title: 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.
authors: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London, WC2B 6NH, UK. patrick.phillips@ucl.ac.uk.
authors: Patrick P J
authors: PP
authors: Phillips
authors: Global Alliance for TB Drug Development, New York, NY, USA.
authors: Carl M
authors: CM
authors: Mendel
authors: Department of Mathematical Statistics and Actuarial Science, University of the Free State, Bloemfontein, South Africa.
authors: Divan A
authors: DA
authors: Burger
authors: Angela M
authors: AM
authors: Crook
authors: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London, WC2B 6NH, UK.
authors: Angela
authors: A
authors: Crook
authors: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London, WC2B 6NH, UK.
authors: Andrew J
authors: AJ
authors: Nunn
authors: Division of Pulmonology and Department of Medicine, University of Cape Town Lung Institute, Mowbray, Cape Town, South Africa.
authors: Rodney
authors: R
authors: Dawson
authors: Division of Physiology, Department of Medical Biochemistry, Stellenbosch University, Tygerberg, Cape Town, South Africa.|TASK Applied Science, Bellville, Cape Town, South Africa.
authors: Andreas H
authors: AH
authors: Diacon
authors: School of Medicine, University of St Andrews, St Andrews, UK.
authors: Stephen H
authors: SH
authors: Gillespie
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use*; D015415:Biomarkers; D003657:Decision Making; D018450:Disease Progression; D004352:Drug Resistance, Microbial; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D005791:Patient Care / Q000379:methods; D013183:Sputum / Q000382:microbiology*; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D015415:Biomarkers