A novel blood test for tuberculosis prevention and treatment

Penn-Nicholson, Adam; Scriba, Thomas J.; Hatherill, Mark; White, Richard G.; Sumner, Tom

doi:10.7196/samj.2017.v107i1.12230

Cited by 8 publications

(5 citation statements)

References 9 publications

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“…Therefore, dozens of individuals would require prophylactic treatment to prevent progression to TB in a single individual (35,36). The World Health Organization recently published guidelines for an incipient TB target product profile to predict TB progression (8) in order to ensure that individuals at high risk of TB progression are not falsely excluded (7,18) but instead are referred for additional investigation for TB or offered prophylactic treatment (37). At sensitivities of 81%, 71%, 62%, and 50%, the RISK4 signature achieved specificities of 34%, 52%, 63%, and 77%, respectively, in healthy asymptomatic individuals by selection of different thresholds (Table E22).…”

Section: Discussionmentioning

confidence: 99%

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis

Suliman

Thompson

Sutherland

et al. 2018

Am J Respir Crit Care Med

210

226

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Rationale: Contacts of patients with tuberculosis (TB) constitute an important target population for preventive measures because they are at high risk of infection with Mycobacterium tuberculosis and progression to disease.Objectives: We investigated biosignatures with predictive ability for incident TB.Methods: In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, PCR, and the pair ratio algorithm in a training/test set approach. Overall, 79 progressors who developed TB between 3 and 24 months after diagnosis of index case and 328 matched nonprogressors who remained healthy during 24 months of follow-up were investigated. Measurements and Main Results:A four-transcript signature derived from samples in a South African and Gambian training set predicted progression up to two years before onset of disease in blinded test set samples from South Africa, the Gambia, and Ethiopia with little population-associated variability, and it was also validated in an external cohort of South African adolescents with latent M. tuberculosis infection. By contrast, published diagnostic or prognostic TB signatures were predicted in samples from some but not all three countries, indicating site-specific variability. Post hoc meta-analysis identified a single gene pair, C1QC/TRAV27 (complement C1q C-chain / T-cell receptor-a variable gene 27) that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events.Conclusions: Collectively, we developed a simple whole blood-based PCR test to predict TB in recently exposed household contacts from diverse African populations. This test has potential for implementation in national TB contact investigation programs.

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Section: Discussionmentioning

confidence: 99%

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis

Suliman

Thompson

Sutherland

et al. 2018

Am J Respir Crit Care Med

210

226

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“…8 We reduced this signature to 11 genes (RISK11) with equivalent performance, 9,10 to allow testing in 96-well PCR format. Zak16 and RISK11 also did well as non-sputum screening tests for prevalent, active tuberculosis in case-control studies, measured by RNA sequencing, microarray, 7,8 or microfluidic RT-qPCR. 9,10 In a 2020 systematic review and patient-level pooled meta-analysis of 17 tran scriptomic signatures for prognosis of incident tuberculosis, Zak16 was among eight signatures that achieved a positive predictive value above the WHO TPP benchmark for incipient tuberculosis tests.…”

Section: Introductionmentioning

confidence: 96%

“…6 We previously developed a 16-gene transcriptomic signature by whole blood RNA sequencing for identification of individuals at high risk of developing tuberculosis (the Zak16 signature). 7,8 Measurement of Zak16 was adapted to quantitative RT-PCR (RT-qPCR), and predictive ability for incident tuberculosis was validated in an independent longitudinal cohort of household contacts of tuberculosis patients. 8 We reduced this signature to 11 genes (RISK11) with equivalent performance, 9,10 to allow testing in 96-well PCR format.…”

Section: Introductionmentioning

confidence: 99%

Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial

Scriba¹,

Fioré-Gartland²,

Penn-Nicholson³

et al. 2021

The Lancet Infectious Diseases

109

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Summary Background Targeted 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. Methods Adult 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 . Findings 20 207 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 3H...

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“…31 Despite recent progress in identifying genomic signatures that are correlates for the risk of progression, 32 tests of either persistent disease or incipient TB are not yet commercially available, although one RNA-based polymerase chain reaction test is in clinical trial. 33 While such a test could improve targeting of infected patients, the role of changing TB determinants that change as a result of the migration pathway (e.g., nutrition) should be addressed in the evaluation of these novel tests. Based on these new diagnostic developments, a subsequent research area is to develop new treatment regimens for incipient TB.…”

Section: Operational and Implementation Research On The Patient Care mentioning

confidence: 99%

Defining a migrant-inclusive tuberculosis research agenda to end TB

Shete

Boccia

Dhavan

et al. 2018

int j tuberc lung dis

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SUMMARY BACKGROUND: Pillar 3 of the End TB Strategy calls for the promotion of research and innovation at the country level to facilitate improved implementation of existing and novel interventions to end tuberculosis (TB). In an era of increasing cross-border migration, there is a specific need to integrate migration-related issues into national TB research agendas. The objective of the present review is to provide a conceptual framework to guide countries in the development and operationalization of a migrant-inclusive TB research agenda. METHODS: We conducted a literature review, complemented by expert opinion and the previous articles in this State of the Art series, to identify important themes central to migration-related TB. We categorized these themes into a framework for a migration-inclusive global TB research agenda across a comprehensive spectrum of research. We developed this conceptual framework taking into account: 1) the biomedical, social and structural determinants of TB; 2) the epidemiologic impact of the migration pathway; and 3) the feasibility of various types of research based on a country’s capacity. DISCUSSION: The conceptual framework presented here is based on the key principle that migrants are not inherently different from other populations in terms of susceptibility to known TB determinants, but that they often have exacerbated or additional risks related to their country of origin and the migration process, which must be accounted for in developing comprehensive TB prevention and care strategies. A migrant-inclusive research agenda should systematically consider this wider context to have the highest impact.

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A novel blood test for tuberculosis prevention and treatment

Cited by 8 publications

References 9 publications

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis

Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial

Defining a migrant-inclusive tuberculosis research agenda to end TB

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