Increased Risk of Serious Non-AIDS-Related Events in HIV-Infected Subjects on Antiretroviral Therapy Associated with a Low CD4/CD8 Ratio

Abstract

BackgroundA low CD4/CD8 ratio has been identified in the general population as a hallmark of inmmunosenescence and a surrogate of all-cause mortality. We aimed to investigate in treated HIV-infected individuals the relationship between the CD4/CD8 ratio and serious non-AIDS events.MethodsCase-control study within a prospective hospital-based cohort of HIV-infected subjects during at least one year of ART-mediated viral suppression. Cases were patients with serious non-AIDS events (non-AIDS malignancies, cardiovascular disease, and end-stage kidney disease), and controls individuals who did not developed non-AIDS events during follow-up. Data were analyzed using ROC analysis and multivariate logistic regression. Conditional logistic regression was performed in 200 cases/controls matched by age, sex, nadir CD4 and proximal CD4 counts.ResultsWe analyzed 407 subjects (109 cases, 298 controls). The CD4/CD8 ratio was lower in cases (0.44 vs. 0.70, P<0.0001), with higher discriminatory ability for the detection of non-AIDS events than the CD4 count, CD8 count and nadir CD4. Multivariate analyses (adjusted for age, sex, nadir CD4, proximal CD4 count, year of ART initiation and ART duration) confirmed the independent association of a low CD4/CD8 ratio with the risk of non-AIDS morbidity (per CD4/CD8 ratio quartile decrease, OR, 2.9; 95% CI, 1.3–6.2) and non-AIDS mortality (OR, 2.8; 95% CI, 1.5–5.3).ConclusionsThe CD4/CD8 ratio provides additional information to the CD4 counts and nadir CD4 in treated HIV-infected individuals, since it is independently associated with the risk of non-AIDS-related morbidity and mortality. This association is robust and maintained within different subgroups of patients.

A Lower Baseline CD4/CD8 T-Cell Ratio Is Independently Associated with Immunodiscordant Response to Antiretroviral Therapy in HIV-Infected Subjects

“…Our data interconnect recent findings regarding the higher risk of morbidity and mortality associated with both low-CD4-recovery subjects (1, 2) and low-CD4/CD8-Tcell-ratio subjects (7,8). More importantly, although the CD8 T-cell pool has not been classically considered relevant in this scenario, our data suggest that homeostasis of the CD8 T-cell pool, probably interacts with the homeostasis of CD4 T cells, also contributing to this scenario.…”

“…The HIV infection leads to an inversion of the CD4/CD8 T-cell ratio (7), and globally, the CD4/CD8 T-cell ratio has been associated with clinical progression, independently of CD4 counts (7)(8)(9). However, whereas a low baseline CD4 count is undoubtedly associated with immunodiscordance, a potential different meaning of the baseline CD4/CD8 T-cell ratio has not yet been explored.…”

Neuroinflammation in treated HIV-positive individuals

“…In virally suppressed PLWH, a lower current CD4/CD8 ratio has been associated with immune activation 33 and cognitive impairments. 34 We hypothesize that the association between lower CD4/CD8 ratio and greater TSPO expression in the brain that we have observed reflects a causal relationship among peripheral immune activation, breakdown of the blood-brain barrier, and subsequent brain immune activation, possibly by facilitating HIV entry into the CNS early during infection.…”

Inflammatory Function of CX3CR1+CD8+T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

“…CD8 + T-cell persistence in treated HIV-infected donors contributes to abnormally low ratios of CD4 + T cells to CD8 + T cells (hereafter, "CD4 + /CD8 + ratios"), now recognized as associated with a greater risk for morbidity, including cardiovascular events [2][3][4][5]. A relationship to vascular health is suggested by observations that an inverted CD4 + /CD8 + ratio is also associated with greater intima media thickness and arterial stiffness, both of which are important predictors of cardiovascular morbidity [4,6]. A recent study examined the characteristics of the expanded circulating CD8 + T cells in patients with inverted CD4 + /CD8 + ratios despite sustaining CD4 + T-cell counts at >500 cells/µL during ART [3].…”

“…CD8 + T-cell expansion and the resultant inversion of the CD4 + /CD8 + ratio in ART recipients predict morbid events, but the determinants of this risk are not understood [3][4][5]. The association between abnormal CD8 + T-cell expansion and morbid outcomes is also apparent in the HIV-uninfected elderly population, yet here, too, the mechanisms underlying these risks are unclear [37].…”