Sex-Related Differences in Inflammatory and Immune Activation Markers Before and After Combined Antiretroviral Therapy Initiation

Abstract

Background: Women progress to death at the same rate as men despite lower plasma HIV RNA (viral load). We investigated sex-specific differences in immune activation and inflammation as a potential explanation.

Methods: Inflammatory and immune activation markers [interferon γ, tumor necrosis factor (TNF) α, IL-6, IL-18, IFN-γ-induced protein 10, C-reactive protein (CRP), lipopolysaccharide, and sCD14] were measured at weeks 0, 24, and 48 after combination antiretroviral therapy (cART) in a random subcohort (n = 215) who achieved virologic suppression in ACTG A5175 (Prospective Evaluation of Antiretrovirals in Resource-Limited Settings). Association between sex and changes in markers post-cART was examined using random effects models. Average marker differences and 95% confidence intervals were estimated using multivariable models.

Results: At baseline, women had lower median log10 viral load (4.93 vs 5.18 copies per milliliter, P = 0.01), CRP (2.32 vs 4.62 mg/L, P = 0.01), detectable lipopolysaccharide (39% vs 55%, P = 0.04), and sCD14 (1.9 vs 2.3 µg/mL, P = 0.06) vs men. By week 48, women had higher interferon γ (22.4 vs 14.9 pg/mL, P = 0.05), TNF-α (11.5 vs 9.5 pg/mL, P = 0.02), and CD4 (373 vs 323 cells per cubic millimeter, P = 0.02). In multivariate analysis, women had greater increases in CD4 and TNF-α but less of a decrease in CRP and sCD14 compared with men.

Conclusions: With cART-induced viral suppression, women have less reduction in key markers of inflammation and immune activation compared with men. Future studies should investigate the impact of these sex-specific differences on morbidity and mortality.

Figure 1. Plasma concentrations of biomarkers of inflammation in HIV-infected patients upon ART initiation

Levels of indicated biomarkers were assessed in HIV-infected patients before and after ART initiation (n=215). (A) A heat map was designed to depict the overall pattern of expression of markers of inflammation and CD4 counts in patients at pre-ART as well as at weeks 24 and 48 after ART initiation. Patients at different study time points were listed in rows, and each biomarker was placed in a different column. Expression scale for each biomarker represents log10 fold-change from the geometric mean of the entire study population at each time point. A two-way hierarchical cluster analysis (Ward's method) of circulating biomarkers by time point was performed. Asterisks indicate markers which exhibited statistically significant differences between the time points assessed by the non-parametric Friedman test (matched samples), except for LPS, which in this study was compared as frequency of detectable values between the groups. (B) Scatter plots of the markers highlighted in (A). To test the overall trend of variation in concentrations of each marker over time on ART, Log10 transformed data were analyzed using Friedman test with a linear trend post-test (P-values are from the linear trend analysis ad hoc test). (C) The data were reanalyzed to compare differences between male (n=110) and female (n=105) patients. Asterisks highlight markers which displayed statistically different comparisons between male and female at a certain time point upon ART initiation assessed by the Wilcoxon rank-sum test. (D) Scatter plots of the markers highlighted in (C). Data were compared using the Wilcoxon rank-sum test. In (B) and (C), lines represent median values and interquartile ranges (except for LPS scatter plot, which does not show IQR because there were many values below the detection limit of the assay).