Discrepancy Between Mtb-specific IFN-γ and IgG Responses in HIV-positive People with Low CD4 Counts

Background Tuberculosis (TB) is a leading infectious cause of death worldwide and treating latent TB infection (LTBI) with TB preventative therapy is a global priority. This study aimed to measure interferon gamma (IFN-gamma) release assay (IGRA) positivity (the current reference standard for LTBI diagnosis) and Mtb-specific IgG antibodies in otherwise healthy adults without HIV and those living with HIV (PLWH).Methods One-hundred and eighteen adults (65 without HIV and 53 antiretroviral-naive PLWH), from a peri-urban setting in KwaZulu-Natal, South Africa were enrolled. IFN-gamma released following stimulation with ESAT-6/CFP-10 peptides and plasma IgG antibodies specific for multiple Mtb antigens were measured using the QuantiFERON-TB Gold Plus (QFT) and customized Luminex assays, respectively. The relationships between QFT status, relative concentrations of anti-Mtb IgG, HIV-status, sex, age and CD4 count were analysed.Findings Older age, male sex and higher CD4 count were independently associated with QFT positivity (p = 0.045, 0.05 and 0.002 respectively). There was no difference in QFT status between people with and without HIV infection (58% and 65% respectively, p = 0.06), but within CD4 count quartiles, people with HIV had higher QFT positivity than people without HIV (p = 0.008 (2nd quartile), < 0.0001 (3rd quartile)). Concentrations of Mtb-specific IFN-gamma were lowest, and relative concentrations of Mtb-specific IgGs were highest in PLWH in the lowest CD4 quartile.Interpretation These results suggest that the QFT assay underestimates LTBI among immunosuppressed people with HIV and Mtb-specific IgG may be a useful alternative biomarker for Mtb infection. Further evaluation of how Mtb-specific antibodies can be leveraged to improve LTBI diagnosis is warranted, particularly in HIV-endemic areas.Copyright (c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).