Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial
Authors: Thomas J Scriba, Andrew Fiore-Gartland, Adam Penn-Nicholson, Humphrey Mulenga, Stanley Kimbung Mbandi, Bhavesh Borate, Simon C Mendelsohn, Katie Hadley, Chris Hikuam, Masooda Kaskar, Munyaradzi Musvosvi, Nicole Bilek, Steven Self, Tom Sumner, Richard G White, Mzwandile Erasmus, Lungisa Jaxa, Rodney Raphela, Craig Innes, William Brumskine, Andriëtte Hiemstra, Stephanus T Malherbe, Razia Hassan-Moosa, Michèle Tameris, Gerhard Walzl, Kogieleum Naidoo, Gavin Churchyard, Mark Hatherill, Kesenogile Baepanye, Tshepiso Baepanye, Ken Clarke, Marelize Collignon, Audrey Dlamini, Candice Eyre, Tebogo Feni, Moogo Fikizolo, Phinda Galane, Thelma Goliath, Alia Gangat, Shirley Malefo-Grootboom, Elba Janse van Rensburg, Bonita Janse van Rensburg, Sophy Kekana, Marietjie Zietsman, Adrianne Kock, Israel Kunene, Aneessa Lakhi, Nondumiso Langa, Hilda Ledwaba, Marillyn Luphoko, Immaculate Mabasa, Dorah Mabe, Nkosinathi Mabuza, Molly Majola, Mantai Makhetha, Mpho Makoanyane, Blossom Makhubalo, Vernon Malay, Juanita Market, Selvy Matshego, Nontsikelelo Mbipa, Tsiamo Mmotsa, Sylvester Modipa, Samuel Mopati, Palesa Moswegu, Primrose Mothaga, Dorothy Muller, Grace Nchwe, Maryna Nel, Lindiwe Nhlangulela, Bantubonke Ntamo, Lawerence Ntoahae, Tedrius Ntshauba, Nomsa Sanyaka, Letlhogonolo Seabela, Pearl Selepe, Melissa Senne, MG Serake, Maria Thlapi, Vincent Tshikovhi, Lebogang Tswaile, Amanda van Aswegen, Lungile Mbata, Constance Takavamanya, Pedro Pinho, John Mdlulu, Marthinette Taljaard, Naydene Slabbert, Sharfuddin Sayed, Tanya Nielson, Melissa Senne, Ni Ni Sein, Lungile Mbata, Dhineshree Govender, Tilagavathy Chinappa, Mbali Ignatia Zulu, Nonhle Bridgette Maphanga, Senzo Ralph Hlathi, Goodness Khanyisile Gumede, Thandiwe Yvonne Shezi, Jabulisiwe Lethabo Maphanga, Zandile Patrica Jali, Thobelani Cwele, Nonhlanhla Zanele Elsie Gwamanda, Celaphiwe Dlamini, Zibuyile Phindile Penlee Sing, Ntombozuko Gloria Ntanjana, Sphelele Simo Nzimande, Siyabonga Mbatha, Bhavna Maharaj, Atika Moosa, Cara-Mia Corris, Fazlin Kafaar, Hennie Geldenhuys, Angelique Kany Kany Luabeya, Justin Shenje, Natasja Botes, Susan Rossouw, Hadn Africa, Bongani Diamond, Samentra Braaf, Sonia Stryers, Alida Carstens, Ruwiyda Jansen, Simbarashe Mabwe, Humphrey Mulenga, Roxane Herling, Ashley Veldsman, Lebohgang Makhete, Marcia Steyn, Sivuyile Buhlungu, Margareth Erasmus, Ilse Davids, Patiswa Plaatjie, Alessandro Companie, Frances Ratangee, Helen Veldtsman, Christel Petersen, Charmaine Abrahams, Miriam Moses, Xoliswa Kelepu, Yolande Gregg, Liticia Swanepoel, Nomsitho Magawu, Nompumelelo Cetywayo, Lauren Mactavie, Habibullah Valley, Elizabeth Filander, Nambitha Nqakala, Elizna Maasdorp, Justine Khoury, Belinda Kriel, Bronwyn Smith, Liesel Muller, Susanne Tonsing, Andre Loxton, Andriette Hiemstra, Petri Ahlers, Marika Flinn, Eva Chung, Michelle Chung, Alicia Sato
Journal: The Lancet Infectious Diseases (2021)

BackgroundTargeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design.MethodsAdult volunteers aged 18–59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov, NCT02735590.Findings20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25–6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3HP-treated RISK11-positive participants compared with untreated RISK11-positive participants (efficacy 7·0%, 95% CI −145 to 65).InterpretationThe RISK11 signature discriminated between individuals with prevalent tuberculosis, or progression to incident tuberculosis, and individuals who remained healthy, but provision of 3HP to signature-positive individuals after exclusion of baseline disease did not reduce progression to tuberculosis over 15 months.FundingBill and Melinda Gates Foundation, South African Medical Research Council.