Wellcome Trust Clinical PhD Programme, University of Liverpool 'Health Priorities in the Developing World' (360G-Wellcome-105392_Z_14_Z)

Tuberculosis is responsible for the death of nearly 1,500,000 people annually. TB treatment takes a minimum of 6 months, and even with excellent adherence, is complicated by the risk of treatment failure and acquired drug resistance. Outcomes are worse in those with HIV-TB co-infection, with higher mortality and greater risk of TB relapse or re-infection after completion of treatment. We hypothesise that the intrapulmonary and intracellular site of Mycobacterium tuberculosis infection represents a sanctuary from drug- and immune-mediated eradication, and is an obstacle to effective and shorter therapy. In the context of a longitudinal cohort study, I will conduct an intrapulmonary study to explore the compartmental pharmacology of anti-TB drugs, and local immunology in the infected lungs, of patients receiving treatment for pulmonary TB. Bronchoalveolar lavage will be performed to collect samples for pharmacokinetic analysis and functional immunologic assays. I will develop population pharmacokinetic models of TB drug exposure in plasma, epithelial lining fluid, and alveolar macrophages, and assess alveolar macrophage function in the presence or absence of HIV early and late in treatment. The relationship between these predictor variables and the endpoints of sputum culture conversion, bacillary elimination rates, and clinical outcomes will be explored in mathematical models.