Effect of new tuberculosis diagnostic technologies on community-based intensified case finding: a multicentre randomised controlled trial

Calligaro, Greg; Zijenah, Lynn S.; Peter, Jonny; Theron, Grant; Buser, V.; McNerney, Ruth; Bara, Wilbert; Bandason, Tsitsi; Govender, Ureshnie; Tomasicchio, Michele; Smith, Liezel; Mayosi, Bongani M.; Dheda, Keertan

doi:10.1016/s1473-3099(16)30384-x

Cited by 74 publications

(53 citation statements)

References 24 publications

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“…While early generations of CE marked commercial NAATs like ProbeTec ET DTB (DTB) (Becton-Dickinson, USA) and COBAS TaqMan MTB (Roche, Switzerland) had relatively low sensitivities, more recent generations like FluoroType MTB (FT-MTB, Hain Lifescience, Germany) and Xpert MTB/RIF (XP-MTB; Cepheid, USA) have improved in this respect, but still markedly lag behind culture [8][9][10]. The cartridge-based XP-MTB additionally identifies Rif-resistance as a marker of MDR-TB [11] and has significantly ameliorated notification of TB and MDR-TB worldwide [12,13]. Now, with the launch of Abbott RealTime MTB and MTB INH/RIF (Abbott, USA), BD MAX™ MDR-TB (BD-MAX, Beckton Dickinson, USA), and Xpert MTB/Rif Ultra (XP-Ultra, Cepheid, USA) (Rif only), a new generation of closed and virtually fully automated qPCR assays detecting DNA of TB bacteria as well as Rif and/or Inh resistance markers are available which, according to the manufacturers', have sensitivities nearing that of culture [14][15][16][17].…”

mentioning

confidence: 99%

A pre-clinical validation plan to evaluate analytical sensitivities of molecular diagnostics such as BD MAX MDR-TB, Xpert MTB/Rif Ultra and FluoroType MTB

Beutler¹,

Plesnik²,

Mihalic³

et al. 2020

PLoS ONE

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Rapid diagnosis of tuberculosis (TB) and antibiotic resistances are imperative to initiate effective treatment and to stop transmission of the disease. A new generation of more sensitive, automated molecular TB diagnostic tests has been recently launched giving microbiologists more choice between several assays with the potential to detect resistance markers for rifampicin and isoniazid. In this study, we determined analytical sensitivities as 95% limits of detection (LoD 95 ) for Xpert MTB/Rif Ultra (XP-Ultra) and BD-MAX MDR-TB (BD-MAX) as two representatives of the new test generation, in comparison to the conventional Fluoro-Type MTB (FT-MTB). Test matrices used were physiological saline solution, human and a mucin-based artificial sputum (MUCAS) each spiked with Mycobacterium tuberculosis in declining culture-and qPCR-controlled concentrations. With BD-MAX, XP-Ultra, and FT-MTB, we measured LoD 95 TB values of 2.1 cfu/ml (CI 95% : 0.9-23.3), 3.1 cfu/ml (CI 95% : 1.2-88.9), and 52.1 cfu/ml (CI 95% : 16.7-664.4) in human sputum; of 6.3 cfu/ml (CI 95% : 2.9-31.8), 1.5 cfu/ml (CI 95% : 0.7-5.0), and 30.4 cfu/ml (CI 95% : 17.4-60.7) in MUCAS; and of 2.3 cfu/ml (CI 95% : 1.1-12.0), 11.5 cfu/ml (CI 95% : 5.6-47.3), and 129.1 cfu/ml (CI 95% : 82.8-273.8) in saline solution, respectively. LoD 95 of resistance markers were 9 to 48 times higher compared to LoD 95 TB . BD-MAX and XP-Ultra have an equal and significantly increased analytical sensitivity compared to conventional tests. MUCAS resembled human sputum, while both yielded significantly different results than normal saline. MUCAS proved to be suitable for quality control of PCR assays for TB diagnostics.

