Sex modifies link between inflammation, vascular events in ART-treated HIV

Sex appears to have a strong influence on many discrete pathways of inflammation that independently predict cardiovascular disease (CVD) and venous thromboembolism (VTE) events in patients with HIV on antiretroviral therapy (ART), according to a study presented at the Conference on Retroviruses and Opportunistic Infections 2021.

Moreover, inflammation more strongly predicts CVD events in women than in men, which suggests the importance of representing women in clinical studies of immune-based interventions in treated HIV infection.

“Sex modifies the association of non-AIDS events and inflammation,” said lead author Samuel Schnittman, MD, from the University of California, San Francisco, US. “This may partially explain the ‘loss of the female advantage’.”

Schnittman and his colleagues used a case-cohort design to randomly sample all participants with available plasma after 1 year of ART-mediated viral suppression (cohort) and from the same timepoint, all of those who were subsequently diagnosed with an incident type 1 (T1MI) or 2 myocardial infarction (T2MI), ischaemic stroke, or VTE (all centrally adjudicated). Composite CVD events included T1MI and ischaemic stroke.

Logistic regression was used to assess the association between 11 plasma biomarkers normalized to the cohort interquartile range (IQR) and subsequent event risk, adjusting for age, natal sex, nadir CD4, and other potential confounders (ie, smoking, history of injecting drug use [IDU], atherosclerotic CVD risk score, and hepatitis C virus history).

Of the 9,430 eligible participants, 979 were sampled in a random subcohort, as well as 103 CVD (75 T1MI, 30 ischaemic stroke), 56 T2MI, and 80 VTE cases. In the subcohort, the median age was 47 years, 82 percent were men, and 17 percent had IDU history. Median atherosclerotic CVD risk was 4 percent, while the median current and nadir CD4 were 576 and 248, respectively. [Schnittman SR, et al, Conference on Retroviruses and Opportunistic Infections 2021]

After adjustment, C-reactive protein (CRP), lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14), soluble urokinase-type plasminogen activator receptor (suPAR), Intercellular Adhesion Molecule 1 (ICAM-1), and cytomegalovirus immunoglobulin G (CMV IgG) were 1.4–2.5-fold higher in women than in men (p<0.03 for all).

Higher CRP, sCD14, and soluble tumor necrosis factor receptor 2 (sTNFR2) correlated with subsequent T1MI (1.3–1.6-fold higher odds per IQR increase; p<0.01 for all), while higher CRP, suPAR, and ICAM-1 correlated with VTE (1.5–1.7-fold higher odds per IQR increase; p<0.01 for all). Except for CRP, LBP, and CMV IgG, all biomarkers predicted the incidence of T2MI (1.4–2.8-fold greater odds per IQR increase; p<0.001 for all).

Notably, the association of inflammatory markers with CVD events was more pronounced among women than men (KT ratio and sCD14 p_interaction=0.005 and 0.08, respectively). However, inflammation tended to correlate with VTE events more strongly in men than women (sCD14 and sTNFR2 p_interaction=0.02 and 0.10, respectively).

“Women have higher levels of inflammation,” Schnittmann said, adding that sex could modify the association between inflammation and non-AIDS events.

The study was limited by the sample size, which restricted detection of clinically significant differences in biomarkers or interactions, by the absence of data on plasma sex hormones, and by the sparse data on transgenders and sex hormone therapy.

“People with HIV on ART have higher risk of vascular complications,” the researchers noted.