Sex-Related Differences in Inflammatory and Immune Activation Markers Before and After Combined Antiretroviral Therapy Initiation

Abstract

Background Women progress to death at the same rate as men despite lower plasma HIV RNA (VL). We investigated sex-specific differences in immune activation and inflammation as a potential explanation. Methods Inflammatory and immune activation markers (IFN-γ, TNF-α, IL-6, IL-18, IP-10, CRP, LPS, sCD14) were measured at weeks 0, 24, and 48 post-cART in a random subcohort (n=215) who achieved virologic suppression in ACTG A5175 (PEARLS). Association between sex and changes in markers post-cART was examined using random effects models. Average marker differences and 95%CI were estimated using multivariable models. Results At baseline, women had lower median log10VL (4.93 vs 5.18 copies/mL, p=0.01), CRP (2.32 vs 4.62 mg/L, p=0.01), detectable LPS (39% vs 55%, p=0.04), and sCD14 (1.9 vs 2.3 mcg/mL, p=0.06) versus men. By week 48, women had higher IFN-γ (22.4 vs 14.9 pg/mL, p=0.05), TNF-α (11.5 vs 9.5 pg/mL, p=0.02), and CD4 (373 vs 323 cells/mm3, p=0.02). In multivariate analysis, women had greater increases in CD4 and TNF-α but less of a decrease in CRP and sCD14 compared to men. Conclusions With cART-induced viral suppression, women have less reduction in key markers of inflammation and immune activation compared with men. Future studies should investigate the impact of these sex-specific differences on morbidity and mortality.

Variability in C-reactive protein is associated with cognitive impairment in women living with and without HIV: a longitudinal study

“…The state of the science is primarily based on largely male-dominant samples and cross-sectional studies. Given substantial evidence of sex differences in neuroimmune activation (Martin et al , 2013; Mathad et al , 2016; Ticona et al , 2015) and cognition (Failde-Garrido et al , 2008; Heaton et al , 2015; Robertson et al , 1996; Royal et al , 2016), previous findings might not be generalizable to HIV-infected women. Moreover, longitudinal studies are needed to enhance our understanding of the time course of CI in relation to altered immune function, including whether absolute levels and/or variability in these biomarkers over time relate to HIV-associated CI.…”

Sex Differences in Select Non-communicable HIV-Associated Comorbidities: Exploring the Role of Systemic Immune Activation/Inflammation

“…There is general consensus that starting ART early prevents or mitigates the severity of select HIV-associated comorbidities(4). Importantly, the PEARLS study, conducted in resource-limited settings, revealed that ART suppresses select indices of systemic immune activation to a lesser degree among WLHIV than among MLHIV(98). This observation may be highly relevant to sex-differences in HIV-associated non-infectious comorbidities.…”

Cardiovascular disease risk among women living with HIV in North America and Europe

“…Separate US studies among WLHIV and among MLHIV have confirmed that ART dampens select indices of systemic immune activation, albeit not down to levels seen in control subjects (40) (41) (42). Of note, however, an AIDS Clinical Trials Group study conducted in a resource-limited setting revealed that ART suppresses select indices of systemic immune activation to a lesser degree among WLHIV than among MLHIV (43). Just as ART exerts immunomodulatory effects in HIV, so too does statin therapy.…”