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Meta-Analysis
. 2022 May 18;5(5):CD014841.
doi: 10.1002/14651858.CD014841.pub2.

Xpert MTB/XDR for detection of pulmonary tuberculosis and resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin

Samantha Pillay #  1 , Karen R Steingart #  2 , Geraint R Davies  3 , Marty Chaplin  4 , Margaretha De Vos  5 , Samuel G Schumacher  5 , Rob Warren  1 , Grant Theron  1
Affiliations
Meta-Analysis

Xpert MTB/XDR for detection of pulmonary tuberculosis and resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin

Samantha Pillay et al. Cochrane Database Syst Rev. .

Abstract

Background: The World Health Organization (WHO) End TB Strategy stresses universal access to drug susceptibility testing (DST). DST determines whether Mycobacterium tuberculosis bacteria are susceptible or resistant to drugs. Xpert MTB/XDR is a rapid nucleic acid amplification test for detection of tuberculosis and drug resistance in one test suitable for use in peripheral and intermediate level laboratories. In specimens where tuberculosis is detected by Xpert MTB/XDR, Xpert MTB/XDR can also detect resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin.

Objectives: To assess the diagnostic accuracy of Xpert MTB/XDR for pulmonary tuberculosis in people with presumptive pulmonary tuberculosis (having signs and symptoms suggestive of tuberculosis, including cough, fever, weight loss, night sweats). To assess the diagnostic accuracy of Xpert MTB/XDR for resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin in people with tuberculosis detected by Xpert MTB/XDR, irrespective of rifampicin resistance (whether or not rifampicin resistance status was known) and with known rifampicin resistance.

Search methods: We searched multiple databases to 23 September 2021. We limited searches to 2015 onwards as Xpert MTB/XDR was launched in 2020.

Selection criteria: Diagnostic accuracy studies using sputum in adults with presumptive or confirmed pulmonary tuberculosis. Reference standards were culture (pulmonary tuberculosis detection); phenotypic DST (pDST), genotypic DST (gDST),composite (pDST and gDST) (drug resistance detection).

Data collection and analysis: Two review authors independently reviewed reports for eligibility and extracted data using a standardized form. For multicentre studies, we anticipated variability in the type and frequency of mutations associated with resistance to a given drug at the different centres and considered each centre as an independent study cohort for quality assessment and analysis. We assessed methodological quality with QUADAS-2, judging risk of bias separately for each target condition and reference standard. For pulmonary tuberculosis detection, owing to heterogeneity in participant characteristics and observed specificity estimates, we reported a range of sensitivity and specificity estimates and did not perform a meta-analysis. For drug resistance detection, we performed meta-analyses by reference standard using bivariate random-effects models. Using GRADE, we assessed certainty of evidence of Xpert MTB/XDR accuracy for detection of resistance to isoniazid and fluoroquinolones in people irrespective of rifampicin resistance and to ethionamide and amikacin in people with known rifampicin resistance, reflecting real-world situations. We used pDST, except for ethionamide resistance where we considered gDST a better reference standard.

