The performance of host blood-based biomarkers for tuberculosis (TB) in HIV-infected patients on antiretroviral therapy (ART) has not been fully assessed. We evaluated the immune phenotype and functionality of antigen-specific T-cell responses in HIV positive (+) participants with TB (n = 12) compared to HIV negative (-) participants with either TB (n = 9) or latent TB infection (LTBI) (n = 9). We show that the cytokine profile of Mtb-specific CD4+ T-cells in participants with TB, regardless of HIV status, was predominantly single IFN-γ or dual IFN-γ/ TNFα. Whilst ESAT-6/CFP-10 responding T-cells were predominantly of an effector memory (CD27-CD45RA-CCR7-) profile, HIV-specific T-cells were mainly of a central (CD27+CD45RA-CCR7+) and transitional memory (CD27+CD45RA+/-CCR7-) phenotype on both CD4+ and CD8+ T-cells. Using receiving operating characteristic (ROC) curve analysis, co-expression of CD38 and HLA-DR on ESAT-6/CFP-10 responding total cytokine-producing CD4+ T-cells had a high sensitivity for discriminating HIV+TB (100%, 95% CI 70-100) and HIV-TB (100%, 95% CI 70-100) from latent TB with high specificity (100%, 95% CI 68-100 for HIV-TB) at a cut-off value of 5% and 13%, respectively. TB treatment reduced the proportion of Mtb-specific total cytokine+CD38+HLA-DR+ CD4+ T-cells only in HIV-TB (p = 0.001). Our results suggest that co-expression of CD38 and HLA-DR on Mtb-specific CD4+ T-cells could serve as a TB diagnosis tool regardless of HIV status.

OBJECTIVE:Tuberculosis (TB) remains one of the leading causes of mortality and morbidity among people living with HIV. We sought to estimate the incidence of TB in a national database of HIV-infected patients receiving antiretroviral therapy (ART) in Botswana. DESIGN:A retrospective analysis of HIV-infected adult patients (≥18years) who initiated ART between 2011 and 2015 in the Botswana ART program. METHODS:Multivariable analysis using Cox regression included sex, age, viral load and CD4 counts. RESULTS:Of 45,729 patients, with a median follow-up of 1·7 years Q1, Q3: 0·5,3·1), 1,791 patients developed TB over a median of 1·5 years (Q1, Q3: 0·3,3·1) of follow-up (IR 1·9 per 100 py; 95% CI 1·8-2·0). At baseline, the median CD4+ T-cell count was 272 cells/μl (Q1:Q3 146, 403). The risk of TB was greatest within the first year of ART (IR 2·9 per 100 py; 95% CI 2·7-3·1) and in patients with CD4 counts below 50 cells/μl (IR 8·3/100 py; 95% CI 7·1-9·7). Patients with viral loads above 10,000 copies/ml at 3 months post ART initiation had two-times higher risk of TB, HR 2.5 (95% CI 1·8-2·3). CONCLUSIONS:We report a high incidence of TB within the first year of ART and in patients with advanced immunodeficiency. Improved screening strategies and virologic monitoring during this early period on ART, coupled with TB preventative treatment, will reduce the burden of TB.