A Pragmatic Randomised Study to Optimise Screening, Prevention and Care for Tuberculosis in Malawi
A Pragmatic Randomised Study to Optimise Screening, Prevention and Care for Tuberculosis in Malawi
A pragmatic open, three-arm individually-randomised controlled trial and economic evaluation
 will be conducted in one primary health care centre in Blantyre, Malawi, where HIV and TB are
 major contributors to early mortality.

 Participants will be adults with symptoms of tuberculosis (cough of any duration) attending
 the primary clinic with an acute care episode. We will exclude adults who have taken
 treatment for TB within the previous 6-months, who are taking isoniazid preventive therapy,
 who are not resident of Blantyre, or who plan to move out of Blantyre in the following
 6-months.

 Participants will be randomly allocated into one of three groups:

 Group 1: Standard of care: Participants will be seen by facility health workers and receive
 clinician-directed screening for HIV and TB according to Malawi national guidelines.

 Group 2: Optimised HIV testing and treatment linkage: Participants will be offered testing
 for HIV using rapid oral fluid kits by research assistants. Those with confirmed HIV
 infection will be linked to the HIV care clinic where facility healthworkers will screen for
 TB using standard sputum-based diagnostics.

 Group 3: Optimised TB diagnosis, HIV screening and treatment linkage: Participants will
 receive a high-throughput and high-sensitivity TB screening intervention, in addition to the
 HIV testing intervention. This will comprise of an initial digital chest x-ray classified by
 the CAD4TB image-recognition software as either "high probability of TB", or "low probability
 of TB". Participants whose x-rays are suggestive of TB will receive confirmatory sputum
 testing with Xpert MTB/Rif Ultra cartridges, whilst participants whose x-rays have a low
 probability of TB will be referred to facility healthworkers for routine care.

 All participants will be seen at the health facility at day 56, where they will be tested for
 HIV (if not on ART) and screened for TB.

 The Primary Trial Outcome will compare between groups the time to tuberculosis treatment
 initiation by day 56. The trial is sufficiently powered to permit 3 pairwise comparisons
 between groups (i.e. Group 1 vs. 2; Group 2 vs. 3; and Group 1 vs. 3).

 This three-arm pragmatic trial design allows us to efficiently answer two separate, important
 public health questions: firstly, by comparing Group 2 to Group 1, we should be able to
 determine whether HIV care should be prioritised for adults with TB symptoms. Additionally,
 by comparing Group 3 to Group 2, we will provide strong evidence for the effectiveness of an
 optimised and integrated HIV and TB diagnostic and treatment linkage approach.
Ambitious global targets have been set to eliminate tuberculosis as a public health problem
 by 2035. However, in Africa, where HIV has driven extremely high incidence rates, progress in
 reducing new infections and TB deaths remains too slow.

 We have previously demonstrated that adults seeking diagnosis and treatment for TB and HIV
 face considerable barriers, and have long delays in starting treatment with high
 pre-treatment mortality.

 Efforts to reduce TB mortality have been hampered by limitations in TB diagnostics, with
 considerable uncertainty about how available and new tests can be best implemented.

 The aim of the PROSPECT Study is therefore to investigate the effectiveness and
 cost-effectiveness of optimised TB/HIV diagnosis and treatment linkage interventions on TB
 and HIV case detection, treatment initiation and mortality.

 Study design A pragmatic open, three-arm individually-randomised controlled trial and
 economic evaluation will be conducted in one primary health care centre in Blantyre, Malawi.

 Study site and participants The study will be conducted at one primary health clinic in
 Blantyre Malawi, where we have established HIV and TB research facilities and previously
 demonstrated high need for improved TB and HIV diagnosis. Sputum-based TB diagnostics (smear
 microscopy, and Xpert MTB/Rif) and treatment, and comprehensive HIV care (including
 provider-initiated HIV testing and antiretroviral therapy) are available free-to-cost to
 patients through the Malawi national TB and HIV programmes.

 Participants will be adults with symptoms of pulmonary tuberculosis (cough of any duration)
 attending the primary clinic with an acute care episode. We will exclude adults who have
 taken treatment for TB within the previous 6-months, or who are taking isoniazid preventive
 therapy, or who do not live in Blantyre, or plan to move out of Blantyre.

 Interventions

 Participants will be randomly allocated into one of three groups:

 Group 1 - Standard of care: Participants will be seen by facility health workers and receive
 clinician-directed screening for HIV and TB according to Malawi national guidelines without
 further study input.

 Group 2 - Optimised HIV testing and treatment linkage: Participants will be offered testing
 for HIV using rapid oral fluid kits by research assistants. Those with confirmed HIV
 infection will be linked to the HIV care clinic where facility healthworkers will screen for
 TB using standard sputum-based diagnostics without further study input.

 Group 3 - Optimised TB diagnosis, HIV screening and treatment linkage: Participants will
 receive a high-throughput and high-sensitivity TB screening intervention, in addition to the
 HIV testing intervention. This will comprise of an initial digital chest x-ray classified by
 the CAD4TB image-recognition software as either "high probability of TB", or "low probability
 of TB". Participants whose x-rays are classified as having high probability of TB will
 receive confirmatory sputum testing with Xpert MTB/Rif cartridges, whilst participants whose
 x-rays have a low probability of TB will be referred to facility healthworkers for routine
 care.

 All participants will be seen at the health facility at day 56, where they will be assessed
 to determine whether they are taking treatment for tuberculosis by inspection of medication,
 inspection of treatment cards, and inspection of facility TB registers. They will also be
 offered testing for HIV (if not on ART) and screened for TB, including by sputum culture,
 Xpert and smear microscopy.

 Outcomes The primary trial outcome will be time in days - from Day 0 up to but not including
 Day 56 - to tuberculosis treatment initiation, evaluated at Day 56 following randomization.
 The trial is sufficiently powered to permit 3 pairwise comparisons between groups (i.e. Group
 1 vs. 2; Group 2 vs. 3; and Group 1 vs. 3).

 This three-arm pragmatic trial design allows us to efficiently answer two separate, important
 public health questions: firstly, by comparing Group 2 to Group 1, we should be able to
 determine whether HIV care should be prioritised for adults with TB symptoms. Additionally,
 by comparing Group 3 to Group 2, we will provide strong evidence for the effectiveness of an
 optimised and integrated HIV and TB diagnostic and treatment linkage approach.

 Statistical considerations Assuming 17% of participants in Group 1 initiate TB treatment by
 8-weeks, and 5% loss to-follow-up, a sample size of n=1455 participants randomised in a 1:1:1
 ratio across the three groups provides at least 80% power to detect a hazard ratio of 1.5
 comparing Group 2 to Group 1, and a hazard ratio of 1.41 comparing Group 3 to Group 2.
Inclusion Criteria:

 -  Attends Study Clinic with an acute care episode

 -  18 years of age or older on the day of clinic attendance

 -  Has symptoms of tuberculosis (cough of any duration)

 -  Is resident within urban Blantyre

 -  Provides informed consent to participate

 Exclusion Criteria:

 -  Taking treatment for tuberculosis on the day of clinic attendance

 -  Has taken any treatment for tuberculosis in the 6-months prior to clinic attendance

 -  Is taking isoniazid preventive therapy

 -  Plans to move out of Blantyre to live elsewhere in the following 6-months