Plain English Summary
Background and study aims
Infection with human immunodeficiency virus (HIV) can lead to an increased risk of developing tuberculous meningitis (TBM), a condition where infection with bacteria called Mycobacterium tuberculosis leads to life-threatening inflammation in the brain and spinal cord. HIV is treated with a life-long drug course called antiretroviral therapy (ART), which can be highly toxic. If a patient is found to have HIV when they are diagnosed with TBM there are concerns that beginning ART immediately could be bad for patients because they are taking a lot of drugs at the same time. Beginning HIV treatment too late, however, can cause the patient to die from other infections because their ability to fight infections is too weak. This study examines when to begin ART in patients with TBM who are also found to have HIV .
Who can participate?
Patients had to be over 15 years old, HIV-positive and diagnosed with TBM.
What does the study involve?
The patients were randomly assigned into two groups. In addition to their treatment for TBM, one group received ART within 72 hours of study entry (immediate ART) and the other group received ART two months after study entry (deferred ART). The patients were then monitored daily in the hospital for general health, fever, coma and other negative health events. At the end of three months, the patients were discharged and followed up monthly as part of the national tuberculosis program. A final follow-up visit took place at 12 months from study entry.
What are the possible benefits and risks of participating?
The patient will not have to pay for anything other than the normal costs of routine inpatient care. All medication and tests related to the study will be paid for. Having a blood test or a lumbar puncture done can be uncomfortable and may cause a bruise. Common side effects of the drug include orange discolouration of body fluids, nausea, vomiting, abdominal pain and headache. While in hospital, the patient will be closely monitored by the study doctor. After the patient leaves hospital, they will be followed up in the clinic every month.
Where is the study run from?
The study was run by researchers at the Oxford University Clinical Research Unit in Vietnam, in partnership with the Hospital for Tropical Diseases and the Pham Ngoc Thach Hospital in Ho Chi Minh City.
When is the study starting and how long is it expected to run for?
The study ran from April 2005 to December 2008.
Who is funding the study?
The Wellcome Trust (UK).
Who is the main contact?
Clinical Trials Unit at the Oxford University Clinical Research Unit in Vietnam
Tel: +84 839 241 983
Trial website
Additional identifiers
EudraCT number
ClinicalTrials.gov number
NCT00433719
Protocol/serial number
076224; OXTREC 023-04
Study information
Scientific title
Study of immediate versus deferred antiretroviral therapy in human immunodeficiency virus-associated tuberculous meningitis
Acronym
DK Study
Study hypothesis
Human Immunodeficiency Virus (HIV) infection is associated with an increased risk of Tuberculosis (TB); in particular Tuberculous Meningitis (TBM). There are limited data describing the influence of HIV infection on the clinical presentation, response to treatment, frequency of adverse events, outcome or the impact of Anti-Retroviral Therapy (ART) in HIV-associated TBM. The optimal time to initiate ART is unknown. There are concerns that immediate ART may worsen rather than improve outcome, because of the development of an Immune Reconstitution Inflammatory Syndrome (IRIS) or combined drug toxicities. Conversely, delaying ART may result in increased HIV-related deaths. We therefore propose to conduct a clinical trial of immediate versus deferred ART in HIV-infected patients presenting with TBM, to assess effect on survival.
As of 13/02/2007 the anticipated end date of this trial was shortened to 20/09/2008.
Ethics approval
Oxford Tropical Research Ethics Committee (OxTREC), 07/02/2005, ref: OxTREC 023-04
Study design
Randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Other
Trial type
Treatment
Patient information sheet
Condition
HIV-associated tuberculous meningitis
Intervention
Randomised double-blind placebo-controlled trial with two parallel arms: immediate Highly Active Anti-Retroviral Therapy (HAART) and deferred HAART (two months). Patients will also receive standard treatment (anti-tuberculous chemotherapy and adjunctive dexamethasone) for tuberculous meningitis.
Intervention type
Drug
Phase
Not Applicable
Drug names
Highly Active Anti-Retroviral Therapy (HAART)
Primary outcome measure
Mortality at 9 months
Secondary outcome measures
1. Mortality at 12 months
2. Fever clearance time
3. Coma clearance time
4. Neurological relapse
5. Progression to new or recurrent Acquired Immuno-Deficiency Syndrome (AIDS) defining illness
6. Any grade three or four adverse event
7. CD4 count response
8. Plasma HIV-1 RiboNucleic Acid (RNA) response
9. Neurological disability: neurological disability will be assessed using the 'simple questions' and Rankin score
Overall trial start date
01/04/2005
Overall trial end date
01/12/2008
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Patients aged 15 or over
2. HIV seropositive
3. Anti-retroviral naive
4. Presenting with tuberculous meningitis
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
222
Participant exclusion criteria
1. Positive Cerebrospinal Fluid (CSF) Gram or India ink stain
2. Known or suspected pregnancy
3. Anti-tuberculous treatment eight to 30 days immediately prior to recruitment
4. Previous antiretroviral therapy
5. Laboratory contraindications to anti-retroviral or anti-tuberculous therapy
6. Lack of consent
Recruitment start date
01/04/2005
Recruitment end date
20/09/2007
Locations
Countries of recruitment
Viet Nam
Trial participating centre
Oxford University Clinical Research Unit
Ho Chi Minh City
District 5
Viet Nam
Funders
Funder type
Charity
Funder name
Wellcome Trust
Alternative name(s)
Wellcome
Funding Body Type
private sector organisation
Funding Body Subtype
international
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2011 results in: https://www.ncbi.nlm.nih.gov/pubmed/21596680