TY - JOUR
T1 - Subtherapeutic rifampicin concentration is associated with unfavorable tuberculosis treatment outcomes
AU - for the Cohort for Tuberculosis Research by the Indo-US Partnership (CTRIUMPh) Team
AU - Ramachandran, Geetha
AU - Chandrasekaran, Padmapriyadarshini
AU - Gaikwad, Sanjay
AU - Agibothu Kupparam, Hemanth Kumar
AU - Thiruvengadam, Kannan
AU - Gupte, Nikhil
AU - Paradkar, Mandar
AU - Dhanasekaran, Kavitha
AU - Sivaramakrishnan, Gomathi Narayan
AU - Kagal, Anju
AU - Thomas, Beena
AU - Pradhan, Neeta
AU - Kadam, Dileep
AU - Hanna, Luke Elizabeth
AU - Balasubramanian, Usha
AU - Kulkarni, Vandana
AU - Murali, Lakshmi
AU - Golub, Jonathan
AU - Gupte, Akshay
AU - Shivakumar, Shri Vijay Bala Yogendra
AU - Swaminathan, Soumya
AU - Dooley, Kelly E.
AU - Gupta, Amita
AU - Mave, Vidya
N1 - Publisher Copyright:
© 2019 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
PY - 2020/3/17
Y1 - 2020/3/17
N2 - 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.
AB - 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.
KW - drug concentrations
KW - pharmacokinetics
KW - subtherapeutic concentrations
KW - tuberculosis
KW - unfavorable treatment outcomes
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U2 - 10.1093/cid/ciz380
DO - 10.1093/cid/ciz380
M3 - Article
C2 - 31075166
AN - SCOPUS:85082097847
SN - 1058-4838
VL - 70
SP - 1463
EP - 1470
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 7
ER -