Davis Angharad G, Wasserman Sean, Maxebengula Mpumi, Stek Cari, Bremer Marise, Daroowala Remy, Aziz Saalikha, Goliath Rene, Stegmann Stephani, Koekemoer Sonya, Jackson Amanda, Lai Sai Louise, Kadernani Yakub, Sihoyiya Thandi, Liang C Jason, Dodd Lori, Denti Paolo, Crede Thomas, Naude Jonathan, Szymanski Patryk, Vallie Yakoob, Banderker Ismail, Moosa Shiraz, Raubenheimer Peter, Lai Rachel P J, Joska John, Nightingale Sam, Dreyer Anna, Wahl Gerda, Offiah Curtis, Vorster Isak, Candy Sally, Robertson Frances, Meintjes Ernesta, Maartens Gary, Black John, Meintjes Graeme, Wilkinson Robert J
The Francis Crick Institute, Midland Rd, London, NW1 1AT, UK.
Faculty of Life Sciences, University College London, London, WC1E 6BT, UK.
Wellcome Open Res. 2021 Jun 1;6:136. doi: 10.12688/wellcomeopenres.16783.1. eCollection 2021.
Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM. In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM. NCT03927313 (25/04/2019).
结核性脑膜炎（TBM）是最致命的结核病形式，在合并感染HIV-1的患者中死亡率约为50%。目前的抗生素治疗方案基于已知对肺结核有效的方案，未考虑药物穿透中枢神经系统（CNS）能力的差异。宿主免疫反应驱动TBM的病理过程，但有效的宿主导向治疗方法很少。有足够的数据表明，更高剂量的利福平（RIF）、额外的利奈唑胺（LZD）和辅助性阿司匹林（ASA）对TBM有益，但需要在HIV相关TBM的背景下对这些干预措施的安全性进行严格研究。我们假设，在HIV-1感染的TBM患者中，联合使用增加剂量的RIF、LZD和ASA，并在治疗的前56天除标准治疗外使用，将是安全且可耐受的。在一项开放标签随机平行研究中，最多100名参与者将接受以下治疗之一：i）标准治疗（n = 40，对照组），ii）标准治疗加增加剂量的RIF（35mg/kg）和LZD（第28天每日1200mg，第28天每日600mg）（n = 30，实验组1），或iii）按实验组1加额外的ASA每日1000mg（n = 30，实验组2）。56天后，参与者将根据国家指南继续标准治疗。主要终点是死亡和56天时发生的与治疗相关的不良事件。在一项计划中的药代动力学（PK）子研究中，我们旨在评估口服与静脉注射利福平的PK/药效学（PD），描述LZD和RIF的PK及脑脊液浓度，探索PK/PD关系，并研究LZD和RIF之间的药物相互作用。本研究的安全性和药代动力学数据将为一项计划中的TBM强化治疗III期研究提供信息。NCT03927313（2019年4月25日）
