Novel methods of pharmacologic monitoring for multidrug resistant tuberculosis treatment in the setting of HIV infection

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Investigator: John J. Metcalfe, MD
Sponsor: NIH National Institute of Allergy and Infectious Disease

Location(s): South Africa

Description

Multidrug resistant tuberculosis (MDR-TB) is a pressing public health problem and a major barrier to achieving effective TB control for our global community, largely because MDR-TB treatment is long, arduous, toxic, and often ineffective, leading to ongoing transmission. Pharmacologic monitoring (analyzing drug levels) during MDR-TB treatment could greatly inform new studies of treatment regimens and improve patient outcomes in real-world settings. Drawing on our past experience in monitoring HIV medication exposure/adherence using hair concentrations, this project will develop and validate a novel, non-invasive method to monitor long-term drug exposure in MDR-TB (especially in HIV-infected patients) by analyzing drug levels in small hair samples.

Multidrug resistant tuberculosis (MDR-TB) is an emerging global public health crisis. Current treatment of MDR-TB requires at least 18 months of decades-old, potentially toxic, and poorly efficacious second-line drugs, too often ending in treatment failure or death. Treatment of MDR-TB in the setting of HIV co-infection, in particular, is complicated by increased pill burden, overlapping drug toxicities, and high mortality. Tremendous financial and scientific resources are directed toward investigation of new drugs for MDR-TB, but efforts to optimize and shorten treatment are hindered significantly by a poor understanding of the individual contribution of each drug to a multidrug regimen, the exposure-response relationship for each drug, and how to best identify those patients who are failing to respond to treatment. In addition, given that MDR-TB treatment is increasingly provided in community settings, better tools are needed to assess adherence and monitor therapy in order to improve individual outcomes and reduce transmission. A major barrier to routine pharmacologic monitoring within clinical trials and among high-risk patients (such as persons with concomitant MDR-TB and HIV) is that current methods to monitor medication exposure (i.e., plasma levels) require phlebotomy, a cold chain, and are generally not repeated frequently enough to characterize drug exposure over time. Moreover, high post-dose exposure in plasma after a directly-observed dose cannot confirm long-term adherence. Our goal in proposing this study is to determine whether an assessment of a panel of second-line TB drug concentrations in small hair samples, an easily accessible biomatrix, determined via liquid-chromatography /tandem mass-spectrometry will improve our ability to predict the risk of treatment failure, acquired drug resistance, or death in patients with MDR-TB, with a particular emphasis on those with HIV co-infection, in two major clinical trials of MDR-TB. Drug concentrations in small hair samples represent drug exposure over the preceding 1-2 months, and collection is noninvasive without need for phlebotomy, sterile equipment, biohazard precautions, or cold storage. We propose to extend our expertise at UCSF in developing hair assays for antiretroviral exposure monitoring for the first time to MDR-TB, embedding our studies within an NIH-supported phase II trial of the safety and pharmacokinetics of bedaquiline and delamanid - the first new drug classes created specifically to treat TB in over 50 years - and a South African Medical Research Council-supported phase III pragmatic randomized controlled trial examining the effectiveness of a novel 6-month, injectable-free MDR-TB regimen. Drug concentrations in hair will be analyzed in a multiplex panel of key second-line TB drugs, including bedaquiline and delamanid. Through intensive development and validation studies involving correlation with plasma pharmacokinetics, adherence measures, and clinical outcomes, our proposed work may have far-reaching implications for