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 - Funding Information:
Financial support. This work was primarily supported by the National Institute of Allergy and Infectious Diseases (NIAID), NIH (grant number R21AI127149 to V. M.). Research data in this manuscript were collected, in part, as part of the Regional Prospective Observational Research for Tuberculosis (RePORT) India Consortium. This work was funded in whole or in part by federal funds from the DBT; the ICMR; the Office of AIDS Research, NIAID/NIH; CRDF Global; the NIH Baltimore- Washington-India Clinical Trials Unit for the NIAID Networks (grant number UM1AI069465 to A. G.); and the NIH (grant number R01AI097494 to J. E. G.).
Funding Information:
Financial support. This work was primarily supported by the National Institute of Allergy and Infectious Diseases (NIAID), NIH (grant number R21AI127149 to V. M.). Research data in this manuscript were collected, in part, as part of the Regional Prospective Observational Research for Tuberculosis (RePORT) India Consortium. This work was funded in whole or in part by federal funds from the DBT; the ICMR; the Office of AIDS Research, NIAID/NIH; CRDF Global; the NIH Baltimore-Washington-India Clinical Trials Unit for the NIAID Networks (grant number UM1AI069465 to A. G.); and the NIH (grant number R01AI097494 to J. E. G.).
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
VL - 70
SP - 1463
EP - 1470
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
SN - 1058-4838
IS - 7
ER -