Quantifying Isoniazid Levels in Small Hair Samples: A Novel Method for Assessing Adherence during the Treatment of Latent and Active Tuberculosis

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Abstract

Background

Tuberculosis (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.

Methods

A 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.

Results

Our 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.

Conclusions

An 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.

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Most cited references 30

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Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability.

Tawanda Gumbo, Edward C. Meek, Jotam Pasipanodya … (2011)

It is believed that nonadherence is the proximate cause of multidrug-resistant tuberculosis (MDR-tuberculosis) emergence. The level of nonadherence associated with emergence of MDR-tuberculosis is unknown. Performance of a randomized controlled trial in which some patients are randomized to nonadherence would be unethical; therefore, other study designs should be utilized. We performed hollow fiber studies for both bactericidal and sterilizing effect, with inoculum spiked with 0.5% rifampin- and isoniazid-resistant isogenic strains in some experiments. Standard therapy was administered daily for 28-56 days, with extents of nonadherence varying between 0% and 100%. Sizes of drug-resistant populations were compared using analysis of variance. We also explored the effect of pharmacokinetic variability on MDR-tuberculosis emergence using computer-aided clinical trial simulations of 10 000 Cape Town, South Africa, tuberculosis patients. Therapy failure was only encountered at extents of nonadherence ≥60%. Surprisingly, isoniazid- and rifampin-resistant populations did not achieve ≥1% proportion in any experiment and did not achieve a higher proportion with nonadherence. However, clinical trial simulations demonstrated that approximately 1% of tuberculosis patients with perfect adherence would still develop MDR-tuberculosis due to pharmacokinetic variability alone. These data, based on a preclinical model, demonstrate that nonadherence alone is not a sufficient condition for MDR-tuberculosis emergence.

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Dried blood spot methods in therapeutic drug monitoring: methods, assays, and pitfalls.

Peter M Edelbroek, Leo Stolk, Rene van der Heijden (2009)

This article reviews dried blood spot (DBS) sampling in therapeutic drug monitoring. The DBS method involves applying whole blood obtained via a fingerprick to a sampling paper. After drying and transportation, the blood spot is extracted and analyzed in the laboratory. Assays of many medicines in DBS have already been reported in the literature and are reviewed here. The technique involved in and factors that may influence the accuracy and reproducibility of DBS methods are also discussed. DBS sampling ultimately seems to be a useful technique for therapeutic drug monitoring that could have many advantages in comparison with conventional venous sampling. However, its benefits must be weighed against the degree of potential errors introduced via the sampling method; there is evidently a need for more standardization, quality assurance, basic research, and assay development.

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Therapeutic drug monitoring in the treatment of tuberculosis.

C Peloquin (2001)

