TB fast track: effect of a point-of-care TB test-and-treat algorithm on early mortality in people with HIV accessing ART. (360G-Wellcome-096473_Z_11_Z)

Background: Early mortality remains high among adults with HIV accessing antiretroviral therapy (ART) in resource-constrained settings, with tuberculosis (TB) a leading cause of death. 20% people accessing ART in South Africa have undiagnosed TB. However, due to insensitivity of sputum microscopy, and a complex diagnostic pathway for smear negative TB, the time to TB diagnosis is protracted, delaying both TB treatment (among those diagnosed with TB) and ART (among all investigated, whether or not TB is diagnosed). We hypothesise that a care pathway using point-of-care technology to rapidly identify individuals presenting for ART at high risk of TB and ensure they start TB treatment, then ART, will markedly reduce early mortality. Objective: To compare 6-month mortality among patients with HIV disease and CD4 150 cells/mul referred to start ART between intervention clinics implementing a point-of-care algorithm to identify individuals with a high probability of active TB, and facilitate rapid initiation of TB treatment, followed by ART; vs. control clinics delivering standard of care management according to South African TB/HIV care guidelines. Methods: This is a cluster-randomised trial, randomising 20 primary health clinics in Gauteng and Limpopo provinces, South Africa. ART-eligible patients (CD4 150, ambulant, no recent TB treatment) at intervention clinics will be assessed using simple point-of-care assays. Patients with any of: positive urine lipoarabinomannan (LAM), haemoglobin (Hb) 10, body mass index (BMI) 18.5 will be considered high probability TB, and start TB treatment immediately, then ART. Asymptomatic patients with negative LAM, Hb 10, BMI 18.5 will be low probability and will start ART. Others ( medium probability ) will be investigated for smear-negative TB as per South African guidelines with review after one week to re-categorise into high or low probability. In control clinics we will recruit similar patients and obtain permission for follow-up; management will be as per national guidelines. The primary outcome is mortality at 6 months after recruitment; secondary outcomes include severe morbidity, measured by duration of hospitalisation. Diagnostic cost per TB case detected, and cost per DALY, will be estimated. We estimate mortality conservatively at 25/100 person years in the control arm; with 10 clusters per arm, 175 patients per cluster, and 95% ascertainment of vital status at 6 months, using between-cluster coefficients of variation of 0.2 and 0.25, there will be 91% and 85% power to assess 40% reduction in mortality,respectively.