Validation of a host blood transcriptomic biomarker for pulmonary tuberculosis in people living with HIV: a prospective diagnostic and prognostic accuracy study
Authors: Simon C Mendelsohn, Andrew Fiore-Gartland, Adam Penn-Nicholson, Humphrey Mulenga, Stanley Kimbung Mbandi, Bhavesh Borate, Katie Hadley, Chris Hikuam, Munyaradzi Musvosvi, Nicole Bilek, Mzwandile Erasmus, Lungisa Jaxa, Rodney Raphela, Onke Nombida, Masooda Kaskar, Tom Sumner, Richard G White, Craig Innes, William Brumskine, Andriëtte Hiemstra, Stephanus T Malherbe, Razia Hassan-Moosa, Michèle Tameris, Gerhard Walzl, Kogieleum Naidoo, Gavin Churchyard, Thomas J Scriba, Mark Hatherill, Charmaine Abrahams, Hadn Africa, Petri Ahlers, Denis Arendsen, Tebogo Badimo, Kagiso Baepanye, Kesenogile Edna Baepanye, Bianca Bande, Nomfuneko Cynthia Batyi, Roslyn Beukes, Laudicia Tshenolo Bontsi, Obakeng Peter Booi, Mari Cathrin Botha, Samentra Braaf, Sivuyile Buhlungu, Alida Carstens, Kgomotso Violet Chauke, Thilagavathy Chinappa, Eva Chung, Michelle Chung, Ken Clarke, Yolundi Cloete, Lorraine Coetzee, Marelize Collignon, Alessandro Companie, Cara-mia Corris, Mooketsi Theophillius Cwaile, Thobelani Cwele, Ilse Davids, Isabella Johanna Davies, Emilia De Klerk, Marwou de Kock, Audrey Lebohang Dhlamini, Bongani Diamond, Maria Didloff, Celaphiwe Dlamini, Palesa Dolo, Candice Eyre, Tebogo Feni, Juanita Ferreira, Christal Ferus, Michelle Fisher, Marika Flinn, Bernadine Fransman, Welseh Phindile Galane, Hennie Geldenhuys, Diann Gempies, Thelma Goliath, Dhineshree Govender, Yolande Gregg, Goodness Gumede, Zanele Gwamada, Senzo Halti, Rieyaat Hassiem, Roxane Herling, Yulandi Herselman, Ellis Hughes, Henry Issel, Blanchard Mbay Iyemosolo, Zandile Jali, Bonita Janse Van Rensburg, Ruwiyda Jansen, James Michael Jeleni, Olebogeng Jonkane, Fabio Julies, Fazlin Kafaar, Christian Mabika Kasongo, Christian Mabika Kasongo, Sophie Keffers, Boitumelo Sophy Kekana, Sebaetseng Jeanette Kekana, Xoliswa Kelepu, Lungile Khanyile, Gomotsegang Virginia Khobedi, Gloria Khomba, Lucky Sipho Khoza, Marietjie King, Gloria Keitumetse Kolobe, Sandra Kruger, Jaftha Kruger, Ndlela Israel Kunene, Sunelza Lakay, Aneesa Lakhi, Nondumiso Langa, Hildah Ledwaba, Lerato Julia Lekagane, Sheiley Christina Lekotloane, Thelma Leopeng, Ilze Jeanette Louw, Angelique Kany Kany Luabeya, Sarah Teboso Lusale, Perfect Tiisetso Maatjie, Immaculate Mabasa, Tshegofatso Dorah Mabe, Kamogelo Fortunate Mabena, Nkosinathi Charles Mabuza, Simbarashe Mabwe, Johanna Thapelo Madikwe, Octavia Mahkosazana Madikwe, Rapontwana Letlhogonolo Maebana, Malobisa Sylvester Magwasha, Molly Majola, Mantai Makhetha, Lebohang Makhethe, Vernon Malay, Vutlhari-I-Vunhenha Fairlord Manzini, Jabu Maphanga, Nonhle Maphanga, Juanita Market, Isholedi Samuel Maroele, Omphile Petunia Masibi, July Rocky Mathabanzini, Tendamudzimu Ivan Mathode, Ellen Ditaba Matsane, Lungile Mbata, Lungile Mbata, Faheema Meyer, Nyasha Karen Mhandire, Thembisiwe Miga, Nosisa Charity Thandeka Mkhize, Caroline Mkhokho, Neo Hilda Mkwalase, Nondzakazi Mnqonywa, Karabo Moche, Brenda Matshidiso Modisaotsile, Patricia Pakiso Mokgetsengoane, Selemeng Matseliso Carol Mokone, Kegomoditswe Magdeline Molatlhegi, Thuso Andrew Molefe, Joseph Panie Moloko, Kabelo Molosi, Motlatsi Evelyn Molotsi, Tebogo Edwin Montwedi, Boikanyo Dinah Monyemangene, Hellen Mokopi Mooketsi, Miriam Moses, Boitumelo Mosito, Tshplpfelo Mapula Mosito, Ireen Lesebang Mosweu, Primrose Mothaga, Banyana Olga Motlagomang, Angelique Mouton, Onesisa Mpofu, Funeka Nomvula Mthembu, Mpho Mtlali, Nhlamulo Ndlovu, Nompumelelo Ngcobo, Julia Noble, Bantubonke Bertrum Ntamo, Gloria Ntanjana, Tedrius Ntshauba, Fajwa Opperman, Nesri Padayatchi, Thandiwe Papalagae, Christel Petersen, Themba Phakathi, Mapule Ozma Phatshwane, Patiswa Plaatjie, Abe Pretorius, Victor Kgothatso Rameetse, Dirhona Ramjit, Frances Ratangee, Maigan Ratangee, Pearl Nomsa Sanyaka, Alicia Sato, Elisma Schoeman, Constance Schreuder, Letlhogonolo Seabela, Kelebogile Magdeline