Background
Accurate, rapid detection of tuberculosis (TB) and TB drug resistance is critical for improving patient care and decreasing TB transmission. Xpert® MTB/RIF assay is an automated test that can detect both TB and rifampicin resistance, generally within two hours after starting the test, with minimal hands-on technical time. The World Health Organization (WHO) issued initial recommendations on Xpert® MTB/RIF in early 2011. A Cochrane Review on the diagnostic accuracy of Xpert® MTB/RIF for pulmonary TB and rifampicin resistance was published January 2013. We performed this updated Cochrane Review as part of a WHO process to develop updated guidelines on the use of the test.

Objectives
To assess the diagnostic accuracy of Xpert® MTB/RIF for pulmonary TB (TB detection), where Xpert® MTB/RIF was used as both an initial test replacing microscopy and an add-on test following a negative smear microscopy result.

To assess the diagnostic accuracy of Xpert® MTB/RIF for rifampicin resistance detection, where Xpert® MTB/RIF was used as the initial test replacing culture-based drug susceptibility testing (DST).

The populations of interest were adults presumed to have pulmonary, rifampicin-resistant or multidrug-resistant TB (MDR-TB), with or without HIV infection. The settings of interest were intermediate- and peripheral-level laboratories. The latter may be associated with primary health care facilities.

Search methods
We searched for publications in any language up to 7 February 2013 in the following databases: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; ISI Web of Knowledge; MEDION; LILACS; BIOSIS; and SCOPUS. We also searched the metaRegister of Controlled Trials (mRCT) and the search portal of the WHO International Clinical Trials Registry Platform to identify ongoing trials.

Selection criteria
We included randomized controlled trials, cross-sectional studies, and cohort studies using respiratory specimens that allowed for extraction of data evaluating Xpert® MTB/RIF against the reference standard. We excluded gastric fluid specimens. The reference standard for TB was culture and for rifampicin resistance was phenotypic culture-based DST.

Data collection and analysis
For each study, two review authors independently extracted data using a standardized form. When possible, we extracted data for subgroups by smear and HIV status. We assessed the quality of studies using QUADAS-2 and carried out meta-analyses to estimate pooled sensitivity and specificity of Xpert® MTB/RIF separately for TB detection and rifampicin resistance detection. For TB detection, we performed the majority of analyses using a bivariate random-effects model and compared the sensitivity of Xpert® MTB/RIF and smear microscopy against culture as reference standard. For rifampicin resistance detection, we undertook univariate meta-analyses for sensitivity and specificity separately to include studies in which no rifampicin resistance was detected.

Main results
We included 27 unique studies (integrating nine new studies) involving 9557 participants. Sixteen studies (59%) were performed in low- or middle-income countries. For all QUADAS-2 domains, most studies were at low risk of bias and low concern regarding applicability.

As an initial test replacing smear microscopy, Xpert® MTB/RIF pooled sensitivity was 89% [95% Credible Interval (CrI) 85% to 92%] and pooled specificity 99% (95% CrI 98% to 99%), (22 studies, 8998 participants: 2953 confirmed TB, 6045 non-TB).
As an add-on test following a negative smear microscopy result, Xpert®MTB/RIF pooled sensitivity was 67% (95% CrI 60% to 74%) and pooled specificity 99% (95% CrI 98% to 99%; 21 studies, 6950 participants).

For smear-positive, culture-positive TB, Xpert® MTB/RIF pooled sensitivity was 98% (95% CrI 97% to 99%; 21 studies, 1936 participants).

For people with HIV infection, Xpert® MTB/RIF pooled sensitivity was 79% (95% CrI 70% to 86%; seven studies, 1789 participants), and for people without HIV infection, it was 86% (95% CrI 76% to 92%; seven studies, 1470 participants).

Among 180 specimens with nontuberculous mycobacteria (NTM), Xpert® MTB/RIF was positive in only one specimen that grew NTM (14 studies, 2626 participants).

Comparison with smear microscopy

In comparison with smear microscopy, Xpert® MTB/RIF increased TB detection among culture-confirmed cases by 23% (95% CrI 15% to 32%; 21 studies, 8880 participants).