Main results: We included two multicentre studies from high multidrug-resistant/rifampicin-resistant tuberculosis burden countries, reporting on six independent study cohorts, involving 1228 participants for pulmonary tuberculosis detection and 1141 participants for drug resistance detection. The proportion of participants with rifampicin resistance in the two studies was 47.9% and 80.9%. For tuberculosis detection, we judged high risk of bias for patient selection owing to selective recruitment. For ethionamide resistance detection, we judged high risk of bias for the reference standard, both pDST and gDST, though we considered gDST a better reference standard. Pulmonary tuberculosis detection - Xpert MTB/XDR sensitivity range, 98.3% (96.1 to 99.5) to 98.9% (96.2 to 99.9) and specificity range, 22.5% (14.3 to 32.6) to 100.0% (86.3 to 100.0); median prevalence of pulmonary tuberculosis 91.3%, (interquartile range, 89.3% to 91.8%), (2 studies; 1 study reported on 2 cohorts, 1228 participants; very low-certainty evidence, sensitivity and specificity). Drug resistance detection People irrespective of rifampicin resistance - Isoniazid resistance: Xpert MTB/XDR summary sensitivity and specificity (95% confidence interval (CI)) were 94.2% (87.5 to 97.4) and 98.5% (92.6 to 99.7) against pDST, (6 cohorts, 1083 participants, moderate-certainty evidence, sensitivity and specificity). - Fluoroquinolone resistance: Xpert MTB/XDR summary sensitivity and specificity were 93.2% (88.1 to 96.2) and 98.0% (90.8 to 99.6) against pDST, (6 cohorts, 1021 participants; high-certainty evidence, sensitivity; moderate-certainty evidence, specificity). People with known rifampicin resistance - Ethionamide resistance: Xpert MTB/XDR summary sensitivity and specificity were 98.0% (74.2 to 99.9) and 99.7% (83.5 to 100.0) against gDST, (4 cohorts, 434 participants; very low-certainty evidence, sensitivity and specificity). - Amikacin resistance: Xpert MTB/XDR summary sensitivity and specificity were 86.1% (75.0 to 92.7) and 98.9% (93.0 to 99.8) against pDST, (4 cohorts, 490 participants; low-certainty evidence, sensitivity; high-certainty evidence, specificity). Of 1000 people with pulmonary tuberculosis, detected as tuberculosis by Xpert MTB/XDR: - where 50 have isoniazid resistance, 61 would have an Xpert MTB/XDR result indicating isoniazid resistance: of these, 14/61 (23%) would not have isoniazid resistance (FP); 939 (of 1000 people) would have a result indicating the absence of isoniazid resistance: of these, 3/939 (0%) would have isoniazid resistance (FN). - where 50 have fluoroquinolone resistance, 66 would have an Xpert MTB/XDR result indicating fluoroquinolone resistance: of these, 19/66 (29%) would not have fluoroquinolone resistance (FP); 934 would have a result indicating the absence of fluoroquinolone resistance: of these, 3/934 (0%) would have fluoroquinolone resistance (FN). - where 300 have ethionamide resistance, 296 would have an Xpert MTB/XDR result indicating ethionamide resistance: of these, 2/296 (1%) would not have ethionamide resistance (FP); 704 would have a result indicating the absence of ethionamide resistance: of these, 6/704 (1%) would have ethionamide resistance (FN). - where 135 have amikacin resistance, 126 would have an Xpert MTB/XDR result indicating amikacin resistance: of these, 10/126 (8%) would not have amikacin resistance (FP); 874 would have a result indicating the absence of amikacin resistance: of these, 19/874 (2%) would have amikacin resistance (FN).

Authors' conclusions: Review findings suggest that, in people determined by Xpert MTB/XDR to be tuberculosis-positive, Xpert MTB/XDR provides accurate results for detection of isoniazid and fluoroquinolone resistance and can assist with selection of an optimised treatment regimen. Given that Xpert MTB/XDR targets a limited number of resistance variants in specific genes, the test may perform differently in different settings. Findings in this review should be interpreted with caution. Sensitivity for detection of ethionamide resistance was based only on Xpert MTB/XDR detection of mutations in the inhA promoter region, a known limitation. High risk of bias limits our confidence in Xpert MTB/XDR accuracy for pulmonary tuberculosis. Xpert MTB/XDR's impact will depend on its ability to detect tuberculosis (required for DST), prevalence of resistance to a given drug, health care infrastructure, and access to other tests.

Trial registration: ClinicalTrials.gov NCT03303963.

PubMed Disclaimer

Conflict of interest statement

SP received funding from USAID, administered by the World Health Organization (WHO) Global Tuberculosis Programme, Switzerland.

KRS received funding from USAID, administered by the WHO Global Tuberculosis Programme, Switzerland. In addition, she has received financial support from Cochrane Infectious Diseases (UK), McGill University (Canada), Baylor College of Medicine (USA), Maastricht University (the Netherlands), and the WHO Global Tuberculosis Programme (Switzerland) for the preparation of related systematic reviews and educational materials; consultancy fees from FIND, Switzerland (for the preparation of systematic reviews and GRADE tables); consultancy fees from Stellenbosch University, South Africa (for guidance on evidence syntheses), and honoraria, and travel support to attend WHO guideline meetings.

GRD received funding from USAID, administered by the WHO Global Tuberculosis Programme, Switzerland.

MC has no known conflicts of interest.

MDV is employed by the Foundation for Innovative New Diagnostics (FIND). FIND has conducted studies and published on Xpert MTB/RIF as part of a collaborative project between FIND, a Swiss non‐profit, Cepheid, a US company, and academic partners. The product arising through this partnership was developed under a contract that obligated FIND to pay for development costs and trial costs and Cepheid to make the test available at specified preferential pricing to the public sector in low‐ and middle‐income countries. In addition, FIND conducted studies for the Xpert MTB/RIF Ultra assay, which have also been published.

SGS was employed by the Foundation for Innovative New Diagnostics (FIND) while conducting the review. FIND has conducted studies and published on Xpert MTB/XDR and Xpert MTB/RIF as part of a collaborative project between FIND, a Swiss non‐profit, Cepheid, a US company, and academic partners. Regarding Xpert MTB/RIF, the product developed through this partnership was developed under a contract that obligated FIND to pay for development costs and trial costs and Cepheid to make the test available at specified preferential pricing to the public sector in low‐ and middle‐income countries. In addition, FIND conducted studies for the Xpert MTB/RIF Ultra assay, which have also been published.

RW has no known conflicts of interest.

