Duration of pretomanid/moxifloxacin/pyrazinamide therapy compared with standard therapy based on time-to-extinction mathematics.

Objectives Animal models have suggested that the combination of pretomanid with pyrazinamide and moxifloxacin (PaMZ) may shorten TB therapy duration to 3-4months. Here, we tested that in the hollow-fibre system model of TB (HFS-TB). Methods A series of HFS-TB experiments were performed to compare the kill rates of the PaMZ regimen with the standard three-drug combination therapy. HFS-TB experiments were performed with bacilli in log-phase growth treated for 28days, intracellular bacilli treated daily for 28days and semi-dormant Mycobacterium tuberculosis treated with daily therapy for 56days for sterilizing effect. Next, time-to-extinction equations were employed, followed by morphism transformation and Latin hypercube sampling, to determine the proportion of patients who achieved a time to extinction of 3, 4 or 6months with each regimen. Results Using linear regression, the HFS-TB sterilizing effect rates of the PaMZ regimen versus the standard-therapy regimen during the 56days were 0.18 (95% credible interval=0.13-0.23) versus 0.15 (95% credible interval=0.08-0.21) log(10)cfu/mL/day, compared with 0.16 (95% credible interval=0.13-0.18) versus 0.11 (95% credible interval=0.09-0.13) log(10)cfu/mL/day in the Phase II clinical trial, respectively. Using time-to-extinction and Latin hypercube sampling modelling, the expected percentages of patients in which the PaMZ regimen would achieve sterilization were 40.37% (95% credible interval=39.1-41.34) and 72.30% (95% credible interval=71.41-73.17) at 3 and 4months duration of therapy, respectively, versus 93.67% (95% credible interval=93.18-94.13) at 6months for standard therapy. Conclusions The kill rates of the PaMZ regimen were predicted to be insufficient to achieve cure in less than 6months in most patients.