Abstract
ABSTRACTThe utility of a line probe assay (Genotype MTBDRplus) performed directly on 2-month sputa to monitor tuberculosis treatment response is unknown. We assessed if direct testing of 2-month sputa with MTBDRplus can predict 2-month culture conversion and long-term treatment outcome. Xpert MTB/RIF-confirmed rifampin-susceptible tuberculosis cases were recruited at tuberculosis diagnosis and followed up at 2 and 5 to 6 months. MTBDRplus was performed directly on 2-month sputa and on all positive cultured isolates at 2 and 5 to 6 months. We also investigated the association of a positive direct MTBDRplus at 2 months with subsequent unsuccessful tuberculosis treatment outcome (failure/death during treatment or subsequent disease recurrence). A total of 279 patients (62% of whom were HIV-1 coinfected) were recruited. Direct MTBDRplus at 2 months had a sensitivity of 78% (95% confidence interval [CI], 65 to 87) and specificity of 80% (95% CI, 74 to 84) to predict culture positivity at 2 months with a high negative predictive value of 93% (95% CI, 89 to 96). Inconclusive genotypic susceptibility results for both rifampin and isoniazid were seen in 26% of MTBDRplus tests performed directly on sputum. Compared to a reference of MTBDRplus performed on positive cultures, the false-positive resistance rate for direct testing of MTBDRplus on sputa was 4% for rifampin and 2% for isoniazid. While a positive 2-month smear was not significantly associated with an unsuccessful treatment outcome (adjusted odds ratio [aOR], 2.69; 95% CI, 0.88 to 8.21), a positive direct MTBDRplus at 2 months was associated with an unsuccessful outcome (aOR 2.87; 95% CI, 1.11 to 7.42). There is moderate utility of direct 2-month MTBDRplus to predict culture conversion at 2 months and also to predict an unfavorable outcome.
Highlights
The utility of a line probe assay (Genotype MTBDRplus) performed directly on 2-month sputa to monitor tuberculosis treatment response is unknown
It uses PCR to amplify regions specific to Mycobacterium tuberculosis complex, areas of the rpoB gene associated with rifampin resistance, and katG and inhA genes associated isoniazid resistance from smear-positive or smear-negative clinical samples [6, 7] or cultured isolates
Hybridization of amplified sequences to a membrane strip identifies specific mutant bands or the absence of wild-type bands. It appears to be more sensitive than Xpert MTB/RIF to detect heteroresistance, defined as the simultaneous presence of DS and DR populations in the same patient, thought likely to be an early step in the pathway of resistance amplification [8]
Summary
The utility of a line probe assay (Genotype MTBDRplus) performed directly on 2-month sputa to monitor tuberculosis treatment response is unknown. Drug pressure may select for mutations conferring resistance or amplify resistance during treatment This process can occur at different time points during treatment, ranging from within the first 2 months, when the bacterial load is highest, to later in treatment, and this can be screened for by using molecular or culture-based drug susceptibility tests on sputum obtained during treatment. Hybridization of amplified sequences to a membrane strip (with immobilized probes for both wild-type and mutant sequences) identifies specific mutant bands or the absence of wild-type bands It appears to be more sensitive than Xpert MTB/RIF to detect heteroresistance, defined as the simultaneous presence of DS and DR populations in the same patient, thought likely to be an early step in the pathway of resistance amplification [8]. We determined the association between a positive 2-month MTBDRplus result and the composite long-term unsuccessful outcome of failure/death during treatment or TB recurrence
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