GT received funding from USAID, administered by the WHO Global Tuberculosis Programme, Switzerland. In addition, he has received in‐kind research consumable donations provided to employer by Cepheid to work on Xpert MTB/RIF and Xpert MTB/RIF Ultra (not Xpert MTB/XDR) for diagnostic accuracy evaluations for tuberculosis detection. He is the group Principal Investigator for this work. Cepheid has also loaned instruments to conduct these studies. These studies are on different products to those potentially considered for inclusion in this Cochrane Review.

Figures

1
1
Possible test results for each target in the Xpert MTB/XDR assay. aEthionamide will not provide an indeterminant by assay design. Copyright © [2020] [Cepheid Inc]: reproduced with permission.
Abbreviations: AMK: amikacin; CAP: capreomycin; ETH: ethionamide; FLQ: fluoroquinolone; INH: isoniazid; KAN: kanamycin; MTB: Mycobacterium tuberculosis.
2
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Clinical pathway for Xpert MTB/XDR (index test). Abbreviations: DST: drug susceptibility testing; INH: isoniazid; RIF: rifampicin; TB: tuberculosis; WRD: WHO‐recommended rapid diagnostic. *Direct testing of sputum is preferred; indirect testing (on cultured isolates) could also be done. **Xpert MTB/XDR may be considered in patients who were Xpert MTB/RIF Ultra rifampicin susceptible prior to treatment and transitioned to Xpert MTB/RIF Ultra rifampicin resistant while on treatment. ***Xpert MTB/XDR may be considered in a rifampicin susceptible patient if INH‐mono‐resistance is suspected. The composition of a TB treatment regimen will depend on other factors, including RIF susceptibility determined by another test. RIF DST can be done before, in parallel, or after Xpert MTB/XDR. For ease of presentation, TB and MTBC are treated equivalently.
3
3
Study flow diagram. *Two multicentre studies were included, one with two study cohorts and one with four study cohorts. Hence, we included six distinct study cohorts in the review. The following definitions are from Page 2021. Report: a document (paper or electronic) supplying information about a particular study. It could be a journal article, preprint, conference abstract, study register entry, clinical study report, dissertation, unpublished manuscript, government report, or any other document providing relevant information. Record: the title or abstract (or both) of a report indexed in a database or website (such as a title or abstract for an article indexed in Medline). Records that refer to the same report (such as the same journal article) are “duplicates”; however, records that refer to reports that are merely similar (such as a similar abstract submitted to two different conferences) should be considered unique.
4
4
Xpert MTB/XDR for detection of pulmonary tuberculosis. Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study.
5
5
Xpert MTB/XDR for detection of resistance to isoniazid. Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study. Risk of bias and applicability concerns were the same for Xpert MTB/XDR for detection of resistance to fluoroquinolone and amikacin.
6
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Xpert MTB/XDR for detection of resistance to ethionamide. Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study.
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Forest plots of Xpert MTB/XDR sensitivity and specificity by direct testing for pulmonary tuberculosis against culture reference standard. TB: tuberculosis; TP = true positive; FP = false positive; FN = false negative; TN = true negative. For detection of pulmonary tuberculosis, only one study reported data for separate study cohorts. For smear‐positive and smear‐negative TB, data were not reported for separate study cohorts.
8
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Forest plots of Xpert MTB/XDR sensitivity and specificity by direct testing for isoniazid resistance by population and reference standard. gDST = genotypic drug resistance testing; pDST = phenotypic drug resistance testing; TP = true positive; FP = false positive; FN = false negative; TN = true negative. Study in the forest plots refers to a study cohort within a multicentre study.
9
9
Forest plots of Xpert MTB/XDR sensitivity and specificity by direct testing for fluoroquinolone resistance by population and reference standard. Study in the forest plots refers to a study cohort within a multicentre study. gDST = genotypic drug resistance testing; pDST = phenotypic drug resistance testing; TP = true positive; FP = false positive; FN = false negative; TN = true negative.
10
10
Forest plots of Xpert MTB/XDR sensitivity and specificity by direct testing for ethionamide resistance by population and reference standard. Study in the forest plots refers to a study cohort within a multicentre study. gDST = genotypic drug resistance testing; pDST = phenotypic drug resistance testing; TP = true positive; FP = false positive; FN = false negative; TN = true negative.
11
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Forest plots of Xpert MTB/XDR sensitivity and specificity by direct testing for amikacin resistance by population and reference standard. Study in the forest plots refers to a study cohort within a multicentre study. gDST = genotypic drug resistance testing; pDST = phenotypic drug resistance testing; TP = true positive; FP = false positive; FN = false negative; TN = true negative.
12
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Forest plots of Xpert MTB/XDR sensitivity and specificity by direct testing for resistance to kanamycin and capreomycin by population and reference standard. Study in the forest plots refers to a study cohort within a multicentre study. pDST = phenotypic drug resistance testing; TP = true positive; FP = false positive; FN = false negative; TN = true negative.
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Forest plots of Xpert MTB/XDR sensitivity and specificity for resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin, testing on sputum (direct testing) versus testing on cultured isolates (indirect testing), composite reference standard. Data were reported for all study cohorts combined. TP = true positive; FP = false positive; FN = false negative; TN = true negative.
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Forest plots of Xpert MTB/XDR sensitivity and specificity by direct testing for resistance to isoniazid, fluoroquinolone, ethionamide, and amikacin, by smear status, composite reference standard. Data were reported for all study cohorts combined. TP = true positive; FP = false positive; FN = false negative; TN = true negative.
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Forest plots of Xpert MTB/XDR sensitivity and specificity by direct testing for resistance to isoniazid, fluoroquinolone, ethionamide, and amikacin in HIV‐positive and HIV‐negative people, composite reference standard. Data were reported for all study cohorts combined. TP = true positive; FP = false positive; FN = false negative; TN = true negative.
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Forest plots of Xpert MTB/XDR sensitivity and specificity by direct testing for resistance to isoniazid, fluoroquinolone, ethionamide, and amikacin in people with and without previous treatment for tuberculosis, composite reference standard. Data were reported for all study cohorts combined. TP = true positive; FP = false positive; FN = false negative; TN = true negative.
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Xpert MTB/XDR, direct, with known rifampicin resistance, ethionamide, pDST
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Xpert MTB/XDR, direct, irrespective of rifampicin resistance, amikacin, pDST
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Xpert MTB/XDR, direct, irrespective of rifampicin resistance, smear‐positive, isoniazid, composite
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Xpert MTB/XDR, direct, irrespective of rifampicin resistance, smear‐negative, isoniazid, composite
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Xpert MTB/XDR, direct, irrespective of rifampicin resistance, smear‐positive, fluoroquinolone, composite
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Xpert MTB/XDR, direct, irrespective of rifampicin resistance, smear‐negative, fluoroquinolone, composite
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Xpert MTB/XDR, direct, irrespective of rifampicin resistance, smear‐negative, ethionamide, composite
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Xpert MTB/XDR, direct, irrespective of rifampicin resistance, smear‐positive, amikacin, composite
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Xpert MTB/XDR, direct, irrespective of rifampicin resistance, smear‐negative, amikacin, composite
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Xpert MTB/XDR, direct, irrespective of rifampicin resistance, HIV‐positive, isoniazid, composite
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Xpert MTB/XDR, direct, irrespective of rifampicin resistance, HIV‐negative, isoniazid, composite
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References

