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. 

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). 

TBM remains the most severe form of tuberculosis, and is especially common in those infected with HIV. Whether corticosteroids confer a survival benefit in HIV-infected patients remains uncertain, with the current evidence base for using corticosteroids in this context restricted to 98 adults recruited to a trial in Vietnam ^8, 13. The ACT HIV trial aims to determine whether dexamethasone is a safe and effective addition to the first 6–8 weeks of anti-tuberculosis treatment of TBM. ACT HIV will be performed in parallel with a randomised double blind placebo controlled trial of adjunctive dexamethasone in HIV-uninfected Vietnamese adults stratified by Leukotriene A4 hydrolase (LTA4H) genotype (LAST ACT, clinical trial registration NCT03100786) ²². Both trials will recruit to seven ancillary studies, including a study to investigate alternative management strategies in a subset of patients who develop DILI, enabling safe continuation of rifampicin and isoniazid therapy whenever possible. In recruiting the target 520 patients into the main trial, this trial has the opportunity to also study the following: Host and bacterial genetic determinants of treatment response; Impact of dexamethasone on CSF inflammation and gross cerebral pathology; Influence of diabetes mellitus on presentation and response to treatment; Influence of Strongyloides infection on presentation and response to treatment. Pathophysiology and treatment of hyponatraemia and raised intracranial pressure; Dexamethasone induced adrenal suppression. These data will be valuable in guiding the management of adjunctive corticosteroid therapy in HIV-infected individuals.

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.