Fractures Are Not Associated with CD8(+) T Cell Activation: An Analysis of the ACTG ALLRT Study.

Editor: In HIV-1-infected individuals, chronic T cell activation despite antiretroviral therapy (ART) has been associated with AIDS-defining outcomes and surrogate markers for non-AIDS outcomes, such as cardiovascular disease.1 Activated T cells promote bone loss in inflammatory diseases, such as rheumatoid arthritis and periodontitis, and play a role in postmenopausal osteoporosis. The role of HIV-associated T cell activation and low bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) has been reported in recent studies with conflicting results.2,3 While previous studies have examined associations between traditional risk factors, frailty, CD4+ T cell count, and ART with fractures in HIV-infected individuals,4,5 none has examined associations between T cell activation and increased fracture. An exploratory retrospective analysis of ACTG A5001 [ACTG Longitudinal Linked Randomized Trial (ALLRT)] examined whether higher levels of markers of CD8+ T cell activation were associated with incident fracture. ALLRT is a longitudinal cohort composed of ART-naive or -experienced participants randomized into 26 ACTG clinical trials (parent studies) with specific interventions, which participants entered either while participating in or shortly after completing their parent study.4 Activated CD8+ T cells (CD8+CD38+HLA-DR+; “activated CD8%”) were measured on fresh peripheral blood mononuclear cell (PBMC) samples using ACTG consensus methods in a subset of the ALLRT cohort. Predictors of fracture were investigated in participants who had activated CD8% measured prior to fracture and after >8 weeks of ART. Associations between risk factors and time-to-first fracture were examined using multivariable Cox proportional hazards models before the addition of activated CD8% (dichotomized based on a threshold analysis). Because only 1,466/4,640 (31.5%) participants from the ALLRT fracture incidence study6 could be included, we acknowledge that this study had very low power to detect associations. Median (Q1, Q3) age and lifetime ART use were 40 (34, 46) and 4.7 (2.6, 7.1) years, respectively; 86% were men and 54% were white. Thirty-six separate fractures were reported in 34 participants. The median (Q1, Q3) time-to-first fracture was 4.6 (3.0, 8.9) years. The median (Q1, Q3) activated CD8% was 24% (15%, 38%), with no difference by fracture status (p=0.71). In the univariable analysis, activated CD8% <12.25% was associated with increased hazard of fracture [HR=2.04, 90% CI=(1.03, 4.00), p=0.084; Table 1], but continuous activated CD8% was not associated with fracture (p=0.69). In the adjusted multivariable analysis, however, activated CD8% <12.25% [HR=1.59, 90% CI=(0.68, 3.70)] was not associated with fractures (p=0.37) after adjusting for older age, HCV infection, and bisphosphonate use. Table 1. Univariable and Multivariable Cox Proportional Hazards Regression Models of Time-to-First Fracture In 78 HIV-1-infected adults, Gazzola et al. found higher proportions of CD4+HLA-DR+ and CD8+HLA-DR+ T cells in subjects with low bone mineral density (BMD) (spine or hip T- or Z-score<−1) versus normal BMD, but no difference if both markers (CD38+HLA-DR+) were examined.3 Similarly, Erlandson et al. found no difference in median proportions of activated (CD38+HLA-DR+) CD4+ and CD8+ cells in 142 HIV-1-infected subjects on ART with low versus normal BMD at the hip or spine.2 Our results indicate that elevation in markers of CD8+ activation (CD8+CD38+HLA-DR+) in HIV-1-infected individuals on ART was not associated with incident fracture. These data do not disprove the role of chronic immune activation with HIV infection in bone loss and fracture; association with other cellular markers, such as monocyte, B cell, or other T cell activation markers, or soluble markers should be investigated to test the hypothesis that chronic immune activation results in increased fractures.