Isoniazid preventive therapy (IPT) is among the most efficacious and cost-effective interventions to reduce tuberculosis (TB) incidence and mortality among people living with HIV (PLHIV) but is grossly underutilized due to our reliance on a symptom-based screening test to rule-out active TB. Studies from Africa have shown that the symptom screen has low specificity (10-30%) for active TB and does not meet the minimum specificity (≥70%) requirement established by the World Health Organization (WHO) for TB screening. This low specificity is a major barrier to IPT scale-up because if current TB screening guidelines were followed, 70-90% of PLHIV without active TB would require unnecessary and costly confirmatory testing prior to initiating IPT. The overall objective of this application is to support planning activities for a trial that will evaluate the impact of a more effective and cost-effective TB screening strategy, which is the next step required for successful uptake of IPT. The central hypothesis is that a TB screening strategy based on C-reactive protein (CRP) levels, measured using a point-of-care (POC) assay, will improve outcomes and reduce the long-term impact of TB among PLHIV, beyond that of a symptom-based strategy. The scientific premise for this hypothesis is based on the applicant’s work that has identified POC CRP as the first tool to meet the minimum sensitivity (≥90%) and specificity (≥70%) targets established by the WHO for TB screening. The rationale for this application is that a one-year planning period is needed to plan an impactful and efficient multicenter comparative effectiveness trial of TB screening strategies. This proposal will support planning activities for an randomized trial of 1654 PLHIV initiating ART from three prototypical HIV clinics in Uganda, randomized to either symptom-based TB screening or POC CRP-based TB screening. The trial will compare the proportion of PLHIV initiating IPT (Aim 1) and two-year patient outcomes (Aim 2), by trial arm. The primary endpoint for Aim 2 will be a composite endpoint that will include cumulative TB incidence and all-cause mortality. Key secondary endpoints for Aim 2 will include individual primary endpoints and isoniazid-resistant TB. Aim 3 will compare the cost-effectiveness and projected epidemiologic impact of POC CRP-based TB screening relative to the current recommendation (symptom screening) and to no screening. This research is innovative because although numerous trials have established the effectiveness of IPT, no trial has evaluated the impact of TB screening on IPT initiation rates or patient outcomes. In addition, CRP testing will be performed using a low-cost ($2 per test), rapid (results in 3 minutes) and simple (levels measured from capillary blood) POC assay, increasing the likelihood that POC CRP-based TB screening will be implemented in even the most peripheral settings. This research is significant because in addition to quantifying the expected clinic, economic, and epidemiologic benefits of TB screening, this work will provide definitive evidence of effectiveness of TB screening with and without POC CRP, potentially moving the field beyond ineffective TB screening as a barrier to IPT and improved patient outcomes.