Repurposing a Lipid Lowering Drug to Treat Tuberculosis: Effectiveness of Statins as Adjuvant to Treatment of Pulmonary Tuberculosis in Nigeria

INTRODUCTION Tuberculosis is a chronic disease responsible for most deaths from infectious disease with an estimated I0 million cases and close to 2million deaths globally. 1 Despite the availability of therapy for TB, the scourge of the disease has not abated especially in the developing countries. The disease is caused by a bacterium called Mycobacterium tuberculosis, a non-spore forming intracellular organism. TB exists in two forms; primary and secondary infection. While primary infection most times goes unnoticed and are usually associated with non-specific symptoms, secondary infections are usually associated with profound symptoms and signs in various organs especially in the lungs. Majority of persons overcome primary infection but the tubercule bacilli may lie dormant in the macrophages.2 Secondary infection occurs as a result of either endogenous reactivation or exogenous re-infection. Pulmonary TB is responsible for more than 85% of the cases.

MTB infect and survive humans by evading the various immune defense systems.3 The organism accumulates and utilizes an abundant amount of lipids and cholesterol for its cell wall, and as a source of carbon for synthesis of virulence factors. 4 Mycobacterium tuberculosis also utilizes cholesterol as a vehicle to enter macrophage, inhibit phagocytosis and inhibit growth and development of phagocytes.5 These greatly impairs the hydrolytic and antimicrobial properties and activities of phagocytes.5,6 Current therapy is as old as the disease itself; is of long duration, hence it is associated with poor compliance. This contributes to frequent relapses and emergence of resistant form of the disease. Average interval between one episode of TB and another range from 6-18 months after completion of therapy. Despite clinical cure, approximately half of patients have permanent lung damage. In Nigeria, TB is a major risk factor for Chronic Obstructive Pulmonary Disease, lung fibrosis/scarring and other diseases. It is clear that new and innovative therapeutic agents are needed to tackle this hydra- headed disease. In order to address these challenges, a lipid lowering agent, atorvastatin is being repurposed.

The use of statins have been demonstrated in infectious diseases and especially in tuberculosis than other organisms.7 In vitro studies have demonstrated that statins could strengthen the host response against M. tuberculosis and inhibit the activation of T cells induced by M. tuberculosis antigens.8,9 In another study, murine bone marrow-derived macrophages that were exposed to simvastatin and were infected with M. tuberculosis, showed a significant reduction in mycobacterial growth, without adverse effects on cell viability.10 Treatment of TB in animal model with statins and anti TB drugs showed that treatment with anti-TB drugs plus simvastatin reduced the percentage of relapses by 50% compared with treatment with only anti-TB drugs.11 Taken together, all these studies in animal model indicate that statins has anti-TB effect, reduces bacillary load, shortens the duration of therapy and decreases relapse rate when used with first-line anti-TB drugs.

Most of the clinical evidence on the role of statins in TB were from retrospective and nested case control studies from Asian continent.12,13 In one study in Taiwan, diabetic subjects older than 65 treated with statins had a lower risk of developing active tuberculosis, with a risk of 0.76 (95% CI, 0.60-0.97). 12 Chronic use of statins (more than 90 days) was associated with the lowest risk (RR 0.62; 95% CI 0.53-0.72) as shown in another study.13 Within the limits of the designs of these studies, the positive and protective role of statins in TB in humans were demonstrated and has provided basis for further studies. This proposal seeks to provide robust evidence in a well designed study, for repurposing statins to treat TB.

If this is successful, the investigators anticipate a significant improvement in health and well being for patients. Patients will have the option of being treated with an effective and safe regimen with minimal side effects including patients with HIV/TB co-infection, as statins can be co-administered safely with antiretroviral drugs. Additionally, the investigators anticipate a reduction in relapse rate, persistence and resistance to Mycobacterium tuberculosis. Currently, patients still experience post treatment non-infectious complications that limit their functionality. The investigators anticipate this treatment will mitigate against this and lead to improvement in the quality of life of patients and survivors. Both direct and indirect costs of the disease can be rechanneled to revamp the health system and other economic potentials of the developing world. If this prove successful, there would be an accelerated and significant progress to achieving the World Health Organization and End TB Sustainable Development Goals. Overall the investigators anticipate a great turn around in the socio-economic life of people and countries of the developing world where TB has caused untoward and unimaginable stagnation.