Reductions in Plasma Cystatin C After Initiation of Antiretroviral Therapy Are Associated With Reductions in Inflammation: ACTG A5224s

Abstract

Background: Among patients with HIV infection, changes in the kidney filtration marker cystatin C after initiation of antiretroviral therapy (ART) may be related to changes in body composition or biomarkers of inflammation.

Methods: ACTG A5224s was a substudy of A5202, which randomly assigned ART-naive HIV-infected subjects to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or ritonavir-boosted atazanavir. This analysis explored changes in cystatin C from 0 to 96 weeks.

Results: Of the 269 subjects, 85% were male and 66% white non-Hispanics; baseline mean CD4 count was 236 cells per cubic millimeter and cystatin C was 0.89 mg/L. Cystatin C decreased significantly within each arm; however, ritonavir-boosted atazanavir attenuated the beneficial effects of ART on cystatin C compared to EFV. Compared to ABC/3TC, TDF/FTC led to a marginally significant attenuation for percent change analyses only. Higher baseline body mass index and HIV RNA were associated with larger reductions in cystatin C in multivariable models. At baseline, cystatin C was positively correlated with high-sensitivity C-reactive protein (Spearman r = 0.25), interleukin 6 (r = 0.34), soluble intercellular adhesion molecule (r = 0.36), soluble vascular cell adhesion molecule (r = 0.54), tumor necrosis factor α (r = 0.57), and soluble TNF-α receptor I (r = 0.70, all P < 0.001). Reductions in cystatin C from 0 to 96 weeks correlated with reductions in all inflammatory biomarkers (r = 0.39-0.58, P < 0.001) except for high-sensitivity C-reactive protein (r = 0.01, P = 0.89) and IL-6 (r = 0.08, P = 0.24).

Conclusions: The beneficial effect of ART on cystatin C concentrations is attenuated by boosted ATV when compared to EFV. Reductions in cystatin C after ART are associated with reductions in systemic inflammation.

Trial registration: ClinicalTrials.gov NCT00118898.

Figure 1. Mean (95% CI) change in plasma cystatin C concentration from 0–96 weeks by treatment group [(A) percentage change from baseline and (B) absolute cystatin C concentrations]

The intention-to-treat analysis is displayed below the graphs (p value for between-group difference).

Figure 2. Correlations of baseline, week 96, and 0–96 week changes in cystatin C with baseline, week 96, and 0–96 week changes in biomarkers of inflammation

Three representative scatter plots of inflammatory cytokines [(A) interleukin-6 and (B) soluble TNF-α receptor II] and a biomarker of endothelial activation [(C) souble vascular cellular adhesion molecule] are shown with a table of correlation coefficients. IL-6, interleukin-6; hs-CRP, high sensitivity C-reactive protein; TNF-α, tumor necrosis factor-α; sTNF-RI and sTNF-RII, soluble TNF-α receptors I & II; sVCAM-1, souble vascular cellular adhesion molecule; sICAM-1, soluble intercellular adhesion molecule.