Accuracy of cobas MTB and MTB-RIF/INH for Detection of Mycobacterium tuberculosis and Drug Resistance

Abstract

This study evaluated the performance of cobas MTB and cobas MTB-RIF/INH for the diagnosis of tuberculosis and detection of rifampicin (RIF) and isoniazid (INH) resistance. Adults presenting with pulmonary tuberculosis symptoms were recruited in South Africa, Moldova, and India. Performance of cobas MTB was assessed against culture, whereas cobas MTB-RIF/INH was assessed using phenotypic drug susceptibility testing and whole-genome sequencing as composite reference standards. Xpert MTB/RIF (Xpert) or Xpert MTB/RIF Ultra (Ultra) was used as a comparator. The overall sensitivity and specificity of cobas MTB were 95% (95% CI, 93%-96%) and 96% (95% CI, 95%-97%). Among smear-negatives, the sensitivity of cobas MTB was 75% (95% CI, 66%-83%). Among participants tested with both cobas MTB and Xpert, sensitivity was 96% (95% CI, 94%-97%) for cobas MTB and 95% (95% CI, 93%-97%) for Xpert. Among participants tested with both cobas MTB and Ultra, sensitivity was 88% (95% CI, 81%-92%) for cobas MTB and 89% (95% CI, 83%-93%) for Ultra. Sensitivity and specificity of cobas MTB-RIF/INH for RIF and INH detection were 90% (95% CI, 84%-94%) and 100% (95% CI, 99%-100%), and 89% (95% CI, 84%-93%) and 99.5% (95% CI, 98%-100%), respectively. The cobas MTB and cobas MTB-RIF/INH assays exhibited high performance in a diverse population and present a suitable option for molecular detection of tuberculosis and RIF and INH resistance.

Figure 1

Study flow for samples provided by participants from Moldova and India (A) and South Africa (B). In Moldova and India, eligible participants were asked to provide two sputum specimens on the same day. The sputum specimens were randomized for testing, where direct cobas and Xpert testing was done on sputum 1, and indirect [after N-acetyl-l-cysteine/sodium hydroxide (NALC-NaOH) decontamination] cobas and Xpert testing was done on sputum 2. In South Africa, eligible participants were asked to provide four sputum specimens on 2 separate days. The two sputum specimens collected on day 1 were not randomized; sputum 1 was used for Ultra testing as per national standard of care, whereas sputum 2 was used for direct Ultra and cobas testing. No culture was done on day 1. Sputum specimens collected on day 2 were randomized for testing, where indirect (after NALC-NaOH decontamination) cobas and Ultra testing were done on sputum 3. ∗Testing was only done if Mycobacterium tuberculosis complex confirmed positive (pos) from BACTEC Mycobacteria Growth Indicator Tube 960 (MGIT) or Löwenstein-Jensen (LJ). †GenoType MTBDRplus was only done on smear-positive NALC-NaoH decontaminated pellets. DST, drug susceptibility testing; PBS, phosphate-buffered saline; WGS, whole-genome sequencing.

Figure 2

Participant flow. ∗Some reasons for exclusion overlap. INH, isoniazid; MTBC, Mycobacterium tuberculosis complex; RIF, rifampicin; TB, tuberculosis.

Figure 3

Sensitivity and specificity of cobas MTB, Xpert, and Ultra for Mycobacterium tuberculosis complex detection (pooled analysis of both sample processing methods). Overall estimates for cobas MTB include results from both sputa collected in Moldova and India, and only results from the sputum 3 (indirect testing) collected on day 2 in South Africa (SA). Results from sputum 2 (direct testing) collected on day 1 were excluded as no culture reference standard was done on day 1. Overall estimates for Xpert MTB/RIF include results from both sputa collected in Moldova and India. Overall estimates for Xpert MTB/RIF Ultra include results from sputum 2 and 3 collected in South Africa. ∗Smear-positive, culture-negative specimens were excluded from the evaluation. D+, reference standard positive; D−, reference standard negative; NA, not applicable; TB, tuberculosis; TN, true negative; TP, true positive.

Figure 4

Sensitivity and specificity of cobas MTB-RIF/INH, Xpert, and Ultra for detection of rifampicin (RIF) and isoniazid (INH) resistance (pooled analysis of both sample processing methods). Overall estimates for cobas MTB-RIF/INH include results from both sputa collected in Moldova and India, and only results from the sputum 3 (indirect testing) collected on day 2 in South Africa (SA). Results from sputum 2 (direct testing) collected on day 1 were excluded as no culture reference standard was done on day 1. Overall estimates for Xpert MTB/RIF include results from both sputa collected in Moldova and India. Overall estimates for Xpert MTB/RIF Ultra include results from sputum 2 and 3 collected in South Africa. D+, reference standard positive; D−, reference standard negative; TN, true negative; TP, true positive.

Supplemental Figure S1

Sensitivity and specificity of cobas MTB, Xpert, and Ultra for Mycobacterium tuberculosis complex detection by HIV status. D+, reference standard positive; D−, reference standard negative; SA, South Africa; TN, true negative; TP, true positive.

Supplemental Figure S2

Sensitivity and specificity of cobas MTB, Xpert, and Ultra for Mycobacterium tuberculosis complex detection by recruitment site (pooled analysis of both sample processing methods). D+, reference standard positive; D−, reference standard negative; TN, true negative; TP, true positive.

Supplemental Figure S3

Sensitivity and specificity of cobas MTB, Xpert, and Ultra for Mycobacterium tuberculosis complex detection by sample processing method. D+, reference standard positive; D−, reference standard negative; SA, South Africa; TN, true negative; TP, true positive.

Supplemental Figure S4

Sensitivity and specificity of cobas MTB, Xpert, and Ultra for Mycobacterium tuberculosis complex detection by history of tuberculosis (TB). D+, reference standard positive; D−, reference standard negative; SA, South Africa; TN, true negative; TP, true positive.