ABSTRACT TB and major depressive disorder (MDD) are the leading infectious cause of death and the leading cause of disability, respectively. Furthermore, they are commonly co-occurring and negatively synergistic. TB and MDD comorbidity is associated with a 2.85 greater chance of death and 8.70 higher risk for loss to follow up (LTFU) from treatment, which has a cascade of negative individual-, community-, societal-, and health system-level implications. As a treatable condition, MDD is a remediable driver of the TB epidemic. The WHO has called for a global policy framework for TB and mental health integration, recommending brief psychological interventions to address mental disorders in primary care settings. Interpersonal counseling (IPC) is a brief version of one such evidence-based intervention that has demonstrated efficacy and effectiveness in treating MDD when delivered by non-mental health specialists, including in South Africa. The purpose of this study is to assess the effectiveness and cost-effectiveness of integrating IPC (for MDD) into the TB care platform to improve TB and MD outcomes, as well as mitigate TB-related catastrophic costs. As the country with the highest TB burden in the world, nearly 60% of whom are co-infected with HIV, South Africa is the ideal setting for this study. We propose a 3-year hybrid type I effectiveness-implementation trial in eight clinics (n~1410 individuals with TB/MDD) in the Eastern Cape of South Africa to integrate IPC to treat MDD comorbidity within the TB care platform with the following aims: Aim 1: To evaluate the effectiveness and implementation outcomes of integrating IPC treatment for MDD into the existing TB care platform to improve TB and MDD outcomes Aim 2: To determine the influence of theoretically based intervention mediators and moderators on TB treatment outcomes Aim 3: To assess the cost-effectiveness of integrating MDD treatment into the TB care platform from the patient and health system perspectives Our team will be led by an Early-Stage Investigator who is a global expert in TB and MDD, supported by senior investigators with extensive experience conducting TB and MH-related effectiveness, cost-effectiveness, and hybrid trials (including in South Africa). This research will provide critical clinical, programmatic, and economic data to inform the WHO global policy framework for TB and mental health integration, and cost-effective clinical practice to improve TB outcomes, especially in low-resource settings.

PROJECT NARRATIVE This hybrid type I effectiveness-implementation trial will increase understanding of the effectiveness and cost- effectiveness of integrating a brief evidence-based treatment for major depressive disorder (MDD) within the tuberculosis (TB) care platform to improve TB and MDD. Findings from this R01 are likely to inform policy and treatment guidelines for the integrated management of TB and MDD in low- and middle-income countries globally.