For TB detection, if pooled sensitivity estimates for Xpert® MTB/RIF and smear microscopy are applied to a hypothetical cohort of 1000 patients where 10% of those with symptoms have TB, Xpert® MTB/RIF will diagnose 88 cases and miss 12 cases, whereas sputum microscopy will diagnose 65 cases and miss 35 cases.

Rifampicin resistance

For rifampicin resistance detection, Xpert® MTB/RIF pooled sensitivity was 95% (95% CrI 90% to 97%; 17 studies, 555 rifampicin resistance positives) and pooled specificity was 98% (95% CrI 97% to 99%; 24 studies, 2411 rifampicin resistance negatives).

For rifampicin resistance detection, if the pooled accuracy estimates for Xpert® MTB/RIF are applied to a hypothetical cohort of 1000 individuals where 15% of those with symptoms are rifampicin resistant, Xpert® MTB/RIF would correctly identify 143 individuals as rifampicin resistant and miss eight cases, and correctly identify 833 individuals as rifampicin susceptible and misclassify 17 individuals as resistant. Where 5% of those with symptoms are rifampicin resistant, Xpert® MTB/RIF would correctly identify 48 individuals as rifampicin resistant and miss three cases and correctly identify 931 individuals as rifampicin susceptible and misclassify 19 individuals as resistant.

Authors' conclusions
In adults thought to have TB, with or without HIV infection, Xpert® MTB/RIF is sensitive and specific. Compared with smear microscopy, Xpert® MTB/RIF substantially increases TB detection among culture-confirmed cases. Xpert® MTB/RIF has higher sensitivity for TB detection in smear-positive than smear-negative patients. Nonetheless, this test may be valuable as an add-on test following smear microscopy in patients previously found to be smear-negative. For rifampicin resistance detection, Xpert® MTB/RIF provides accurate results and can allow rapid initiation of MDR-TB treatment, pending results from conventional culture and DST. The tests are expensive, so current research evaluating the use of Xpert® MTB/RIF in TB programmes in high TB burden settings will help evaluate how this investment may help start treatment promptly and improve outcomes.

/pdf/xpert-mtb-rif-assay-for-pulmonary-tuberculosis-and-1ruthojy6l.pdf

Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

/pdf/official-american-thoracic-society-centers-for-disease-58jzocxv6d.pdf

Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

Summary The aim of diagnostic point-of-care testing is to minimise the time to obtain a test result, thereby allowing clinicians and patients to make a quick clinical decision. Because point-of-care tests are used in resource-limited settings, the benefits need to outweigh the costs. To optimise point-of-care testing in resource-limited settings, diagnostic tests need rigorous assessments focused on relevant clinical outcomes and operational costs, which differ from assessments of conventional diagnostic tests. We reviewed published studies on point-of-care testing in resource-limited settings, and found no clearly defined metric for the clinical usefulness of point-of-care testing. Therefore, we propose a framework for the assessment of point-of-care tests, and suggest and define the term test efficacy to describe the ability of a diagnostic test to support a clinical decision within its operational context. We also propose revised criteria for an ideal diagnostic point-of-care test in resource-limited settings. Through systematic assessments, comparisons between centralised testing and novel point-of-care technologies can be more formalised, and health officials can better establish which point-of-care technologies represent valuable additions to their clinical programmes.

/pdf/diagnostic-point-of-care-tests-in-resource-limited-settings-17a86851cu.pdf

Diagnostic point-of-care tests in resource-limited settings

Madhukar Pai and colleagues discuss a framework for envisioning how point-of-care testing can be applied to infectious diseases in low- and middle-income countries.

