Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

Abstract

Background: Despite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials.

Methods: Using data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome.

Results: Time to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP.

Conclusions: Culture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383.

Fig. 1

Fit of non-linear mixed effects model of MGIT TTP during the first 56 days of treatment with three anti-tuberculosis regimens

Fig. 2

Trial-level surrogacy plot. a Time to culture negative status on LJ. b Time to culture negative status in MGIT. c BA(0–56), daily rate of change in log10(TTP) to day 56. The difference between treatments on the intermediate marker is plotted against the difference in unfavourable outcome with 95 % confidence intervals. Points lying outside the yellow regions indicate that the treatment difference is in the opposite direction on the intermediate marker from the long-term clinical outcome

Fig. 3

Estimates of probability of an unfavourable outcome by treatment arm and by intermediate marker. a Time to culture negative status on LJ. b Time to culture negative status in MGIT. c BA(0–56), daily rate of change in log₁₀(TTP) to day 56. d Time to smear negative. Vertical solid and dashed lines show various centiles of the intermediate markers for patients in the control arm in the REMoxTB trial

Fig. 4

Receiver operating characteristic (ROC) curves. All curves represent models adjusted for baseline covariates. a Control arm. b Isoniaizid arm. c Ethambutol arm