Hesseling Anneke C, Purchase Susan E, Martinson Neil A, Fairlie Lee, Schaaf H Simon, Brigden Joanna, Staples Suzanne, Gibb Diana M, Garcia-Prats Anthony, Conradie Francesca, McGowan Charlotte, Layton Charlotte, Batist Elize, Demers Anne-Marie, Nyamathe Samukelisiwe, Frigati Lisa, Turner Rebecca, Duong Trinh, Seddon James A
From the Department of Pediatrics and Child Health, Desmond Tutu TB Centre, Stellenbosch University, Stellenbosch (A.C.H., S.E.P., H.S.S., A.G.-P., E.B., A.-M.D., S.N., J.A.S., L. Frigati), the Perinatal HIV Research Unit (N.A.M.) and the Faculty of Health Sciences, Wits Research Health Institute (L. Fairlie), University of the Witwatersrand, and Isango Lethemba TB Research Unit, Port Elizabeth, Wits Health Consortium (F.C.), Johannesburg, and the Tuberculosis and HIV Investigative Network, Durban (S.S.) - all in South Africa; the Johns Hopkins Center for TB Research, Baltimore (N.A.M.); the Medical Research Council Clinical Trials Unit at University College London (J.B., D.M.G., C.M., C.L., R.T., T.D.) and the Department of Infectious Disease, Imperial College London (J.A.S.) - both in London; the Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison (A.G.P.); and the Division of Microbiology, Department of Laboratory Medicine, Centre Hospitalier Universitaire Sainte-Justine, and the Department of Microbiology, Immunology, and Infectious Diseases, Faculty of Medicine, University of Montreal - both in Montreal (A.-M.D.).
N Engl J Med. 2024 Dec 19;391(24):2315-2326. doi: 10.1056/NEJMoa2314318.
Worldwide, approximately 2 million children younger than 15 years of age are infected with multidrug-resistant (MDR) , with MDR tuberculosis developing in approximately 30,000 annually. Evidence from randomized, controlled trials on tuberculosis preventive treatment in persons exposed to MDR tuberculosis is lacking.
In this community-based, multisite, double-blind, cluster-randomized, placebo-controlled trial in South Africa, we assessed the efficacy and safety of levofloxacin as preventive treatment in children with household exposure to an adult with bacteriologically confirmed MDR pulmonary tuberculosis. Children younger than 5 years of age were eligible for inclusion regardless of interferon-γ release assay result or human immunodeficiency virus (HIV) status, and children 5 to 17 years of age were eligible if they had a positive interferon-γ release assay or HIV infection. Households were randomly assigned to a trial regimen, and children in the household received levofloxacin or placebo once daily for 24 weeks. The primary efficacy end point was incident tuberculosis, which included death from tuberculosis, by week 48 after randomization. The primary safety end point was any adverse event of grade 3 or higher during the treatment period that was at least possibly related to the trial regimen.
Of 922 participants from 497 households, 453 were assigned to receive levofloxacin and 469 to placebo; 91.0% of the participants were younger than 5 years of age. At least 80% of the assigned doses of levofloxacin or placebo were received by 86% of the participants in each trial group. By week 48, tuberculosis had developed in 5 participants (1.1%) in the levofloxacin group and in 12 participants (2.6%) in the placebo group (hazard ratio, 0.44; 95% confidence interval [CI], 0.15 to 1.25). The results of sensitivity analyses were consistent with those of the primary analysis. Grade 3 or higher adverse events during the treatment period that were considered to be at least possibly related to the trial regimen occurred in 4 participants in the levofloxacin group and in 8 participants in the placebo group (hazard ratio, 0.52; 95% CI, 0.16 to 1.71). Grade 2 tendonitis occurred in 1 child in the levofloxacin group.
Although preventive treatment with levofloxacin led to a lower incidence of tuberculosis than placebo among children with household exposure to MDR tuberculosis, the difference was not significant. (Supported by Unitaid and others; TB-CHAMP ISRCTN Registry number, ISRCTN92634082.).
在全球范围内，约200万15岁以下儿童感染了耐多药菌，每年约有30000例发展为耐多药结核病。缺乏针对接触耐多药结核病患者的人群进行结核病预防性治疗的随机对照试验证据。
在南非开展的这项基于社区的多中心、双盲、整群随机、安慰剂对照试验中，我们评估了左氧氟沙星作为预防性治疗药物，用于家中接触经细菌学确诊的耐多药肺结核成人患者的儿童的疗效和安全性。5岁以下儿童无论干扰素-γ释放试验结果或人类免疫缺陷病毒（HIV）状态如何均符合纳入标准，5至17岁儿童若干扰素-γ释放试验结果为阳性或感染HIV则符合纳入标准。家庭被随机分配到试验方案组，家庭中的儿童每天接受一次左氧氟沙星或安慰剂治疗，持续24周。主要疗效终点是随机分组后第48周时的新发结核病，包括结核病死亡。主要安全性终点是治疗期间发生的至少可能与试验方案相关的3级或更高等级的任何不良事件。
来自497个家庭的922名参与者中，453人被分配接受左氧氟沙星治疗，469人接受安慰剂治疗；91.0%的参与者年龄小于5岁。每个试验组中86%的参与者接受了至少80%分配剂量的左氧氟沙星或安慰剂。到第48周时，左氧氟沙星组有5名参与者（1.1%）发生了结核病，安慰剂组有12名参与者（2.6%）发生了结核病（风险比，0.44；95%置信区间[CI]为0.15至1.25）。敏感性分析结果与主要分析结果一致。治疗期间被认为至少可能与试验方案相关的3级或更高等级不良事件在左氧氟沙星组有4名参与者发生，在安慰剂组有8名参与者发生（风险比，0.52；95%CI为0.16至1.71）。左氧氟沙星组有1名儿童发生了2级肌腱炎。
尽管在家庭接触耐多药结核病的儿童中，左氧氟沙星预防性治疗导致的结核病发病率低于安慰剂，但差异不显著。（由国际药品采购机制等资助；TB-CHAMP国际标准随机对照试验注册号，ISRCTN92634082。）
