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Abstract：
BACKGROUND: HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB.
METHODS: This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events.
CONCLUSIONS: Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice.
BACKGROUND: ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986.
METHODS: This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events.
CONCLUSIONS: Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice.
BACKGROUND: ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986.
摘要：
背景：HIV相关结核病（TB）对全球结核病死亡率的影响不成比例。在诊断为HIV相关的播散性结核病时住院的患者通常病情严重，尽管开始了结核病治疗，但仍有很高的死亡风险。该研究的目的是评估强化结核病治疗（高剂量利福平加左氧氟沙星）和糖皮质激素免疫调节作为干预措施的安全性和有效性，以降低HIV相关播散性结核病住院患者的早期死亡率。
方法：这是一项III期随机对照优势试验，以2×2析因设计评估两种干预措施:(1)前14天与标准结核治疗相比,高剂量利福平(35mg/kg/天)加左氧氟沙星加入标准结核治疗;(2)前14天与相同安慰剂相比,联合糖皮质激素(泼尼松1.5mg/kg/天).研究人群是被诊断患有播散性结核病的HIV阳性患者（定义为通过以下至少一种检测呈阳性：尿液AlereLAM，入院时尿液XpertMTB/RIFUltra或血液XpertMTB/RIFUltra）。主要终点是12周时的全因死亡率，首先,接受强化结核病治疗的患者达到护理标准，第二,接受皮质类固醇的患者与接受安慰剂的患者。主要终点的分析将通过意向治疗。次要终点包括2周和24周时的全因死亡率。安全性和耐受性终点包括肝毒性评估和皮质类固醇相关的不良事件。
结论：播散性结核病的特点是分枝杆菌负荷较高，患者在就诊时往往病情危重，具有败血症的特征，具有很高的死亡风险。减少这种高分枝杆菌负荷或调节相关免疫激活的干预措施可能会降低死亡率。如果发现安全有效，本试验中评估的干预措施可以很容易地在临床实践中实施.
背景：ClinicalTrials.govNCT04951986。2021年7月7日注册https://clinicaltrials.gov/study/NCT04951986。
方法：这是一项III期随机对照优势试验，以2×2析因设计评估两种干预措施:(1)前14天与标准结核治疗相比,高剂量利福平(35mg/kg/天)加左氧氟沙星加入标准结核治疗;(2)前14天与相同安慰剂相比,联合糖皮质激素(泼尼松1.5mg/kg/天).研究人群是被诊断患有播散性结核病的HIV阳性患者（定义为通过以下至少一种检测呈阳性：尿液AlereLAM，入院时尿液XpertMTB/RIFUltra或血液XpertMTB/RIFUltra）。主要终点是12周时的全因死亡率，首先,接受强化结核病治疗的患者达到护理标准，第二,接受皮质类固醇的患者与接受安慰剂的患者。主要终点的分析将通过意向治疗。次要终点包括2周和24周时的全因死亡率。安全性和耐受性终点包括肝毒性评估和皮质类固醇相关的不良事件。
结论：播散性结核病的特点是分枝杆菌负荷较高，患者在就诊时往往病情危重，具有败血症的特征，具有很高的死亡风险。减少这种高分枝杆菌负荷或调节相关免疫激活的干预措施可能会降低死亡率。如果发现安全有效，本试验中评估的干预措施可以很容易地在临床实践中实施.
背景：ClinicalTrials.govNCT04951986。2021年7月7日注册https://clinicaltrials.gov/study/NCT04951986。
