Kynurenine/tryptophan ratio for detection of active tuberculosis in adults with HIV prior to antiretroviral therapy

Objective: The aim of this study was to assess the performance of kynurenine/tryptophan ratio for tuberculosis (TB) case-finding among antiretroviral therapy (ART)-naive people with HIV (PWH), and to investigate other factors associated with kynurenine/tryptophan ratio in this population. Design: A nested case-control study based on a cohort of 812 ambulatory PWH in the Oromia region, Ethiopia. Methods: At enrolment, all participants submitted sputum samples for bacteriological TB investigations. Concentrations of kynurenine and tryptophan in plasma were quantified using liquid chromatography-mass spectrometry. Receiver operator characteristic curves were constructed to assess diagnostic performance (area under the curve; AUC) for kynurenine, tryptophan, and kynurenine/tryptophan ratio. Sensitivity, specificity, and predictive values were calculated. Kynurenine/tryptophan ratios were correlated to plasma levels of nine inflammation mediators, plasma HIV RNA levels, CD4+cell count, BMI, and mid-upper arm circumference (MUAC). Results: We included 124 individuals with HIV-TB coinfection (HIV+/TB+) and 125 with HIV mono-infection (HIV+/TB-). Tryptophan levels were lower in HIV+/TB+ than in HIV+/TB-(median 19.5 vs. 29.8 μmol/l, P < 0.01), while kynurenine levels were similar between these groups (median 2.95 vs. 2.94 μmol/l, P = 0.62). Median kynurenine/tryptophan ratio was 0.15 in HIV+/TB+, significantly higher compared with HIV+/TB-(0.11; P < 0.01), with AUC 0.70 for TB detection. Kynurenine/tryptophan ratio was positively correlated to plasma HIV RNA levels, IP-10, IL-18, and IL-27, and negatively correlated to CD4+cell count, BMI, and MUAC (all P < 0.01). Conclusion: Among ART-naive PWH, kynurenine/tryptophan ratio has modest potential for TB discrimination, limiting its utility for TB case-finding in this population

Performance of Galectin-9 for Identification of HIV Viremia in Adults Receiving Antiretroviral Therapy in a Resource-Limited Setting

Background: Targeted viral load (VL) testing has been proposed for antiretroviral treatment (ART) monitoring in resource-limited settings. In this study, we have investigated the performance of the host biomarker galectin-9 (Gal-9), alone and in combination with interferon-γ-inducible protein 10 (IP-10), in identifying individuals at increased likelihood of viremia during ART.Setting:Cohort of HIV-positive adults receiving ART at Ethiopian health centers.Methods:We included participants with detectable viremia (VL ≥150 copies/mL) 12 months after starting ART and sex-matched nonviremic controls. Performance to identify individuals with VL ≥1000 copies/mL was determined for Gal-9 and the Gal-9/IP-10 combination, respectively, using receiver operating characteristic (ROC) analysis.Results:Among 191 participants (50.3% women), 46 (24.1%) had VL ≥1000 copies/mL, 23 (12.0%) had 150-999 copies/mL, and 122 (63.9%) had <150 copies/mL. Gal-9 and VL were positively correlated (rs= 0.451, P < 0.001). Sensitivity and specificity for Gal-9 to identify individuals with VL ≥1000 copies/mL were 91.3% (95% CI: 79.2-97.6) and 54.5% (95% CI: 46.0-62.8), respectively. The area under the ROC curve for Gal-9 was 0.810 (95% CI: 0.745-0.875), which was similar to that of the combination of Gal-9 and IP-10 [0.849 (95% CI: 0.792-0.905)]. Assuming 10% prevalence of VL ≥1000 copies/mL, using Gal-9 for targeted VL testing instead of universal VL testing would reduce the number of VL tests from 10 to 5 to identify 1 viremic individual, with misclassification of 1 in 10 viremic individuals.Conclusions:Gal-9 is a potential screening marker for targeted VL monitoring in ART recipients. Further studies are needed to determine optimal threshold levels

Plasma profiles of inflammatory markers associated with active tuberculosis in antiretroviral therapy-naive human immunodeficiency virus-positive individuals

Background. Diagnosis of tuberculosis (TB) in human immunodeficiency virus (HIV)-coinfected individuals is challenging. We hypothesized that combinations of inflammatory markers could facilitate identification of active TB in HIV-positive individuals. Methods. Participants were HIV-positive, treatment-naive adults systematically investigated for TB at Ethiopian health centers. Plasma samples from 130 subjects with TB (HIV+/TB+) and 130 subjects without TB (HIV+/TB−) were tested for concentration of the following markers: CCL5, C-reactive protein (CRP), interleukin (IL)-6, IL12-p70, IL-18, IL-27, interferon-γ-induced protein-10 (IP-10), procalcitonin (PCT), and soluble urokinase-type plasminogen activator receptor (suPAR). Analyzed markers were then assessed, either individually or in combination, with regard to infection status, CD4 cell count, and HIV ribonucleic acid (RNA) levels. Results. The HIV+/TB+ subjects had higher levels of all markers, except IL12p70, compared with HIV+/TB− subjects. The CRP showed the best performance for TB identification (median 27.9 vs 1.8 mg/L for HIV+/TB+ and HIV+/TB−, respectively; area under the curve [AUC]: 0.80). Performance was increased when CRP was combined with suPAR analysis (AUC, 0.83 [0.93 for subjects with CD4 cell count <200 cells/mm3]). Irrespective of TB status, IP-10 concentrations correlated with HIV RNA levels, and both IP-10 and IL-18 were inversely correlated to CD4 cell counts. Conclusions. Although CRP showed the best single marker discriminatory potential, combining CRP and suPAR analyses increased performance for TB identification

Alternative biomarkers for classification of latent tuberculosis infection status in pregnant women with borderline Quantiferon plus results

Borderline interferon-gamma (IFN-γ) results (near the cut-off level 0.35 IU/ml) occur in QuantiFERON (QFT) assays. We investigated the performance of alternative biomarkers for classification of latent tuberculosis infection (LTBI) status in pregnant women with borderline QFT IFN-γ responses. Pregnant women (n = 96) were identified from a cohort study in Ethiopia, based on QFT-Plus IFN-γ results (QFT-low: 0.70 IU/ml, n = 32), including 12 HIV-positive individuals in each group and with 20 HIV-negative non-pregnant women from the same cohort with QFT IFN-γ <0.20 IU/ml as controls. Concentrations of 8 markers (IL-1ra, IL-6, IL-8, IP-10, MCP-1, MCP-2, osteopontin and resistin) were measured in whole blood QFT supernatants, stimulated separately with TB1 and TB2 antigens. K-nearest neighbor analysis (KNN) was used to classify participants with regard to likelihood of LTBI. Concentrations of MCP-2, IP-10 and IL-1ra were higher in QFT-borderline compared to QFT-low participants in both antigen stimulations (p < 0.001). KNN classification indicated high likelihood of LTBI in 13/31 (42%) women with QFT-borderline IFN-γ results. MCP-2, IP-10 and IL-1ra expressed in whole blood after TB antigen stimulation may be considered as alternative biomarkers for classification of LTBI status in pregnant women with borderline QFT IFN-γ results