Longitudinal Model-Based Biomarker Analysis of Exposure-Response Relationships in Adults with Pulmonary Tuberculosis.
Longitudinal Model-Based Biomarker Analysis of Exposure-Response Relationships in Adults with Pulmonary Tuberculosis.
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DOI：
10.1128/aac.01794-20
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发表时间：
2021-09-17
影响因子：
4.9
通讯作者：
Tuberculosis Trials Consortium of the Centers for Disease Control and Prevention
中科院分区：
文献类型：
--
作者：
Gewitz AD;Solans BP;Mac Kenzie WR;Heilig C;Whitworth WC;Johnson JL;Nsubuga P;Dorman S;Weiner M;Savic RM;Tuberculosis Trials Consortium of the Centers for Disease Control and Prevention
识别敏感、特异和可靠的生物标志物，可以在结核病治疗的早期阶段进行量化，并预测长期结果，是开发有效的短程治疗方案的关键。阳性时间(TTP)是抗结核分枝杆菌治疗结果的生物标志物，它衡量分枝杆菌生长指示管肉汤培养中的纵向细菌生长，并可能预测标准的稳定培养转换时间(TSCC)。在两个研究剂量范围利福喷丁的2b期随机试验(研究29和29x)中，662名参与者收集了6个月的痰，对TTP、TSCC和培养转化时间进行了量化。这项特别研究的目标是确定纵向TTP图谱的特征，并确定与延迟培养转换时间相关的个体患者特征。为此，建立了描述纵向TTP的非线性混合效应模型。通过特定受试者和人群水平的轨迹评估，与细菌清除量增加(TTP增加)相关的独立变量是较高的利福喷丁暴露，较低的痰抗酸杆菌涂片基线等级，无生产性咳嗽，以及X线片上较低的肺部浸润度。重要的是，敏感性分析显示，2b期试验中的主要学习里程碑，如显著的暴露-反应和协变量关系，最早可以在治疗开始后6 周使用截短的ttp数据检测到，这建议了替代的2b期研究设计。建立的TTP模型描述了一种新的2b期替代终点，该终点可以为使用较短和新的结核病治疗方案治疗的患者的实验治疗效果和治疗失败或复发的早期评估提供信息，从而提高第二阶段临床试验的效率。(本文讨论的研究已在ClinicalTrials.gov上注册，标识为NCT00694629和NCT01043575。)
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.)