Cytokine trajectory over time in men and women with HIV on long-term antiretroviral therapy

Objective: Although antiretroviral therapy (ART) suppresses viral replication and reduces inflammation, it does not lead to the normalization of cytokines. The long-term effects of ART beyond viral suppression have not been studied and are mostly limited to cross-sectional research. Design: The impact of long-term ART on the trajectory of 40 cytokines/chemokines in 31 men and 59 women who maintained viral suppression over a median period of 6 years (317 visits ranging from 24 to 384 weeks post ART initiation) were measured by Luminex. Methods: We used a generalized additive model with a Gaussian distribution and identity link function to model concentrations over time and investigate sex and race differences. Results: While most cytokine/chemokine trajectories remained stable, the trajectory of nine markers of monocyte/macrophage activation (IP-10, I-TAC, MIG, sCD163, sCD14, MCP-1, MIP-3 beta, CXCL13, TNF-alpha) decreased over time (adj. P < 0.05). Despite continuous viral suppression, M-CSF, IL-15, and LBP increased over time (adj. P < 0.05). sCD14 was the only cytokine whose trajectory differed by sex (adj. P = 0.033). Overall, women had lower mean levels of IL-18 but higher levels of sCD14 than did men (adj. P < 0.05). GRO alpha, LBP, and sCD14 showed significant differences between races (adj. P < 0.05). No association between cytokines and cellular HIV DNA/RNA was found. Conclusion: Our study reveals a continuous decline in markers of monocyte/macrophage activation over 6 years of suppressive ART, indicating that long-term treatment may mitigate inflammaging and cardiovascular-related outcomes. The higher levels of sCD14 observed in women are consistent with them having greater innate immune activation than men do.