Transformation Morphisms and Time-to-Extinction Analysis That Map Therapy Duration from Preclinical Models to Patients with Tuberculosis: Translating from Apples to Oranges

22Citations
Citations of this article
43Readers
Mendeley users who have this article in their library.

Abstract

Background. A major challenge in medicine is translation of preclinical model findings to humans, especially therapy duration. One major example is recent shorter-duration therapy regimen failures in tuberculosis. Methods. We used set theory mapping to develop a computational/modeling framework to map the time it takes to extinguish the Mycobacterium tuberculosis population on chemotherapy from multiple hollow fiber system model of tuberculosis (HFS-TB) experiments to that observed in patients. The predictive accuracy of the derived translation transformations was then tested using data from 108 HFS-TB Rapid Evaluation of Moxifloxacin in Tuberculosis (REMoxTB) units, including 756 colony- forming units (CFU)/mL. Derived transformations, and Latin hypercube sampling-guided simulations were used to predict cure and relapse after 4 and 6 months of therapy. Outcomes were compared to observations, in 1932 patients in the REMoxTB clinical trial. Results. HFS-TB serial bacillary burden and serial sputum data in the derivation dataset formed a structure-preserving map. Bactericidal effect was mapped with a single step transformation, while the sterilizing effect was mapped with a 3-step transformation function. Using the HFS-TB REMoxTB data, we accurately predicted the proportion of patients cured in the 4-month REMoxTB clinical trial. Model-predicted vs clinical trial observations were (i) the ethambutol arm (77.0% [95% confidence interval {CI}, 74.4%-79.6%] vs 77.7% [95% CI, 74.3%-80.9%]) and (ii) the isoniazid arm (76.4% [95% CI, 73.9%-79.0%] vs 79.5% [95% CI, 76.1%-82.5%]). Conclusions. We developed a method to translate duration of therapy outcomes from preclinical models to tuberculosis patients.

Cite

CITATION STYLE

APA

Magombedze, G., Pasipanodya, J. G., Srivastava, S., Deshpande, D., Visser, M. E., Chigutsa, E., … Gumbo, T. (2018). Transformation Morphisms and Time-to-Extinction Analysis That Map Therapy Duration from Preclinical Models to Patients with Tuberculosis: Translating from Apples to Oranges. Clinical Infectious Diseases, 67, S349–S358. https://doi.org/10.1093/cid/ciy623

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free