Baseline pRescription According to Direct from Sputum Sequencing and TArgeted drug Concentration Strategy (BRASS TACS)

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Project Summary Tuberculosis is the bacterial infection that kills the most people worldwide, especially in India, which has the highest burden in of multidrug-resistant tuberculosis (MDR-TB) in the world. Delays in adequate treatment due to slow diagnostic tests and the usual one-size-fits-all MDR-TB treatment strategy lead to additional drug resistance, terrible treatment-associated side effects, and high mortality. Rapid next generation sequencing (NGS) from uncultured samples is a novel diagnostic tool that can predict resistance and minimum inhibitory concentration (MIC) ranges for MDR-TB within 2 days of presentation–weeks before culture-based susceptibility tests provide results. NGS-predictions allow providers to tailor MDR-TB treatment and choose doses to target specific drug levels at the start of treatment. Most MDR-TB drugs reach steady state within 2 weeks, so early therapeutic drug monitoring (TDM) supported by direct observation of therapy could verify that predicted efficacy targets are achieved as soon as possible, ensuring that patients get the right drugs at the right dose as early as possible and before suffering side effects from poorly tailored treatment. This would be a dramatic improvement over current culture-based methods of regimen selection, where results return 2 months later, if at all. Our clinical site has previously enrolled ~800 participants with MDR-TB into cohort studies for longitudinal follow-up, monitored participants for side effects and treatment outcomes, and developed on-site workflows for phenotypic drug resistance, MIC testing, NGS from uncultured sputum, and plasma drug level testing of MDR-TB drugs. Each of these tools is available at our site, but they are only employed sporadically, are rarely used in the same patients, and have not been systematically analyzed for their relative contributions to patient outcomes. We will conduct a single-site observational cohort study of 210 adult participants with pulmonary smear-positive, rifampin-resistant TB to systematically evaluate the impact of a combination Baseline pRescription According to Direct from Sputum Sequencing and TArgeted drug Concentration Strategy (BRASS TACS) for personalized MDR-TB therapy as access to these tools expands. The specific aims of this proposal are to: 1) determine the proportion of patients with MDR-TB in Mumbai, India with resistance-associated mutations that would prevent treatment with moxifloxacin, linezolid, bedaquiline, clofazimine, or cycloserine using culture-free NGS; 2) identify the proportion of cohort participants with MDR-TB that achieve model-derived steady-state plasma levels meeting efficacy and toxicity targets; and 3) assess the time to final regimen, frequency of treatment-associated side effects, time to culture conversion, and final outcome of cohort participants who complete culture-free NGS and TDM. The results of this observational cohort will determine the combined benefit of these tools as they are deployed at a referral center with clinical and laboratory expertise in complex drug resistance. These data will describe the real-world outcomes of MDR-TB care using NGS and TDM for MDR-TB in a unique setting and will inform the future application of these tools to improved strategies for personalized MDR-TB treatment worldwide.