/pdf/point-of-care-testing-for-infectious-diseases-diversity-oz200eb220.pdf

Point-of-care testing for infectious diseases: diversity, complexity, and barriers in low- and middle-income countries.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(11)60358-9.pdf

Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(11)60438-8.pdf

Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study

Background: Simultaneous use of genotypic and phenotypic diagnostic tools for detection of rifampicin (RIF) susceptibility may yield discrepant results. Objective: To measure the discordance between the RIF-susceptibility results by Xpert MTB/RIF and Mycobacterium Growth Indicator Tube (MGIT), to evaluate if application of both tests to the same sample affects the discrepancy, and to evaluate treatment outcome in patients with the discordant strains. Design: Sputa from patients with tuberculosis managed in the penitentiary system of Azerbaijan during 2011–2015 were examined for RIF susceptibility using Xpert MTB/RIF and MGIT. Strains with discrepant results were sequenced. Results: Of 532 patients included, 6.2% had discordant RIF-susceptibility results. No significant association of the discordant RIF-susceptibility results with application of both tests on one sample versus sequential samples was found. L511P mutation accounted significantly (p = 0.006) for the discrepancy among those RIF resistant on X...

Mitigation of Discordant Rifampicin-Susceptibility Results Obtained by Xpert Mycobacterium tuberculosis/Rifampicin and Mycobacterium Growth Indicator Tube

Purpose of review The tide of HIV, hepatitis C virus (HCV) and drug-resistant tuberculosis (TB) is a challenge for the penitentiary system in Eastern Europe Central Asia (EECA) region. We have analyzed the existing services for incarcerated individuals with HIV, HCV and TB to assess the current situation in the EECA region. Recent findings Because of the current criminal-legal system, key risk population with strong linkage to the blood-borne and airborne infections has a high proportion among prisoners. Management of these diseases includes a set of services, such as early detection, counseling, testing and treatment, prevention, harm reduction programme, wide educational and information efforts, and organization of continuity care after release. WHO has developed a set of targets, the only precise achievement of which will reduce the burden of these infections and eliminate them as a public health problem. Summary It is necessary to closely monitor the delivery of HIV, HCV and TB care services in penitentiary system of the EECA countries. The comprehensive operational research will help to develop the most effective practices allowing to achieve the care provision for the entire contingent of the penitentiary system and its continuity in the civil sector. Sustainable and sufficient funding is required as well as enough attention to ensure healthcare services at an appropriate level in the penitentiary system.

HIV/tuberculosis/hepatitis C virus services for incarcerated populations in Azerbaijan and the Eastern Europe Central Asia region.

XpertMTB/RIF is a rapid molecular diagnostic tool detecting MTB and RIF-susceptibility within two hours. However, indeterminate RIF-susceptibility results occur and cause uncertainty about clinical judgment. Objective: To evaluate the level of indeterminate RIF-susceptibility results by XpertMTB/RIF, to assess the RIF-susceptibility of such strains and to determine the method that should be used for reference. Methods: Sputum from patients with TB diagnosed in Azerbaijan prisons during 2013-2015 were directly examined by XpertMTB/RIF. Strains with indeterminate RIF-susceptibility results were examined with MGIT-based DST and rpoB sequencing. For comparison, frozen MGIT cultures collected from other TB patients at diagnosis during 2010-2012 were revived and examined with XpertMTB/RIF retrospectively. Results: Of 275 samples examined with XpertMTB/RIF directly and of 232 revived cultures examined retrospectively, 8(2.9%) and 0 had indeterminate RIF-susceptibility results, respectively (p=0.009). MGIT results indicated full concordance with sequencing among the samples showing indeterminate RIF-susceptibility results by XpertMTB/RIF.
 Conclusion: The indeterminate RIF-susceptibility detected on sputum samples directly by XpertMTB/RIF is significant. However, this drawback may be resolved with the use of Xpert MTB/RIF on cultures. MGIT may be referred to in cases of indeterminate RIF-susceptibility by XpertMTB/RIF.

Rafail Mehdiyev

Papers

Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study

Mitigation of Discordant Rifampicin-Susceptibility Results Obtained by Xpert Mycobacterium tuberculosis/Rifampicin and Mycobacterium Growth Indicator Tube

HIV/tuberculosis/hepatitis C virus services for incarcerated populations in Azerbaijan and the Eastern Europe Central Asia region.

Interpretation of indeterminate RIF-susceptibility results obtained by rapid molecular diagnostics test