Subtherapeutic rifampicin concentration is associated with unfavourable tuberculosis treatment outcomes

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. Maximum plasma concentration of each drug was determined at month 1 and 5 using blood samples drawn 2 hours post-dose. Sub-therapeutic cut-offs were: rifampicin <8µg/mL; isoniazid <3µg/mL; pyrazinamide <20µg/mL. Factors associated with lower log-transformed drug concentrations, unfavourable outcomes (composite of treatment failure, all-cause mortality, and recurrence) as well as individual outcomes were examined using Poisson regression models.

RESULTS:
Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were sub-therapeutic in 85%, 29%, and 12% at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with HIV co-infection (1.6 µg/ml vs 4.6 µg/ml; p = 0.015). Unfavourable outcome was observed in 19%; a 1 ug/ml decrease in rifampicin concentration was independently associated with unfavourable outcome (aIRR 1.21, 95% CI: 1.01 - 1.47) and treatment failure (aIRR: 1.16; 95% CI: 1.05 - 1.28). A 1 ug/ml decrease in pyrazinamide concentration was associated with recurrence (aIRR: 1.05; 95% CI: 1.01-1.11).

CONCLUSIONS:
Rifampicin concentrations were sub-therapeutic 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.