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Transformation Morphisms and Time-to-Extinction Analysis That Map Therapy Duration From Preclinical Models to Patients With Tuberculosis: Translating From Apples to Oranges.
Magombedze, Gesham; Pasipanodya, Jotam G; Srivastava, Shashikant; Deshpande, Devyani; Visser, Marianne E; Chigutsa, Emmanuel; McIlleron, Helen; Gumbo, Tawanda.
Affiliation
  • Magombedze G; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, Texas.
  • Pasipanodya JG; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, Texas.
  • Srivastava S; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, Texas.
  • Deshpande D; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, Texas.
  • Visser ME; Division of Pharmacology, Department of Medicine, University of Cape Town, Observatory, South Africa.
  • Chigutsa E; Division of Pharmacology, Department of Medicine, University of Cape Town, Observatory, South Africa.
  • McIlleron H; Division of Pharmacology, Department of Medicine, University of Cape Town, Observatory, South Africa.
  • Gumbo T; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, Texas.
Clin Infect Dis ; 67(suppl_3): S349-S358, 2018 11 28.
Article in En | MEDLINE | ID: mdl-30496464
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tuberculosis / Ethambutol / Moxifloxacin / Isoniazid / Mycobacterium tuberculosis / Antitubercular Agents Type of study: Prognostic_studies Limits: Humans Language: En Journal: Clin Infect Dis Journal subject: DOENCAS TRANSMISSIVEIS Year: 2018 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tuberculosis / Ethambutol / Moxifloxacin / Isoniazid / Mycobacterium tuberculosis / Antitubercular Agents Type of study: Prognostic_studies Limits: Humans Language: En Journal: Clin Infect Dis Journal subject: DOENCAS TRANSMISSIVEIS Year: 2018 Document type: Article Country of publication: United States