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A randomised double blind placebo controlled trial of adjunctive dexamethasone for the treatment of HIV-infected adults with tuberculous meningitis (ACT HIV)

Short title: Adjunctive Corticosteroids for Tuberculous meningitis in HIV-infected adults (The ACT HIV trial)

Sponsor : University of Oxford

Funder : Wellcome Trust, UK


Chief Investigator : Professor Guy Thwaites

Co-Investigators :

Dr Le Tien Dung

Dr Nguyen Van Vinh Chau

Dr Nguyen Hoan Phu

Dr Nguyen Thi Hoang Mai

Dr Nguyen Thuy Thuong Thuong

Dr Darma Imran Sp.S(K)

Dr Erlina Burhan Sp.P(K)

Professor Kevin Baird

Dr Raph Hamers

Professor Reinout van Crevel

 

The ACT-HIV is a collaborative clinical trial

  • Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam
  • Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
  • OUCRU, Vietnam
  • RSCM Hospital Universitas Indonesia, Jakarta, Indonesia
  • RSUP Persahabatan Hospital,Universitas Indonesia, Jakarta, Indonesia
  • Eijkman-Oxford Clinical Research Unit, Jakarta, Indonesia

 


Background

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. Interruptions in anti-tuberculosis chemotherapy for any reason is an independent risk factor for death from TBM. 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.

Methods

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 management strategies in DILI in the intensive phase of anti-tuberculosis treatment. We will perform an open, randomised comparison of three management strategies with the aim of demonstrating which strategy results in the least interruption in rifampicin and isoniazid treatment.

Study Hypothesis

Neurological complications are both common and devastating in TBM. Dexamethasone may reduce complications arising from an early intracerebral inflammatory response, including neurological IRIS. Dexamethasone has been shown to improve survival in HIV-unaffected individuals with TBM. Our primary hypothesis is that adjunctive dexamethasone increases survival from TBM in HIV co-infected adults. The secondary hypothesis is that current guidelines for the management of anti-tuberculosis DILI in those with TBM result in the premature interruption of rifampicin and isoniazid (the critical active drugs in early therapy) and are thereby placing participants at risk of poor outcomes.

Discussion

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. These data will be valuable in guiding the management of adjunctive corticosteroid therapy in HIV-infected individuals. 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.

Trial registration number: NCT03092817

Trial registration date: 21st March 2017

 

Related unit(s):

Coordinator: Raph Hamers