Title: Assessing cost-effectiveness of testing and treating latent TB infection (LTBI) and active TB disease in the UK: using an integrated transmission-dynamic health-economic model to evaluate different strategies of targeting and different test technologies, and account for infections averted
Funder: Department of Health and Social Care

Abstract: The UK has one of the highest rates of tuberculosis (TB) in Western Europe, several times higher than the rate of the US. TB is caused by the bacterium Mycobacterium tuberculosis, which can be passed from person-to person through the air. A person infected with TB first develops latent TB infection (LTBI). This is when M. tuberculosis bacteria are in the person’s body but does not cause symptoms of TB, and the person is not infectious. Over time, some people with LTBI develop active TB disease because the bacteria reactivate (“wake up”). If this active TB affects a person’s airways then they will be infectious. Reactivation can be prevented by treating people who have LTBI._x000D_ _x000D_ Health services try to identify people who have had contact with infectious TB cases to find out if they also have active TB disease or LTBI, and offer treatment if required. This process takes up a lot of time and is expensive, so we need effective, evidence-based guidelines on which contacts are at the most risk._x000D_ _x000D_ Most cases of TB in the UK are found in people from countries where TB is common. They would have got the infection before moving to the UK and it later reactivated, causing active TB disease. NHS England, Public Health England (PHE), and the National Institute for Health and Care Excellence (NICE) recommend testing new entrants from countries where TB is common, so that those with LTBI can be offered treatment. However, NICE recommends testing people from more countries (with lower TB rates) than PHE is currently testing. NICE also recommends using a different test from the one PHE is using._x000D_ _x000D_ New analysis is needed to understand which groups of new entrants and contacts of active TB cases are at high-enough risk for it to be worth testing them, and to decide which test to use. LTBI tests sometimes give “false positive” results in people who don’t have infection. In people with low risk of infection most positive test results are false, so testing and treating those people is wasteful of money and some might have side-effects from treatment without benefiting from it._x000D_ _x000D_ PHE uses a blood test called interferon-gamma release assay (IGRA), but NICE recommends the tuberculin skin test (TST, also called Mantoux). The cost per test of TST can be lower but TST gives false-positive results more often than IGRA, particularly in people who have had the BCG vaccine (this is a vaccine against TB). Also, TST requires people to be seen by a clinician twice: once for an injection into the skin, and again 2-3 days later to “read” the result – and not all people do this._x000D_ _x000D_ In this research, we will assess the value for money of the different combinations of options for which people (new entrants from particular countries, and people having had contact with active TB cases) are offered testing and with which test. We will do this by building a computer model to combine and analyse information from a range of new published studies and from new analysis of data becoming available from PHE’s LTBI screening programme and contact tracing activities. We will consider the overall (net) cost of a policy (the cost of the intervention minus the cost savings from preventing active TB), and the net effect on health (preventing active TB benefits health but LTBI treatment side-effects harm health)._x000D_ _x000D_ Our team has highly-experienced clinicians, epidemiologists, infectious-disease modellers/health economists, statisticians and policy experts, who have a track record of influential work, advised by a group of experts from across the UK._x000D_ _x000D_ Patients and members of our public involvement panel have helped write this proposal. Relevant patient groups will be involved in the study and dissemination of findings.

Lay abstract: RESEARCH QUESTION: What are the most clinically and cost effective strategies for tuberculosis (TB) testing and treatment in the UK for new entrants and recent TB contacts?_x000D_ _x000D_ BACKGROUND: England is investing in screening of new entrants from high-TB-incidence countries for latent TB infection (LTBI) to prevent progression to active TB, which is potentially fatal and infectious. Additionally, contact tracing finds individuals exposed to active TB cases in the UK, to test them for LTBI and active TB, and treat if required. To be cost-effective, testing must be targeted according to risk factors. However, current NICE guidance regarding targeting and the test to use are inconsistent with current practice. NICE favours the tuberculin skin test (TST), and screening new entrants from countries with TB incidence >40/100,000p.a., whilst Public Health England (PHE) uses blood-test interferon gamma release assays (IGRAs) and uses TB incidence >150/100,000p.a. as the new-entrant “screening threshold”._x000D_ _x000D_ AIMS & OBJECTIVES:_x000D_ • To develop a comprehensive health-economic decision-analytic model of the complete testing-and-treatment pathway for new entrants and recent contacts of active TB cases, to assess the cost-effectiveness of using TST vs IGRA, and of targeting different risk groups._x000D_ • To use transmission-dynamic modelling to correctly account for future health gains and cost savings from reduced TB transmission._x000D_ _x000D_ METHODS: We will analyse new data to determine the risk and rate of progression from LTBI to active TB and the prognostic value of positive and negative test results with TST and two IGRA tests (TSPOT. TB and QuantiFERON) from the PREDICT cohort study of contacts and new entrants, complemented by data on the incidence of active TB in new entrants and contacts from another of our data-linkage studies. We will also analyse new data on the “real-world” performance of the new-entrant PHE LTBI screening programme, including the prevalence of LTBI in migrants tested from different countries, and their rates of uptake of testing, uptake of treatment (by those testing positive), and completion of treatment (by those who start). Additionally, we will use information from contact tracing._x000D_ _x000D_ Informed by public and patient perspectives, and expert opinion, we will develop a model incorporating: a population comprised of social/ethnic groups, which can differ in their size, age-structure, rates of immigration and emigration, cofactors such as BCG vaccination status & HIV status if appropriate, rates of occurrence and detection/diagnosis of latent and active TB; TB transmission within and between groups, calibrated to surveillance data using Bayesian methods; the processes of acquiring infection, progression to active TB, diagnosis and treatment (LTBI and active TB); pathways of testing and treatment of new entrants, active TB cases, and contacts. We will use detailed demographic data to parameterise the model population._x000D_ _x000D_ Health-economic analysis using the model will report costs (from an NHS perspective) and QALYs over the lifetime of the initial population, discounted at 3.5%p.a., and present incremental cost-effectiveness ratios or incremental net benefit (as appropriate)._x000D_ _x000D_ ANTICIPATED IMPACT: Cost-effective use of NHS resources, facilitated by local-level decisions informed by a user-friendly model interface allowing use of local data. Our patient and public involvement network and policy colleagues will enhance dissemination.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: INFECTION