Work package 1: latent tuberculosis infection and blood-borne virus prevalence in people experiencing homelessness in London

Our study findings relating to latent tuberculosis infection and blood-borne virus in homeless populations have previously been published.2 Parts of this section have been reproduced or adapted from Aldridge et al.2 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The text includes minor additions and formatting changes to the original text.

In our original application, work package 1 also included latent tuberculosis infection and blood-borne virus screening in prisoners but, for clarity, we present the prison results alongside the results of the evaluation of prison radiographic screening for tuberculosis in work package 2.

Introduction

Individuals experiencing homelessness have high rates of tuberculosis infection and often present late to health-care services.3 Latent tuberculosis infection is common in homeless populations in low-burden countries,4,5 although limited data are available in the UK.

Homelessness and tuberculosis in homeless populations are both increasingly important problems in London. In 2014, it was estimated that 3.6% (89/2498) of tuberculosis cases with social risk factor information available had a history of homelessness.6 The point prevalence of active tuberculosis in people experiencing homelessness in London has been estimated at 788 per 100,000, compared with 27 per 100,000 in the overall London population.3

Developments in testing for latent tuberculosis infection and treatment of blood-borne viruses provide new opportunities to improve the health of people experiencing homelessness.7,8 Poor adherence and potentially severe hepatotoxicity exacerbated by high rates of alcohol- or viral-related liver disease remain concerns for latent tuberculosis infection treatment in people experiencing homelessness.9 Health services may not be well tailored to deliver care for identified infections in people experiencing homelessness, potentially limiting the value of screening.

We undertook a cross-sectional survey to estimate latent tuberculosis infection and blood-borne virus prevalence among individuals in homeless hostels in London and examined outcomes of referral to health-care services after 12 months.

Methods

Design

A cross-sectional survey of latent tuberculosis infection, hepatitis B, hepatitis C and HIV prevalence in residents of homeless hostels in London was carried out in May 2011 and June 2013, with 12-month follow-up of onward referrals.

Implementation

The study was conducted by NHS nurses employed by the study working alongside the NHS Find&Treat service. Find&Treat identifies cases of active tuberculosis using digital chest radiography and supports patients to complete treatment.10 The eligibility criteria were aged ≥ 18 years, resident at a homeless hostel on the day of the Find&Treat screening, tuberculosis screening chest radiograph within the last 6 months (to help rule out active tuberculosis) and able to provide written informed consent. The study team collected sociodemographic and risk factor data using a paper questionnaire. In keeping with NICE guidance, up to March 2012 the study nurses offered individuals diagnosed with latent tuberculosis infection advice about tuberculosis symptoms.11 After March 2012, we referred those with latent tuberculosis infection who were aged < 35 years to local health services, in line with revised NICE guidance for identifying and managing tuberculosis among hard-to-reach groups.12 We referred individuals with current hepatitis B or hepatitis C infection and previously undiagnosed HIV infection to 14 local health services and the research team collected outcomes 12 months after referral by telephoning clinicians and nurses to whom the patients were referred.

The study received approval from the East of England – Essex National Research Ethics Service Committee (number 10/H0302/5).

Laboratory testing

We collected whole venous blood samples to test for latent tuberculosis infection and blood-borne viruses. We measured latent tuberculosis infection using the QuantiFERON-TB Gold gamma interferon release assay (Cellestis International Pty Ltd, Chadstone, VIC, Australia) following the manufacturer’s instructions for interpretation (Table 1).

We used the Architect immunoassay (Abbott Diagnostics GmbH, Wiesbaden, Germany) to detect hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc) and antibody to hepatitis B surface antigen (anti-HBs). We classified hepatitis B infection as current in participants who tested positive for HBsAg at screening with confirmation by HBsAg neutralisation. We classified hepatitis B as ‘confirmed past’ in those who were HBsAg negative, anti-HBc positive and anti-HBs positive, and as ‘probable past’ in those who were HBsAg negative, anti-HBc positive and anti-HBs negative. We combined the confirmed and probable past groups into one group (referred to as ‘past hepatitis B infection’). We defined non-immune hepatitis B status by absence of all hepatitis B markers.