References to studies included in this review

Omar 2020 {unpublished data only}
    1. Omar S.Shining a new light on TB diagnostics: clinical evaluation of the Xpert® MTB/XDR assay. 51st Union World Conference on Lung Health, virtual conference (accessed 21 October 2020).
Omar 2020 China {unpublished data only}
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Omar 2020 South Africa {unpublished data only}
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Penn‐Nicholson 2021 {published and unpublished data}
    1. Penn-Nicholson A, Georghiou SB, Ciobanu N, Kazi M, Bhalla M, David A, et al.Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre diagnostic accuracy study. Lancet Infectious Diseases 2021;Oct 7 [Epub ahead of print]. [DOI: 10.1016/S1473-3099(21)00452-7] - DOI - PubMed
Penn‐Nicholson 2021 India (Mumbai) {published and unpublished data}
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Penn‐Nicholson 2021 India (New Delhi) {published and unpublished data}
    1. Penn-Nicholson A, Georghiou SB, Ciobanu N, Kazi M, Bhalla M, David A, et al.Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre diagnostic accuracy study. Lancet Infectious Diseases 2021;Oct 7 [Epub ahead of print]. [DOI: 10.1016/S1473-3099(21)00452-7] - DOI - PubMed
Penn‐Nicholson 2021 Moldova {published and unpublished data}
    1. Penn-Nicholson A, Georghiou SB, Ciobanu N, Kazi M, Bhalla M, David A, et al.Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre diagnostic accuracy study. Lancet Infectious Diseases 2021;Oct 7 [Epub ahead of print]. [DOI: 10.1016/S1473-3099(21)00452-7] - DOI - PubMed
Penn‐Nicholson 2021 South Africa {published and unpublished data}
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References to studies excluded from this review

Andreevskaya 2020 {published data only}
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Beutler 2020 {published data only}
    1. Beutler M, Plesnik S, Mihalic M, Olbrich L, Heinrich N, Schumacher S, et al.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. PLOS One 2020;15(1):e0227215. - PMC - PubMed
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Cao 2021 {published data only}
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References to ongoing studies

NCT03303963 {published data only}
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References to other published versions of this review

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