Project: Preventing TB relapse and chronic lung disease: A proof-of-concept, double-blind, randomised, placebo-controlled trial to evaluate the safety and efficacy of pravastatin to reduce inflammation after TB treatment completion in HIV-infected and HIV-uninfected adults measured by FDG-PET/CT

Acronym	PravaTB (Reference Number: RIA2017T-2004)
Duration	01/01/2019 - 31/12/2022
Project Topic	Mycobacterium tuberculosis (Mtb) causes 1.8 million deaths annually. Sub-Saharan Africa carries the highest burden of tuberculosis (TB) with recurrent TB rates between 3-5% after treatment completion accounting for 10– 30% of all cases within some TB control programs. Multiple risk factors have been identified to cause recurrent diseases. A recent study has identified persistent lesion activity by PET/CT suggesting ongoing inflammation and Mtb mRNA suggesting ongoing infection after cure. The presence of inflammation and mRNA implies that current curative treatment options for PTB may not eradicate Mtb in most patients and more potent treatment options including host-directed therapy (HDT) to sterilize during or after TB treatment is required. Mtb accumulates host cholesterol ester in foamy macrophages, and utilizes cholesterol for its persistence within macrophages. Statins lower cholesterol in cardiovascular diseases through inhibition of HMG-CoA reductase, the rate-controlling enzyme of the mevalonate pathway. In addition, statins also have broad-range immune-modulatory and anti-inflammatory properties. We previously reported in pre-clinical models that statins reduced Mtb burden by enhancing autophagy, phagosomal maturation and decreasing pulmonary pathology, suggesting a role for statins as HDT in TB. Others reported that statins as adjunctive therapy reduced the time for TB cure and decreased lung pathology in mice. A recent population-based study consisting of 1 million people reported that statin treatment was associated with a decreased risk of active TB. This protocol builds upon successful studies suggesting that directly monitoring lung pathology using PET/CT correlates better with treatment outcome than culture and persistent inflammation measured by PET/CT is present after tuberculosis cure in most patients. We propose a proof-of-concept phase IIB, double-blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of 40 mg pravastatin per os daily to reduce persistent inflammation after TB treatment completion in HIV-infected and HIV-uninfected adults measured by PET/CT. We hypothesize that 12 weeks of pravastatin initiated at the end of TB treatment in HIV-infected and HIVuninfected adults will significantly reduce persistent lung inflammation on PET/CT. Our primary objective is to compare total lung glycolysis on PET/CT after 12 weeks of pravastatin or placebo. If successful, this trial has proven that statins as HDT can be safe and effective adjunctive therapy to TB treatment in general and further efficacy trials can be undertaken to translate the results of this trial into reduced TB relapse rate and reduced post-TB chronic lung disease, thus decreased long-term TB-related morbidity.
Network	EDCTP2
Call	Treatment innovations for poverty-related diseases

Project partner

Number	Name	Role	Country
1	University of Cape Town	Coordinator	South Africa
3	Imperial College of Science Technology and Medicine	Partner	United Kingdom
5	LINQ Management GmbH	Partner	Germany
7	Universitaet Zuerich	Partner	Switzerland
9	University of Namibia	Partner	Namibia, Republic of