TB or not TB? That is the question (and here’s the test that can answer it)

Key message: Xpert® MTB/RIF is a diagnostic test which can quickly detect TB in adults with a high degree of accuracy and without the need for laboratory facilities. It can accurately detect rifampicin resistance in adults thought to have multi-drug resistant TB, allowing treatment to be started quickly. It may be useful, too, as an add-on test after smear microscopy in smear-negative patients.

Tuberculosis (TB) has been with us since ancient times and remains one of the world’s most significant infectious causes of illness and death. TB, caused by the bacterium Mycobacterium tuberculosis, is spread from person to person through the air and most commonly affects the lungs (pulmonary TB) but may affect any organ or tissue. According to the World Health Organization, in 2012 8.6 million people developed active TB for the first time and 1.3 million died of TB. Of these, 13% and 25% respectively, were also infected with HIV. Drug-resistant TB, including multidrug-resistant TB (MDR-TB), defined as resistance to at least isoniazid and rifampicin (anti-TB drugs), is a major problem.

Tuberculosis bacteria

If found and treated effectively, TB is largely curable, but many, many people remain undiagnosed. Further, fewer than 3% of those diagnosed with TB are tested to find the pattern of drug -resistance. Quickly and accurately detecting TB, including drug-resistant TB and smear-negative TB (which gives a negative result on sputum smear microscopy) is really important for improving patient outcomes. Mycobacterial culture, generally considered the best available reference standard (test) for TB diagnosis and the first step in detecting drug resistance, is a fairly complex and slow procedure, needing specialized laboratories and highly skilled staff. In 2011, WHO issued initial recommendations on a new test, the Xpert® MTB/RIF assay, that can simultaneously detect TB and rifampicin resistance within two hours (WHO Policy Xpert MTB/RIF 2011). As well as being quick, the test uses an automated process in a single, self-contained unit, the GeneXpert cartridge, which doesn’t need to be done in a laboratory.

A Cochrane review looking at the diagnostic accuracy of Xpert® MTB/RIF for pulmonary TB detection and rifampicin resistance detection in adults, first published a year ago, has just been updated to assist the WHO with guidelines on the use of this test. The addition of nine studies, bringing the total to 27, has confirmed the conclusions of the review and, amongst other additions in this version, the Summary of Findings table now includes clinical scenarios with prevalence levels recommended by WHO. All were cross-sectional studies, 16 from low- or middle-income countries, and it’s good evidence, at low risk of bias. Two important things to know about a diagnostic test are how sensitive it is – that is, how well it identifies people who have the disease of interest, and how specific – how good it is at identifying those who are free of the disease.

What did they find?

• Xpert® MTB/RIF  was highly sensitive and specific for detecting TB in adults presumed to have it (pooled sensitivity 89%, pooled specificity 99%). This was so for people with or without HIV infection
• Xpert® MTB/RIF may also be valuable as an add-on test following smear microscopy (pooled sensitivity 67%, pooled specificity 99%)
• When used as an initial test replacing phenotypic culture-based DST, Xpert® MTB/RIF provided accurate results for rifampicin resistance detection (pooled sensitivity 95%, pooled specificity 98%)
• Compared with smear microscopy, Xpert® MTB/RIF increased TB detection among culture-confirmed cases by 23%. This means in1000 patients where 10% of those with symptoms have TB, Xpert® MTB/RIF will diagnose 88 cases and miss 12 cases, whereas sputum (smear) microscopy will diagnose 65 cases and miss 35 cases
• There was no conclusive evidence supporting the impact of either specimen preparation or country income on Xpert® MTB/RIF sensitivity for TB detection
• Few Xpert® MTB/RIF results were uninterpretable

Dr Robert Koch discovered the tuberculosis bacillus in 1882

It’s great that the evidence was good quality and the reviewers had low concern about its applicability in different settings. They also draw attention to a recent randomized controlled trial (RCT) which found that Xpert® MTB/RIF run by nurses at primary care clinics had similar accuracy as when it was used by technicians in central laboratories. The review included only two studies using Xpert® MTB/RIF G4, the version in current use, but their findings suggest that G4 has comparable or increased accuracy for rifampicin resistance detection compared with earlier Xpert® MTB/RIF versions.

The studies included in this review were not the sort that would allow for the systematic evaluation of patient outcomes. Whilst time to diagnosis is greatly reduced by the use of this test, this won’t lead to better outcomes if this isn’t followed by appropriate treatment and support. The reviewers note that several RCTs have recently been completed which explore user acceptability, operational performance, and patient-important outcomes; these and other studies will need to be systematically reviewed.

What about costs? A recent analysis found that globally the use of Xpert® MTB/RIF to diagnose MDR- TB, and to diagnose TB in those living with HIV, was less than the cost of conventional diagnostics. However, in almost all countries, using Xpert® MTB/RIF in everyone with signs and symptoms of TB costs more than conventional tests. WHO has endorsed its use and Xpert® MTB/RIF is being rolled out in over 20 countries via UNITAID, with a price drop from $16.86 to $9.98 (US) per cartridge, a price that will remain in effect until 2022 (The Gates Foundation 2012; UNITAID 2012).

As we look ahead to World TB Day on 24th March, with its emphasis on reaching the three million people a year who get sick with TB but don’t get the TB services they need, it looks like the Xpert® MTB/RIF diagnostic test could be part of the solution to the challenge of achieving ‘a TB test, treatment and cure for all’.

You can follow @StopTB (the Stop TB Partnership) on Twitter for #WorldTBDay news and events and you can follow us @ukcochranecentr

Links:

Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD009593. DOI: 10.1002/14651858.CD009593.pub3.

World Health Organization. Global tuberculosis report 2013. WHO/HTM/TB/2013.11. Geneva: World Health Organization, 2013.

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, TB-NEAT Team. 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. Lancet, Early Online Publication, 28 October 2013, DOI: 10.1016/S0140-6736(13)62073-5. Available from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62073-5/fulltext

Pantoja A, Fitzpatrick C, Vassall A, Weyer K, Floyd K. Xpert MTB/RIF for diagnosis of tuberculosis and drug-resistant tuberculosis: a cost and affordability analysis. European Respiratory Journal 2013;42(3):708-20.