Subtherapeutic Rifampicin Concentration Is Associated With Unfavorable Tuberculosis Treatment Outcomes

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.

Keywords: drug concentrations; pharmacokinetics; subtherapeutic concentrations; tuberculosis; unfavorable treatment outcomes.

Figure 1.

Plasma concentrations of tuberculosis (TB) drugs at months 1 and 5 among adults with favorable and unfavorable TB treatment outcomes. Median 2-hour postdose plasma concentrations with interquartile range are shown (horizontal line within rectangle) for rifampicin, isoniazid, and pyrazinamide during the acute (month 1) and continuous (month 5) phases of TB treatment by treatment outcome. “Favorable” is defined as cure or treatment completion; “unfavorable” is defined as treatment failure or recurrence or all-cause mortality up to 24 months following treatment initiation. Horizontal dashed lines represent subtherapeutic cutoffs for each drug. Rifampicin levels were largely subtherapeutic throughout anti-TB treatment and significantly lower among patients with unfavorable outcome at month 5 (denoted by the asterisk).