PI-009 - PREDICTORS AFFECTING SPUTUM CULTURE CONVERSION IN PATIENTS WITH DRUG-SUSCEPTIBLE PULMONARY TUBERCULOSIS TREATED WITH A SHORTENED DRUG REGIMEN.

P. Van Brantegem¹, V. Chang¹, M. Imperial¹, R. Savic¹, A. Tuberculosis Trials Consortium²; ¹University of California, San Francisco, San Francisco, CA, USA, ²AIDS Clinical Trials Group and the Tuberculosis Trials Consortium, , USA.

Background: Sputum cultures (SCs) are the gold-standard biomarker to assess response to tuberculosis (TB) treatment (1). The aim was to identify predictors of SC conversion (SCC) for various regimens of drug susceptible (DS) TB.

Methods: S31/A5349 is a phase 3, randomized, controlled trial investigating a 4-month rifapentine with (HPZM) or without (HPZE) moxifloxacin regimen compared to the WHO recommended 6-month regimen (HRZE) for DSTB (n = 2343). SCs were collected at each study visit (inclusion, 2, 4, 8, 12, 17, 22 and right censored at 26 weeks). SCC was defined as 2 consecutive negative SCs (2).
Patient characteristics, disease burden and drug pharmacokinetics (AUC) were explored as univariate predictors of SCC using Cox proportional hazard regression (R software).

Results: Measures of disease burden were the most significant predictors of SCC: GeneXpert cycle threshold (bacterial burden; hazard ratio [95% confidence interval]: 1.92 [1.55-2.37] in HPZM), presence of cavities in chest radiographs (>= 4 cm vs no cavities; 0.69 [0.57-0.82] in HPZM), extent of disease in chest radiographs (lesions >= 1/2 vs lesions < 1/2 of the thoracic area; 0.71 [0.58-0.87] in HPZM). Similar results were obtained in HRZE and HPZE.
SCC was shortened in participants with increased AUC of rifapentine (1.04 for 100 µg*h/mL increase [1.00-1.09] in HPZE and 1.08 [1.04-1.12] in HPZM), moxifloxacin (1.14 for 10 µg*h/mL increase [1.03-1.25] in HPZM), and pyrazinamide (1.10 for 100 µg*h/mL increase [1.00-1.19] in HRZE and 1.15 [1.06-1.24] in HPZM). Significant patient characteristics are African site, sex and age.

Conclusion: Disease burden factors are the most impactful determinants on SCC, followed by drug exposures. These findings are relevant for the design of future dose-finding studies in DSTB.

1. Falzon D, Jaramillo E, Schünemann HJ, Arentz M, Bauer M, Bayona J, et al. WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J. 2011 Sep;38(3):516–28.
2. Dorman SE, Nahid P, Kurbatova EV, Goldberg SV, Bozeman L, Burman WJ, et al. High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial. Contemp Clin Trials. 2020 Mar;90:105938.