Predicting stringent QuantiFERON-TB Gold Plus conversions in contacts of tuberculosis patients.

OBJECTIVES: To assess associations between disease severity in index TB patients and QuantiFERON-TB Gold Plus (QFT-Plus) results in contacts, and predictors for QFT-Plus conversion in contacts over 6-12 months. METHODS: TB patients (n = 295) and the contacts (n = 1051) were enrolled during 2018-2021 with QFT-Plus performed at baseline and months 6 and 12. A strong CD8 response was defined as TB2 interferon gamma (IFN-γ) response minus TB1 >0.6 IU/ml and stringent conversion as change from QFT-plus negative to high-positive QFT-Plus (TB1 or TB2 IFN-γ responses >0.7 IU/ml). RESULTS: Contacts with index TB patients with sputum smear >1+ was associated with positive QFT-Plus compared to those without (p < 0.001). Contacts with index TB patients with bilateral lung disease were more likely to have strong CD8 responses than those without (p = 0.038). QFT-Plus stringent conversion occurred in 9.7% of contacts over 6-12 months. A TB1 IFN-γ response ≥0.03 IU/ml combined with a TB2 ≥0.06 IU/ml was predictive of a 19-fold increased risk for QFT-Plus stringent conversion in contacts (odd ratio 19.565 [8.484-45.116], p < 0.001). CONCLUSION: Bacterial burden and bilateral lung disease of index TB patients were associated with positive QFT-Plus and strong CD8 responses in contacts. TB1 and TB2 IFN-γ responses were synergistically predictive of stringent conversion in contacts

Cost analysis of rapid diagnostics for drug-resistant tuberculosis

CITATION: Groessl, E. J., et al. 2018. Cost analysis of rapid diagnostics for drug-resistant tuberculosis. BMC Infectious Diseases, 18:102, doi:10.1186/s12879-018-3013-0.The original publication is available at https://bmcinfectdis.biomedcentral.comBackground: Growth-based drug susceptibility testing (DST) is the reference standard for diagnosing drug-resistant tuberculosis (TB), but standard time to result (TTR) is typically ≥ 3 weeks. Rapid tests can reduce that TTR to days or hours, but accuracy may be lowered. In addition to the TTR and test accuracy, the cost of a diagnostic test may affect whether it is adopted in clinical settings. We examine the cost-effectiveness of rapid diagnostics for extremely drug-resistant TB (XDR-TB) in three different high-prevalence settings. Methods: 1128 patients with confirmed TB were enrolled at clinics in Mumbai, India; Chisinau, Moldova; and Port Elizabeth, South Africa. Patient sputum samples underwent DST for first and second line TB drugs using 2 growth-based (MGIT, MODS) and 2 molecular (Pyrosequencing [PSQ], line-probe assays [LPA]) assays. TTR was the primary measure of effectiveness. Sensitivity and specificity were also evaluated. The cost to perform each test at each site was recorded and included test-specific materials, personnel, and equipment costs. Incremental cost-effectiveness ratios were calculated in terms of $/day saved. Sensitivity analyses examine the impact of batch size, equipment, and personnel costs. Results: Our prior results indicated that the LPA and PSQ returned results in a little over 1 day. Mean cost per sample without equipment or overhead was$23, $28,$33, and $41 for the MODS, MGIT, PSQ, and LPA, respectively. For diagnosing XDR-TB, MODS was the most accurate, followed by PSQ, and LPA. MODS was quicker and less costly than MGIT. PSQ and LPA were considerably faster but cost more than MODS. Batch size and personnel costs were the main drivers of cost variation. Conclusions: Multiple factors must be weighed when selecting a test for diagnosis of XDR-TB. Rapid tests can greatly improve the time required to diagnose drug-resistant TB, potentially improving treatment success, and preventing the spread of XDR-TB. Faster time to result must be weighed against the potential for reduced accuracy, and increased costs.National Institute of Allergy and Infectious Diseases (NIAID) grant U01-AI082229https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-018-3013-0Publisher's versio

The Global Consortium for Drug-resistant Tuberculosis Diagnostics (GCDD) : design of a multi-site, head-to-head study of three rapid tests to detect extensively drug-resistant tuberculosis

