Rosuvastatin as host-directed therapy for drug-sensitive pulmonary tuberculosis

Tuberculosis (TB) treatment remains prolonged despite highly effective antimicrobial regimens, reflecting persistent host-mediated inflammation and tissue damage. Host-directed therapies (HDTs) have emerged as a complementary strategy to improve treatment response by modulating maladaptive immune pathways without contributing to antimicrobial resistance. This thesis explores the role of HDT in drug-susceptible pulmonary tuberculosis (ds-PTB), with a specific focus on the HMG-CoA reductase inhibitor rosuvastatin as a repurposed therapeutic adjunct. The thesis begins with a comprehensive narrative review of candidate HDT agents for TB, undertaken at a time of growing interest but limited clinical evidence. This review informed the selection of rosuvastatin and its evaluation in a randomised, double-blind, placebo-controlled Phase IIb clinical trial (ROSETTA: ROSuvastatin Evaluation as a Tuberculosis Treatment Adjunct). The design, conduct, and implementation of the ROSETTA trial are described in detail. The primary analysis assessed the effect of adjunctive rosuvastatin on time to sputum culture conversion, with secondary outcomes including clinical recovery, safety, and tolerability. Two embedded substudies evaluated host-directed effects beyond microbiological endpoints. A circulating cytokine and chemokine substudy examined immunological modulation during treatment. In parallel, a systematic review evaluated the utility of positron emission tomography–computed tomography (PET-CT) for assessing TB disease activity and treatment response, providing context for a nested PET-CT substudy within ROSETTA that quantified changes in lung metabolic activity during therapy. Adjunctive rosuvastatin was safe and well tolerated but did not significantly shorten time to culture conversion overall. However, rosuvastatin was associated with modulation of inflammatory pathways and changes in PET-CT–defined disease activity. Collectively, these findings highlight the complexity of HDT effects in TB and support a precision medicine approach integrating advanced imaging and immunological biomarkers to identify patients most likely to benefit from host-directed interventions.