Abstract
BackgroundHIV-1 infection increases plasma levels of inflammatory markers. Combination antiretroviral therapy (cART) does not restore inflammatory markers to normal levels. Since intensification of cART with raltegravir reduced CD8 T-cell activation in the Discor-Ral and IntegRal studies, we have evaluated the effect of raltegravir intensification on several soluble inflammation markers in these studies.MethodsLongitudinal plasma samples (0–48 weeks) from the IntegRal (n = 67, 22 control and 45 intensified individuals) and the Discor-Ral studies (44 individuals with CD4 T-cell counts<350 cells/µl, 14 control and 30 intensified) were assayed for 25 markers. Mann-Whitney, Wilcoxon, Spearman test and linear mixed models were used for analysis.ResultsAt baseline, different inflammatory markers were strongly associated with HCV co-infection, lower CD4 counts and with cART regimens (being higher in PI-treated individuals), but poorly correlated with detection of markers of residual viral replication. Although raltegravir intensification reduced inflammation in individuals with lower CD4 T-cell counts, no effect of intensification was observed on plasma markers of inflammation in a global analysis. An association was found, however, between reductions in immune activation and plasma levels of the coagulation marker D-dimer, which exclusively decreased in intensified patients on protease inhibitor (PI)-based cART regimens (P = 0.040).ConclusionsThe inflammatory profile in treated HIV-infected individuals showed a complex association with HCV co-infection, the levels of CD4 T cells and the cART regimen. Raltegravir intensification specifically reduced D-dimer levels in PI-treated patients, highlighting the link between cART composition and residual viral replication; however, raltegravir had little effect on other inflammatory markers.
Highlights
Human immunodeficiency virus type 1 (HIV-1) infection leads to immune activation that has been related to massive CD4 T-cell depletion occurring mainly in the gut associated lymphoid tissue (GALT), which in turn favors the translocation of bacterial products from the intestinal lumen to the circulation and tissues [1]
Univariate analysis showed some relationship of soluble markers with age, the detection of 2LTR circles during intensification and with hepatitis C virus (HCV) co-infection, while inflammatory status appeared to be more related to sex, Combination antiretroviral therapy (cART) composition, nadir and current CD4 T-cells values
While markers of inflammation showed positive and negative associations with the detection of 2-LTR circles, a more consistent scenario was observed for other parameters: higher plasma levels were identified in patients on a protease inhibitor (PI)-based cART and in individuals with low CD4 T-cell counts or with low nadir CD4 T cell values
Summary
Human immunodeficiency virus type 1 (HIV-1) infection leads to immune activation that has been related to massive CD4 T-cell depletion occurring mainly in the gut associated lymphoid tissue (GALT), which in turn favors the translocation of bacterial products from the intestinal lumen to the circulation and tissues [1]. Combination antiretroviral therapy (cART) effectively suppresses viral replication and in most cases increases CD4 T-cell counts, but only partly reduces T-cell activation, cell death and soluble inflammatory markers [7, 12,13,14,15]. This observation is clinically relevant since many authors have associated increased levels of inflammatory, coagulation or endothelial function markers in cART treated individuals to several clinical outcomes, including death [16], subclinical cardiovascular risk [17, 18], AIDS defining events or non-AIDS defining events [19, 20]. Between reductions in immune activation and plasma levels of the coagulation
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