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Longitudinal Model-Based Biomarker Analysis of Exposure-Response Relationships in Adults with Pulmonary Tuberculosis.
Gewitz, Andrew D; Solans, Belén P; Mac Kenzie, William R; Heilig, Chad; Whitworth, William C; Johnson, John L; Nsubuga, Pheona; Dorman, Susan; Weiner, Marc; Savic, Radojka M.
Afiliação
  • Gewitz AD; University of California San Francisco Schools of Pharmacy and Medicine, San Francisco, California, USA.
  • Solans BP; University of California San Francisco Schools of Pharmacy and Medicine, San Francisco, California, USA.
  • Mac Kenzie WR; Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
  • Heilig C; Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
  • Whitworth WC; Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
  • Johnson JL; Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
  • Nsubuga P; Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda.
  • Dorman S; Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda.
  • Weiner M; Johns Hopkins Universitygrid.21107.35 School of Medicine, Baltimore, Maryland, USA.
  • Savic RM; Veterans Administration Medical Center, San Antonio, Texas, USA.
Antimicrob Agents Chemother ; 65(10): e0179420, 2021 09 17.
Article em En | MEDLINE | ID: mdl-34252302
The identification of sensitive, specific, and reliable biomarkers that can be quantified in the early phases of tuberculosis treatment and predictive of long-term outcome is key for the development of an effective short-course treatment regimen. Time to positivity (TTP), a biomarker of treatment outcome against Mycobacterium tuberculosis, measures longitudinal bacterial growth in mycobacterial growth indicator tube broth culture and may be predictive of standard time to stable culture conversion (TSCC). In two randomized phase 2b trials investigating dose-ranging rifapentine (Studies 29 and 29X), 662 participants had sputum collected over 6 months where TTP, TSCC, and time to culture conversion were quantified. The goals of this post hoc study were to characterize longitudinal TTP profiles and to identify individual patient characteristics associated with delayed time to culture conversion. In order to do so, a nonlinear mixed-effects model describing longitudinal TTP was built. Independent variables associated with increased bacterial clearance (increased TTP), assessed by subject-specific and population-level trajectories, were higher rifapentine exposure, lower baseline grade of sputum acid-fast bacillus smear, absence of productive cough, and lower extent of lung infiltrates on radiographs. Importantly, sensitivity analysis revealed that major learning milestones in phase 2b trials, such as significant exposure-response and covariate relationships, could be detected using truncated TTP data as early as 6 weeks from start of treatment, suggesting alternative phase 2b study designs. The TTP model built depicts a novel phase 2b surrogate endpoint that can inform early assessment of experimental treatment efficacy and treatment failure or relapse in patients treated with shorter and novel TB treatment regimens, improving efficiency of phase 2 clinical trials. (The studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT00694629 and NCT01043575.).
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tuberculose Pulmonar / Mycobacterium tuberculosis Tipo de estudo: Clinical_trials / Prognostic_studies / Risk_factors_studies Limite: Adult / Humans Idioma: En Revista: Antimicrob Agents Chemother Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tuberculose Pulmonar / Mycobacterium tuberculosis Tipo de estudo: Clinical_trials / Prognostic_studies / Risk_factors_studies Limite: Adult / Humans Idioma: En Revista: Antimicrob Agents Chemother Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos