Abstract
BackgroundTreatment monitoring of drug-resistant tuberculosis (DR-TB) in resource-limited settings is challenging. We developed a multi-analyte assay for eleven anti-TB drugs in small hair samples as an objective metric of drug exposure.MethodsSmall hair samples were collected from participants at various timepoints during directly observed RR-TB treatment at an inpatient tertiary referral facility in South Africa (DR-TB cohort). We assessed qualitative determination (i.e., detection above limit of detection) of bedaquiline, linezolid, clofazimine, pretomanid, levofloxacin, moxifloxacin, pyrazinamide, isoniazid, ethambutol, ethionamide, and prothionamide in an LC-MS/MS index panel assay against a reference standard of inpatient treatment records. Because treatment regimens prior to hospitalization were not available, we also analyzed specificity (for all drugs except isoniazid) using an external cohort of HIV-positive patients treated for latent TB infection with daily isoniazid (HIV/LTBI cohort) in Uganda.ResultsAmong the 57 DR-TB patients (58% with pre-XDR/XDR-TB; 70% HIV-positive) contributing analyzable hair samples, the sensitivity of the investigational assay was 94% or higher for all drugs except ethionamide (58.5, 95% confidence interval [CI], 40.7–99.9). Assay specificity was low across all tested analytes within the DR-TB cohort; conversely, assay specificity was 100% for all drugs in the HIV/LTBI cohort.ConclusionsHair drug concentrations reflect long-term exposure, and multiple successive regimens commonly employed in DR-TB treatment may result in apparent false-positive qualitative and falsely elevated quantitative hair drug levels when prior treatment histories within the hair growth window are not known.
Highlights
Treatment monitoring of drug-resistant tuberculosis (DR-TB) in resource-limited settings is challenging
Participants A total of 111 participants with DR-TB were enrolled from July 12, 2016 to December 6, 2017 (Fig. 1)
57 participants with MDR/Extensively drug-resistant tuberculosis (XDR-TB) were eligible for inclusion in the study
Summary
Treatment monitoring of drug-resistant tuberculosis (DR-TB) in resource-limited settings is challenging. We developed a multi-analyte assay for eleven anti-TB drugs in small hair samples as an objective metric of drug exposure. Treatment of RR-TB in the setting of HIV co-infection is complicated by high pill burden [1], overlapping drug toxicities [2], poor drug absorption [3, 4], and high mortality [5]. Because of non-invasive collection, easy storage, and long-term detection window, hair concentrations of anti-TB medications represent an important objective determination of patient adherence and a measure of individual pharmacodynamics. Determination of drug concentrations in small hair samples has long informed forensic investigation and environmental exposure assessment, where the liquid chromatography- tandem mass spectrometry (LC-MS/ MS) measures are considered highly sensitive and specific. Stringent in vitro validation procedures provide international guidance for method development [7], though real-world assessments occasionally lead to falsepositive (e.g., external contamination) or false-negative (e.g., cosmetic hair treatments) results
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