A comparison of DILI management strategies may allow the safe continuation of rifampicin and isoniazid. 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. An identical ancillary study will also be perfomed in the linked randomised controlled trial of dexamethasone in HIV-infected adults with TBM (ACT HIV).ĭiscussion: 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 also perform a randomised comparison of three management strategies for anti-tuberculosis DILI. 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. The trial will enrol approximately 720 HIV-uninfected adults with a clinical diagnosis of TBM, from two hospitals in Ho Chi Minh City, Vietnam. The primary endpoint will be death or new neurological event. 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 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. 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. 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. Thwaites, Conceptualization, Funding Acquisition, Supervision, Writing – Review & Editing 1, 2īackground: Tuberculosis kills more people than any other bacterial infection worldwide. Geskus, Formal Analysis, 1, 2 Tran Tinh Hien, Methodology, Supervision, 1 Evelyne Kestelyn, Methodology, Supervision, Writing – Review & Editing, 1, 2 Marcel Wolbers, Formal Analysis, 1 Nguyen Van Vinh Chau, Methodology, Supervision, 3 and Guy E. Joseph Donovan, Methodology, Supervision, Writing – Original Draft Preparation, a, 1, 2 Nguyen Hoan Phu, Methodology, Supervision, 3 Le Thi Phuong Thao, Formal Analysis, 1 Nguyen Huu Lan, Methodology, Project Administration, Supervision, 4 Nguyen Thi Hoang Mai, Investigation, Methodology, 3 Nguyen Thi Mai Trang, Methodology, Project Administration, Supervision, 4 Nguyen Thi Thu Hiep, Investigation, Project Administration, 1 Tran Bao Nhu, Investigation, Project Administration, 3 Bui Thi Bich Hanh, Investigation, Project Administration, 3 Vu Thi Phuong Mai, Project Administration, 1 Nguyen Duc Bang, Methodology, Project Administration, Supervision, 4 Do Chau Giang, Methodology, Project Administration, Supervision, 4 Dang Thi Minh Ha, Methodology, Project Administration, Supervision, 4 Jeremy Day, Methodology, 1, 2 Nguyen TT Thuong, Methodology, 1, 2 Nguyen Nang Vien, Investigation, Supervision, 4 Ronald B.
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