Rapid molecular TB diagnosis: evidence, policy making and global implementation of Xpert MTB/RIF.

If tuberculosis (TB) is to be eliminated as a global health problem in the foreseeable future, improved detection of patients, earlier diagnosis and timely identification of rifampicin resistance will be critical. New diagnostics released in recent years have improved this perspective but they require investments in laboratory infrastructure, biosafety and staff specialisation beyond the means of many resource-constrained settings where most patients live. Xpert MTB/RIF, a new assay employing automated nucleic acid amplification to detect Mycobacterium tuberculosis, as well as mutations that confer rifampicin resistance, holds the promise to largely overcome these operational challenges. In this article we position Xpert MTB/RIF in today's TB diagnostic landscape and describe its additional potential as an adjunct to surveillance and surveys, taking into account considerations of pricing and ethics. In what could serve as a model for the future formulation of new policy on diagnostics, we trace the unique process by which the World Health Organization consulted international expertise and systematically assessed published evidence and freshly emerging experience from the field ahead of its endorsement of the Xpert MTB/RIF technology in 2010, summarise subsequent research findings and guidance on who to test and how, and provide perspectives on scaling up the new technology.

Effectiveness of Xpert MTB/RIF and the Line Probe Assay tests for the rapid detection of drug-resistant tuberculosis in the Central African Republic.

The Xpert MTB/RIF and Line Probe Assay (LPA) tests are more and more frequently used in mycobacteria testing laboratories for the rapid diagnosis of multi-drug resistance (MDR-TB). In this study, we demonstrate the effectiveness of these tests in the Central African Republic. Rifampicin resistance cases detected by the Xpert MTB/RIF during the year 2020 are also underwent first- and second-line LPA, and a first-line of drug susceptibility testing (DST) on solid medium and we compared these results. 101 rifampicin resistance cases based on the Xpert MTB/RIF were detected. Mean age was 34 years [16-81]. The 20-40 years age group represented 73.2% and the male-to-female sex ratio was 1.9:1. Patient profiles were dominated by treatment failure cases (40.6%) followed by relapsed cases (30.7%) and new cases (18.8%). These 101 rifampicin resistance were also detected with the first-line LPA and were confirmed by the DST. Similarly, the isoniazid results obtained with the first-line LPA, were confirmed by the DST, giving a concordance of 100% for these antibiotics. Rifampicin resistance were for the most part due to the absence of the WT8 sequence (56%) and the presence of the Mut3 mutation (53.4%). The majority of the isoniazid resistance (94.2%) were due to the Mut1 mutation in the katG gene and 4.2% of the cases involved both the katG gene and the inhA gene promoter with the Mut1 mutation. The second-line LPA test no resistance to second-line antibiotics. This study demonstrated the effectiveness of the Xpert MTB/RIF and the LPA tests for the rapid diagnosis of MDR-TB in the Central African Republic. However, due to their high cost, these tests have not been extensively deployed in the country. Public authorities and their TB-partners can help make these molecular tests more accessible to fight MDR-TB in the country.

Discordance of the Repeat GeneXpert MTB/RIF Test for Rifampicin Resistance Detection Among Patients Initiating MDR-TB Treatment in Uganda.

BACKGROUND: The Global Laboratory Initiative (GLI) guidelines recommend repeat for GeneXpertMTB/RIF (XpertMTB/RIF) in patients with a low pretest probability of rifampicin resistance (RR). METHODS: This was a cross-sectional study using results of sputum specimens collected from participants screened for the STREAM 2 trial. We recruited all patients with XpertMTB/RIF RR-TB detected who were referred for RR/multidrug-resistant (MDR) TB treatment initiation at Mulago National Referral Hospital, Kampala, between September 2017 and October 2019. At baseline, smear microscopy, repeat XpertMTB/RIF, Xpert Ultra, and MTBDRplus assays were done on sputum specimens. Culture-based drug susceptibility testing (DST) was performed on discordant specimens. We analyzed the prevalence and factors associated with discordance between initial and repeat XpertMTB/RIF RR and false XpertMTB/RIF RR. False XpertMTB/RIF RR was defined as no RR detected by any of Xpert Ultra, LPA, or culture DST (reference comparator). RESULTS: A total of 126/130 patients had repeat XpertMTB/RIF results, of whom 97 (77.0%) had M. tuberculosis detected, 81 (83.5%) had RR detected, and 1 (1.0%) had RR indeterminate. The prevalence of discordant XpertMTB/RIF RR was 15/96 (15.6%), whereas false XpertMTB/RIF RR prevalence was 10/96 (10.4%).Low-bacillary load sputum specimens were more likely to have discordant XpertMTB/RIF RR and false XpertMTB/RIF RR results (adjusted odds ratio [aOR], 0.04; 95% CI, 0.00-0.37; P = .01; aOR, 0.02; 95% CI, 0.01-0.35; P = .01, respectively). CONCLUSIONS: Our findings show a high false-positive rifampicin resistance rate in low-TB burden patients, which calls for repeat testing in order to prevent unnecessary prescription of anti-MDR-TB therapy.

Implementation of quality management systems and progress towards accreditation of National Tuberculosis Reference Laboratories in Africa.

BACKGROUND: Laboratory services are essential at all stages of the tuberculosis care cascade, from diagnosis and drug resistance testing to monitoring response to treatment. Enabling access to quality services is a challenge in low-resource settings. Implementation of a strong quality management system (QMS) and laboratory accreditation are key to improving patient care. OBJECTIVES: The study objective was to determine the status of QMS implementation and progress towards accreditation of National Tuberculosis Reference Laboratories (NTRLs) in the African Region. METHOD: An online questionnaire was administered to NTRL managers in 47 World Health Organization Regional Office for Africa member states in the region, between February and April 2015, regarding the knowledge of QMS tools and progress toward implementation to inform strategies for tuberculosis diagnostic services strengthening in the region. RESULTS: A total of 21 laboratories (43.0%) had received SLMTA/TB-SLMTA training, of which 10 had also used the Global Laboratory Initiative accreditation tool. However, only 36.7% of NTRLs had received a laboratory audit, a first step in quality improvement. Most NTRLs participated in acid-fast bacilli microscopy external quality assurance (95.8%), although external quality assurance for other techniques was lower (60.4% for first-line drug susceptibility testing, 25.0% for second-line drug susceptibility testing, and 22.9% for molecular testing). Barriers to accreditation included lack of training and accreditation programmes. Only 28.6% of NTRLs had developed strategic plans and budgets which included accreditation. CONCLUSION: Good foundations are in place on the continent from which to scale up accreditation efforts. Laboratory audits should be conducted as a first step in developing quality improvement action plans. Political commitment and strong leadership are needed to drive accreditation efforts; advocacy will require clear evidence of patient impact and cost-benefit.