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Subtherapeutic rifampicin concentration is associated with unfavourable tuberculosis treatment outcomes
Clinical Infectious Diseases
The relationships between first-line drug concentrations and clinically-important outcomes among patients with tuberculosis (TB) remain poorly understood.
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.
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).
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.
Ramachandran G, Chandrasekaran P, Gaikwad S, Hemanth Kumar AK, Thiruvengadam K, Gupte N, Paradkar M, Dhanasekaran K, Sivaramakrishnan GN, Kagal A, Thomas B, Pradhan N, Kadam D, Hanna LE, Balasubramanian U, Kulkarni V, Murali L, Golub J, Gupte A, Shivakumar SVBY, Swaminathan S, Dooley KE, Gupta A, Mave V; C-TRIUMPh team. Subtherapeutic rifampicin concentration is associated with unfavourable tuberculosis treatment outcomes. Clin Infect Dis. 2019 May 10. pii: ciz380. doi: 10.1093/cid/ciz380. [Epub ahead of print]. PMID: 31075166.