Statins as Host-Directed Therapy for Tuberculosis

Abstract

Statins are a class of drugs that inhibit HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis, and are commonly used for primary and secondary prevention of cardiovascular disease. In addition to lowering cholesterol, statins also have broad immunomodulatory properties, and their use has been associated with improved clinical outcomes in patients with community-acquired pneumonia and sepsis. Multiple retrospective cohort studies have shown that statin use is associated with reduced tuberculosis (TB) incidence. Although at clinically recommended drug exposures they lack direct activity against Mycobacterium tuberculosis (Mtb), statins enhance the ability of Mtb-infected macrophages to clear intracellular infection by promoting autophagy and phagosome maturation. Recent data have revealed that these biological effects are dependent on inhibition of cholesterol biosynthesis and are mediated through the AMPK-mTORC1-TFEB-autophagy axis. Animal model studies have supported a role for statin adjunctive therapy against TB. Thus, the addition of simvastatin to the first-line antitubercular regimen reduced the duration of curative treatment by one month in the standard mouse model of chronic tuberculosis (TB), and pravastatin similarly showed potent, dose-dependent adjunctive activity in this model, as well as in a novel mouse model with human-like necrotic TB lung granulomas. An ongoing randomized clinical trial, Statin Adjunctive Therapy for TB (StAT-TB) is evaluating the safety, pharmacokinetics and adjunctive activity of pravastatin in patients with drug-susceptible, pulmonary TB.