Testing for Tuberculosis in the United Kingdom HIV Infected Population
Testing for Tuberculosis in the United Kingdom HIV Infected Population
Human Immunodeficiency Virus (HIV) is the strongest individual risk factor for the
 reactivation of tuberculosis (TB) after previous exposure to Mycobacterium tuberculosis
 (MTb). This risk is reduced but not completely eliminated when HIV is treated with
 antiretroviral therapy (ART). Both the British HIV Association (BHIVA) and National Institute
 of Health and Care Excellence (NICE) suggest testing for latent TB infection in HIV infected
 individuals, but use different criteria. The cost -effectiveness of either approach has not
 been assessed, nor is testing widespread. A certain proportion of HIV infected subjects in
 Africa have MTb detectable in their sputum despite not having symptoms (such as cough or
 weight loss), nor changes on a chest x ray. It is unclear if this happens in lower TB
 prevalence areas such as the United Kingdom (UK). We intend to test a cohort of HIV infected
 subjects for evidence of latent TB using a tuberculin skin test (TST) and Interferon Gamma
 Release Assay (IGRA), ask about symptoms (using a standardised questionnaire) and to induce
 sputum using a saline nebuliser, to detect MTb using microscopy and culture, and newer
 nucleic acid amplification (genetic) techniques. Some patients, despite being exposed to TB
 in the past, will not mount a response using an IGRA or TST, which maybe due to an abnormal
 immune response. This lack of response seems more common in HIV. By investigating the number
 of patients with positive TST, IGRA, chest X ray and evidence of MTb in their sputum, in the
 context of place of birth, previous exposure to TB, CD4 count and other medications, we can
 assess the cost- effectiveness of systematic TB screening and the use anti-TB antibiotics to
 prevent reactivation of TB. In time, we will be able to answer important questions about the
 time taken to reactivate TB in individuals with HIV who do or don't take preventative anti-TB
 medications in the UK.
The investigators would like to assess a cohort of human immunodeficiency virus (HIV)
 infected individuals at the Ian Charleson Centre, Royal Free Hospital to assess the rates of
 latent tuberculosis infection (LTBI) using both tuberculin skin test (TST) and interferon
 gamma release assay (IGRA), systematically investigating for active tuberculosis (TB) with a
 symptom questionnaire and chest X ray, and test for Mycobacterium tuberculosis (MTb) in their
 sputum, both coughed up spontaneously where possible and by inducing sputum using a saline
 nebuliser and testing this using microscopy and culture (the established method for detecting
 MTb), nucleic acid amplification testing (using Xpert.TB, a new genetic test for TB that
 decreases the time required for detection) and a novel 16S ribosomal ribonucleic acid (RNA)
 test, used to look for TB burden.

 A cohort of people with HIV infection will be invited to take part in the study. Subjects
 will have varying place of origin, TB exposure risk, blood cluster of differentiation 4 (CD4)
 cell count, HIV viral load, exposure to antiretroviral drugs used to treat HIV. All patients
 with a new diagnosis of HIV will be invited, as will a group of subjects already undergoing
 HIV care (selected by stratified sampling) in order to recruit 180 subjects originating from
 sub-Saharan African countries and 120 from lower TB incidence countries (such as the United
 Kingdom, UK and Western Europe). The study is powered to detect a difference between all
 forms of TB infection in subjects from sub-Saharan Africa to those from the UK (or other low
 TB prevalence countries) with 80% power, allowing a 5% type I error.

 The participants will be recruited and a questionnaire, X ray, sputum induction, TST and IGRA
 can be taken in one visit. They will need to return 48--72 hours later to have the TST read
 on their arm. Those with evidence of LTBI (with positive TST or IGRA) will be invited to
 TB/HIV clinic and quality of life scores recorded as part of the study.

 Research Questions:

 1. To determine the feasibility, yield and cost--effectiveness of testing for M.
 tuberculosis infection in UK HIV infected individuals.

 2. To determine the prevalence of subclinical and active TB in a UK HIV infected clinic

 3. To determine the sensitivity and specificity of systematic screening questionnaires for
 detecting cases of active TB outside of high TB prevalence settings

 4. To determine concordance between TST and blood IGRA (T-Spot.TB) in latent TB infection

 5. To identify risk factors for latent TB infection in the clinic population

 6. To determine the underlying frequency of airways disease (using spirometry) and of
 respiratory symptoms

 7. To determine the sensitivity and specificity of 'Xpert MTB/RIF' polymerase chain
 reaction (PCR) testing of sputum and induced sputum compared to mycobacterial microscopy
 and culture

 8. To compare the Molecular Bacterial Load (MBL) assay, based on 16S rRNA, and other
 available molecular assays, with Xpert MTB/RIF for detection of Mtb

 9. To determine quality of life scores (EQ-5D) for those with HIV infection, with and
 without latent TB infection and/or undergoing treatment

 On those with evidence of LTBI:

 10. To determine uptake of latent TB therapy (6 months isoniazid treatment)

 11. To determine cost of latent TB treatment (including screening costs, clinic time)

 12. To determine quality of life and rate and severity of adverse events on latent TB
 treatment

 13. To determine rate and time until active TB in those with LTBI on or off antiretroviral
 therapy (ART) and/or isoniazid prophylaxis

 In all patients (over 20 year follow up):

 14. To determine the rate of incident active TB

 15. To determine the time until progression to active TB with in patients with abnormal
 radiographic changes consistent with old tuberculosis exposure or disease

 Data will be generated by the Research team and University College London (UCL) Statistics
 team.
Inclusion Criteria:

 -  New diagnosis of HIV or established in care in HIV clinic by stratified sampling

 -  Able to give informed consent

 Exclusion Criteria:

 -  Diagnosis of active TB or undergoing treatment for active or latent TB

 -  Inability to produce sputum by coughing (e.g. recent rib fracture, chest pain,
 pneumothorax)

 -  Pregnancy

 -  Use of steroids (equivalent to 15mg prednisolone for ≥4 weeks) or any other
 immunosuppressive drugs (e.g. azathioprine) - relative

 -  Active solid organ or haematological malignancy (excluding Kaposi's sarcoma)

 -  Previous hypersensitivity to purified protein derivative (PPD)

 -  Extensive eczema