Interferon-γ ELISPOT as a Biomarker of Treatment Efficacy in Latent Tuberculosis Infection A Clinical Trial
Interferon-γ ELISPOT as a Biomarker of Treatment Efficacy in Latent Tuberculosis Infection A Clinical Trial
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DOI：
10.1164/rccm.201208-1352oc
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发表时间：
2013-02-15
影响因子：
24.7
通讯作者：
Hill, Philip C.
中科院分区：
文献类型：
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作者：
Adetifa, Ifedayo M.;Ota, Martin O. C.;Hill, Philip C.
理由：迫切需要可用于评估针对潜伏性结核感染 (LTBI) 的新干预措施并预测结核病再激活的生物标志物。目标：评估 ESAT-6 和 CFP-10 (EC) IFN-gamma ELISPOT 作为 LTBI 治疗效果的生物标志物。方法：这是一项在 EC ELISPOT 和 Mantoux 测试阳性中对 INH 进行的随机、盲法和安慰剂对照试验测量和主要结果：参与者接受为期 6 个月的疗程，每周两次 900 毫克 INH 或匹配的安慰剂。确定 INH 乙酰化物基因型并检测尿液中 INH 代谢物以确认依从性。使用混合效应逻辑回归模型比较治疗组之间 CFP-10 和 ESAT-6 阳性反应者的比例。拟合 Tweedie（复合泊松）模型以允许定量响应的零膨胀和过度离散。 EC ELISPOT 阳性受试者的比例随着时间的推移而减少 (P < 0.001)，但不同研究组之间没有差异 (P = 0.36)。 ESAT-6 和 CFP-10 的中位点形成单位也随时间显着下降 (P < 0.001)，但不同研究组之间没有差异（P 分别为 0.74 和 0.71）。就 ELISPOT 结果而言，没有证据表明乙酰化状态与 INH 治疗之间存在相互作用。结论：在接触 LTBI 时，INH 治疗对观察到的结核分枝杆菌抗原特异性 T 细胞反应随时间的减少没有作用。 IFN-gamma ELISPOT 可能不是 LTBI 治疗效果的有用生物标志物。已在 www.clinicaltrials.gov 注册的临床试验（NCT 00130325）。
Rationale: Biomarkers that can be used to evaluate new interventions against latent tuberculosis infection (LTBI) and predict reactivation TB disease are urgently required.Objectives: To evaluate ESAT-6 and CFP-10 (EC) IFN-gamma ELISPOT as a biomarker for treatment efficacy in LTBI.Methods: This was a randomized, blinded, and placebo-controlled trial of INH in EC ELISPOT and Mantoux test positive participants.Measurements and Main Results: Participants received a 6-month course of 900 mg INH twice weekly or a matching placebo. INH acetylator genotypes were determined and urine tested for INH metabolites to confirm adherence. The proportion of positive responders for CFP-10 and ESAT-6 between treatment arms was compared using mixed effects logistic regression models. A Tweedie (compound Poisson) model was fitted to allow for zero inflation and overdispersion of quantitative response. The proportions of EC ELISPOT-positive subjects reduced over time (P < 0.001) but did not differ by study arm (P = 0.36). Median spot-forming units for ESAT-6 and CFP-10 also declined significantly with time (P < 0.001) but did not differ by study arm (P = 0.74 and 0.71, respectively). There was no evidence of an interaction between acetylator status and INH treatment with respect to ELISPOT results over time.Conclusions: In contacts with LTBI, INH therapy plays no role in observed decreases in Mycobacterium tuberculosis antigen specific T-cell responses over time. IFN-gamma ELISPOT is probably not a useful biomarker of treatment efficacy in LTBI.Clinical trial registered with www.clinicaltrials.gov (NCT 00130325).