We detected antibodies to hepatitis C virus (anti-HCVs) using the Vitros chemiluminescence assay (Ortho Clinical Diagnostics, Raritan, NJ, USA). We measured hepatitis C ribonucleic acid (RNA) using either a real-time PCR assay based on the method described by Komurian-Pradel et al.,14 or the Abbott M2000 RealTime hepatitis C assay (Abbott Laboratories, Abbott Park, IL, USA). Samples reactive for anti-HCV but with undetectable hepatitis C RNA underwent anti-HCV confirmation by the Recombinant ImmunoBlot Assay (RIBA) Chiron (Novartis Vaccines and Diagnostics, Inc, Cambridge, MA, USA) or the line immunoassay, Inno-Lia^® (Fujirebio Europe N.V., Ghent, Belgium). Hepatitis C infection was classed as current in anti-HCV-positive participants who tested hepatitis C RNA positive, and past in those who showed undetectable hepatitis C RNA with confirmed anti-HCV positivity (see Table 1). We performed HIV screening using the Architect combined HIV antibody/p24 antigen chemiluminescence assay (Abbott Diagnostics).

Analysis

The primary outcome was the proportion of participants with a positive QuantiFERON-TB Gold assay result. Based on previous US studies,4,5,15 we expected a minimum of 10% of participants to test positive for latent tuberculosis infection. We required 500 participants to measure this within 95% confidence intervals (CIs) between 8% and 13%. The secondary outcomes were 12-month referral outcomes for hepatitis B, hepatitis C and HIV status. We undertook a descriptive analysis of baseline variables and their association with primary and secondary outcomes. We used logistic regression modelling to examine potential risk factors for latent tuberculosis infection (history of imprisonment, history of drug and alcohol use, history of homelessness and country of birth) and considered age, a priori, as a confounder. As those from high-incidence countries are already eligible for screening, we conducted a separate analysis of risk factors in those who were born in the UK. Data were analysed in Stata® version 14 (StataCorp LP, College Station, TX, USA).

Results

Study population

We invited 804 individuals to participate following Find&Treat mobile radiographic screening. A total of 542 out of 804 (67.4%) individuals consented to take part (Figure 2). We subsequently excluded 51 (9.4%) individuals, mainly because of a lack of venous access for blood sampling (n = 31); therefore, we included 491 individuals in the analysis.

FIGURE 2 Recruitment flow chart for work package 1. a, It was operationally extremely intensive to collect data on the number of individuals who were eligible, approached and refused screening, therefore these data were collected only at the start of the study for the first 474 eligible patients. The numbers presented are estimates based on this initial sample. (Figure not reproduced here; see the original article.)

Most participants were men (437/491, 89.0%) aged 30–49 years (257/491, 52.3%) who were born in the UK (305/491, 62.1%), were current tobacco smokers (394/491, 80.2%) and reported being homeless for ≥ 1 year (443/491, 90.2%). Of those not born in the UK, 45 were from other Western European countries, 18 were from Central Europe, Eastern Europe or Central Asia, 23 were from the Eastern Mediterranean, Middle East, North, East or West Africa, 41 were from Central or sub-Saharan Africa, 25 were from South or South East Asia or the Indian subcontinent, five were from East Asia, 18 were from Latin America or the Caribbean and 11 were from other regions. Just over half (263/481, 54.7%) had spent time in prison. Drug use was common, with 107 out of 491 (21.8%) having ever smoked heroin or crack cocaine and 86 out of 491 (17.5%) having ever injected either crack cocaine or heroin. A high proportion (202/477, 42.3%) had ever been concerned about their drinking, or had had a health worker express concern about this. Latent tuberculosis infection and blood-borne virus results are shown in Tables 1 and 2.

Latent tuberculosis infection

We estimated latent tuberculosis infection prevalence at 16.5% (81/491) (95% CI 13.2% to 19.8%). Prevalence was higher in the foreign-born patients (52/186, 28.0%, 95% CI 21.4% to 34.4%) than in the UK-born patients (29/305, 9.5%, 95% CI 6.2% to 12.8%). In the UK-born patients, there was evidence that a history of imprisonment was associated with an increased risk of latent tuberculosis infection [odds ratio (OR) 3.49, 95% CI 1.10 to 11.04; p = 0.018] after adjusting for age, length of time spent homeless and any illicit drug use (Table 3).

