Tuberculosis (TB)

Next-generation Xpert® MTB/RIF Ultra assay recommended by WHO

The World Health Organization (WHO) today recommended the use in all settings of a next-generation Xpert® MTB/RIF assay (called Xpert® MTB/RIF Ultra) as a replacement for the current Xpert MTB/RIF® cartridge.

The Ultra cartridge, that has been developed by Cepheid (Sunnyvale, USA), showed significantly better performance (increased sensitivity) compared to the current Xpert® MTB/RIF cartridge for the detection of Mycobacterium tuberculosis in specimens with low numbers of bacilli, especially in smear-negative, culture-positive specimens (such as those from persons with HIV co-infection), in paediatric specimens and in extra-pulmonary specimens (notably cerebrospinal fluid). The accuracy in detection of rifampicin resistance was also better although not enough data were available to conclusively confirm this.

The recommendation on the Ultra cartridge is based on a recent WHO Expert Group evaluation of data from a study coordinated by FIND, in collaboration with the Tuberculosis Clinical Diagnostics Research Consortium (CDRC). The study compared the Ultra assay with the current Xpert® MTB/RIF assay for diagnostic accuracy and non-inferiority across 10 study sites in eight countries. 1,520 patients with signs and symptoms of TB were enrolled in these countries for a direct comparison of the performance of Ultra against Xpert MTB/RIF on the same specimen.

“Innovations in technology and the strong science behind it have brought significant breakthroughs in TB diagnosis over the last 10 years” said Dr Mario Raviglione, Director of the WHO Global TB Programme. “Achieving the targets in the WHO End TB Strategy necessitates urgent scale-up of these innovations at all levels and in all settings for early and rapid diagnosis of TB and rifampicin resistance in all persons with signs or symptoms of TB.”

About the Ultra cartridge

Changes inside the Ultra cartridge include a larger chamber for DNA amplification (ie. a larger amount of sputum is used for amplification and detection of DNA) and two additional molecular targets to detect TB. These modifications largely explain the increased sensitivity of Ultra, having improved the ability of the assay to detect low numbers of bacilli (16 bacilli per ml sputum compared to 131 per ml for Xpert® MTB/RIF).

The new Xpert® MTB/RIF Ultra cartridge can be used on the same GeneXpert® equipment (GeneXpert® instrument, computer, monitor, keypad, bar code reader) and will be available at the same concessional price of USD 9.98 for all eligible countries. Cepheid plans to have both assays available for the foreseeable future to allow countries with long regulatory cycles to continue to use their current Xpert® MTB/RIF stocks while gradually switching over to the Ultra cartridge.

The increased sensitivity of the Ultra assay is almost exclusively due to its low TB detection limit. However, similar to other diagnostic tests, the increased sensitivity is off-set by a decrease in specificity, probably as a result of well-described limitations of the reference standard (culture) used to compare the two versions of the molecular assays. Ultra may also be more prone to detecting small numbers of non-replicating or non-viable bacilli present, particularly in patients with a recent history of TB treatment, reducing the specificity of the assay. Reduced specificity may give rise to false positive results for TB detection. In the FIND-coordinated studies, such results occurred in fewer than 5% of persons with signs or symptoms suggestive of TB. Due to the internal molecular configuration of the Ultra cartridge, rifampicin resistance detection is not similarly affected.

“The improved sensitivity of the Ultra assay – especially in children and those with HIV infection – and the likely better performance of the assay for detecting rifampicin resistance without compromising accuracy, call for acceleration of universal access to testing, in line with our World TB Day theme of ending the TB epidemic by leaving no-one behind” said Dr Karin Weyer, Coordinator of the Unit for TB Laboratories, Diagnostics and Drug Resistance at the WHO GLobal TB Programme. “A balance between potential harms of overtreatment for TB and the benefits of early detection of disease in the vast majority of individuals at risk always needs to be considered. This should also serve as a reminder to always treat the patient, not only the laboratory result.”

The current WHO recommendations for the use of Xpert MTB/RIF also apply to the use of Ultra as the initial diagnostic test for all adults and children with signs and symptoms of TB. More details on the WHO Technical Expert Consultation for the use of Ultra are available in the full Meeting Report and Frequently Asked Questions (FAQs) sheet.