Abstract
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.
Highlights
Tuberculous meningitis (TBM) is the most severe form of tuberculosis, resulting in death or neurological disability in approximately 40% of HIV-uninfected sufferers, and 70% of those co-infected with HIV
Secondary aims Our secondary aim is to investigate alternative management strategies in a subset of patients who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy whenever possible
Exclusion criteria for the DILI strategy study are: a) tuberculous meningitis (TBM) known to be caused by isoniazid resistant or MDR M. tuberculosis or standard first-line anti-tuberculosis drugs unable to be given for any reason other than DILI
Summary
Background Tuberculous meningitis (TBM) is the most severe form of tuberculosis, resulting in death or neurological disability in approximately 40% of HIV-uninfected sufferers, and 70% of those co-infected with HIV. Effective anti-tuberculosis chemotherapy has been available for more than 50 years, yet tuberculosis kills more people than any other single bacterial infection worldwide. Rifampicin (R), isoniazid (H), pyrazinamide (Z) and ethambutol (E) are the first-line antibiotics for all forms of drugsusceptible tuberculosis. These agents, used daily and in combination, kill the bacteria and prevent the emergence of resistance. 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 HIVuninfected individuals. Ravindra Kumar Garg , King George's Medical University, Lucknow, India
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
