AUTHOR=Darboe Fatoumatta , Mbandi Stanley Kimbung , Naidoo Kogieleum , Yende-Zuma Nonhlanhla , Lewis Lara , Thompson Ethan G. , Duffy Fergal J. , Fisher Michelle , Filander Elizabeth , van Rooyen Michele , Bilek Nicole , Mabwe Simbarashe , McKinnon Lyle R. , Chegou Novel , Loxton Andre , Walzl Gerhard , Tromp Gerard , Padayatchi Nesri , Govender Dhineshree , Hatherill Mark , Karim Salim Abdool , Zak Daniel E. , Penn-Nicholson Adam , Scriba Thomas J. , The SATVI Clinical Immunology Team TITLE=Detection of Tuberculosis Recurrence, Diagnosis and Treatment Response by a Blood Transcriptomic Risk Signature in HIV-Infected Persons on Antiretroviral Therapy JOURNAL=Frontiers in Microbiology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.01441 DOI=10.3389/fmicb.2019.01441 ISSN=1664-302X ABSTRACT=

HIV-infected individuals are at high risk of tuberculosis disease and those with prior tuberculosis episodes are at even higher risk of disease recurrence. A non-sputum biomarker that identifies individuals at highest tuberculosis risk would allow targeted microbiological testing and appropriate treatment and also guide need for prolonged therapy. We determined the utility of a previously developed whole blood transcriptomic correlate of risk (COR) signature for (1) predicting incident recurrent tuberculosis, (2) tuberculosis diagnosis and (3) its potential utility for tuberculosis treatment monitoring in HIV-infected individuals. We retrieved cryopreserved blood specimens from three previously completed clinical studies and measured the COR signature by quantitative microfluidic real-time-PCR. The signature differentiated recurrent tuberculosis progressors from non-progressors within 3 months of diagnosis with an area under the Receiver-operating characteristic (ROC) curve (AUC) of 0.72 (95% confidence interval (CI), 0.58–0.85) amongst HIV-infected individuals on antiretroviral therapy (ART). Twenty-five of 43 progressors (58%) were asymptomatic at microbiological diagnosis and thus had subclinical disease. The signature showed excellent diagnostic discrimination between HIV-uninfected tuberculosis cases and controls (AUC 0.97; 95%CI 0.94–1). Performance was lower in HIV-infected individuals (AUC 0.83; 95%CI 0.81–0.96) and signature scores were directly associated with HIV viral loads. Tuberculosis treatment response in HIV-infected individuals on ART with a new recurrent tuberculosis diagnosis was also assessed. Signature scores decreased significantly during treatment. However, pre-treatment scores could not differentiate between those who became sputum negative before and after 2 months. Direct application of the unmodified blood transcriptomic COR signature detected subclinical and active tuberculosis by blind validation in HIV-infected individuals. However, prognostic performance for recurrent tuberculosis, and performance as diagnostic and as treatment monitoring tool in HIV-infected persons was inferior to published results from HIV-negative cohorts. Our results suggest that performance of transcriptomic signatures comprising interferon stimulated genes are negatively affected in HIV-infected individuals, especially in those with incompletely suppressed viral loads.