This NIHR programme grant for applied research allowed us to investigate a series of approaches to improving the management and control of tuberculosis in socially excluded groups that have high rates of tuberculosis, delayed diagnosis, drug resistance, loss to follow-up, and often poor treatment adherence and high mortality. Key groups include people experiencing homelessness, prisoners and drug users. Through a series of work packages, we investigated (1) the value of screening for latent tuberculosis infection alongside blood-borne virus screening and radiographic screening for tuberculosis (work packages 1 and 2); (2) the use of a peer intervention to increase uptake of mobile radiographic screening for tuberculosis in hostels for people experiencing homelessness (work package 3); (3) the value of introducing rapid molecular tests for tuberculosis alongside mobile radiographic screening for active tuberculosis (work package 4); (4) the use of a smartphone-enabled approach to supporting adherence to tuberculosis treatment (VOT) compared with face-to-face DOT (work package 5); and (5) the cost-effectiveness of screening people experiencing homelessness for latent tuberculosis infection and of VOT. The key methodologies and results of these work packages are summarised below. Full results for most aspects of the work have been published elsewhere, as indicated in the text.
Evolution of the programme components
In view of these challenges, we designed a programme of research that was submitted to NIHR for consideration of funding. This included the following studies:
- study 1 – cross-sectional survey on the prevalence of latent tuberculosis infection, human immunodeficiency virus (HIV), hepatitis B and hepatitis C in prisoners, drug users and people experiencing homelessness to inform a mathematical model (study 7) of the impact and cost-effectiveness of screening socially complex groups
- study 2 – observational study of the effectiveness of a new prison radiographic screening service
- study 3 – cluster randomised controlled trial (CRCT) evaluating interventions to increase the uptake of mobile radiographic screening in homeless populations
- study 4 – establishment and evaluation of a rapid diagnostic pathway to reduce loss to follow-up prior to diagnosis
- study 5 – individually randomised controlled trial of clinic-based DOT versus community-based DOT to inform optimal treatment delivery for socially complex groups
- study 6 – evaluation of a specialist clinical service providing in-reach high-quality tuberculosis care in prison
- study 7 – qualitative research to ensure that proposed interventions are acceptable and accessible to the target population and to inform understanding of barriers to services
- study 8 – development of a dynamic transmission model to predict public health impact of the interventions and inform economic analysis comparing costs with the savings made through averting future cases.
Following peer review, the funders requested the following changes to this programme of work:
- Removal of studies 6 and 7 in response to the programme being perceived as overambitious and the team having insufficient qualitative research expertise.
- Simplification of study 3, which was originally conceived as a three-arm CRCT comparing usual practice with financial incentives and with peer educators as interventions to improve mobile radiographic screening uptake. We were requested to remove one study arm and, therefore, simplified this to a proposed trial of incentives versus usual practice.
- Addressing concerns about the safety of conducting smear microscopy on the mobile radiographic unit. To address this issue, we proposed evaluating how the pan-London service would use a single NHS trust for rapid sputum smear microscopy.
- Cost-effectiveness analyses – it was requested that the cost-effectiveness of the adherence interventions also included a societal perspective.
Subsequent to funding, a number of developments led to further modifications of the study proposal, which were agreed with funders at regular reviews. These are summarised below.
Surveys of latent tuberculosis infection
The scale of these surveys needed to be reduced because of the challenges of recruiting and consenting participants across homeless, drug user and prison settings, and of obtaining detailed baseline questionnaires and blood samples. The work was focused on homeless and prison settings, recognising that these settings would also capture many drug users. In view of the decreased sample size, the objective to measure progression rates to active tuberculosis, and the data linkage that this required, was removed.
Evaluation of the prison radiographic screening programme
Despite the NHS being funded to conduct a prison screening programme in key prisons, at the time of the study none of the selected prisons had implemented this. To address this, we provided radiological time to the study prison to enable a pilot of the screening programme to take place. This meant that the number of prisoners going through screening was considerably lower than anticipated in a routine comprehensive service. The objective of comparing cases identified through screening with cases that were identified through passive case finding also needed to be removed because of the small number of identified cases.
Cluster randomised controlled trial to increase the uptake of radiographic screening for tuberculosis in homeless hostels
Concerns about staff safety when regularly carrying and dispensing financial incentives were agreed to limit the feasibility of routine use of financial incentives to encourage uptake. The intervention was changed to peer education (which had originally been the third arm of the three-arm trial).
Substantial developments in the technology for rapid polymerase chain reaction (PCR)-based diagnostics led to the possibility of deploying highly compact PCR assays rather than smear microscopy. These technologies have been shown to be more sensitive than sputum smear microscopy, have the advantage of identifying rifampicin resistance (and are a good proxy for MDRTB) and require limited sample handling and lower levels of training than sputum microscopy. They also provided rapid turnaround times. The trust that had agreed to provide the rapid sputum microscopy service agreed to support the development and accreditation of the use of this technology on the mobile radiographic unit, including the development of valved sputum pots that removed the need for subsequent handling of sputum, safety standard operating procedures and staff training. A RCT was designed to evaluate the impact of this technology when used alongside mobile radiographic screening.
Randomised controlled trial to improve adherence to treatment
Although this was originally proposed as a trial of community-based DOT versus usual practice (clinic-based DOT), during the course of set-up, community-based DOT became much more commonly used in response to patients’ needs. This prevented the proposed randomisation. At the same time, Find&Treat had been developing in-house video-observed therapy with apparently high success. The University of San Diego had developed a smartphone application (app) to increase the simplicity and security of this approach. With the agreement of funders, we therefore changed this to a trial of smartphone-enabled VOT compared with face-to-face DOT (either clinic or community based). This required the need to overcome a range of technical and information governance challenges before the trial could commence. At the same time, the numbers of cases of tuberculosis in London had declined compared with when the original study was designed. In response, we extended recruitment to clinics outside London. It became apparent that cases randomised to DOT frequently did not take up this form of observation. In view of this and the slower than expected recruitment, the funders requested an interim analysis to inform the decision about whether or not the study should continue. Following publication of an interim analysis plan with agreed stopping rules, the trial was discontinued because of the overwhelming superiority of the VOT arm.
Cost-effectiveness analyses
During the course of the programme grant, a cost-effectiveness analysis of screening for latent tuberculosis infection and active tuberculosis in prisoners was conducted by the National Institute for Health and Care Excellence (NICE). In view of this new analysis, this aspect of the economic evaluation was removed. As the peer intervention to improve screening uptake showed no evidence of effectiveness, cost-effectiveness analyses were considered unnecessary. Similarly, as we were unable to demonstrate that the use of a rapid diagnostic approach improved outcomes, a cost-effectiveness analysis was deemed unnecessary. Finally, as the VOT intervention proved substantially more effective and cheaper than DOT, no cost-effectiveness analysis was required. This work package, therefore, focused on the cost-effectiveness of screening for latent tuberculosis infection alongside mobile radiographic screening in the homeless, and cost comparison of DOT and VOT.
Following these changes, we divided the work into six work packages as outlined in Figure 1.
FIGURE 1 Overview of work packages. a, Testing of prisoners for blood-borne viruses and latent tuberculosis infection was originally included in WP1 but for clarity and improved contextualisation of the results we have included the description of this activity in WP2. WP, work package. (Figure not reproduced here; see the original article.)
Study data handling
Study nurses with relevant honorary NHS contracts had access to a look-up table between patient identifiers and study numbers to enable them to make referrals and follow up patients who had consented to this. This look-up table was held on University College London’s data safe haven. Anonymised data sets were used by other staff for analyses and were kept on secure servers with access to named individuals only.