Award Title: Research to Improve the Detection and Treatment of Latent Tuberculosis Infection (RID-TB)
Funder: Department of Health and Social Care

Abstract: Aims and objectives: We will identify the factors influencing uptake of latent TB infection (LTBI) testing and completion of treatment among migrants entering the UK, develop materials to communicate and support LTBI testing and treatment interventions, evaluate the effectiveness and cost-effectiveness of a new Mycobacterium tuberculosis RD1-specific C-Tb skin test compared to interferon-gamma release-assay (IGRA) and assess the effectiveness and cost-effectiveness of a 12-dose rifapentine-based regimen with and without adherence support compared to current standard of care.     Background: Following declines in the incidence of tuberculosis (TB) during the 20th century, there was a resurgence of the disease in England from the late 1980s to 2005. Consequently, NHS England and Public Health England (PHE) launched a strategy in 2015 to bring about a sustained decline with screening for latent TB infection (LTBI) as a funded element of the plan. LTBI testing and treatment reduces tuberculosis incidence by preventing reactivation, and is expected to create a cost saving to the NHS after about five years (NHS England). However, high rates of testing, treatment uptake and treatment completion are essential prerequisites to accrue these benefits.     Research plan: In this 5-year programme of research, we have designed studies to improve access to diagnosis and enhance treatment uptake and completion in individuals with or at risk of LTBI. Through four interrelated workpackages conducted in parallel, we will combine a behavioural science theory-based approach together with clinical trials, health economics and modelling to assess interventions designed to support uptake of testing and treatment, and treatment completion. Studies will be conducted in high-volume primary and secondary care settings that are part of the LTBI screening programme in London.     Workpackage 1 focuses on diagnostics. Study 1 will assess the diagnostic performance (concordance, sensitivity, specificity and predictive values) of the C-Tb test against the IGRA (the current standard of care). A minimum of 692 IGRA-tested individuals are required to provide 90% power to demonstrate C-Tb sensitivity and specificity against IGRA to within 5% of 94% accuracy. Study 2 will be a pragmatic randomised controlled trial (RCT) to assess C-Tb use within the NHS.  Impact will be measured by comparing the proportion of patients who begin LTBI treatment after a positive C-Tb result to the proportion starting treatment after a positive IGRA. 400 individuals per arm are required in Study 2 to demonstrate non-inferiority of tests with 90% power, at 10% delta, assuming 60% attendance for treatment per arm and 5% one-sided alpha.     Workpackage 2 will focus on behavioural science using mixed-methods. This will include qualitative work exploring people s experiences of LTBI testing (workpackage 1) and treatment (workpackage 3), including reasons for declining either or both of these, and quantitative assessments using validated measures of beliefs around illness and treatment. Through a process of co-creation, we will iteratively develop educational materials aimed at identified perceptual barriers to uptake and completion of testing and treatment.     Workpackage 3 will address adherence and treatment completion. In a pragmatic, four-arm RCT, we will trial two interventions, alone and in combination, in comparison to standard care: a novel 12-dose weekly rifapentine/isoniazid LTBI treatment regimen vs. the standard daily rifampicin/isoniazid for 12 weeks, both with and without a novel adherence support intervention. 600 individuals will enable detection of an increase of at least 20% in any of the intervention arms (pairwise comparisons) with 90% power, assuming 5% significance 2-sided. Adherence support will comprise an electronic medication monitor reminder box (which also measures adherence) and educational materials developed in Workpackage 2 (see above).     Workpackage 4 will employ economic analysis to calculate if changes to diagnosis and/or treatment are cost-effective. An integrated transmission-dynamic health-economic model will synthesise data obtained within the RID-TB programme and evidence from sources including the scientific literature, census data and life-tables from national statistics, the LTBI/TB screening and TB surveillance data. The model will consider different age-groups, and different social/ethnic groups, subdivided into UK-born and foreign-born individuals, which can differ in their size, age-structure, rates of migration, rates of occurrence of latent and active TB, and in the patterns of social mixing within and between different groups that affect TB transmission rates. This will allow estimation of the long-term, national-level benefits of the studied interventions.     Projected outputs: Our patient and public involvement network will facilitate dissemination of findings and educational materials to groups most affected by LTBI. Co-applicants include senior staff at PHE, who are well-placed to ensure that study results are considered in national policy. We will present to clinicians and researchers at national and international conferences, and publish in open-access peer-reviewed journals.     Benefits to patients and the NHS: If successful, these novel interventions will improve uptake and completion of LTBI treatment; if cost-effective, they will save the NHS money. Benefits would arise from reduced risk of developing active TB for individuals, and reduced risk of onward transmission in the population.

Lay Abstract: Background: The number of tuberculosis (TB) cases in the UK has increased over the past three decades, and remains high despite a recent decline. There were over 6,000 cases in 2016. The UK has the second highest rate of TB in Western Europe and four times that of the US. NHS England and Public Health England (PHE) have published a national TB strategy, which recommends testing new migrants entering the UK from countries where TB disease and latent TB infection (LTBI) are common. Someone has LTBI if they are infected with Mycobacterium tuberculosis but do not have signs of active disease. Around a third of immigrants to the UK from countries where TB is common may have LTBI. This is important because LTBI can later progress to active disease, making the person ill and putting them at risk of passing the infection to other people. This can be avoided by treating people who have LTBI, but it can be difficult to ensure they are diagnosed and supported to take treatment. We will investigate approaches to improve how these measures are delivered.     Testing: In 2011 national guidelines stated that a blood test for LTBI provided good value for money. However, more recent analysis suggests that a skin test (tuberculin skin test, TST) may be better value. Currently the LTBI screening programme uses blood tests, called interferon-gamma release assays (IGRA). The TST may not always correctly identify who has LTBI as reliably as IGRA. This can lead to unnecessary treatment if results are falsely positive. There is now a new skin test available, called C-Tb, which research suggests is as good as IGRA in correctly identifying LTBI. We propose to compare the C-Tb test to IGRA to see whether it is more accurate, easier to obtain a diagnosis, and offers better value for money for the NHS as part of the national migrant-screening programme. We will also do research to understand what people think of C-Tb, and their experience of testing for LTBI.     Treatment: Only between one-third-to-two-thirds of people offered LTBI treatment take it. We will do research to understand why people agree to be tested and treated, and what factors stop them. This will allow us to develop support materials that help people complete treatment. We will also assess whether people are more likely to complete treatment if it consists of weekly tablets rather than the current approach of using daily tablets. We will do this comparison with and without the support materials, so that we can tell how well they also work. We will assess the value for money of each intervention.     Our team has the skills needed to undertake this research including patients, scientists, NHS managers and policy experts.

Research Activity Codes: 7.1 INDIVIDUAL CARE NEEDS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: INFECTION