Journal Article

Subtherapeutic Rifampicin Concentration Is Associated With Unfavorable Tuberculosis Treatment Outcomes

Gupte, Akshay, Chandrasekaran, Padmapriyadarshini, Gupte, Nikhil, Kadam, Dileep, Dooley, Kelly E., Sivaramakrishnan, Gomathi Narayan, Pradhan, Neeta, Kagal, Anju, Hanna, Luke Elizabeth, Kulkarni, Vandana, Kupparam, Hemanth Kumar Agibothu, Paradkar, Mandar, Gaikwad, Sanjay, Gupta, Amita, Ramachandran, Geetha, Thomas, Beena, Balasubramanian, Usha, Swaminathan, Soumya, Dhanasekaran, Kavitha, Mave, Vidya, Thiruvengadam, Kannan, Golub, Jonathan, Murali, Lakshmi, Shivakumar, Shri Vijay Bala Yogendra

2020

Overview

Abstract Background The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood. Methods We enrolled a prospective cohort of patients with new pulmonary TB receiving thrice-weekly treatment in India. The maximum plasma concentration of each drug was determined at months 1 and 5 using blood samples drawn 2 hours postdose. Subtherapeutic cutoffs were: rifampicin <8 µg/mL, isoniazid <3 µg/mL, and pyrazinamide <20 µg/mL. Factors associated with lower log-transformed drug concentrations, unfavorable outcomes (composite of treatment failure, all-cause mortality, and recurrence), and individual outcomes were examined using Poisson regression models. Results Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were subtherapeutic in 85%, 29%, and 13%, respectively, at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with human immunodeficiency virus coinfection (median, 1.6 vs 4.6 µg/mL; P = .015). Unfavorable outcome was observed in 19%; a 1-μg/mL decrease in rifampicin concentration was independently associated with unfavorable outcome (adjusted incidence rate ratio [aIRR], 1.21 [95% confidence interval {CI}, 1.01–1.47]) and treatment failure (aIRR, 1.16 [95% CI, 1.05–1.28]). A 1-μg/mL decrease in pyrazinamide concentration was associated with recurrence (aIRR, 1.05 [95% CI, 1.01–1.11]). Conclusions Rifampicin concentrations were subtherapeutic in most Indian patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide concentrations were associated with poor outcomes. Higher or more frequent dosing is needed to improve TB treatment outcomes in India. In a prospective cohort of patients with newly diagnosed pulmonary tuberculosis receiving standard thrice-weekly antituberculosis treatment in India, lower rifampicin concentration was associated with Human Immunodeficiency Virus coinfection and independently associated with unfavorable treatment outcomes.

• Publisher: Oxford University Press
• Subject: and Commentaries / Antitubercular Agents - therapeutic use / ARTICLES AND COMMENTARIES / Humans / India - epidemiology / Isoniazid / Prospective Studies / Pyrazinamide - therapeutic use / Rifampin - therapeutic use / Treatment Outcome / Tuberculosis - drug therapy