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Professor
Grant Theron

South Africa

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Profile EDCTP Fellowship 1

Project Title

What is the feasibility, accuracy, and optimal manner in which next-generation tests for tuberculosis can be used in high-burden setting? (The OPTIMAL DIAGNOSIS study)

Project Objectives

To evaluate the point-of-care feasibility, accuracy and effectiveness of highly sensitive, next-generation diagnostics for the diagnosis of pulmonary TB, extra-pulmonary TB, and drug-resistant TB, whilst assembling a comprehensive, well-characterised biobank for the future research, training, and capacity development.

Results & Outcomes

The OPTIMAL DIAGNOSIS study (https://bit.ly/2X0k8rq) is a package of sub-studies in Cape Town, South Africa, that will advance the diagnosis of pulmonary TB, drug-resistant TB, and extra-pulmonary TB. It also aims to train a new generation of TB diagnostic researchers based in Africa and, importantly, make the specimens and meta-data available for their training and scientific projects. These studies evaluate new tests on traditional and novel specimens with a view to generate evidence for optimisation, use, and eventual adoption. In its fifth year, the study has continued to leverage the three new recruitment and point-of-care laboratory sites in Cape Town that it helped establish to finish recruitment and bring data closer to publication. This infrastructure has resulted in the recruitment of hundreds of patients with and without HIV (many of whom, despite not having symptoms, are diagnosed with TB), extra-pulmonary TB (via Tygerberg General Hospital), or drug-resistant TB (via a partnership with the National Health and Laboratory Service). All these patients have given specimens to the biorepository. This activity has already resulted in important scientific findings. This includes detailing large specificity decrements for Xpert Ultra (a new TB test) in patients with previous TB and how sensitivity increments over the previous generation Xpert are likely small in some populations but not higher in patients with earlier stage disease. This has already contributed to policy changes in South Africa and the World Health Organization. We have also generated important data showing that Xpert Ultra represents a new diagnostic standard of care for extrapulmonary TB and that the MTBDRsl version 2 line probe assay should be done directly even on smear-negative specimens.

Host Organisation

Department Institution Country
TB Unit Stellenbosch University (SU) ZA

EDCTP Project

TMA2015SF1041

EDCTP Program

EDCTP2

EDCTP Project Call

Senior Fellowship (SF)

Study Design

Diagnostic evaluation

Project Summary

Tuberculosis kills ~1.4 million people annually and is a leading cause of death in sub-Saharan Africa. Sensitive and rapid point-of-care tests are expected to substantially reduce TB incidence and mortality, however, until recently, tests that meet these criteria are yet to become available. We propose a package of novel diagnostic studies to build local capacity and evaluate the feasibility, accuracy, and effectiveness of new, ultra-sensitive point-of-care tests for TB and drug-resistance in our high-burden, high HIV setting of Cape Town, South Africa. Firstly, we will evaluate the accuracy and impact of Xpert Ultra (using the Omni system) and AlereQ TB testing for pulmonary TB at the point-of-care in clinics (n=360 patients). These tests, which likely have sensitivity equivalent to a culture, may have utility in patients with few or no symptoms (~1 in 5 TB cases are missed by screening algorithms). We will evaluate the utility of new screening tools, such as automated digital chest radiography, which may reduce costs and inform the optimal use and scale-up of new molecular tests. In the second sub-study, we will, in collaboration with clinician-scientists, evaluate the accuracy and impact of Xpert Ultra and AlereQ TB for extra-pulmonary TB (pleural, cerebral spinal, and pericardial fluid; n=430 in total) compared to Xpert MTB/RIF at a major tertiary-level hospital, and examine whether they obviate the need for routinely performed tests. In the third sub-study, we will evaluate the accuracy and impact (time-to-diagnosis, time-to-treatment) of next-generation tests (MTBDRsl v2.0, Xpert XDR) for second-line drug resistance on sputum, by accessing samples from a high throughput routine laboratory (n=960). Unlike current diagnostics for second-line resistance, these tests may be done directly on specimens, and thereby reduce patient attrition and delay associated with methods that require mycobacterial culture. The fourth component is the creation of a well-characterised sample biobank from each sub-study (sputum, isolates, serum, urine, pleural fluid, cerebral spinal fluid, pericardial fluid) to serve as a platform for future research (e.g., evaluation of emerging diagnostic technologies, biomarker discovery) and student training. At least three postgraduate students will train as part of this project. In addition to novel data on the accuracy and potential impact of new point-of-care tests for TB, this project will inform on how they can be optimally used (e.g., with automated digital chest radiography). This project addresses one of the most devastating poverty-associated diseases in Africa and has excellent fit with the objectives of EDCTP2.