Therapeutic drug monitoring (TDM) is a standard clinical technique used for many disease states, including many infectious diseases. As for these other conditions, the use of TDM in the setting of tuberculosis (TB) allows the clinician to make informed decisions regarding the timely adjustment of drug therapy. Such adjustments may not be required for otherwise healthy individuals who are responding to the standard, four-drug TB regimens. However, some patients are slow to respond to treatment, have drug-resistant TB, are at risk of drug-drug interactions or have concurrent disease states that significantly complicate the clinical situation. Such patients may benefit from TDM and early interventions may preclude the development of further drug resistance. It is not possible to collect multiple blood samples in the clinical setting for logistical and financial reasons. Therefore, one typically is limited to one or two time points. When only one sample can be obtained, the 2-hour post-dose concentrations of isoniazid, rifampin, pyrazinamide and ethambutol are usually most informative. Unfortunately, low 2-hour values do not distinguish between delayed absorption (late peak, close to normal range) and malabsorption (low concentrations at all time points). A second sample, often collected at 6-hour post-dose, can differentiate between these two scenarios. The second time point can also provide some information about clearance and half-life, assuming that drug absorption was nearly completed by 2 hours. TDM requires that samples are promptly centrifuged, and that the serum is promptly harvested and frozen. Isoniazid and ethionamide, in particular, are not stable in human serum at room temperature. Rifampin is stable for more than 6 hours under these conditions. During TB treatment, isoniazid causes the greatest early reduction in organisms and is considered to be one of the two most important TB drugs, along with rifampin. Although isoniazid is highly active against TB, low isoniazid concentrations were associated with poorer clinical and bacteriological outcomes in US Public Health Services (USPHS) TB Trial 22. Several earlier trials showed a clear dose-response for rifampin and pyrazinamide, so low concentrations for those two drugs also may correlate with poorer treatment outcomes. At least in USPHS TB Trial 22, the rifampin pharmacokinetic parameters were not predictive of the outcome variables. In contrast, low concentrations of unbound rifapentine may have been responsible, in part, for the worse-than-anticipated performance of this drug in clinical trials. The 'second-line' TB drugs, including p-aminosalicylic acid, cycloserine and ethionamide, are relatively weak TB drugs. Under the best conditions, treatment with these drugs takes over 2 years, as opposed to 6 to 9 months with isoniazid- and rifampin-containing regimens. Therefore, TB centres such as National Jewish Medical and Research Center in Denver, CO, USA, measure serum concentrations of the 'second-line' TB drugs early in the course of treatment. That way, poor drug absorption can be dealt with in a timely manner. This helps to minimise the time that patients are sputum smear- and culture-positive with multidrug-resistant TB, and may prevent the need for even longer treatment durations. Patients with HIV are at particular risk for drug-drug interactions. Because the published guidelines typically reflect interactions only between two drugs, these guidelines are of limited value when the patient is treated with three or more interacting drugs. Under such complicated circumstances, TDM often is the best available tool for sorting out these interactions and placing the patient the necessary doses that they require. TDM is only one part of the care of patients with TB. In isolation, it is of limited value. However, combined with clinical and bacteriological data, it can be a decisive tool, allowing the clinician to successfully treat even the most complicated TB patients.

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Author and article information

Contributors

Mark Patrick Nicol: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 18 May 2016

Publication date Collection: 2016

Volume: 11

Issue: 5

Electronic Location Identifier: e0155887

Affiliations

[1 ]Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco (UCSF), San Francisco, CA, United States of America

[2 ]Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California San Francisco (UCSF), San Francisco, CA, United States of America

[3 ]Department of Medicine, Division of HIV, Infectious Diseases, and Global Medicine, University of California San Francisco (UCSF), San Francisco, CA, United States of America

[4 ]Department of Epidemiology and Biostatistics, University of California San Francisco (UCSF), San Francisco, CA, United States of America

University of Cape Town, SOUTH AFRICA

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: RG. Performed the experiments: AW RG. Analyzed the data: PB MG JM. Contributed reagents/materials/analysis tools: MG JM CAK ATC. Wrote the paper: RG MG PB JM ATC CAK AW. Collected hair samples from latent or active TB patients: JM ATC CAK AW.

* E-mail: monica.gandhi@ 123456ucsf.edu

Article

Publisher ID: PONE-D-16-07494

DOI: 10.1371/journal.pone.0155887

PMC ID: 4871544

PubMed ID: 27191185

SO-VID: 816a086e-b1d2-4a2b-a6ef-e5443804f81e

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 21 February 2016

Date accepted : 5 May 2016

Page count

Figures: 2, Tables: 2, Pages: 11

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: RO1 AI098472

Award Recipient : Monica Gandhi

Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: RO1 AI123024

Award Recipient : John Metcalfe

National Institute of Allergy and Infectious Diseases ( https://www.niaid.nih.gov) RO1 AI098472 (PI M.G.), National Institute of Allergy and Infectious Diseases ( https://www.niaid.nih.gov) RO1 AI123024 (co-PIs J.M., M.G.).

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Quantifying Isoniazid Levels in Small Hair Samples: A Novel Method for Assessing Adherence during the Treatment of Latent and Active Tuberculosis

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Abstract

Background

Methods

Results

Conclusions

Related collections

PLOS Climate

Most cited references 30

Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability.

Dried blood spot methods in therapeutic drug monitoring: methods, assays, and pitfalls.

Therapeutic drug monitoring in the treatment of tuberculosis.

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