The Oxford University Clinical Research Unit (OUCRU) has announced the results of the LAST ACT trial, published in Nature Medicine. This is the first tuberculosis trial to assess personalised treatment based on a host genetic variant. The trial examined whether dexamethasone, a corticosteroid commonly used in tuberculous meningitis (TBM), could be withheld in patients with certain genetic markers without compromising outcomes.
Previous research identified LTA4H (leukotriene A4 hydrolase) genotypes associated with different levels of inflammation in TBM. The LAST ACT trial enrolled 613 HIV-negative Vietnamese adults with LTA4H genotypes linked to medium- or low-inflammation and randomised them to receive either dexamethasone or placebo. The primary endpoint (death or new neurological event within 12 months) was similar in both groups, and non-inferiority of placebo was not demonstrated.
Importantly, dexamethasone was found to be safe across all genotype groups. Combined with earlier trial data, dexamethasone remains associated with a modest but statistically significant reduction in mortality among adults with TBM and no HIV co-infection.
Dr Joseph Donovan, Lead Author of the study, said: “Tuberculous meningitis is a catastrophic neurological infection, and understanding adverse intracerebral inflammation and how it can be controlled, is vital. In the LAST ACT trial, we were unable to show that placebo was non-inferior to dexamethasone in medium- and low-inflammatory genotypes without HIV. A better understanding of tuberculous meningitis pathophysiology is urgently needed.”
The findings underscore the complexity of inflammation in TBM and highlight the need for more effective and personalised anti-inflammatory therapies for this devastating infection. The trial was supported by Wellcome and conducted in collaboration with Pham Ngoc Thach Hospital and the Hospital for Tropical Diseases in Ho Chi Minh City.
Read the full publication: Genotype-stratified adjunctive dexamethasone for tuberculous meningitis in HIV-negative adults: a randomized controlled phase 3 trial