Comparative Analysis of Tuberculosis Preventive Therapy Efficacies in HIV Patients

Latent Tuberculosis Infection (LTBI) is associated with increased immune activation and a heightened risk of cardiovascular diseases. The ACTG A5279 trial, a phase 3 study presented at the Conference on Retroviruses and Opportunistic Infections (CROI), investigated the activation patterns of monocytes in individuals with HIV (PWH). This trial compared the efficacy of 4 weeks of daily rifapentine (RFP) and isoniazid (INH) against 9 months of daily INH for Tuberculosis Preventive Therapy (TPT). At baseline and week 48, PWH with LTBI, compared to those with negative TST/IGRA results, demonstrated changes in monocytes indicative of ongoing activation and tissue migration.

By week 48, LTBI participants, in contrast to the TST/IGRA-negative group, showed higher percentages and mean fluorescence intensity (MFI) of CD64 across all monocyte subsets, along with varied expression of CD80, CD163, and CX3CR1 on specific subsets. Following LPS stimulation, no significant differences in IL-6 or TNF-α production were observed according to TST/IGRA status, LTBI was associated with higher MFI of CD36 and CCR2, and lower MFI of CX3CR1 on total monocytes and their subsets showcasing a pattern consistent with increased MFI of CD64 (unstimulated) and CCR2 (post-LPS) at both baseline and week 48 across monocyte subsets.
The study examined cryopreserved peripheral blood mononuclear cells (PBMCs) from A5279 trial participants who were on antiretroviral therapy, had an HIV viral load ≤200 copies/mL, and tested either positive or negative for TST or IGRA at entry. These PBMCs, collected at baseline (pre-TPT) and week 48 (post-TPT), were unstimulated and then stained with markers to identify monocyte subsets, activation, chemotaxis, and lipid uptake. Multiparameter flow cytometry assessed monocyte markers and IL-6 and TNF-α expression post in vitro LPS stimulation. The primary comparisons were between TST/IGRA-positive (indicating LTBI) and TST/IGRA-negative groups, with linear regression of log10-transformed markers adjusted for age, sex at birth, country, and CD4 count.

The cohort comprised 58 participants from 4 countries, with a median age of 38 years (interquartile range of 34 – 47), including 33 (57%) males and 25 (43%) females. From the start, those with LTBI (n=31) displayed elevated levels and/or MFI of CD64 and CCR2 on all and notably on classical monocytes when compared to TST/IGRA-negative individuals (n=27).

This research, part of the ACTG A5279 trial, underscores the impact of LTBI on the immune system and the potential for targeted treatments. Future longitudinal studies are anticipated to build on these findings, offering management LTBI in HIV-infected populations, and emphasizing the need for ongoing research in this area.

Reference

Huaman K, Garzon M, McKhann A, Du, X, et, al. Monocyte Activation in Persons With HIV and Latent TB Co-Infection in the ACTG A5279/BRIEF TB Trial. poster #883 presented at CROI 2024. March 3-6, 2023. Denver, CO.