Reply to Lai et al

To the Editor—We read with interest the letter by Lai et al [1] in response to our article on adjunctive host-directed therapy with statins for tuberculosis in preclinical models [2]. The authors have sought to assess potential differences among various statins, including atorvastatin, simvastatin, rosuvastatin, fluvastatin, and pravastatin, in their ability to prevent tuberculosis. They performed a population-based, nested case-control study of patients with active tuberculosis as case patients and healthy individuals as controls. Case patients and controls were matched by age, sex, and time of study recruitment. The authors performed regression analysis with very rigorous methods to control for all potential confounders.

Lai et al found that current statin use (ie, statin prescription filled within 30 days of the index date) was associated with a reduced risk of active tuberculosis, with an adjusted rate ratio of 0.79 (95% confidence interval [CI], .68–.92) [1]. When stratified by the type of statin used, only pravastatin use was associated with a significant reduction in the risk of active tuberculosis (adjusted rate ratio, 0.54; 95% CI, .30–.98). Although the other statins did not show a significant reduction in the risk of new-onset tuberculosis, the analysis did not have adequate power to compare tuberculosis incidence among the different statin groups due to a very low prevalence of statin use among cases and controls.

The findings of Lai et al [1] are largely consistent with those of systematic reviews based on observational studies by Duan et al [3] and Li et al [4], which showed that statin use reduces the risk of active tuberculosis disease with pooled risk ratios of 0.78 (95% CI, .63–.95) and 0.6 (.45–.75), respectively. This conclusion remained unchanged irrespective of subgroup analyses based on sex, diabetes status, and study design during meta-analysis. Neither of these meta-analyses stratified outcomes based on the type of statin used.

We have shown that statins have host-directed, antitubercular activity and that their use as adjunctive agents enhances Mycobacterium tuberculosis killing by the standard regimen in mice [2, 5]. Findings of our preclinical studies also suggest that this activity represents a class effect [6] mediated by cholesterol-driven autophagy via the AMP-activated protein kinase (AMPK)-mechanistic target of rapamycin complex 1 (mTORC1)-Transcription factor EB (TFEB) axis in macrophages [7].

To our knowledge, to date only one clinical study, by Chen et al [8], has evaluated the effect of statin use on outcomes of patients with tuberculosis. Although this population-based cohort study found that tuberculosis treatment completion rates did not improve after statin therapy, its conclusions were limited, in that the data were derived from an insurance database. Furthermore, no previous study has evaluated the effect of statin use on important clinical outcomes, such as mortality or long-term lung function, or on microbiological outcomes following tuberculosis treatment. Based on the available evidence, and given the favorable safety profile of statins, we believe randomized clinical trials are warranted to determine their potential utility in reducing tuberculosis incidence among latently infected individuals at high risk for tuberculosis reactivation, such as those with human immunodeficiency virus coinfection, and in improving clinical and microbiological outcomes in patients treated for active tuberculosis.

Notes

Acknowledgments. This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grants UH3AI122309 and K24AI143447 to P. C. K.).

Potential conflicts of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.