Researchers from the South African Tuberculosis Vaccine Initiative at the University of Cape Town, the Aurum Institute, the Centre for the AIDS Programme of Research in South Africa, Stellenbosch University, the London School of Hygiene and Tropical Medicine and the Fred Hutchinson Cancer Research Centre have published the results from a study of a blood-based RNA biomarker which tested diagnostic and prognostic performance for tuberculosis (TB) in people living with HIV.
Almost a quarter of the world’s population is estimated to be infected with the bacterium (M. tuberculosis) responsible for TB disease. Importantly, only 5-10% of people with the infection are at risk of progression to TB disease and would benefit from antibiotic treatment. Existing tests for M. tuberculosis infection (the tuberculin skin test [TST] or interferon gamma release assay [IGRA]) would result in considerable over-treatment with preventive therapy.
Traditional TB symptom screening would miss the majority of undiagnosed TB in people living with HIV in community settings, as the majority of early TB is asymptomatic. The repercussions of a missed TB diagnosis in people living with HIV are potentially catastrophic: severe illness, hospitalisation, long-term lung damage, and death. A delayed diagnosis could also potentially allow onward transmission of TB to family members and close contacts.
This publication advances the development of a point-of care blood test with which health practitioners could accurately identify people at risk of TB disease, who would then require confirmatory diagnostic testing and treatment, or others who are likely to progress from M. tuberculosis infection to active TB disease and make it possible to apply available TB preventive antibiotic regimens selectively to those who are most likely to benefit in communities. The research team set out to test the diagnostic and prognostic performance of a blood-based RNA biomarker of TB risk (RISK11) in people living with HIV.
The study was conducted between 2017 and 2019 across five distinct geographic communities across South Africa.
A total of 861 adults living with HIV from communities in Worcester, Ravensmead, Durban, Klerksdorp, and Rustenberg were screened for participation. All participants were intensively tested for TB at baseline, if symptomatic during the 15-months of follow up, and again at the end of the study. More than 70% of detected TB cases did not have any symptom compatible with TB disease and would not have been detected by current TB screening strategies, which require symptoms as the entry point to investigation.
The RISK11 blood test differentiated between individuals with current TB disease or those who would progress to incident TB within 15 months after testing, and individuals who remained healthy, with excellent performance.
The risk of current TB was 13-times higher in those with a positive RISK11 test versus a negative RISK11 test, and the risk of developing TB within 15 months of testing was 16-times higher in those with a positive RISK11 test versus a negative RISK11 test.
The recorded performance of RISK11 as a screening test for active disease in people living with HIV with TB symptoms exceeds the World Health Organisation requirements for a triage test. Diagnostic performance in asymptomatic participants also approached these requirements.
The RISK11 signature was able to predict TB disease progression within 15 months of testing in this trial population with prognostic performance approaching, but not meeting, the WHO requirements for a TB prognostic test.
Current South African guidelines advocate 12 months of universal isoniazid preventive therapy for people living with HIV who have not yet received TB preventive therapy, irrespective of M. tuberculosis infection status. This study suggests that an RNA biomarker of TB risk, such as RISK11, might be more specific in determining need for targeted preventive therapy for people living with HIV.
Two-thirds of the 38m people living with HIV worldwide are on antiretroviral therapy and, with the advent of well tolerated and effective short-course TB preventive regimens, annual or semi-annual community-based testing of people living with HIV might be useful to monitor risk of progression to TB and target those likely to benefit from repeat courses of preventive therapy.
This study was funded by the Bill & Melinda Gates Foundation and the South African Medical Research Council.
Comments from research study leaders
Professor Mark Hatherill, principal investigator of the study, said: “These results bring us one step closer to a TB blood test for use at point of care to guide curative and preventive TB therapy for people living with HIV”.
Professor Tom Scriba, laboratory director of the South African Tuberculosis Vaccine Initiative, where the test was developed, commented that: “These promising results are similar to those seen in a trial of the RISK11 biomarker in HIV-uninfected persons. They highlight the importance of finding people with undiagnosed, subclinical TB.”
Professor Gavin Churchyard, group CEO, The Aurum Institute said that “the ability to identify people living with HIV that are at high risk of developing active TB disease that may benefit from TB preventive treatment is a major scientific advance.”
Professor Kogie Naidoo, study co-investigator at the CAPRISA site, said: “TB remains the leading cause of death among people living with HIV/AIDS. These results bring hope for more efficient diagnosis of current active TB, and for detection of those at heightened risk of progression to active TB disease, thereby enabling effective patient triage to TB treatment or prevention.”
Study details
Validation of a host blood transcriptomic biomarker for pulmonary tuberculosis in people living with HIV: a prospective diagnostic and prognostic accuracy study
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, on behalf of the CORTIS-HR Study Team
Published in The Lancet Global Health on 13 April 2021
Abstract
Background
A 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.
Methods
In 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.
Findings
Between 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.
Interpretation
RISK11 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.