Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test. Lancet Infect Dis

Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
The Lancet Infectious Diseases (Impact Factor: 22.43). 03/2013; 13(4). DOI: 10.1016/S1473-3099(13)70008-2
Source: PubMed


Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. New technologies have been developed and assessed, and are now being implemented. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers.

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    • "Therefore, larger improvements in ISTC-adherent care may be needed to identify more smear-positive TB cases and would also maximize the impact of the ongoing scale-up of the Xpert MTB/RIF assay. The 2–3 fold higher sensitivity of Xpert MTB/RIF relative to smear microscopy [16] will lead to meaningful increases in case detection only if children with TB symptoms and signs are identified and referred to testing. However, because even Xpert MTB/RIF has sub-optimal sensitivity among children and sputum collection may not be feasible in community settings, improving the quality of TB evaluation should also focus on training providers to make a diagnosis of childhood TB on clinical grounds. "
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    ABSTRACT: BackgroundImproving childhood tuberculosis (TB) evaluation and care is a global priority, but data on performance at community health centers in TB endemic regions are sparse.ObjectiveTo describe the current practices and quality of TB evaluation for children with cough ≥2 weeks' duration presenting to community health centers in Uganda.MethodsCross-sectional analysis of children (<15 years) receiving care at five Level IV community health centers in rural Uganda for any reason between 2009–2012. Quality of TB care was assessed using indicators derived from the International Standards of Tuberculosis Care (ISTC).ResultsFrom 2009–2012, 1713 of 187,601 (0.9%, 95% CI: 0.4–1.4%) children presenting to community health centers had cough ≥ 2 weeks' duration. Of those children, only 299 (17.5%, 95% CI: 15.7–19.3%) were referred for sputum microscopy, but 251 (84%, 95% CI: 79.8–88.1%) completed sputum examination if referred. The yield of sputum microscopy was only 3.6% (95% CI: 1.3–5.9%), and only 55.6% (95% CI: 21.2–86.3%) of children with acid-fast bacilli positive sputum were started on treatment. Children under age 5 were less likely to be referred for sputum examination and to receive care in accordance with ISTC. The proportion of children evaluated in accordance with ISTC increased over time (4.6% in 2009 to 27.9% in 2012, p = 0.03), though this did not result in increased case-detection.ConclusionThe quality of TB evaluation was poor for children with cough ≥2 weeks' duration presenting for health care. Referrals for sputum smear microscopy and linkage to TB treatment were key gaps in the TB evaluation process, especially for children under the age of five.
    PLoS ONE 08/2014; 9(8):e105935. DOI:10.1371/journal.pone.0105935 · 3.23 Impact Factor
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    • "Additionally, liquid culture has a considerably higher sensitivity than smear microscopy. While the limit of detection for culture in liquid media is 10–50 colony forming units/ml, samples must contain about 10,000 colony forming units/ml to be positive on smear microscopy [14]. Nevertheless liquid culture can require more days to weeks until the results are available and therefore cannot be used for rapid decision-making concerning TB-therapy. "
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    ABSTRACT: Sputum smear microscopy is widely used for tuberculosis diagnosis and treatment monitoring. We evaluated the correlation between smear microscopy and time to liquid culture positivity during early tuberculosis treatment. The study included patients with smear-positive pulmonary tuberculosis hospitalized at a tuberculosis reference centre in Germany between 01/2012 and 05/2013. Patient records were reviewed and clinical, radiological and microbiological data were analysed. Sputum samples were collected before treatment initiation and weekly thereafter. A number of 310 sputum samples from 30 patients were analysed. Time to liquid culture positivity inversely correlated with smear grade (Spearman's rho -0.439, p<0.001). There was a better correlation within the first two months vs. after two months of therapy (-0.519 vs. -0.416) with a trend to a more rapid increase in time to positivity between baseline and week 2 in patients who culture-converted within the first two months (5.9 days vs. 9.4 days, p = 0.3). In conclusion, the numbers of acid-fast bacilli in sputum smears of patients with pulmonary tuberculosis and time to culture positivity for M. tuberculosis cultures from sputum are correlated before and during tuberculosis treatment. A considerable proportion of patients with culture conversion after two months of therapy continued to have detectable acid-fast bacilli on sputum smears.
    PLoS ONE 08/2014; 9(8):e106075. DOI:10.1371/journal.pone.0106075 · 3.23 Impact Factor
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    • "It simultaneously tests for the presence of M. tuberculosis and RIF resistance. Even though this technology is having a positive impact on TB control by offering high sensitivity and reducing the time to TB diagnosis, the associated costs and infrastructural requirements (e.g. a constant power supply, machine maintenance) remain limiting for many high-burden countries [32, 33]. Hence, on-going efforts in product development focus on cheaper and simpler so-called ‘point-of-care’ diagnostics [34]. "
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    ABSTRACT: Drug-resistant tuberculosis is a growing threat to global public health. Recent efforts to understand the evolution of drug resistance have shown that changes in drug-target interactions are only the first step in a longer adaptive process. The emergence of transmissible drug-resistant Mycobacterium tuberculosis is the result of a multitude of additional genetic mutations, many of which interact, a phenomenon known as epistasis. The varied effects of these epistatic interactions include compensating for the reduction of the biological cost associated with the development of drug resistance, increasing the level of resistance, and possibly accommodating broader changes in the physiology of resistant bacteria. Knowledge of these processes and our ability to detect them as they happen informs the development of diagnostic tools and better control strategies. In particular, the use of whole genome sequencing combined with surveillance efforts in the field could provide a powerful instrument to prevent future epidemics of drug-resistant tuberculosis.
    Drugs 06/2014; 74(10). DOI:10.1007/s40265-014-0248-y · 4.34 Impact Factor
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