Pirfenidone is a recently approved antifibrotic drug for the treatment of
idiopathic pulmonary fibrosis (IPF). Because
tuberculosis (TB) is characterized by granulomatous
inflammation in conjunction with parenchymal destruction and replacement
fibrosis, we sought to determine whether the addition of
pirfenidone as an adjunctive, host-directed
therapy provides a beneficial effect during antimicrobial treatment of TB. We hypothesized that
pirfenidone's antiinflammatory and antifibrotic properties would reduce inflammatory lung damage and increase antimicrobial drug penetration in
granulomas to accelerate treatment response. The effectiveness of adjunctive
pirfenidone during TB
drug therapy was evaluated using a murine model of chronic TB. Mice treated with standard
therapy 2HRZ/4HR (H,
isoniazid; R,
rifampin; and Z,
pyrazinamide) were compared with 2 alternative regimens containing
pirfenidone (Pf) (2HRZPf/4HRPf and 2HRZPf/4HR). Contrary to our hypothesis, adjunctive
pirfenidone use leads to reduced bacterial clearance and increased relapse rates. This treatment failure is closely associated with the emergence of
isoniazid monoresistant bacilli, increased cavitation, and significant lung pathology. While
antifibrotic agents may eventually be used as part of adjunctive host-directed
therapy of TB, this study clearly demonstrates that caution must be exercised. Moreover, as
pirfenidone becomes more widely used in clinical practice, increased patient monitoring would be required in endemic TB settings.