Abstract
Background:Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Co-infection with HIV increases the risk of developing TBM, complicates treatment, and substantially worsens outcome. Whether corticosteroids confer a survival benefit in HIV-infected patients with TBM remains uncertain. Hepatitis is the most common drug-induced serious adverse event associated with anti-tuberculosis treatment, occurring in 20% of HIV-infected patients. The suggested concentration thresholds for stopping anti-tuberculosis drugs are not evidence-based. This study aims to determine whether dexamethasone is a safe and effective addition to the first 6-8 weeks of anti-tuberculosis treatment of TBM in patients with HIV, and 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. Methods:We will perform a parallel group, randomised (1:1), double blind, placebo-controlled multi-centre Phase III trial, comparing the effect of dexamethasone versus placebo on overall survival in HIV-infected patients with TBM, in addition to standard anti-tuberculosis and antiretroviral treatment. The trial will be set in two hospitals in Ho Chi Minh City, Vietnam, and two hospitals in Jakarta, Indonesia. The trial will enrol 520 HIV-infected adults. An ancillary study will perform a randomised comparison of three DILI management strategies with the aim of demonstrating which strategy results in the least interruption in rifampicin and isoniazid treatment. An identical ancillary study will also be performed in the linked randomised controlled trial of dexamethasone in HIV-uninfected adults with TBM stratified by LTA4H genotype (LAST ACT). Discussion:Whether corticosteroids confer a survival benefit in HIV-infected patients remains uncertain, and the current evidence base for using corticosteroids in this context is limited. Interruptions in anti-tuberculosis chemotherapy is a risk factor for death from TBM. Alternative management strategies in DILI may allow the safe continuation of rifampicin and isoniazid therapy.
Highlights
Mycobacterium tuberculosis causes approximately 10.4 million new cases of tuberculosis and 1.5 million deaths annually, with an additional 0.4 million deaths in individuals co-infected with human immunodeficiency virus (HIV)[1]
Treatment of Tuberculous meningitis (TBM) Rifampicin, isoniazid, pyrazinamide and ethambutol are recommended in current international guidelines for the treatment of drug-susceptible TBM, in adults with or without HIV, with treatment recommended for 9–12 months[3,4]
TBM remains the most severe form of tuberculosis, and is especially common in those infected with HIV
Summary
Background Mycobacterium tuberculosis causes approximately 10.4 million new cases of tuberculosis and 1.5 million deaths annually, with an additional 0.4 million deaths in individuals co-infected with human immunodeficiency virus (HIV)[1]. Tuberculous meningitis (TBM) is the most severe form of tuberculosis, killing around 30% of all sufferers despite appropriate anti-tuberculosis chemotherapy[2]. TBM is especially common in young children and in those with advanced immunodeficiency secondary to HIV, and is characterised by a slowly progressive meningo-encephalitis with necrotising granulomatous inflammation predominantly affecting the basal meninges. The treatment of drug resistant TBM is more challenging. Adjunctive anti-inflammatory treatment with corticosteroids (dexamethasone) has been shown to improve survival in TBM, in predominantly HIV-uninfected individuals in a small number of trials[5]
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