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mentioning

confidence: 99%

A pre-clinical validation plan to evaluate analytical sensitivities of molecular diagnostics such as BD MAX MDR-TB, Xpert MTB/Rif Ultra and FluoroType MTB

Beutler¹,

Plesnik²,

Mihalic³

et al. 2020

PLoS ONE

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“…This finding, along with the apparent effect of chest radiographs on RISK6 scores, highlights the importance of including clinical and epidemiological factors in studies of diagnostic biosignatures. Community-based case finding studies and prevalence surveys have shown that a substantial proportion of microbiologicallyconfirmed TB cases are asymptomatic [26][27][28] , highlighting the need for TB case finding in asymptomatic communities. RISK6 showed excellent diagnostic performance in differentiating is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”

Section: Discussionmentioning

confidence: 99%

“…We acknowledge that the effect of HIV was not assessed in all of the validation cohorts and more such analyses are necessary to definitively establish the effects of underlying HIV infection on RISK6 performance. Regardless, other published blood-based transcriptomic TB signatures showed reduced diagnostic performance in HIV-infected compared to uninfected persons 6,[26][27][28][29] . Since most transcriptomic TB signatures detect the elevation of ISG expression during TB, this effect of HIV is not surprising given that strong Type I IFN responses constitute the typical anti-viral response 29 .…”

Section: Discussionmentioning

confidence: 99%

RISK6, a universal 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response

Penn-Nicholson

Mbandi

Thompson

et al. 2019

Preprint

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Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts. Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood samples collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies.

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“…And yet both are imperative for TB control, and ultimately for TB elimination (3). To find infectious TB cases earlier among people with and without HIV infection requires a greater awareness of TB and HIV among people at risk, and a more active approach to TB diagnosis at home, in the community and in health facilities (18)(19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

Antiretroviral therapy is a major cause of tuberculosis decline in southern and eastern Africa

2018

Preprint

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SignificanceTuberculosis (TB) is still the leading cause of death from a single infectious agent. To cut the TB incidence rate by 80% between 2015 and 2030, in line with the WHO End TB Strategy, demands a five-fold increase in the rate of decline worldwide, from 2% to 10%/year. We find that the reduction in TB incidence rate in 12 African countries, at up to 8%/year, is due mainly to the expanded provision of antiretroviral therapy (ART) to people living with HIV, rather than to improvements in the treatment of TB infection and disease. ART should remain central to TB control where rates of TB-HIV coinfection are high, but new efforts are needed to maximize the direct benefits of treating TB infection and disease. Abstract The incidence of tuberculosis (TB) in southern and eastern Africa was driven sharply upwards during 1980s and 1990s by coinfection with Mycobacterium tuberculosis and the human immunodeficiency virus (HIV). Although drug treatments for TB infection (isoniazid preventive therapy) and disease (combinations of TB drugs) can reduce TB incidence if implemented effectively, we find that antiretroviral therapy (ART) given to people with HIV infection was strongly and systematically associated with the accelerated decline of TB in 12 of the worst affected African countries between 2003 and 2016.Inferring that ART was a significant cause of TB decline, ART prevented approximately 1.88 ± 0.23 million HIV-positive TB cases, or 15.7 ± 1.9 percent of the total number expected. There is no evidence that drug treatment of TB infection (IPT) or disease (combination chemotherapy) played more than a minor role in accelerating TB decline after 2003. In these 12 countries, over the period 2003-16, ART made a major contribution towards achieving international targets for the reduction of TB incidence.

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Effect of new tuberculosis diagnostic technologies on community-based intensified case finding: a multicentre randomised controlled trial

Cited by 74 publications

References 24 publications

A pre-clinical validation plan to evaluate analytical sensitivities of molecular diagnostics such as BD MAX MDR-TB, Xpert MTB/Rif Ultra and FluoroType MTB

A pre-clinical validation plan to evaluate analytical sensitivities of molecular diagnostics such as BD MAX MDR-TB, Xpert MTB/Rif Ultra and FluoroType MTB

RISK6, a universal 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response

Antiretroviral therapy is a major cause of tuberculosis decline in southern and eastern Africa

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