Leukotriene A4 Hydrolase Stratified Trial Of Adjunctive Corticosteroids For HIV-Uninfected Adults With Tuberculous Meningitis (The LAST ACT Trial)


2016 – 2023

Clinical Trial Registration
Registration number: NCT03100786

Principal Investigator: 
Professor Guy Thwaites

The LAST ACT Trial is a parallel-group, randomised (1:1), double-blind, placebo-controlled, multi-centre Phase III non-inferiority trial comparing dexamethasone versus placebo for 6-8 weeks in addition to standard anti-tuberculosis treatment in HIV-uninfected patients with TBM stratified by LTA4H genotype.


In tuberculous meningitis (TBM), a common functional promoter variant (C/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H) predicts pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected individuals.

How dexamethasone, as an adjunctive anti-inflammatory treatment, can improve survival in TBM patients, especially in HIV-uninfected individuals, and whether they do so in all patients remain uncertain and is the focus of this trial.


Our primary aim 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, we not only determine whether placebo is non-inferior to dexamethasone in patients having LTA4H CT or CC-genotype, in terms of:

  • Survival rate;
  • Incidence of new neurological events;
  • Disability, as assessed by the modified Rankin scale;
  • Frequency of severe and serious adverse events;
  • Need for rescue corticosteroids.

Our secondary aim is to 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 whenever possible.


Julie Huynh, Nhat Hoang Thanh Le, Bao Hoai Le Nguyen, Hai Thanh Hoang, Thu Anh Dang Do, Tram Thi Bich Trinh, Dung Thi Mong Vu, Vinh Dinh Do, Ngoc My Nghiem, Joseph Donovan, Phu Hoan Nguyen, Thanh Van Dang, Thu Thi Anh Nguyen, Bang Duc Nguyen, Ha Minh Thi Dang, Nghia Trung Dang Ho, Tan Van Le, Van Hong Le, Guy Thwaites, Nguyen Thuy Thuong Thuong
J Infect Dis
January 3, 2024
DOI: 10.1093/infdis/jiad606
Joseph Donovan, Nguyen D Bang, Darma Imran, Ho D T Nghia, Erlina Burhan, Dau T T Huong, Nguyen T T Hiep, Lam H B Ngoc, Dang V Thanh, Nguyen T Thanh, Anna L S Wardhani, Kartika Maharani, Cakra P Gasmara, Nguyen H H Hanh, Pham K N Oanh, Riwanti Estiasari, Do D A Thu, Ardiana Kusumaningrum, Le T Dung, Do C Giang, Dang T M Ha, Nguyen H Lan, Nguyen V V Chau, Nguyen T M Nguyet, Ronald B Geskus, Nguyen T T Thuong, Evelyne Kestelyn, Raph L Hamers, Nguyen H Phu, Guy E Thwaites; ACT HIV Investigators
N Engl J Med
October 12, 2023
DOI: 10.1056/NEJMoa2216218
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Joseph Donovan

Dr Joseph Donovan

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Hospital For Tropical Diseases


Pham Ngoc Thach Hospital

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