Monocyte Activation in People With HIV and Tuberculosis Coinfection and Effect of Tuberculosis Preventive Therapy: An Analysis of the ACTG A5279/BRIEF TB Trial.

Background: Monocyte activation contributes to the pathogenesis of inflammation-driven comorbidities in people with HIV (PWH). We investigated the impact of tuberculin skin test (TST)/interferon-γ release assay (IGRA) status and tuberculosis preventive therapy (TPT) on monocyte activation in PWH. Methods: We analyzed peripheral blood mononuclear cells from participants from the A5279/BRIEF-TB trial, which compared 1 month of rifapentine/isoniazid (1HP) versus 9 months of isoniazid (9H) as TPT in PWH. All included participants were on suppressive antiretroviral therapy and had available TST or IGRA results at study entry. Samples collected at week 0 (pre-TPT) and week 48 (post-TPT) were analyzed. Monocyte subset and activation markers were measured using multiparameter flow cytometry. Proinflammatory cytokines (IL-6 and TNF-α) were assessed after 6-hour lipopolysaccharide (LPS) stimulation. Linear regression models were used for primary comparisons of monocyte markers by TST/IGRA status, adjusted for age, sex, country, and CD4 count. Results: In adjusted models, compared with TST/IGRA-negative participants (n = 27), TST/IGRA-positive participants (n = 30) had ∼2-fold relative increases in the median fluorescence intensity of CD64 (unstimulated) and CCR2 (post-LPS) on total monocytes and across monocyte subsets, pre- and post-TPT. Among TST/IGRA-positive participants, 1HP was associated with decreased fold changes over time for the percentage of CCR2+ monocytes and blunted IL-6/TNF-α responses compared with 9H. Conclusions: PWH with a positive TST or IGRA exhibited signals of monocyte activation pre- and post-TPT. TPT with 1HP led to blunted proinflammatory monocyte changes compared with 9H.