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PLoS One. 2015 Apr 29;10(4):e0125403. doi: 10.1371/journal.pone.0125403. eCollection 2015.

Month 2 culture status and treatment duration as predictors of recurrence in pulmonary tuberculosis: model validation and update.

Author information

1
Aurum Institute, Johannesburg, South Africa.
2
Certara, LP, St. Louis, Missouri, United States of America.

Abstract

BACKGROUND:

New regimens capable of shortening tuberculosis treatment without increasing the risk of recurrence are urgently needed. A 2013 meta-regression analysis, using data from trials published from 1973 to 1997 involving 7793 patients, identified 2-month sputum culture status and treatment duration as independent predictors of recurrence. The resulting model predicted that if a new 4-month regimen reduced the proportion of patients positive at month 2 to 1%, it would reduce to 10% the risk of a relapse rate >10% in a trial with 680 subjects per arm. The 1% target was far lower than anticipated.

METHODS:

Data from the 8 arms of 3 recent unsuccessful phase 3 treatment-shortening trials of fluoroquinolone-substituted regimens (REMox, OFLOTUB, and RIFAQUIN) were used to assess and refine the accuracy of the 2013 meta-regression model. The updated model was then tested using data from a treatment shortening trial reported in 2009 by Johnson et al.

FINDINGS:

The proportions of patients with recurrence as predicted by the 2013 model were highly correlated with observed proportions as reported in the literature (R2 = 0.86). Using the previously proposed threshold of 10% recurrences as the maximum likely considered acceptable by tuberculosis control programs, the original model correctly identified all 4 six-month regimens as satisfactory, and 3 of 4 four-month regimens as unsatisfactory (sensitivity = 100%, specificity = 75%, PPV = 80%, and NPV = 100%). A revision of the regression model based on the full dataset of 66 regimens and 11181 patients resulted in only minimal changes to its predictions. A test of the revised model using data from the treatment shortening trial of Johnson et al found the reported relapse rates in both arms to be consistent with predictions.

INTERPRETATION:

Meta-regression modeling of recurrence based on month 2 culture status and regimen duration can inform the design of future phase 3 tuberculosis clinical trials.

PMID:
25923700
PMCID:
PMC4414505
DOI:
10.1371/journal.pone.0125403
[Indexed for MEDLINE]
Free PMC Article

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