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

Chris T Longenecker, Douglas Kitch, Paul E Sax, Eric S Daar, Camlin Tierney, Samir K Gupta, Grace A McComsey, AIDS Clinical Trials Group Study A5224s Team, Susan L Koletar, Diane Gochnour, Geyoul Kim, Mark Rodriguez, Elizabeth Lindsey, Tamara James, Ann C Collier, Jeffrey Schouten, Jorge L Santana Bagur, Santiago Marrero, Jenifer Baer, Carl Fichtenbaum, Patricia Walton, Barbara Philpotts, Princy Kumar, Joseph Timpone, Donna Pittard, David Currin, Julie Hoffman, Edward Seefried, Susan Swindells, Frances Van Meter, Deborah McMahon, Barbara Rutecki, Michael P Dube, Martha Greenwald, Ilene Wiggins, Eric Zimmerman, Judith Aberg, Margarita Vasquez, Martin McCarter, M Graham Ray, Mamta Jain, Tianna Petersen, Emily Stumm, Pablo Tebas, Mary Albrecht, Neah Kim, Paul Edward Sax, Joanne Delaney, Christine Hurley, Roberto Corales, Keith Henry, Bette Bordenave, Wendy Armstrong, Ericka R Patrick, Jane Reid, Mary Adams, Gene D Morse, Michael P Dube, Martha Greenwald, Kimberly Y Smith, Joan A Swiatek, Nancy Hanks, Debra Ogata-Arakaki, Ardis Moe, Maria Palmer, Jeffery Meier, Jack T Stapleton, Gary Matthew Cox, Martha Silberman, Gerianne Casey, William O'Brien, Valery Hughes, Todd Stroberg, Nyef El-Daher, Chris T Longenecker, Douglas Kitch, Paul E Sax, Eric S Daar, Camlin Tierney, Samir K Gupta, Grace A McComsey, AIDS Clinical Trials Group Study A5224s Team, Susan L Koletar, Diane Gochnour, Geyoul Kim, Mark Rodriguez, Elizabeth Lindsey, Tamara James, Ann C Collier, Jeffrey Schouten, Jorge L Santana Bagur, Santiago Marrero, Jenifer Baer, Carl Fichtenbaum, Patricia Walton, Barbara Philpotts, Princy Kumar, Joseph Timpone, Donna Pittard, David Currin, Julie Hoffman, Edward Seefried, Susan Swindells, Frances Van Meter, Deborah McMahon, Barbara Rutecki, Michael P Dube, Martha Greenwald, Ilene Wiggins, Eric Zimmerman, Judith Aberg, Margarita Vasquez, Martin McCarter, M Graham Ray, Mamta Jain, Tianna Petersen, Emily Stumm, Pablo Tebas, Mary Albrecht, Neah Kim, Paul Edward Sax, Joanne Delaney, Christine Hurley, Roberto Corales, Keith Henry, Bette Bordenave, Wendy Armstrong, Ericka R Patrick, Jane Reid, Mary Adams, Gene D Morse, Michael P Dube, Martha Greenwald, Kimberly Y Smith, Joan A Swiatek, Nancy Hanks, Debra Ogata-Arakaki, Ardis Moe, Maria Palmer, Jeffery Meier, Jack T Stapleton, Gary Matthew Cox, Martha Silberman, Gerianne Casey, William O'Brien, Valery Hughes, Todd Stroberg, Nyef El-Daher

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.

Conflict of interest statement

Conflicts of Interest:

DK has no disclosures.

Figures

Figure 1. Mean (95% CI) change in…
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,…
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.

Source: PubMed

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