Atorvastatin-containing Treatment Regimens for Pulmonary Tuberculosis: A Randomized, Open-label, Controlled phase2C/3 Clinical Trial

INTRODUCTION Tuberculosis is a chronic disease responsible for most deaths from infectious disease with an estimated I0 million cases and close to 2 million deaths globally. 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. 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. 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. Mycobacterium tuberculosis also utilizes cholesterol as a vehicle to enter macrophage, inhibit phagocytosis and inhibit growth and development of phagocytes. These greatly impairs the hydrolytic and antimicrobial properties and activities of phagocytes. 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 ranges 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. 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. 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. 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. 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. 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). 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.

The ATORTUB investigators recently completed two phase 2 studies to assess the safety, tolerability and efficacy of atorvastatin administered with the current standard of care. The first study was a phase IIA study involving 40 patients randomized to receive standard of care alone and standard of care with oral (40mg) dose atorvastatin. Primary outcome at 2 weeks was safety, tolerability and early bactericidal activity over a 2 week period. The study showed that atorvastatin was generally safe and well tolerated. The rate of decline of colony forming unit was higher among the atorvastatin group. Even though there was no early bactericidal activity demonstrated at 2 weeks, atorvastatin group had significantly number of participants with more than 0.5 log10 decline in colony forming unit. This was quite significant. At the phase IIB study, 150 eligible participant's were randomly assigned to either of the two arms. All the participants had rifampicin sensitive active non complicated TB. Other drug resistance testing were not done. Oral dose of 40mg of atorvastatin was given for 2 months together with standard of care drugs and afterwards the standard of care drugs were continued for the patients to complete 6 months of therapy. Primary outcome were safety and tolerability atorvastatin , efficacy measured by the number of sputum conversion at 2 months. Secondary outcome was chest x-ray severity score at 2 months. AT the end of the phase IIB trial, it was shown that atorvastatin was generally safe and in fact participants in that group had reduced incidence of peripheral neuropathy. More participants achieved sputum conversion compared with the standard of care group. The mean improvement in chest x-ray severity score was higher in the experimental group Atorvastatin in combination with standard antituberculosis drugs achieved a significantly higher rate of sputum culture negativity and reduction in mycobacterial burden in sputum at 2 months compared with antituberculosis drugs alone. The difference in sputum negativity and the mean fall in colony forming unit per ml of sputum per month were significantly higher among the intervention group. The use of atorvastatin was also significantly associated with a negative sputum result. These may be indicative of the anti-mycobactericidal effect of atorvastatin, which had been earlier reported in murine models, other invitro studies and consistent with the earlier phase IIA result .