Abstract
BackgroundTuberculosis (TB) is the leading cause of death from an infectious pathogen worldwide and the most prevalent opportunistic infection in people living with HIV. Isoniazid preventive therapy (IPT) reduces the incidence of active TB and reduces morbidity and mortality in HIV-infected patients independently of antiretroviral therapy. However, treatment of latent or active TB is lengthy and inter-patient variability in pharmacokinetics and adherence common. Current methods of assessing adherence to TB treatment using drug levels in plasma or urine assess short-term exposure and pose logistical challenges. Drug concentrations in hair assess long-term exposure and have demonstrated pharmacodynamic relevance in HIV.MethodsA large hair sample from a patient with active TB was obtained for assay development. Methods to pulverize hair and extract isoniazid were optimized and then the drug detected by liquid chromatography/ tandem mass spectrometry (LC/MS-MS). The method was validated for specificity, accuracy, precision, recovery, linearity and stability to establish the assay’s suitability for therapeutic drug monitoring (TDM). Hair samples from patients on directly-observe isoniazid-based latent or active TB therapy from the San Francisco Department of Public Health TB clinic were then tested.ResultsOur LC/MS-MS-based assay detected isoniazid in quantities as low as 0.02ng/mg using 10–25 strands hair. Concentrations in spiked samples demonstrated linearity from 0.05–50ng/mg. Assay precision and accuracy for spiked quality-control samples were high, with an overall recovery rate of 79.5%. In 18 patients with latent or active TB on treatment, isoniazid was detected across a wide linear dynamic range.ConclusionsAn LC-MS/MS-based assay to quantify isoniazid levels in hair with performance characteristics suitable for TDM was developed and validated. Hair concentrations of isoniazid assess long-term exposure and may be useful for monitoring adherence to latent or active TB treatment in the setting of HIV.
Highlights
Tuberculosis (TB) remains one of the greatest threats to public health today, surpassing HIV as the leading cause of death from an infectious pathogen in 2015 [1]
Tuberculosis (TB) is the leading cause of death from an infectious pathogen worldwide and the most prevalent opportunistic infection in people living with HIV
TB is the leading cause of death among HIV-infected individuals worldwide and the provision of isoniazid preventive therapy (IPT) to those with HIV reduces the risk of HIV-associated illness or death significantly and independently of antiretroviral therapy (ART) [2, 3]
Summary
Tuberculosis (TB) remains one of the greatest threats to public health today, surpassing HIV as the leading cause of death from an infectious pathogen in 2015 [1]. The requirement of prolonged treatment courses for latent and active TB threatens sustained adherence, and considerable inter-patient pharmacokinetic (PK) variability for commonly-used TB medications, including isoniazid (INH), may contribute to the emergence of resistance [4, 5] and adverse treatment outcomes. Given the importance of monitoring adherence and exposure to anti-TB medications during the treatment of both latent TB infection (LTBI) and active disease, the routine incorporation of therapeutic drug monitoring (TDM), where drug levels are monitored in a biomatrix, has been recommended[6]. A low-cost, noninvasive, -collected, alternative method for assessing adherence and exposure to TB drugs among HIV-infected and uninfected patients could provide an important clinical tool for both LTBI and active TB treatment. Drug concentrations in hair assess long-term exposure and have demonstrated pharmacodynamic relevance in HIV
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