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

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.

Fig 1. Observed and predicted proportions of subjects with tuberculosis recurrence in the 8 arms of the 3 trials comprising the validation dataset, based on all recurrences (left panel) and only those with full culture confirmation (right panel).

Recurrences were predicted using the original mathematical model as reported in reference [5]. Axes indicate logit-transformed recurrence risk; inset scales indicate corresponding percentages. Red symbols indicate 4 month regimens; green symbols indicate 6 month regimens. Error bars indicate 80% confidence intervals (10%-90%). Vertical and horizontal dotted lines indicate recurrence rates of 10% (-2.2 after logit transformation).

Fig 2. Predicted proportion of patients with recurrence based on the proportion positive after 2 months of treatment, for regimens of 4 and 6 months duration.

Axes indicate logit-transformed proportions; inset scales indicate corresponding percentages. Solid and dotted lines indicate updated and original model predictions, respectively. Shading indicates 80% confidence intervals for the updated estimates.