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

Abstract

SummaryBackgroundThe Xpert MTB/RIF test (Cepheid, Sunnyvale, CA, USA) can detect tuberculosis and its multidrug-resistant form with very high sensitivity and specificity in controlled studies, but no performance data exist from district and subdistrict health facilities in tuberculosis-endemic countries. We aimed to assess operational feasibility, accuracy, and effectiveness of implementation in such settings.MethodsWe assessed adults (≥18 years) with suspected tuberculosis or multidrug-resistant tuberculosis consecutively presenting with cough lasting at least 2 weeks to urban health centres in South Africa, Peru, and India, drug-resistance screening facilities in Azerbaijan and the Philippines, and an emergency room in Uganda. Patients were excluded from the main analyses if their second sputum sample was collected more than 1 week after the first sample, or if no valid reference standard or MTB/RIF test was available. We compared one-off direct MTB/RIF testing in nine microscopy laboratories adjacent to study sites with 2–3 sputum smears and 1–3 cultures, dependent on site, and drug-susceptibility testing. We assessed indicators of robustness including indeterminate rate and between-site performance, and compared time to detection, reporting, and treatment, and patient dropouts for the techniques used.FindingsWe enrolled 6648 participants between Aug 11, 2009, and June 26, 2010. One-off MTB/RIF testing detected 933 (90·3%) of 1033 culture-confirmed cases of tuberculosis, compared with 699 (67·1%) of 1041 for microscopy. MTB/RIF test sensitivity was 76·9% in smear-negative, culture-positive patients (296 of 385 samples), and 99·0% specific (2846 of 2876 non-tuberculosis samples). MTB/RIF test sensitivity for rifampicin resistance was 94·4% (236 of 250) and specificity was 98·3% (796 of 810). Unlike microscopy, MTB/RIF test sensitivity was not significantly lower in patients with HIV co-infection. Median time to detection of tuberculosis for the MTB/RIF test was 0 days (IQR 0–1), compared with 1 day (0–1) for microscopy, 30 days (23–43) for solid culture, and 16 days (13–21) for liquid culture. Median time to detection of resistance was 20 days (10–26) for line-probe assay and 106 days (30–124) for conventional drug-susceptibility testing. Use of the MTB/RIF test reduced median time to treatment for smear-negative tuberculosis from 56 days (39–81) to 5 days (2–8). The indeterminate rate of MTB/RIF testing was 2·4% (126 of 5321 samples) compared with 4·6% (441 of 9690) for cultures.InterpretationThe MTB/RIF test can effectively be used in low-resource settings to simplify patients' access to early and accurate diagnosis, thereby potentially decreasing morbidity associated with diagnostic delay, dropout and mistreatment.FundingFoundation for Innovative New Diagnostics, Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials Partnership (TA2007.40200.009), Wellcome Trust (085251/B/08/Z), and UK Department for International Development.

Understanding the incremental value of novel diagnostic tests for tuberculosis

“…Unfortunately, most diagnostic tests are evaluated primarily in well-funded trials and demonstration studies, without good evidence of how they perform in the real world. For example, Xpert MTB/RIF was recommended on the basis of high-quality data about its accuracy and cost-effectiveness under controlled conditions and in a large field trial 26 ; however, emerging evidence has suggested that, in many settings, the characteristics of Xpert may be different when implemented in the field -including its sensitivity 69 , calibration 70 , positive predictive value (owing to low pre-test probability) 71 , and accuracy for rifampin resistance 72 . To make accurate assessments of the incremental value of diagnostics, we should collect such data early after launch, and update expectations and recommendations as those data become available.…”

“…If, for example, people with TB contact the health system on average every 6 months with a 50% chance of being diagnosed at each visit, the mean duration of infectiousness will be 1 year (approximately the prevalence/incidence ratio estimated by the World Health Organization 1 ). If a more sensitive test (for example, replacing sputum smear microscopy with Xpert MTB/RIF 26,27 ) can increase that probability of diagnosis from 0.5 to 0.75, the mean duration of disease, and thus the transmission per active case, could be cut by one-third. As a result, the projected epidemiological impact of a more sensitive diagnostic test in this framework is tremendous.…”

Optimizing Tuberculosis Case Detection Through a Novel Diagnostic Device Placement Model: The Case of Uganda

“…Smear microscopy, HIV-negative 0.654 [5,8,13] Smear microscopy, HIV-positive 0.404 [5,8,13] Xpert MTB/RIF, smear-positive TB cases 0.983 [5,8] Xpert MTB/RIF, smear-negative, HIV-negative cases 0.793 [5,8] Xpert MTB/RIF, smear-negative, HIV-positive cases 0.718 [5,8] Xpert MTB/RIF rifampin testing 0.983 [5,8] Clinical diagnosis of TB 0.444 [5,8] Specificity Smear microscopy 0.982 [5,8,13] Xpert MTB/RIF 0.990 [5,8] Xpert MTB/RIF rifampin testing 0.983 [5,8] Clinical diagnosis of TB 0.869 [5,8] Return for results, probability (range)…”

“…The feasibility and cost-effectiveness of the Xpert have been well studied and support the implementation of the device in resource-limited settings [4][5][6][7][8]. When allocating new diagnostics, it has been recommended that public health decision-makers utilize not only data from such technical studies and registration trials, but also examine the existing epidemiology, health care infrastructure and clinical practice to optimize implementation and scale up [9].…”

Can improved diagnostics reduce mortality from Tuberculous meningitis? Findings from a 6.5-year cohort in Uganda

“…However for pulmonary TB, Xpert has not been shown to decrease mortality 16– 18 . Yet, lessening diagnostic delay in persons with TBM may be more likely to lead to improved outcomes as compared to pulmonary TB given the high early mortality of TBM 19 .…”