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Precision Medicine DTP - Non-adherence to medication and drug toxicity: tuberculosis treatment in the era of the World Health Organization’s End Tuberculosis Strategy


College of Medicine and Veterinary Medicine

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Prof J Dear , Dr H Stagg No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Additional supervisor: Dr Derek Sloan (University of St Andrews)

Background

Tuberculosis (TB) is the top infectious disease killer in the world among established pathogens; an estimated ~1.5 million people die of the condition per year.1 Given its importance globally, particularly among the most vulnerable and underserved populations, the World Health Organization (WHO) issued an End TB Strategy in 2014 to combat the global epidemic. A core component of this strategy is to ensure that everyone with the disease has access to adequate treatment and care. Since the 1990s, the global burden of drug resistant TB has resulted in concern about how well patients adhere to treatment. Internationally, unease was such that the WHO recommended that patients were observed taking every single dose of their medication. Only recently, however, has the technology become available to accurately collect data on how patients miss doses of their treatment and what this means for the likely success of their regimen.2

Knowing how people miss doses of their treatment, and at what stage this becomes important, is only part of the picture. We also need to know why people miss doses in order to build effective interventions to help them take their treatment. One of the reasons patients may miss doses of their treatment is the development of drug toxicity (side effects), e.g. liver toxicity caused by commonly used anti-TB drugs such as isoniazid or rifampicin. Toxicity can both be a cause of clinically mandated and non-clinically mandated non-adherence, and can recur when essential treatment is restarted. Safely re-starting treatment after an interruption due to toxicity (and avoiding a recurrence of toxicity) is a clinical challenge; the evidence base regarding which drugs to reintroduce first (or at all) and how rapidly to increase drug doses is weak. 3 For patients with severe side effects, individualised precision medicine approaches are required to re-establish treatment. Current diagnostic toxicity markers are sub-optimal. There are new mechanistically informative liver toxicity biomarkers with qualifying data from large USA and European studies.4 However, these markers have not been tested in TB treatment and/or in Africa. Given the global burden of TB this inequality must be addressed. The global picture on the extent to which non-adherence occurs due to treatment side effects and how drugs can be reintroduced safely is minimal and poorly consolidated. Both areas have important implications for regimen design.

Aims

To investigate the relationship between non-adherence to, and side effects from, TB treatment and the implications of this for the reintroduction of medication and treatment outcomes.

Objectives

1) Determine the burden and patterns of non-adherence due to side effects from treatment using epidemiological approaches.

2) Characterise the types and severity of side effects experienced by patients during their TB treatment course and their relationship with different non-adherence patterns.

3) Among individuals hospitalised with liver toxicity, characterise the frequency and clinical features of toxicity recurrence following medicine re-introduction using conventional tools and novel high sensitivity mechanistic biomarkers. Additionally, determine if a severe recurrence can be detected earlier using these biomarkers versus traditional clinical tests. We have generated pilot data which support enhanced biomarker sensitivity in this global context of use.

Training Outcomes

Completion of this PhD will provide the student with a sought-after skill set in statistics, epidemiology, toxicology and clinical pharmacology, and transferrable skills. There is a shortage of professionals in pharmacoepidemiology, giving the student career options in the academic sphere, pharmaceuticals industry and policy arena. The student will have the opportunity to attend training courses in pharmacology (e.g. King’s College London) and pharmacoepidemiology (e.g. London School of Hygiene & Tropical Medicine), as well as benefit from in-house training within the research groups of the three supervisors.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2021

Qualifications criteria: Applicants applying for an MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualification, in an appropriate science/technology area. The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,285 (UKRI rate 2020/21).

Full eligibility details are available: http://www.mrc.ac.uk/skills-careers/studentships/studentship-guidance/student-eligibility-requirements/

Enquiries regarding programme: [Email Address Removed]

References

1. World Health Organization. Global tuberculosis report 2019. https://www.who.int/tb/publications/global_report/en/

2. Stagg HR, Flook M, Martinecz A, Kielmann K, Abel Zur Wiesch P, Karat AS, Lipman MCI, Sloan DJ, Walker EF, Fielding KL. All non-adherence is equal, but is some more equal than others? TB in the digital era. ERJ Open Res (2020), in press

3. National Institute for Health and Care Excellence. NG33: Tuberculosis. 2016. https://www.nice.org.uk/guidance/ng33

4. Rupprechter S, Sloan S, Oosthuyzen W, Bachmann T, Hill A, Dhaliwal K, Templeton K, Matovu J, Sekaggya-Wiltshire C, Dear J. MicroRNA-122 and cytokeratin-18 have potential as a biomarkers of drug-induced liver injury in European and African patients on treatment for tuberculosis. Preprint.


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