Bacterial Factors That Predict Relapse after Tuberculosis Therapy.
Bacterial Factors That Predict Relapse after Tuberculosis Therapy.
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DOI：
10.1056/nejmoa1715849
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发表时间：
2018-08-30
期刊：
影响因子：
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通讯作者：
DMID 01-009/Tuberculosis Trials Consortium Study 22 Teams
中科院分区：
文献类型：
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作者：
Colangeli R;Jedrey H;Kim S;Connell R;Ma S;Chippada Venkata UD;Chakravorty S;Gupta A;Sizemore EE;Diem L;Sherman DR;Okwera A;Dietze R;Boom WH;Johnson JL;Mac Kenzie WR;Alland D;DMID 01-009/Tuberculosis Trials Consortium Study 22 Teams
大约5%的药物敏感性结核病患者在一线治疗6个月后复发，大约20%的患者在短期治疗4个月后复发。我们假设，通过分析从随后复发或治愈的患者中获得的结核分枝杆菌预处理分离株，我们可以确定低于标准耐药折点的药物的最低抑菌浓度（MIC）与治疗后复发风险之间的任何相关性。使用来自结核病试验联盟研究22（开发队列）的数据，我们评估了复发和治愈分离株，以确定低于标准耐药断点（异烟肼为0.1 μg/ml，利福平为1.0 μg/ml）的异烟肼和利福平的MIC值。我们将该分析与临床，放射学和实验室数据相结合，以生成预测复发模型，我们通过分析DMID 01-009研究（验证队列）的数据进行验证。在发展队列中，复发组低于断点的异烟肼平均（±SD）MIC为0.0334±0.0085 μg/ml，治愈组为0.0286±0.0092 μg/ml，复发组的数值高出1.17倍（P=0.02）。利福平的MIC值分别为0.0695±0.0276和0.0453±0.0223 μg/ml，复发组的MIC值比对照组高1.53倍（P<0.001）。在多变量分析中，较高的MIC值仍然与复发相关，包括其他显著的组间差异。在基于这些MIC值的复发的接受者操作特征曲线的分析中，曲线下面积（AUC）为0.779。在开发队列中，包括MIC值的多变量模型中的AUC为0.875。在验证队列中，MIC值单独或与其他患者特征组合也可预测复发，AUC值分别为0.964和0.929。在交叉验证分析中，使用异烟肼和利福平MIC值的模型评分以达到75.0%的灵敏度，预测复发，在开发队列中的特异性为76.5%，在验证队列中的灵敏度为70.0%，特异性为100%。预处理M.当异烟肼或利福平的MIC值低于标准耐药折点时，较高的MIC值与较低的MIC值相比更大的复发风险相关。（由国家过敏和传染病研究所资助。
Approximately 5% of patients with drug-susceptible tuberculosis have a relapse after 6 months of first-line therapy, as do approximately 20% of patients after 4 months of short-course therapy. We postulated that by analyzing pretreatment isolates of Mycobacterium tuberculosis obtained from patients who subsequently had a relapse or were cured, we could determine any correlations between the minimum inhibitory concentration (MIC) of a drug below the standard resistance breakpoint and the relapse risk after treatment. Using data from the Tuberculosis Trials Consortium Study 22 (development cohort), we assessed relapse and cure isolates to determine the MIC values of isoniazid and rifampin that were below the standard resistance breakpoint (0.1 μg per milliliter for isoniazid and 1.0 μg per milliliter for rifampin). We combined this analysis with clinical, radiologic, and laboratory data to generate predictive relapse models, which we validated by analyzing data from the DMID 01–009 study (validation cohort). In the development cohort, the mean (±SD) MIC of isoniazid below the breakpoint was 0.0334±0.0085 μg per milliliter in the relapse group and 0.0286±0.0092 μg per milliliter in the cure group, which represented a higher value in the relapse group by a factor of 1.17 (P=0.02). The corresponding MIC values of rifampin were 0.0695±0.0276 and 0.0453±0.0223 μg per milliliter, respectively, which represented a higher value in the relapse group by a factor of 1.53 (P<0.001). Higher MIC values remained associated with relapse in a multivariable analysis that included other significant between-group differences. In an analysis of receiver-operating-characteristic curves of relapse based on these MIC values, the area under the curve (AUC) was 0.779. In the development cohort, the AUC in a multivariable model that included MIC values was 0.875. In the validation cohort, the MIC values either alone or combined with other patient characteristics were also predictive of relapse, with AUC values of 0.964 and 0.929, respectively. The use of a model score for the MIC values of isoniazid and rifampin to achieve 75.0% sensitivity in cross-validation analysis predicted relapse with a specificity of 76.5% in the development cohort and a sensitivity of 70.0% and a specificity of 100% in the validation cohort. In pretreatment isolates of M. tuberculosis with decrements of MIC values of isoniazid or rifampin below standard resistance breakpoints, higher MIC values were associated with a greater risk of relapse than lower MIC values. (Funded by the National Institute of Allergy and Infectious Diseases.)