Persistent, Albeit Reduced, Chronic Inflammation in Persons Starting Antiretroviral Therapy in Acute HIV Infection

Abstract

Background: Serious non-AIDS events cause substantial disease and death despite human immunodeficiency virus (HIV) suppression with antiretroviral therapy (ART). Biomarkers of inflammation, coagulation cascade activation, and fibrosis predict these end-organ events. We aimed to determine whether ART initiation during acute HIV infection would attenuate changes in these biomarker levels.

Methods: Plasma samples were obtained from participants starting ART during acute or chronic HIV infection and from HIV-uninfected participants from Bangkok, Thailand. Biomarkers of inflammation (C-reactive protein [CRP], interleukin 6, soluble interleukin 6 receptor [sIL-6R], soluble gp130, tumor necrosis factor [TNF]), enterocyte turnover (intestinal fatty acid binding protein [I-FABP]), lipopolysaccharide-induced monocyte activation (soluble CD14 [sCD14]), coagulation cascade activation [D-dimer], and fibrosis (hyaluronic acid [HA]) were measured at baseline and through 96 weeks of ART.

Results: CRP, TNF, sIL-6R, I-FABP, sCD14, D-dimer, and HA levels were elevated in acute HIV infection. Early ART was associated with increased I-FABP levels but normalization of TNF, sIL-6R, and D-dimer levels. CRP, sCD14, and HA levels decreased during ART but remained elevated compared with HIV-uninfected participants. Higher sCD14, CRP, and D-dimer levels were associated with higher peripheral blood mononuclear cell and gut integrated HIV DNA levels. Decreases in sCD14 and CRP levels were correlated with increases in CD4 T-cell counts.

Conclusions: ART initiated in early acute HIV infection was associated with normalization of the coagulation cascade and several systemic inflammatory biomarkers, but the acute-phase response, enterocyte turnover, monocyte activation, and fibrosis biomarkers remained elevated. Additional interventions to attenuate inflammation may be needed to optimize clinical outcomes in persons with HIV infection.

Keywords: acute HIV infection; antiretroviral therapy; inflammation; monocyte activation; sIL-6R.

Figure 1.

Inflammatory biomarker levels in human immunodeficiency virus (HIV)–uninfected participants from Thailand (black dots); in participants with acute HIV infection diagnosed in fourth-generation stage 1 (4thG1; blue), stage 2 (4thG2; green), or stage 3 (4thG3; red); and in participants with chronic untreated HIV infection (purple). A–E, Plasma biomarker levels at study entry before starting antiretroviral therapy (ART), including C-reactive protein (CRP) (A), tumor necrosis factor (TNF) (B), interleukin 6 (IL-6) (C), soluble IL-6 receptor (sIL-6R) (D), and soluble gp130 (sgp130) (E). Horizontal bars represent median values. F–J, Changes in the same plasma biomarker levels over 96 weeks of ART initiated during acute HIV infection. Purple dashed line represents median biomarker level in participants during treated chronic HIV infection; black dotted lines, median biomarker levels in HIV-uninfected participants from Thailand. ^† P < .05 for comparison with treated chronically HIV-infected participants; *P < .05 for comparison with HIV-uninfected participants. Median values are shown with interquartile range bars.

Figure 2.

Biomarkers of enterocyte turnover (intestinal fatty acid binding protein [I-FABP]) (A, C) and lipopolysaccharide-induced monocyte activation (soluble CD14 [sCD14]) (B, D). A, B, Plasma biomarker levels at diagnosis before initiation of antiretroviral therapy (ART). 4thG1, fourth-generation (4thG) stage 1; 4thG2, 4thG stage 2; 4thG3, 4thG stage 3. C, D, Changes in plasma biomarker levels over 96 weeks of ART initiated during acute human immunodeficiency virus (HIV) infection. Purple dashed lines represent median biomarker levels in participants starting ART during chronic HIV infection; black dotted lines, median biomarker levels in HIV-uninfected participants from Thailand. ^† P < .05 for comparison with treated chronically HIV-infected participants; *P < .05 for comparison with HIV-uninfected participants. Median values are shown with interquartile range bars.

Figure 3.

Biomarkers of coagulation cascade activation (D-dimer) (A, C) and a profibrotic state (hyaluronic acid [HA]) (B, D). A, B, Plasma biomarker levels at diagnosis before starting antiretroviral therapy (ART). 4thG1, fourth-generation (4thG) stage 1; 4thG2, 4thG stage 2; 4thG3, 4thG stage 3. C, D, Changes in plasma biomarker levels over 96 weeks of ART initiated during acute human immunodeficiency virus (HIV) infection. Purple dashed lines represent median biomarker levels in participants starting ART during chronic HIV infection; black dotted lines, median biomarker levels in HIV-uninfected participants from Thailand. ^† P < .05 for comparison with treated chronically HIV-infected participants; *P < .05 for comparison with HIV-uninfected participants. Median values are shown with interquartile range bars.