Leukotriene A4 Hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-uninfected Adults With Tuberculous Meningitis

There is a longstanding hypothesis that death from TBM results from an excessive intracerebral inflammatory response. The corollary of this hypothesis has been that adjunctive anti-inflammatory treatment with corticosteroids (e.g. dexamethasone) improves survival, which has been demonstrated in predominantly HIV-uninfected individuals in a small number of trials. Yet how corticosteroids improve survival, and whether they do so in all patients, remain uncertain and is the focus of the LAST ACT trial.

Adjunctive dexamethasone might improve outcomes from TBM by controlling the early intracerebral inflammatory response, reducing cerebral oedema and intra-cranial pressure, and it may prevent the potentially life-threatening complications of hydrocephalus, infarction and tuberculoma formation. Despite the careful study of all participants enrolled into the last dexamethasone trial conducted in Vietnam, an anti-inflammatory effect linked to outcome was not found. An explanation for these puzzling findings was only forthcoming upon the subsequent discovery that a common functional promoter variant (C/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H), which determines the balance of pro- and anti-inflammatory eicosanoids, appeared to predict pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected participants.

In a retrospective study, analysing HIV-uninfected Vietnamese adults with TBM enrolled into the earlier randomized controlled trial of adjunctive dexamethasone, the investigators found that the survival benefit of dexamethasone was restricted to the hyper-inflammatory LTA4H TT-genotype patients, with possible harm suggested in the hypo-inflammatory CC-genotype patients. These preliminary findings suggested LTA4H genotype might be a critical determinant of inflammation and consequently of adjunctive anti-inflammatory treatment response.

Recently, the investigators have extended these original observations in a new cohort of 786 prospectively characterized Vietnamese adults with TBM, all of whom received corticosteroids. In this new cohort the investigators found that LTA4H genotype influences the survival of HIV-uninfected patients, but not those infected with HIV in patients receiving dexamethasone. TT-genotype patients were significantly more likely to survive than CC-genotype patients by both univariable and multivariable analysis, which confirms the previous findings.

The investigators now have two independent studies that suggest LTA4H influences pre-treatment inflammatory phenotype in HIV-uninfected Vietnamese adults and dexamethasone-induced survival. The investigators now want to conduct a practice-defining RCT that addresses the hypothesis that in HIV-uninfected adults with TBM, LTA4H genotype can be used to select those most likely to benefit from dexamethasone.

The data strongly suggest 'hyperinflammatory' LTA4H TT genotype patients with TBM benefit from dexamethasone. Therefore, these patients will be enrolled to the trial and followed-up for 12 months but will receive open label dexamethasone for the first 6-8 weeks of anti-tuberculosis treatment.

The data supports the hypothesis that adjunctive dexamethasone does not benefit, and may cause harm, when given to LTA4H CT or CC-genotype Vietnamese adults with TBM. Therefore, participants with these two genotypes will be randomised to receive 6-8 weeks of placebo or dexamethasone in addition to anti-tuberculosis drugs.

The primary objective is to determine whether LTA4H genotype, defined at randomisation, determines dexamethasone's clinical effectiveness when added to the first 6-8 weeks of anti-tuberculosis treatment of TBM. In making this assessment the investigators not only determine whether dexamethasone increases survival and reduces the incidence of new neurological events (the primary endpoint), but also whether it reduces disability assessed by the modified Rankin score 12 months after the start of treatment. The primary endpoint is death or new neurological event (defined as a fall in Glasgow coma score by ≥2 points for ≥2 days from the highest previously recorded Glasgow coma score (including baseline) or the onset of any of the following clinical adverse events: cerebellar symptoms, focal neurological signs, or new onset of seizures) during 12 months from randomisation.

The secondary objective is to investigate alternative management strategies in a subset of patients who develop drug-induced liver injury that will enable the safe continuation of rifampicin and isoniazid therapy whenever possible. The investigators will perform an open, randomised comparison of three management strategies with the aim of demonstrating which strategy results in the least interruption in R and H treatment. All patients enrolled in the trial will be eligible to take part in this study, with the exception of those known to have TBM caused by isoniazid resistant or MDR M. tuberculosis. Consent will be sought at enrolment, with an option given to patients to enrol in the main study, but not the 'drug-induced liver injury strategy study'.

Eligible patients will be randomised to one of three strategies:

1. Observe: measure transaminases, bilirubin, and INR every 3 days; do not change/stop anti-tuberculosis drugs unless transaminases rise to ≥10x normal, or total bilirubin rises >2.0mg/dl (>34 µmol/L), or INR >1.5 or symptoms of hepatitis worsen (nausea, vomiting, abdominal pain), in which case go to Strategy 3.
2. Stop Pyrazinamide (Z) alone. Observe, measuring transaminases, bilirubin, and INR every 3 days. If transaminases do not fall to < 5x ULN by day 5, or total bilirubin rises >2.0mg/dl (>34 µmol/L), or INR >1.5 or symptoms of hepatitis worsen at any time (nausea, vomiting, abdominal pain), go to Strategy 3.
3. Current standard of care (the current USA CDC guidelines): stop rifampicin (R), isoniazid (H) and Z immediately and add levofloxacin and an aminoglycoside to ethambutol. Restart R (at full dose) once transaminases are <2X ULN and no hepatitis symptoms. If no increase in transaminases after 7 days add isoniazid (at full dose) and stop levofloxacin and aminoglycoside. If transaminases remain normal on full dose R and H, Z was the likely cause and it should not be re-started and treatment duration should be extended to ≥12 months. If transaminases rise ≥ 5x ULN, or ≥3x ULN with symptoms, at any time after re-introduction of R and/or H the physician should stop R and/or H (depending on which was associated with the transaminase rise). If neither R or H can be used, treat with levofloxacin, an aminoglycoside and ethambutol. If R can be used, but not H, treat with R, levofloxacin and ethambutol. If H can be used, but not R, treat with H, levofloxacin and ethambutol.

The primary endpoint is the proportion of time in the 60 days following randomisation during which neither rifampicin nor isoniazid are given (or the subject is dead). For example, if RH is interrupted for 18 days and the participant dies 48 days after randomization, the endpoint will be 50% [(18+(60-48))/60]. Rifampicin and isoniazid are considered critical drugs in early TBM treatment; inability to use these agents (either through bacterial resistance or patient intolerance) is associated with poor outcome. The vast majority of interruptions are expected to be shorter than one month for strategy 3 (standard of care) but as management strategies 1 and 2 delay the time point of the interruption, a longer cut-off of 60 days was chosen.