may contribute to high mortality in this population.

Keywords: HIV; antiretroviral therapy; cardiovascular; inflammation; nutrition; sub-Saharan Africa.

Figure. Changes in inflammation biomarkers and cardiovascular parameters over 12 weeks of antiretroviral therapy

Yellow lines represent paired samples and blue lines represent smoothed (loess) curves fit to the data. As in the statistical models, the inflammation biomarkers are log-transformed and the cardiovascular markers are on the unit scale. Wilcoxon signed rank test was used to assess statistical significance.