Blood-borne viruses

Seven out of 489 patients (1.4%, 95% CI 0.4% to 2.5%) had current hepatitis B infection as confirmed by HBsAg neutralisation. In addition, 10.4% (51/489) (95% CI 7.7% to 13.1%) of patients had evidence of past hepatitis B infection. A total of 59.5% (291/489) (95% CI 55.1% to 63.9%) of patients were non-immune to hepatitis B; this was lower for those who had ever injected drugs (27.1%, 23/85) (95% CI 17.4% to 36.7%; Figure 3). Most non-immune individuals (77.7%, 226/291) did not recall whether or not they had been previously vaccinated for hepatitis B, and 29 out of 291 (10.0%) patients reported having never received vaccination. A total of 41.2% of these non-immune individuals (120/291) had spent time in a UK prison. Only four non-immune individuals reported being vaccinated against hepatitis B more than once.

FIGURE 3 Work package 2 flow diagram. BBV, blood-borne virus; CXR, chest X-ray; LTBI, latent tuberculosis infection. (Figure not reproduced here; see the original article.)

Among a total of 64 out of 491 (13.0%, 95% CI 10.0% to 16.0%) participants with anti-HCV seropositivity, 51 (10.4%, 95% CI 7.8% to 13.1%) tested positive for hepatitis C RNA, indicating current infection. The remaining 13 participants (2.7%, 95% CI 1.2% to 4.1%) showed confirmed anti-HCV reactivity in the absence of hepatitis C RNA, indicating a resolved infection. Individuals who had ever injected drugs had a much higher prevalence of hepatitis C (46/86, 53.4%, 95% CI 42.4% to 64.3%) than those who reported no injecting history (12/405, 3.0%, 95% CI 1.3% to 4.6%). In those diagnosed with latent tuberculosis infection, the frequency of co-infection with either hepatitis B or hepatitis C (past or current) was 37.0% (95% CI 26.3% to 47.8%), and co-infection with both hepatitis B and hepatitis C (past or current) was 16.2% (95% CI 9.7% to 24.7%).

The prevalence of HIV seropositivity was 1.02% (95% CI 0.1% to 1.9%); all cases were due to HIV-1 and all participants were previously aware of their diagnosis.

Clinical management and outcome

There were 81 individuals who had a positive latent tuberculosis infection test result, none of whom was co-infected with HIV. Three individuals who were diagnosed with latent tuberculosis infection, after March 2012 and the introduction of updated NICE treatment guidelines, were referred to local health services for chemoprophylaxis (Table 4). One participant declined referral, and, at 12 months’ follow-up, the remaining two had disengaged with services and had not started treatment.

Among participants with a current hepatitis B infection, all seven accepted a referral; six out of seven were seen at least once in specialist services, none of whom was deemed to require immediate antiviral therapy over 12 months following diagnosis.

A total of 96.1% (49/51) of those with current hepatitis C accepted a referral to specialist services but only two initiated treatment (interferon based), with one having completed treatment and one still on treatment at 12 months’ follow-up. A further 19 (37.3%; 19/51) participants were seen at least once over 12 months of follow-up and remained under review in the absence of treatment; 28 (54.9%; 28/51) individuals were lost to follow-up after referral.

Discussion

This study demonstrates a high burden of latent tuberculosis infection and blood-borne virus infections in a London homeless population at levels that are substantially higher than in the general population. For example, the prevalence of latent tuberculosis infection in inflammatory bowel disease patients screened for latent tuberculosis infection before the initiation of anti-tumour necrosis factor alpha (anti-TNFα) therapy in the UK is 1.6% (95% CI 0.2% to 5.7%)16 and the prevalence of hepatitis C infection in the general population is 0.4%.17

Although the highest latent tuberculosis infection prevalence was in foreign-born participants, around 10% of UK-born patients experiencing homelessness were infected. Prison history increased the risk threefold in UK-born participants. During the study, referral rates for treatment for latent tuberculosis infection were low because of the criteria in operation at the time. Under the most recent (2016) NICE guidelines,11 all those with a positive test aged up to 65 years would be eligible for referral for treatment; therefore, instead of three people (4%; 3/81) being referred, 76 (93.8%; 76/81) would now be eligible.

