Detection of Tuberculosis Recurrence, Diagnosis and Treatment Response by a Blood Transcriptomic Risk Signature in HIV-Infected Persons on Antiretroviral Therapy

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 tre...

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Published in:	Frontiers in microbiology 2019-06, Vol.10, p.1441-1441
Main Authors:	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
Format:	Article
Language:	eng
Subjects:	diagnosis HIV Microbiology recurrence transcriptomic signature treatment tuberculosis
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Summary:	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.
ISSN:	1664-302X 1664-302X