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

Karen R Steingart, Ian Schiller, David J Horne, Madhukar Pai, Catharina C Boehme, Nandini Dendukuri, Karen R Steingart, Ian Schiller, David J Horne, Madhukar Pai, Catharina C Boehme, Nandini Dendukuri

Abstract

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%; 7 studies, 1789 participants), and for people without HIV infection, it was 86% (95% CrI 76% to 92%; 7 studies, 1470 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). Among 180 specimens with nontuberculous mycobacteria (NTM), Xpert® MTB/RIF was positive in only one specimen that grew NTM (14 studies, 2626 participants).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.

Conflict of interest statement

The CIDG provided funding in part for this review. KRS serves as Co‐ordinator of the Evidence Synthesis and Policy Subgroup of Stop TB Partnership's New Diagnostics Working Group. KRS received funding to carry out the original Cochrane Review from CIDG and McGill University and the updated Cochrane Review from the United States Agency for International Development (USAID), USA. MP is a recipient of a New Investigator Award from the Canadian Institutes of Health Research (CIHR) and a salary award from Fonds de recherche du Québec ‐ Santé. MP serves as an external consultant for the Bill & Melinda Gates Foundation. CCB is employed by the Foundation for Innovative New Diagnostics (FIND) and 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 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 developing countries. The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the review apart from those disclosed. IS received funding to carry out the updated Cochrane Review from CIDG and USAID.

Figures

Figure 1
Figure 1
Readout of Xpert® MTB/RIF assay for a TB positive, rifampicin‐susceptible specimen. Courtesy: Karin Weyer, the Global TB Programme, WHO
Figure 2
Figure 2
Flow diagram of studies in the review
Figure 3
Figure 3
Risk of bias and applicability concerns graph: review authors' judgements about each domain presented as percentages across the 36 included study centres (27 studies). The reference standard domain pertains to TB as the target condition. See text for the reference standard relating to rifampicin resistance.
Figure 4
Figure 4
Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study centre.
Figure 5
Figure 5
Forest plots of Xpert MTB/RIF sensitivity and specificity for TB detection, Xpert MTB/RIF used as an initial test replacing smear microscopy. The individual studies are ordered by decreasing sensitivity. TP = True Positive; FP = False Positive; FN = False Negative; TN = True Negative. Between brackets are the 95% CI of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). Xpert MTB/RIF specificity could not be estimated in one study.
Figure 6
Figure 6
Summary plots of Xpert MTB/RIF sensitivity and specificity for TB detection, Xpert MTB/RIF used as an initial test replacing smear microscopy. Each individual study is represented by an empty square. The size of the square is proportional to the sample size of the study such that larger studies are represented by larger squares. The filled circle is the median pooled estimate for sensitivity and specificity. The solid curves represent the 95% credible region around the summary estimate; the dashed curves represent the 95% prediction region.
Figure 7
Figure 7
Study results of smear microscopy (green circle) versus Xpert MTB/RIF (red circle) plotted in ROC space. The specificity of smear was assumed to be 100%.
Figure 8
Figure 8
Forest plots of Xpert MTB/RIF for TB detection in studies reporting data for smear‐negative patients. We also used these data as a proxy for the accuracy of Xpert MTB/RIF used as an add‐on test following a negative smear microscopy result. TP = True Positive; FP = False Positive; FN = False Negative; TN = True Negative. Between brackets the 95% CI of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line).
Figure 9
Figure 9
Summary plots of Xpert MTB/RIF sensitivity and specificity for TB detection, Xpert MTB/RIF used as an add‐on test following a negative smear microscopy result. Each individual study is represented by an empty square. The size of the square is proportional to the sample size of the study such that larger studies are represented by larger squares. The filled circle is the median pooled estimate for sensitivity and specificity. The solid curve represents the 95% credible region around the summary estimate; the dashed curves represent the 95% prediction region.
Figure 10
Figure 10
Forest plot of Xpert MTB/RIF sensitivity for TB detection in studies reporting data for smear‐positive patients. The squares represent the sensitivity and specificity of one study, the black line its CI. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Xpert MTB/RIF specificity could not be estimated in these studies.
Figure 11
Figure 11
Forest plots of Xpert MTB/RIF sensitivity and specificity for TB detection in HIV‐positive and HIV‐negative subgroups. The squares represent the sensitivity and specificity of one study and the black line represent its CI. TP = true positive; FP = false positive; FN = false negative; TN = true negative.
Figure 12
Figure 12
Forest plots of Xpert MTB/RIF sensitivity and specificity for detection of rifampicin resistance, Xpert used as an initial test replacing conventional DST as the initial test. The individual studies are ordered by decreasing sensitivity and decreasing number of true positives. The squares represent the sensitivity and specificity of one study, the black line its CI. TP = true positive; FP = false positive; FN = false negative; TN = true negative.
Figure 13
Figure 13
Bayesian bivariate hierarchical model, likelihood.
Figure 14
Figure 14
Bayesian bivariate hierarchical model, prior distributions.
Test 1
Test 1
TB detection, all studies.
Test 2
Test 2
Add on.
Test 3
Test 3
Smear positive.
Test 4
Test 4
Smear negative.
Test 5
Test 5
HIV positive.
Test 6
Test 6
HIV negative.
Test 7
Test 7
TB detection, condition of specimen.
Test 8
Test 8
TB detection, specimen preparation.
Test 9
Test 9
Proportion TB cases.
Test 10
Test 10
Income status.
Test 11
Test 11
RIF resistance detect.
Test 12
Test 12
Xpert version.
Test 13
Test 13
Proportion RIF resistance.

References

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References to ongoing studies
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References to other published versions of this review
    1. Steingart KR, Sohn H, Schiller I, Kloda LA, Boehme CC, Pai M, Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database of Systematic Reviews 2013, Issue 1. [DOI: 10.1002/14651858.CD009593.pub2]

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