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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

          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 references30

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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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              Strong Relationship between Oral Dose and Tenofovir Hair Levels in a Randomized Trial: Hair as a Potential Adherence Measure for Pre-Exposure Prophylaxis (PrEP)

              Albert Liu, Qiyun Yang, Yong Huang … (2014)
              Background Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults. Methods A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs). Results Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60–93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair. Conclusions This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs. Trial Registration ClinicalTrials.gov +NCT00903084.
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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.

                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
                Copyright © © 2016 Gerona et al
                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 :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: RO1 AI123024
                Award Recipient :
                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.).
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Infectious Diseases
                Subject: Bacterial Diseases
                Subject: Tuberculosis
                Subject: Medicine and Health Sciences
                Subject: Tropical Diseases
                Subject: Tuberculosis
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Integumentary System
                Subject: Hair
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Integumentary System
                Subject: Hair
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Drugs
                Subject: Isoniazid
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Drug Therapy
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Drug Interactions
                Subject: Drug-Drug Interactions
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Drug Adherence
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Microbial Control
                Subject: Antimicrobial Resistance
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Antimicrobial Resistance
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Medical Microbiology
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Immunodeficiency Viruses
                Subject: HIV
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Pathogens
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Immunodeficiency Viruses
                Subject: HIV
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Viral Pathogens
                Subject: Immunodeficiency Viruses
                Subject: HIV
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Immunodeficiency Viruses
                Subject: HIV
                Subject: Biology and life sciences
                Subject: Organisms
                Subject: Viruses
                Subject: RNA viruses
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: HIV
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Medical Microbiology
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: HIV
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Pathogens
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: HIV
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Viral Pathogens
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: HIV
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                Data Availability All relevant data are embedded within the paper.

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