Genotype stratified adjunctive dexamethasone for tuberculous meningitis in HIV-negative Adults: the LAST ACT trial

Tuberculous meningitis (TBM) is the most severe form of tuberculosis.
Adjunctive corticosteroids are recommended for HIV-negative adults,
although their benefit appears modest and may depend on host leukotriene
A4 hydrolase (LTA4H) genotype. The LAST ACT trial (NCT03100786) was a
genotype-stratified, randomised, double-blind, placebo-controlled Phase
III trial that evaluated dexamethasone in HIV-negative Vietnamese adults
with TBM. A total of 613 adults with LTA4H CC or CT genotypes were
randomised to receive dexamethasone or placebo; 89 TT-genotype
participants received open-label dexamethasone. The trial found no benefit
from adjunctive dexamethasone in CC/CT-genotype participants. This dataset
supports the analysis of a secondary outcome: changes in blood and CSF
inflammatory responses. Whole-blood RNA sequencing was performed for 202
participants after quality control (day 0: n=202; day 14: n=188; day 60:
n=153). CSF inflammatory proteins were measured in 646 participants using
the Olink Explore 384 Inflammation panel (day 0: n=638; day 30: n=391),
resulting in 1029 CSF samples with high-quality data after quality
control. Ten pre-specified cytokines were targeted, but four (IL-2, IL-4,
IL-5, IL-13) were excluded due to poor detection. Analyses focused on five
inflammation-related pathways: TNF signalling, interferons, cytokines,
neutrophils, and eicosanoids. Pathway activity (enrichment scores) was
calculated using single-sample gene set enrichment analysis (ssGSEA) and
z-score metrics. Longitudinal changes (rate of reduction) in pathway
activity by treatment and LTA4H genotype were assessed using Bayesian
joint models (JMbayes2), which combined linear mixed effects and survival
components, accounting for early mortality bias. This dataset enabled a
detailed investigation of corticosteroid effects on host inflammatory
responses in TBM.