Month 2 culture status and treatment duration as predictors of tuberculosis relapse risk in a meta-regression model

Abstract

Background: New drugs and regimens with the potential to transform tuberculosis treatment are presently in early stage clinical trials.

Objective: The goal of the present study was to infer the required duration of these treatments.

Method: A meta-regression model was developed to predict relapse risk using treatment duration and month 2 sputum culture positive rate as predictors, based on published historical data from 24 studies describing 58 regimens in 7793 patients. Regimens in which rifampin was administered for the first 2 months but not subsequently were excluded. The model treated study as a random effect.

Results: The model predicted that new regimens of 4 or 5 months duration with rates of culture positivity after 2 months of 1% or 3%, would yield relapse rates of 4.0% or 4.1%, respectively. In both cases, the upper limit of the 2-sided 80% prediction interval for relapse for a hypothetical trial with 680 subjects per arm was <10%. Analysis using this model of published month 2 data for moxifloxacin-containing regimens indicated they would result in relapse rates similar to standard therapy only if administered for ≥5 months.

Conclusions: This model is proposed to inform the required duration of treatment of new TB regimens, potentially hastening their accelerated approval by several years.

Conflict of interest statement

Competing Interests: All authors are Pfizer employees and shareholders. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Two views of the interrelationship of relapse, duration, and month 2 culture status, as predicted by meta-regression analysis.

Left: Relapse vs. month 2 culture positivity for regimens of 4, 5, and 6 months duration. Right: Relapse vs. duration for regimens with month 2 positive rates of 1 to 17%.