Segaetsho, Ni Ni Sein, Raesibe Agnes Pearl Selepe, Melissa Neo Senne, Melissa Neo Senne, Alison September, Cashwin September, Moeti Serake, Justin Shenje, Thandiwe Shezi, Sifiso Cornelius Shezi, Phindile Sing, Chandrapharbha Singh, Zona Sithetho, Dorothy Solomons, Kim Stanley, Marcia Steyn, Bongiwe Stofile, Sonia Stryers, Liticia Swanepoel, Anne Swarts, Mando Mmakhora Thaba, Lethabo Collen Theko, Philile Thembela, Mugwena Thompo, Asma Toefy, Khayalethu Toto, Dimakatso Sylvia Tsagae, Ayanda Tsamane, Vincent Tshikovhi, Lebogang Isaac Tswaile, Petrus Tyambetyu, Susanne Tönsing, Habibullah Valley, Linda van der Merwe, Elma van Rooyen, Ashley Veldsman, Helen Veldtsman, Kelvin Vollenhoven, Londiwe Zaca, Elaine Zimri, Mbali Zulu
Journal: The Lancet Global Health (2021)

BackgroundA rapid, blood-based triage test that allows targeted investigation for tuberculosis at the point of care could shorten the time to tuberculosis treatment and reduce mortality. We aimed to test the performance of a host blood transcriptomic signature (RISK11) in diagnosing tuberculosis and predicting progression to active pulmonary disease (prognosis) in people with HIV in a community setting.MethodsIn this prospective diagnostic and prognostic accuracy study, adults (aged 18–59 years) with HIV were recruited from five communities in South Africa. Individuals with a history of tuberculosis or household exposure to multidrug-resistant tuberculosis within the past 3 years, comorbid risk factors for tuberculosis, or any condition that would interfere with the study were excluded. RISK11 status was assessed at baseline by real-time PCR; participants and study staff were masked to the result. Participants underwent active surveillance for microbiologically confirmed tuberculosis by providing spontaneously expectorated sputum samples at baseline, if symptomatic during 15 months of follow-up, and at 15 months (the end of the study). The coprimary outcomes were the prevalence and cumulative incidence of tuberculosis disease confirmed by a positive Xpert MTB/RIF, Xpert Ultra, or Mycobacteria Growth Indicator Tube culture, or a combination of such, on at least two separate sputum samples collected within any 30-day period.FindingsBetween March 22, 2017, and May 15, 2018, 963 participants were assessed for eligibility and 861 were enrolled. Among 820 participants with valid RISK11 results, eight (1%) had prevalent tuberculosis at baseline: seven (2·5%; 95% CI 1·2–5·0) of 285 RISK11-positive participants and one (0·2%; 0·0–1·1) of 535 RISK11-negative participants. The relative risk (RR) of prevalent tuberculosis was 13·1 times (95% CI 2·1–81·6) greater in RISK11-positive participants than in RISK11-negative participants. RISK11 had a diagnostic area under the receiver operating characteristic curve (AUC) of 88·2% (95% CI 77·6–96·7), and a sensitivity of 87·5% (58·3–100·0) and specificity of 65·8% (62·5–69·0) at a predefined score threshold (60%). Of those with RISK11 results, eight had primary endpoint incident tuberculosis during 15 months of follow-up. Tuberculosis incidence was 2·5 per 100 person-years (95% CI 0·7–4·4) in the RISK11-positive group and 0·2 per 100 person-years (0·0–0·5) in the RISK11-negative group. The probability of primary endpoint incident tuberculosis was greater in the RISK11-positive group than in the RISK11-negative group (cumulative incidence ratio 16·0 [95% CI 2·0–129·5]). RISK11 had a prognostic AUC of 80·0% (95% CI 70·6–86·9), and a sensitivity of 88·6% (43·5–98·7) and a specificity of 68·9% (65·3–72·3) for incident tuberculosis at the 60% threshold.InterpretationRISK11 identified prevalent tuberculosis and predicted risk of progression to incident tuberculosis within 15 months in ambulant people living with HIV. RISK11's performance approached, but did not meet, WHO's target product profile benchmarks for screening and prognostic tests for tuberculosis.FundingBill & Melinda Gates Foundation and the South African Medical Research Council.