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

Background: The 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.

Methods: We 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.

Findings: We 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.

Interpretation: The 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.

Funding: Foundation 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.

Figure 1

Study profile MTB=Mycobacterium tuberculosis. RIF=rifampicin. MDR=multidrug resistant. DST=drug-susceptibility testing. *Some patients met several exclusion criteria and are listed more than once. † In South Africa only. ‡680 suspected cases of MDR tuberculosis were not included in the case-detection analysis to avoid patient-selection bias (patients were expected to have a higher tuberculosis prevalence and supposedly higher bacillary load); a subgroup analysis for these patients is shown in webappendix p 3.

Figure 2

Proportion of tuberculosis cases detected by each method in culture-positive patients Percentages are the maximum proportion of cases detected by every method. (A) Tuberculosis case detection. (B) Detection of rifampicin resistance. Time to detection was defined as time between date of sputum sample collection and date of positive result. MTB=Mycobacterium tuberculosis. RIF=rifampcicin.

Figure 3

Proportion of results reported to the clinics for each method from date of first sputum sample Percentages are the maximum proportion of results received by the clinic within 30 days of recorded date of smear microscopy, MTB/RIF test, or culture, or within 150 days of sputum collection for drug-susceptibility testing (DST). TB=Mycobacterium tuberculosis. RIF=rifampcicin.

Figure 4

Time to treatment during validation phase (treatment based on conventional methods only) and implementation phase (treatment based on MTB/RIF test and conventional methods) for patients with smear-positive, culture-positive tuberculosis, smear-negative, culture-positive tuberculosis, or multidrug-resistant tuberculosis Box plots show median time to treatment (black line), mean (dashed black line), 25th and 75th percentiles, and minimum and maximum reported time to treatment (whiskers). Time to treatment was calculated from the date of first sputum collection to the date of treatment initiation. For the time to multidrug-resistant treatment, treatment decisions during this study were only made on the basis of routine drug-susceptibility testing methods. MTB=Mycobacterium tuberculosis. RIF=rifampcicin.