CITATION: Hillery, N. et al. 2014. The Global Consortium for Drug-resistant Tuberculosis Diagnostics (GCDD): design of a multi-site, head-to-head study of three rapid tests to detect extensively drug-resistant tuberculosis. Trials, 15(1):434, doi:10.1186/1745-6215-15-434.The original publication is available at http://www.trialsjournal.com/content/15/1/434Background: Drug-resistant tuberculosis (DR-TB) remains a threat to global public health, owing to the complexity and delay of diagnosis and treatment. The Global Consortium for Drug-resistant Tuberculosis Diagnostics (GCDD) was formed to develop and evaluate assays designed to rapidly detect DR-TB, so that appropriate treatment might begin more quickly. This paper describes the methodology employed in a prospective cohort study for head-to-head assessment of three different rapid diagnostic tools. Methods Subjects at risk of DR-TB were enrolled from three countries. Data were gathered from a combination of patient interviews, chart reviews, and laboratory testing from each site’s reference laboratory. The primary outcome of interest was reduction in time from specimen arrival in the laboratory to results of rapid drug susceptibility tests, as compared with current standard mycobacterial growth indicator tube (MGIT) drug susceptibility tests. Results Successful implementation of the trial in diverse multinational populations is explained, in addition to challenges encountered and recommendations for future studies with similar aims or populations. Conclusions The GCDD study was a head-to-head study of multiple rapid diagnostic assays aimed at improving accuracy and precision of diagnostics and reducing overall time to detection of DR-TB. By conducting a large prospective study, which captured epidemiological, clinical, and biological data, we have produced a high-quality unique dataset, which will be beneficial for analyzing study aims as well as answering future DR-TB research questions. Reduction in detection time for XDR-TB would be a major public health success as it would allow for improved treatment and more successful patient outcomes. Executing successful trials is critical in assessment of these reductions in highly variable populations. Trial registration ClinicalTrials.gov NCT02170441.jfl201601Publishers’ versio

Additional file 1: of Cost analysis of rapid diagnostics for drug-resistant tuberculosis

Table S1 Clinical and Laboratory Characteristics of the Patients. Table S2 Agreement between three rapid tests and MGIT for detection of resistance for isoniazid (INH), rifampin (RIF), amikacin (AMK), capreomycin (CAP), kanamycin (KAN), moxifloxacin (MOX), and ofloxacin (OFX). Table S3 Proportion of total assay runs that produced interpretable results from three diagnostic platforms (LPA, PSQ and MODS) with the ability to detect resistance to isoniazid (INH), rifampin (RIF), amikacin (AMK), capreomycin (CAP), kanamycin (KAN), moxifloxacin (MOX), and ofloxacin (OFX). (DOCX 35 kb

Performance Comparison of Three Rapid Tests for the Diagnosis of Drug-Resistant Tuberculosis

<div><p>Background</p><p>The aim of this study was to compare the performance of several recently developed assays for the detection of multi- and extensively drug-resistant tuberculosis (M/XDR-TB) in a large, multinational field trial.</p><p>Methods</p><p>Samples from 1,128 M/XDR-TB suspects were examined by Line Probe Assay (LPA), Pyrosequencing (PSQ), and Microscopic Observation of Drug Susceptibility (MODS) and compared to the BACTEC MGIT960 reference standard to detect M/XDR-TB directly from patient sputum samples collected at TB clinics in India, Moldova, and South Africa.</p><p>Results</p><p>Specificity for all three assays was excellent: 97–100% for isoniazid (INH), rifampin (RIF), moxifloxacin (MOX) and ofloxacin (OFX) and 99–100% for amikacin (AMK), capreomycin (CAP) and kanamycin (KAN) resistance. Sensitivities were lower, but still very good: 94–100% for INH, RIF, MOX and OFX, and 84–90% for AMK and CAP, but only 48–62% for KAN. In terms of agreement, statistically significant differences were only found for detection of RIF (MODS outperformed PSQ) and KAN (MODS outperformed LPA and PSQ) resistance. Mean time-to-result was 1.1 days for LPA and PSQ, 14.3 days for MODS, and 24.7 days for MGIT.</p><p>Conclusions</p><p>All three rapid assays evaluated provide clinicians with timely detection of resistance to the drugs tested; with molecular results available one day following laboratory receipt of samples. In particular, the very high specificity seen for detection of drug resistance means that clinicians can use the results of these rapid tests to avoid the use of toxic drugs to which the infecting organism is resistant and develop treatment regiments that have a higher likelihood of yielding a successful outcome.</p></div

Flowchart of patient enrollment, clinical sample processing for Line Probe Assay (LPA), Microscopic Observation of Drug Susceptibility (MODS), and Pyrosequencing (PSQ) for seven anti-TB drugs: isoniazid (INH), rifampin (RIF), moxifloxacin (MOX), ofloxacin (OFX), amikacin (AMK), kanamycin (KAN), and capreomycin (CAP).

<p>Includes one null PSQ sample result (denoted as 'a'). R: Resistant, S: Susceptible, and I: Indeterminate.</p

Sensitivity, specificity and percent agreement between three rapid drug susceptibility tests and MGIT for seven drugs: isoniazid (INH), rifampin (RIF), moxifloxacin (MOX), ofloxacin (OFX), amikacin (AMK), kanamycin (KAN), and capreomycin (CAP).

<p>Mean values and 95% confidence intervals for each comparison are represented in the figure; full data is included as a supplementary table.</p