Significantly higher levels of current and past hepatitis B infection were seen in this study than in the general population (1.4% and 10.4%, respectively). Hepatitis B vaccination was higher in those reporting injecting drug use, possibly as a result of targeted vaccination in this population, but there remained a substantial proportion of this homeless population who were non-immune and who would benefit from vaccination. No patients were initiated on treatment; however, this is not necessarily unexpected given the prolonged clinical assessment (typically two or three appointments spaced out by a few months) that was required before treatment initiation for hepatitis B.

Hepatitis C prevalence was high (13%). This was mainly among those who reported injecting drug use, but even those without such a history had higher levels than the general population. Engagement with health services was poor in those diagnosed with current hepatitis C infection, with just over half of those referred either not attending appointments or being lost to follow-up. In only a minority of those referred was antiviral therapy initiated within 12 months. Until recently, hepatitis C care in general has been characterised by a small number of treatment initiations relative to the number of people needing and accessing care.17 With the introduction of interferon-free regimens of short duration (typically 12 weeks), there is a new emphasis on increasing treatment coverage, but the impact on this vulnerable population has not yet been formally investigated. In individuals diagnosed with latent tuberculosis infection, co-infection with either hepatitis B or hepatitis C (past or current) was high, at 37.0%, as was co-infection with both hepatitis B and hepatitis C, at 16.2%. The implications of this for latent tuberculosis infection treatment and risk of hepatotoxicity need to be carefully considered.

We used convenience sampling as it was not possible to use a formal sampling framework in a study conducted alongside a very-high-throughput NHS clinical service dealing with complex groups. The requirement for individuals to be able to consent meant that our results do not include individuals who were intoxicated (by drugs or alcohol) and, therefore, are likely to under-represent those at highest risk of blood-borne virus infection. Despite this, the homeless population in this study included a high proportion of previous rough sleepers, people with either current or previous high-risk drug use, and people with harmful and hazardous alcohol use. The population sampled is broadly demographically comparable to homeless populations nationally according to the Find&Treat data collected from extensive screening outside London, and Homeless Link’s (London, UK) health needs audit.18

To our knowledge, this study provides the first measure of latent tuberculosis infection and blood-borne virus prevalence in people experiencing homelessness in the UK. Previous studies in other high-income countries (including Italy, Japan, South Korea and the USA) have reported latent tuberculosis infection prevalence in homeless populations and found rates varying from 16% to 75.9%.5,19–22

A meta-analysis of active tuberculosis and blood-borne virus prevalence in homeless populations internationally found that hepatitis C virus (HCV) infection ranged from 3.9% to 36.2%, and HIV infection ranged from 0.3% to 21.1%.23 None of the studies testing for HIV was conducted in the UK, but one hepatitis C study, which recruited individuals experiencing homelessness from shelters, special projects and medical centres in Oxford, found 26.5% of individuals to be HCV infection positive using oral fluid testing.24

Low levels of hepatitis B immunity indicate inadequate access to vaccination in this high-risk group. This finding is consistent with our previous work demonstrating the inverse care law with respect to influenza vaccination.25 Our data demonstrated that the eligibility of people experiencing homelessness for influenza vaccination as a result of clinical risk factors was 38.9%, compared with 13.0% in the general population, but only 23.7% of those eligible were vaccinated compared with national levels of 53.2%. Given the unmet need for hepatitis B vaccination, there is a strong rationale for offering universal provision of hepatitis B vaccination to people experiencing homelessness through existing services engaged with this group.26 The work also indicates the need to strengthen the prison hepatitis B vaccination programme and vaccination alongside drug treatment services. Individuals who tested HBsAg positive generally maintained links with services after referral, whereas those diagnosed with hepatitis C infection showed suboptimal retention by care services. Further studies are required to determine whether or not expanded availability of interferon-free regimens of short duration will increase engagement in this population.

Since 2010, the number of people seen rough sleeping has doubled nationally.27,28 People experiencing homelessness represent the extreme end of health inequalities in high-income countries and they experience a high burden of preventable morbidity and mortality from infectious and non-infectious disease.29,30 We demonstrated the high prevalence of undiagnosed latent tuberculosis infection, hepatitis B infection and hepatitis C infection in homeless populations in the UK, and a large unmet need for hepatitis B vaccination. We also demonstrated the need for intensive case management and ongoing support to ensure that testing can translate into treatment opportunities. High rates of co-infection highlight the importance of service integration through combined testing and treatment pathways.31 NICE now recommends that persons accessing targeted mobile radiology should be offered tests for blood-borne viruses11 and our data provide the basis to estimate the cost-effectiveness of this approach. The recent national collaborative tuberculosis strategy32 commits to new investment in a national outreach service in line with the proven Find&Treat outreach model.10

