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Title: A study of the intrapulmonary pharmacology and immunology of tuberculosis therapy
Author: McCallum, Andrew
ISNI:       0000 0004 7964 3198
Awarding Body: Liverpool School of Tropical Medicine
Current Institution: Liverpool School of Tropical Medicine
Date of Award: 2018
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Background: Shorter, more efficacious, treatments for pulmonary tuberculosis (TB) are required. Knowledge of the contributions of drug therapy and the immune system to TB cure will inform efforts to optimise treatment. This study investigates whether antibiotic exposure at the site of infection determines the rate of bacterial clearance and clinical treatment response; and whether impaired alveolar macrophage function in HIV-infection limits the ability of the immune system to eradicate TB. Methods: Malawian adults with microbiologically-confirmed pulmonary TB were recruited to a longitudinal cohort study. Participants received standard first-line therapy, and supplied serial sputum samples to assess TB bacillary elimination in the sputum. Two-month sputum culture status was recorded, and rates of failure or relapse to one-year post-treatment. Plasma and intrapulmonary samples were collected at 8 and 16 weeks into treatment, and drug concentrations measured. Population PK modelling generated estimates of drug exposure in plasma, epithelial lining fluid (ELF), and alveolar cells. Alveolar macrophage function was assessed using quantitative flow cytometry-based reporter bead assays, and ELF cytokine levels measured by ELISA. Results: 157 participants were recruited. Despite weight-based dosing, peak plasma concentrations of first-line drugs were low relative to therapeutic drug monitoring targets. All 4 drugs achieved higher concentrations in ELF and alveolar cells, with isoniazid and pyrazinamide 20 and 50-fold higher in ELF than plasma respectively. Ethambutol concentrations were highest in alveolar cells. Rifampicin and isoniazid AUC/Cmax in plasma and ELF were related to treatment response across several endpoints. Peak concentrations of both drugs in plasma were associated with a shorter time to sputum culture negativity, and more favourable final outcomes. AUC/Cmax in ELF were associated with more rapid bacillary elimination, shorter time to sputum culture negativity, and for rifampicin Cmax in plasma, more favourable late outcomes. HIV infection modulated alveolar macrophage innate immune functions in pulmonary TB. Interferon-γ concentrations in ELF remained high out to 4-months of treatment in HIV-infected participants, with corresponding high superoxidative burst activity and blunted phagocytosis. Initiation of antiretroviral therapy in new HIV diagnoses, with a degree of immune reconstitution, may contribute to ongoing pulmonary inflammation in co-infected patients. Conclusions: Higher plasma and ELF rifampicin and isoniazid drug concentrations in pulmonary TB are associated with improved treatment response. Combining agents with good intra- and extra-cellular drug penetration may be important when designing new regimens for TB. TB/HIV co-infection is associated with alterations in the innate immune environment within the lungs that may reflect impaired control of TB infection. Ongoing efforts to expand test-and-treat and target hard to reach groups may reduce the number of late presenters with TB/HIV co-infection.
Supervisor: Mwandumba, Henry ; Sloan, Derek ; Khoo, Saye Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: WF 250 Immunological aspects ; WF 300 Pulmonary tuberculosis ; WF 310 Therapy ; WF 360 Drug therapy