New tools and strategies for tuberculosis diagnosis, care, and elimination: A PLOS Medicine special

This week, publication of a special issue on tuberculosis (TB) begins in PLOS Medicine, advised by guest editors Richard Chaisson of Johns Hopkins University, Claudia Denkinger of the University of Heidelberg, and Mark Hatherill of the South African Tuberculosis Vaccine Institute.

An estimated 10 million people developed tuberculosis (TB) and 1.6 million died of TB globally in 2017, making it the number one cause of death from a single infectious agent. Last year the United Nations held a High Level Meeting on TB, where heads of state pledged to eliminate the disease by 2030.

The Special Issue opens with publication of two original research articles:

In the first article, Radojka M. Savic, of the University of California, San Francisco, and colleagues, develop a model for estimating the distribution of TB drugs in patients' lung lesions. They used data on 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types obtained from 15 patients (10 men, 5 women) undergoing lung resection surgery, to develop and evaluate a site-of-action mechanistic pharmacokinetic model for 7 major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine[CFZ], pyrazinamide [PZA], and kanamycin [KAN]). The researchers found that patients receiving standard doses of RIF and INH, who are at the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the patient population. The investigators also found that the majority of TB drugs showed poor penetration into the cavitary lesions, leading to inadequate drug levels at the site of disease and increased risk of developing drug resistance. The authors note that this was a small group of patients from a unique population of TB patients who failed treatment and underwent lung resection surgery. Still, the authors note that the finding that TB drugs do not penetrate equally in different tissues suggests that a patient-focused approach to optimize drug regimen to the disease extent, lesion type, and individual drug-susceptibility profiles may eventually be useful to guide selection of tailored drug regimens with improved outcomes. They provide a web-based tool to further explore this model and results at http:// saviclab.org/tb-lesion/.

In the second article, Ankur Gupta-Wright, of London School of Hygiene & Tropical Medicine, and colleagues develop a clinical risk score for identifying HIV-positive patients diagnosed with TB with an increased chance of dying within 2 months. The risk score includes 6 factors that can be measured upon hospital admission, including a urine TB diagnostic test to detect the protein lipoarabinomannan [LAM], age, sex, previous experience on antiretroviral treatment, anaemia, and ability to walk unaided. The score was derived in a cohort of 315 patients from the STAMP TB screening trial in Malawi and South Africa, and externally validated in 644 patients from 2 other studies done in South Africa, Zambia, Zimbabwe, Tanzania, and Kenya. For patients identified by the score as high-risk, the odds of dying within 2 months were about 5 times greater (odds ratio 5.3, 95% confidence interval 2.2-9.5) compared to patients classified as low-risk in the validation cohort. The authors note that this risk score depends on access to urine LAM testing, does not measure all potential predictors of mortality (e.g., TB drug resistance), and further validation in larger and diverse cohorts is necessary. However, this risk score may be able to identify patients who could benefit from enhanced clinical care, follow-up, and/or adjunctive interventions.

In addition to the research articles this week, the Special Issue includes a blog on Speaking of Medicine featuring the stories of six survivors of TB, discussing their experiences with different aspects of the TB care cascade, and how it led them to advocate at a local and global level to improve TB care.

The Special Issue will continue with further research and discussion articles appearing over the next several weeks.

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This work was carried out with funding from US National Institutes of Health (NIH) grants R01AI106398-01 and R01AI111967 (RS and VD), grant OPP1066499 (VD) from the Bill and Melinda Gates Foundation, the Intramural Research Program of the NIH National Institute of Allergy and Infectious Diseases (CEB), the Critical Path to TB Drug Regimens (CPTR) Initiative, Bill and Melinda Gates Foundation, grants OPP1031105 and the GC11 Grand Challenges in Global project, which was jointly funded by the Bill and Melinda Gates Foundation (37882) and the Wellcome Trust (077381). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests:

The authors have declared that no competing interests exist.

Strydom N, Gupta SV, Fox WS, Via LE, Bang H, Lee M, et al. (2019) Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization. PLoS Med 16(4): e1002773. https://doi.org/10.1371/journal.pmed.1002773

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America

Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, Maryland, United States of America

International Tuberculosis Research Center, Changwon, Republic of Korea

Asan Medical Center, Seoul, Republic of Korea

Public Health Research Institute and New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America

In your coverage please use this URL to provide access to the freely available paper: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002773

The funding for the STAMP trial was provided by the Joint Global Health Trials Scheme of the UK Department of Health and Social Care, the Department for International Development, the Global Challenges Research Fund, the Medical Research Council and Wellcome Trust (MR/M007375/1). AG-W has received a Royal College of Physicians London JMGP Fellowship, ELC has received a Wellcome Trust Fellowship (WT200901/Z/16/Z). Funding for LAM-RCT was provided by the European Developing Clinical Trials Partnership the South African Medical Research Council, and the South African National Research Foundation for the TB Neat project. The MSF cohort study at Homa Bay County Hospital, Kenya was funded by Médecins Sans Frontières. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests:

I have read the journal's policy and the authors of this manuscript have the following competing interests: KD has obtained speaker fees at industry-sponsored symposia and non-financial support from Alere in the form of kits and test strips, outside the submitted work. No other authors declare competing interests.

Citation:

Gupta-Wright A, Corbett EL, Wilson D, van Oosterhout JJ, Dheda K, Huerga H, et al. (2019) Risk score for predicting mortality including urine lipoarabinomannan detection in hospital inpatients with HIV-associated tuberculosis in sub-Saharan Africa: Derivation and external validation cohort study. PLoS Med 16(4): e1002776. https://doi.org/10.1371/journal.pmed.1002776

TB Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom

Clinical Research Department, London School of Hygiene & Tropical Medicine, London, United Kingdom

Malawi-Liverpool- Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi

Department of Medicine, Edendale Hospital, University of KwaZulu-Natal, Pietermaritzburg, South Africa

Dignitas International, Zomba, Malawi

Department of Medicine, College of Medicine, University of Malawi, Blantyre, Malawi

Centre for Lung Infection and Immunity, University of Cape Town, Cape Town, South Africa

Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa

Epicentre, Paris, France

Division of Allergology and Clinical Immunology, Department of Medicine, University of Cape Town, Cape Town, South Africa

Institute of Research for Development (IRD), UMI 233 TransVIHMI-UM-INSERM U1175, Montpellier, France

Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom

University of the Witwatersrand, Johannesburg, South Africa

In your coverage please use this URL to provide access to the freely available paper: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002776