World Tuberculosis Day 2014: Reaching the missing 3 million

24 March 2014

Every year 9 million people contract tuberculosis (TB). Of these nine million people, approximately 3 million are “missed” by public health systems. We must find, treat, track and cure them. We must aggressively scale up effective TB interventions and improve access to health care. Investment in research for better tools – diagnostics, drugs and vaccines is necessary. EDCTP supports these goals through its funding of clinical research to develop these tools. An essential step in finding and treating all ‘missing’ patients is accurate, fast and affordable diagnostic tools.

The need for TB diagnostics

The necessity for new and improved diagnostics for TB, as well as the need to evaluate the implementation of diagnostics in real-life settings was emphasised at several of the EDCTP stakeholder meetings, especially in Paris in 2008 and 2013.

The 2008 Paris meeting resulted in an EDCTP call for proposals on TB diagnostics (2009), which prioritised research regarding diagnostic products that could be used as point-of-care tools and tests specifically suitable for making accurate diagnoses in children. Three major clinical trials of diagnostic tools, TB-NEAT, AE-TBC and TB-CHILD, received funding totalling almost 10 million euros.

A new series of stakeholder meetings was organised in preparation for the second EDCTP programme (EDCTP2), including one on TB and other mycobacterial infections in Paris on 28-29 October 2013. EDCTP was encouraged again to fund clinical research of TB diagnostics as there are still gaps in available tools within the following areas: point-of-care diagnostics, tools targeting specific patient populations, including children, and non-sputum tests.

For the second EDCTP programme, diagnostics is recognised as an important component of the portfolio, with improved case detection crucial for the rational use of drugs within over-stretched health services in resource-limited settings. The EDCTP2 Strategic Business Plan sets out an ambitious target to support trials of five new or improved diagnostics.

Results from EDCTP-funded studies on TB diagnostics

The majority of EDCTP’s 13 diagnostics studies focus on tuberculosis, with several testing the performance of the point-of-care Xpert MTB/RIF test for tuberculosis.

Research carried out under Professor Mark Nicol’s EDCTP Senior Fellowship contributed to the evaluation trial that showed that Xpert MTB/RIF test can be used effectively in low-resource settings to simplify patients’ access to early and accurate diagnosis. The trial findings informed the WHO recommendation that Xpert MTB/RIF should be used as the initial diagnostic test in individuals suspected of MDR-TB or HIV-associated TB.

TB-NEAT
Since the WHO recommendation, Xpert MTB/RIF test for tuberculosis is being rolled out in many countries. Professor Keertan Dheda’s EDCTP project (TB-NEAT) has been gathering evidence on the implementation of Xpert MTB/RIF and its impact on tuberculosis-related morbidity. A recent, high-profile publication by Prof Dheda’s group reported on the assessment of the feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing at primary-care health-care facilities in southern Africa.

TB-NEAT: TB diagnostics in low-resource settings

The findings indicated that ‘Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. However, the benefits did not translate into lower tuberculosis-related morbidity’ 1). A commentary on this publication concluded that ‘the substantial financial burden of Xpert MTB/RIF rollout needs to be reassessed to see if it provides value for the cost’ 2).

AE-TBC
Professor Gerhard Walzl’s EDCTP project (AE-TBC) also addressed the need for additional rapid point-of-care TB diagnostics, aiming to utilize immunological signatures detected within a patient’s blood to diagnose active tuberculosis infections with 24h. This study ended on 15 December 2013, and the outcomes of this study are expected soon. Diagnosis of tuberculosis in children remains a significant challenge.

TB-CHILD
The TB CHILD project, led by Dr Fred I. Lwilla, evaluated 10 new diagnostic platforms in adults and children. The group recently presented their preliminary findings at the 44th World Conference on Lung Health held in Paris in November 2013. Results from three diagnostic approaches were presented 3). The most promising results came from their biomarker work (IP-10) and a novel immune-based test called TAM-IGRA.

The group found that IP-10 can be detected in children’s urine who have lung disease. The ease of collecting urine samples as opposed to children producing sputum gives the IP-10 test a significant advantage. Tam-IGRA, a novel immune-based test with diagnostic turn-around time of 24h, was able to differentiate latent versus active TB in symptomless children – offering the hope of improved and rapid diagnosis of paediatric TB.

EDCTP’s continued commitment to TB diagnostics development

Ongoing EDCTP-funded projects on TB diagnostics include three of the recently awarded Strategic Primer Grants, PROMISE-TB, NEAT-MDRTB and MBMAMS. These three studies all address different gaps in TB diagnostics:

  • PROMISE-TB, led by Professor Philippe van de Perre (University of Montpellier 1, France), targets the challenge of diagnosing TB in young children and is an early evaluation study investigating the utility of novel immunological assays for accurate diagnoses in this patient population.
  • Addressing the increasing incidence of drug resistant TB, Professor Luis E. Cuevas (Liverpool School of Tropical Medicine, United Kingdom) conducts NEAT-MDRTB, an evaluation study addressing the need for new and improved point-of-care TB diagnostics, including those that can detect and monitor drug resistant TB.
  • MBMAMS, which is led by Professor Stephen Gillespie (University of St Andrews, United Kingdom), aims to identify novel biomarkers which may simplify TB diagnosis.

References

  • Theron G, Zijenah L, Chanda D, Clowes P, Rachow A, Lesosky M, Bara W, Mungofa S, Pai M, Hoelscher M, Dowdy D, Pym A, Mwaba P, Mason P, Peter J, Dheda K (2014). Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial. The Lancet Vol. 383:424-435
  • Weijse, C (2014) Point-of-care diagnostics for tuberculosis elimination? The Lancet Vol 383: 388-390
  • 44th Union World Conference on Lung Health, Abstract Book, S56, K. Reither et al. Diagnostic methods for childhood tuberculosis: an update from the TB CHILD study