Does an index composed of clinical data reflect effects of inflammation, coagulation, and monocyte activation on mortality among those aging with HIV?

Abstract

Background: When added to age, CD4 count and human immunodeficiency virus type 1 (HIV-1) RNA alone (Restricted Index), hemoglobin, FIB-4 Index, hepatitis C virus (HCV), and estimated glomerular filtration rate improve prediction of mortality. Weighted and combined, these 7 routine clinical variables constitute the Veterans Aging Cohort Study (VACS) Index. Because nonroutine biomarkers of inflammation (interleukin 6 [IL-6]), coagulation (D-dimer), and monocyte activation (sCD14) also predict mortality, we test the association of these indices and biomarkers with each other and with mortality.

Methods: Samples from 1302 HIV-infected veterans on antiretroviral therapy were analyzed. Indices were calculated closest to date of collection. We calculated Spearman correlations stratified by HIV-1 RNA and HCV status and measured association with mortality using C statistics and net reclassification improvement (NRI).

Results: Of 1302 subjects, 915 had HIV-1 RNA <500 copies/mL and 154 died. The VACS Index was more correlated with IL-6, D-dimer, and sCD14 than the Restricted Index (P < .001). It was also more predictive of mortality (C statistic, 0.76; 95% confidence interval [CI], .72-.80) than any biomarker (C statistic, 0.66-0.70) or the Restricted Index (C statistic, 0.71; 95% CI, .67-.75). Compared to the Restricted Index alone, NRI resulted from incremental addition of VACS Index components (10%), D-dimer (7%), and sCD14 (4%), but not from IL-6 (0%).

Conclusions: Among HIV-infected individuals, independent of CD4, HIV-1 RNA, and age, hemoglobin and markers of liver and renal injury are associated with inflammation. Addition of D-dimer and sCD14, but not IL-6, improves the predictive accuracy of the VACS Index for mortality.

Figure 1.

Scatterplots of biomarkers of inflammation and Veterans Aging Cohort Study (VACS) Index Scores. Spearman correlation coefficients were as follows: A, Interleukin (IL)–6 and VACS Index (r = 0.42); B, D-dimer and VACS Index (r = 0.39); C, Soluble CD14 (sCD14) and VACS Index (r = 0.35); D, D-dimer and IL-6 (r = 0.41); E, sCD14 and IL-6 (r = 0.45); and F, D-dimer and sCD14 (r = 0.24). Abbreviations: IL, interleukin; sCD14, soluble CD14; VACS, Veterans Aging Cohort Study.

Figure 2.

Spearman correlation coefficients of biomarkers in 1302 human immunodeficiency virus (HIV)–infected veterans with at least 180 days of combination antiretroviral therapy among those with HIV-1 RNA <500 copies/mL, hepatitis C virus (HCV) uninfected (n = 505) (A); HIV-1 RNA <500 copies/mL, HCV infected (n = 413) (B); HIV-1 RNA >500 copies/mL, HCV uninfected (n = 200) (C); and HIV-1 RNA >500 copies/mL, HCV infected (n = 184) (D). Abbreviations: eGFR, estimated glomerular filtration rate; FIB, fibrosis index; IL, interleukin; Rest. Index, Restricted Index; VACS, Veterans Aging Cohort Study.

Figure 3.

Net reclassification improvement shown in detail for adding D-dimer to the Veterans Aging Cohort Study (VACS) Index (A) and final result only (B) for adding VACS Index components to the Restricted Index, adding D-dimer to the VACS Index, and further addition of soluble CD14. Abbreviations: NRI, net reclassification improvement; sCD14, soluble CD14; VACS, Veterans Aging Cohort Study.