Adjunctive dexamethasone for the treatment of HIV-uninfected adults with tuberculous meningitis stratified by Leukotriene A4 hydrolase genotype (LAST ACT): Study protocol for a randomised double blind placebo controlled non-inferiority trial.
Adjunctive dexamethasone for the treatment of HIV-uninfected adults with tuberculous meningitis stratified by Leukotriene A4 hydrolase genotype (LAST ACT): Study protocol for a randomised double blind placebo controlled non-inferiority trial.
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DOI：
10.12688/wellcomeopenres.14007.1
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Thwaites, Guy E
中科院分区：
文献类型：
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作者：
Donovan, Joseph;Phu, Nguyen Hoan;Thwaites, Guy E
背景：结核病比世界上任何其他细菌感染造成的死亡人数都多。在结核性脑膜炎（TBM）中，编码白三烯A4水解酶（LTA 4 H）的基因中的常见功能性启动子变体（C/T转换）可预测未感染HIV的个体治疗前的炎症表型和对地塞米松的反应。本研究的主要目的是确定LTA 4 H基因型是否决定未感染HIV的越南成年TBM患者接受地塞米松治疗的益处或危害。次要目的是研究药物性肝损伤（DILI）患者的替代治疗策略，以确保利福平和异烟肼治疗的安全性。方法：我们将进行一项平行组、随机（1：1）、双盲、安慰剂对照、多中心III期非劣效性试验，在根据LTA 4 H基因型分层的未感染HIV的TBM患者中，除了标准抗结核治疗外，还比较地塞米松与安慰剂6-8周。主要终点为死亡或新发神经系统事件。该试验将从越南胡志明市的两家医院招募约720名临床诊断为TBM的未感染HIV的成年人。将640名具有CC或CT-LTA 4 H基因型的受试者随机分配至地塞米松组或安慰剂组，其余TT基因型受试者将接受标准治疗地塞米松治疗。我们还将对抗结核药物性肝损伤的三种管理策略进行随机比较。在HIV感染成人TBM患者中进行的地塞米松相关随机对照试验（ACT HIV）中也将进行相同的辅助研究。讨论：先前的数据表明，LTA 4 H基因型可能是TBM炎症的关键决定因素，因此是连续抗炎治疗反应的关键决定因素。我们将根据未感染HIV的成人中的LTA 4 H基因型对地塞米松治疗进行分层，这可能表明根据LTA 4 H C/T转换的变化进行靶向抗炎治疗的作用。DILI管理策略的比较可能允许利福平和异烟肼的安全持续。
Background:Tuberculosis kills more people than any other bacterial infection worldwide. In tuberculous meningitis (TBM), a common functional promoter variant (C/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H), predicts pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected individuals. The primary aim of this study is to determine whether LTA4H genotype determines benefit or harm from adjunctive dexamethasone in HIV-uninfected Vietnamese adults with TBM. The secondary aim is to investigate alternative management strategies in individuals who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy. Methods:We will perform a parallel group, randomised (1:1), double blind, placebo-controlled, multi-centre Phase III non-inferiority trial, comparing dexamethasone versus placebo for 6-8 weeks in addition to standard anti-tuberculosis treatment in HIV-uninfected patients with TBM stratified by LTA4H genotype. The primary endpoint will be death or new neurological event. The trial will enrol approximately 720 HIV-uninfected adults with a clinical diagnosis of TBM, from two hospitals in Ho Chi Minh City, Vietnam. 640 participants with CC or CT- LTA4H genotype will be randomised to either dexamethasone or placebo, and the remaining TT- genotype participants will be treated with standard-of-care dexamethasone. We will also perform a randomised comparison of three management strategies for anti-tuberculosis DILI. An identical ancillary study will also be perfomed in the linked randomised controlled trial of dexamethasone in HIV-infected adults with TBM (ACT HIV). Discussion:Previous data have shown that LTA4H genotype may be a critical determinant of inflammation and consequently of adjunctive anti-inflammatory treatment response in TBM. We will stratify dexamethasone therapy according to LTA4H genotype in HIV-uninfected adults, which may indicate a role for targeted anti-inflammatory therapy according to variation in LTA4H C/T transition. A comparison of DILI management strategies may allow the safe continuation of rifampicin and isoniazid.