Deviations from the protocol

The protocol for work package 1 and other studies as submitted to NIHR are provided in Report Supplementary Material 1. The key deviation from the protocol was in the numbers of patients screened for latent tuberculosis infection and blood-borne viruses. The original target had been 3000 (1500 in prison and 1500 in homeless hostels). This target number had been based on power calculations that would enable the progression rates from latent to active tuberculosis to be measured with accuracy through data linkage to national surveillance data. We were able to recruit only one-third of this target (491 individuals in homeless hostels and 515 individuals in prison). In the homeless populations, we conducted the screening alongside the mobile radiographic unit, which has a high turnover. It was not possible to approach, consent and take blood samples from a high proportion of eligible participants under this arrangement. As completion of radiographic screening (to help rule out active disease in those with evidence of latent tuberculosis infection) was an eligibility criterion, this limited the recruitment. In addition, it often proved difficult to identify private spaces in which to take blood. Similarly, in the prison we were restricted to screening those who had undergone radiographic screening. This greatly limited numbers as the prison radiographic screening that was due to be delivered by the NHS had major implementation problems, as described in work package 2. As the number of recruits was lower than anticipated, the recruitment number was renegotiated with NIHR as it was agreed that the lower number would still enable accurate measurement of latent tuberculosis infection and blood-borne viruses; however, the second objective of measuring rates of progression through data linkage was abandoned because of insufficient numbers.

Successes/added value

Findings from this study contributed to the NICE public health programme guidelines Identifying and Managing Tuberculosis Among Hard-to-Reach Groups.33 Citing high rates of infection has, in part, influenced the recommendation to screen people experiencing homelessness for tuberculosis and to refer latent tuberculosis infection cases for further clinical investigation if the individual is aged < 35 years. Our research showing high levels of latent tuberculosis infection in those screened on the mobile radiographic ray unit has led to latent tuberculosis infection screening being commissioned on the mobile radiographic unit to migrants experiencing homelessness across London who are from high-incidence countries and to the commissioning of hepatitis B vaccination on the mobile radiographic unit.

Further work, alongside this study, identified a high unmet need for influenza vaccination among people experiencing homelessness.25 The mobile radiographic unit has now been commissioned to provide influenza vaccination. Work carried out alongside this study also showed the high prevalence of chronic disease including cardiovascular disease in people experiencing homelessness screened by the mobile radiographic unit.29,34 This has recently provided support for a successful application for a NIHR programme development grant on Cardiovascular Disease in People Experiencing Homelessness (Chief Investigator – Ami Banerjee). The work also led to a Department of Health and Social Care policy research programme, the HALT Hepatitis Study, a randomised control trial of the use of peers to support full diagnosis and treatment completion for hepatitis B and hepatitis C among socially complex groups (URL: www.isrctn.com/ISRCTN24707359; accessed 25 September 2020). The charity Groundswell (London, UK) is now commissioned in parts of London to support patients experiencing homelessness to attend HCV appointments.

The study also contributed to the successful procurement of a European Union-funded grant on hepatitis C screening in Europe, which is funding hepatitis C screening and portable liver FibroScan^® (Echosens, Paris, France) screening alongside the mobile radiographic unit to assess disease severity.35

Although the objective of data linkage was dropped from this study, the work was used to fund the development of probabilistic data linkage methodologies at PHE. The algorithms developed have been validated by members of our team.36 They have also been used to link data from the mobile radiographic unit to national tuberculosis surveillance in order to confirm which patients who were screened went on to develop active tuberculosis. This has enabled members of our group to measure the sensitivity and specificity of mobile radiographic screening for tuberculosis26 and to evaluate the accuracy of computer-aided detection of tuberculosis from radiographic images.37 The Find&Treat team is currently purchasing a licence to allow the use of computer-aided diagnostics technology on its radiographic database. The linkage has also been used to link data from the pre-entry migrant screening programme to national tuberculosis surveillance data, enabling the measurement of the incidence of tuberculosis post migration. This was published in The Lancet38 and the lead author (RW Aldridge) based a successful Wellcome Trust (London, UK) postdoctoral fellowship application on this approach.