• Humphrey Mulenga, Munyaradzi Musvosvi, Simon C Mendelsohn, Adam Penn-Nicholson, Kimbung MbandiStanleySSouth African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, and., Andrew Fiore-Gartland, Michèle Tameris, Simbarashe Mabwe, Hadn Africa, Nicole Bilek, Fazlin Kafaar, Shabaana A Khader, Balie Carstens, Katie Hadley, Chris Hikuam, Mzwandile Erasmus, Lungisa Jaxa, Rodney Raphela, Onke Nombida, Masooda Kaskar, Mark P Nicol, Slindile Mbhele, Judi Van Heerden, Craig Innes, William Brumskine, Andriëtte Hiemstra, Stephanus T Malherbe, Razia Hassan-Moosa, Gerhard Walzl, Kogieleum Naidoo, Gavin Churchyard, Mark Hatherill, Thomas J Scriba, and CORTIS Study Team.
• South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, and.
• Am. J. Respir. Crit. Care Med. 2021 Dec 15; 204 (12): 1463-1472.

AbstractRationale: Performance of blood transcriptomic tuberculosis (TB) signatures in longitudinal studies and effects of TB-preventive therapy and coinfection with HIV or respiratory organisms on transcriptomic signatures has not been systematically studied. Objectives: We evaluated longitudinal kinetics of an 11-gene blood transcriptomic TB signature, RISK11, and effects of TB-preventive therapy (TPT) and respiratory organisms on RISK11 signature score, in HIV-uninfected and HIV-infected individuals. Methods: RISK11 was measured in a longitudinal study of RISK11-guided TPT in HIV-uninfected adults, a cross-sectional respiratory organisms cohort, or a longitudinal study in people living with HIV (PLHIV). HIV-uninfected RISK11+ participants were randomized to TPT or no TPT; RISK11- participants received no TPT. PLHIV received standard-of-care antiretroviral therapy and TPT. In the cross-sectional respiratory organisms cohort, viruses and bacteria in nasopharyngeal and oropharyngeal swabs were quantified by real-time quantitative PCR. Measurements and Main Results: RISK11+ status was transient in most of the 128 HIV-negative participants with longitudinal samples; more than 70% of RISK11+ participants reverted to RISK11- by 3 months, irrespective of TPT. By comparison, reversion from a RISK11+ state was less common in 645 PLHIV (42.1%). Non-HIV viral and nontuberculous bacterial organisms were detected in 7.2% and 38.9% of the 1,000 respiratory organisms cohort participants, respectively, and among those investigated for TB, 3.8% had prevalent disease. Median RISK11 scores (%) were higher in participants with viral organisms alone (46.7%), viral and bacterial organisms (42.8%), or prevalent TB (85.7%) than those with bacterial organisms other than TB (13.4%) or no organisms (14.2%). RISK11 could not discriminate between prevalent TB and viral organisms. Conclusions: Positive RISK11 signature status is often transient, possibly due to intercurrent viral infection, highlighting potentially important challenges for implementation of these biomarkers as new tools for TB control.

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