Background and aims: The World Health Organization (WHO) recommendation for regular tuberculosis (TB) screening of people living with HIV (PLHIV) using a symptom screen (WHO tool), with Xpert MTB/RIF (Xpert) as the initial diagnostic test has major resource implications. This thesis examined alternative investigation pathways, including Determine TB-LAM (LF-LAM) for TB screening, a clinical score to triage symptomatic individuals for Xpert, and repeating Xpert if the initial test was negative. Design and setting: Prospective cohort of PLHIV, attending four HIV clinics in South Africa. Methods: A systematic sample of adults attending for routine HIV care were enrolled in the XPHACTOR study, which tested a novel algorithm for prioritising investigation with Xpert. At enrolment sputum was collected from all and sent for immediate Xpert if any of: current cough, fever ≥3 weeks, body mass index (BMI) <18.5kg/m2, CD4 <100 cells/mm3 (or <200 if pre-ART) or weight loss ≥10%; otherwise, sputum was stored. Urine was stored if CD4 <200 cells/mm3. At attendance for immediate Xpert result, further investigations were facilitated per national guidelines. For those at highest risk of TB, who had negative initial Xpert result, a repeat sputum sample was stored. Participants were reviewed monthly to 3 months, when sputum and blood were taken for mycobacterial culture. At study completion stored sputa were tested with Xpert, and urine with LF-LAM. We defined TB as “confirmed” if Xpert, line probe assay or culture for M. tuberculosis within six months of enrolment were positive, and “clinical” if TB treatment was started without microbiological confirmation. Results: 3722 participants enrolled into XPHACTOR, and 167/3678 (4.5%) fulfilled case definitions for TB (124 confirmed, 43 clinical); 32.6% reported WHO tool symptoms. Amongst 424 participants with LF-LAM results, 56/424 (13%) had TB (40 confirmed, 16 clinical). Using grade 1 cut-off on pre-2014 reference card, LF-LAM sensitivity for confirmed TB (all clinical TB excluded) in CD4<100 vs. CD4 ≥100 was 16.7% (95% CI 4.7%, 37.4%) vs. 6.3% (95% CI 0.2%, 30.2%). 1048 participants who were WHO tool positive at enrolment provided data for development of a clinical prediction model for TB. The final model comprised ART status; BMI; CD4; number of WHO symptoms. When converted to a clinical score, a cut-off score of ≥3 identified those with TB with sensitivity and specificity of 91.8% and 34.3% respectively. If investigation was prioritised for individuals with score of ≥3, 68% (717/1048) symptomatic individuals would be tested, among whom the prevalence of TB would be 14.1% (101/717); 32% (331/1048) of tests would be avoided, but 3% (9/331) with TB would be missed amongst those not tested. Amongst 227 participants with an initial negative Xpert result, 28 (12%) had TB diagnosed during study follow-up (16 confirmed, 12 clinical); stored sputum tested positive on Xpert in 5/227 (2%). Conclusion: Sensitivity of LF-LAM as a screening test is too low for use. Our clinical score, which requires external validation, may help prioritise TB investigation among symptomatic individuals. Amongst PLHIV with a negative Xpert result, further investigation using appropriate diagnostic modalities is more likely to lead to TB treatment than immediately repeating sputum for Xpert. More efficient TB case finding strategies are needed for PLHIV established in care, to minimise unnecessary investigation of large numbers who do not have TB
