Simulations Plus, Inc, 42505 10th Street W, Lancaster, CA, 93534, USA.
DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
BMC Infect Dis. 2022 Apr 2;22(1):327. doi: 10.1186/s12879-022-07308-3.
Despite the high global disease burden of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) infection, novel treatments remain an urgent medical need. Development efforts continue to be hampered by the reliance on culture-based methods, which often take weeks to obtain due to the slow growth rate of Mtb. The availability of a "real-time" measure of treatment efficacy could accelerate TB drug development. Sputum lipoarabinomannan (LAM; an Mtb cell wall glycolipid) has promise as a pharmacodynamic biomarker of mycobacterial sputum load.
The present analysis evaluates LAM as a surrogate for Mtb burden in the sputum samples from 4 cohorts of a total of 776 participants. These include those from 2 cohorts of 558 non-TB and TB participants prior to the initiation of treatment (558 sputum samples), 1 cohort of 178 TB patients under a 14-day bactericidal activity trial with various mono- or multi-TB drug therapies, and 1 cohort of 40 TB patients with data from the first 56-day treatment of a standard 4-drug regimen.
Regression analysis demonstrated that LAM was a predictor of colony-forming unit (CFU)/mL values obtained from the 14-day treatment cohort, with well-estimated model parameters (relative standard error ≤ 22.2%). Moreover, no changes in the relationship between LAM and CFU/mL were observed across the different treatments, suggesting that sputum LAM can be used to reasonably estimate the CFU/mL in the presence of treatment. The integrated analysis showed that sputum LAM also appears to be as good a predictor of time to Mycobacteria Growth Incubator Tube (MGIT) positivity as CFU/mL. As a binary readout, sputum LAM positivity is a strong predictor of solid media or MGIT culture positivity with an area-under-the-curve value of 0.979 and 0.976, respectively, from receiver-operator curve analysis.
Our results indicate that sputum LAM performs as a pharmacodynamic biomarker for rapid measurement of Mtb burden in sputum, and thereby may enable more efficient early phase clinical trial designs (e.g., adaptive designs) to compare candidate anti-TB regimens and streamline dose selection for use in pivotal trials. Trial registration NexGen EBA study (NCT02371681).
尽管结核病（TB）全球疾病负担很高，这种疾病是由结核分枝杆菌（Mtb）感染引起的，但仍急需新型疗法。由于 Mtb 生长缓慢，培养为基础的方法通常需要数周时间才能获得，这一方法的依赖严重阻碍了研发工作的进展。如果有一种“实时”的治疗效果衡量标准，可能会加速结核病药物的开发。分枝杆菌细胞外脂阿拉伯甘露聚糖（LAM；一种 Mtb 细胞壁糖脂）作为分枝杆菌痰负荷的药效学生物标志物具有一定的潜力。
本分析评估了 LAM 作为来自 776 名参与者的 4 个队列的痰样本中 Mtb 负荷的替代指标。这些队列包括 2 个队列的 558 名非 TB 和 TB 参与者在开始治疗前（558 份痰样本）、1 个队列的 178 名 TB 患者接受各种单药或多药 TB 药物治疗的 14 天杀菌活性试验、以及 1 个队列的 40 名 TB 患者接受标准 4 药方案的前 56 天治疗的数据。
回归分析表明，LAM 是来自 14 天治疗队列的 CFU/mL 值的预测因子，模型参数估计良好（相对标准误差≤22.2%）。此外，在不同的治疗中，LAM 与 CFU/mL 之间的关系没有变化，这表明在治疗存在的情况下，痰 LAM 可以合理地估计 CFU/mL。综合分析表明，痰 LAM 似乎也是预测分枝杆菌生长孵育管（MGIT）阳性时间的良好指标，与 CFU/mL 一样。作为一个二值读数，痰 LAM 阳性是固体培养基或 MGIT 培养阳性的一个强有力的预测因子，来自接收器操作特征曲线分析的曲线下面积值分别为 0.979 和 0.976。
我们的结果表明，痰 LAM 可作为快速测量痰中 Mtb 负荷的药效学生物标志物，从而可能使更有效的早期临床试验设计（例如，适应性设计）能够比较候选抗结核方案，并简化用于关键试验的剂量选择。试验注册 NexGen EBA 研究（NCT02371681）。
