Immediate Versus Deferred Antiretroviral Therapy for HIV-Associated Tuberculous Meningitis

Randomised Controlled Trial of Immediate Versus Deferred Antiretroviral Therapy for HIV-Associated Tuberculous Meningitis

The optimal time to initiate antiretroviral therapy (ART) in HIV-associated tuberculous meningitis (TBM) unknown. There are concerns that immediate ART may worsen rather than improve outcome, because drug interactiond and toxicities or development of an intracerebral immune reconstitution inflammatory syndrome (IRIS). Conversely, delaying ART may result in increased HIV-related deaths. To answer this question, we are conducting a randomised, double-blind placebo-controlled trial comparing immediate and deferred ART in HIV-infected patients presenting with TBM, to assess effect on survival.

Study Overview

• Status: Unknown
• Conditions: HIV Infections; Tuberculous Meningitis
• Intervention / Treatment: Drug: Combivir and efavirenz

Detailed Description

Title: Study of immediate versus deferred antiretroviral therapy in HIV-associated tuberculous meningitis Study design: A randomized, double blind, placebo-controlled trial with 2 parallel arms Sample size: 247 Inclusion criteria: Age 15 years or older; HIV antibody positive; clinical diagnosis of TBM.

Exclusion criteria: positive CSF Gram or India ink stain, known or suspected pregnancy; antituberculous treatment 8 to 30 days immediately prior to recruitment; previous antiretroviral therapy; laboratory contraindications to antiretroviral or antituberculous therapy; lack of consent.

Consent: Written informed consent will be sought for all patients. Verbal consent will be considered acceptable when written consent is impossible. In unconscious patients, the consent of 2 independent physicians will be considered acceptable.

Randomization: Patients will be stratified according to TBM disease severity at presentation (modified MRC grade I to III). Within each stratum, patients will be randomized to 1 of the 2 treatment arms: immediate or deferred (2 months) ART.

Antituberculous treatment: Initial therapy will be with isonazid, rifampicin, pyrazinamide and ethambutol for 3 months. After 3 months, patients will continue on rifampicin and isoniazid for a further 6 months.

Corticosteroid treatment: Dexamethasone 0.3 - 0.4mg/kg will be administered and tapered over 6 - 8 weeks, according to TBM grade.

Antiretrovira l treatment: Antiretrovirals (zidovudine, lamivudine and efavirenz)or identical placebo tablets will be commenced at study entry and continued for 2 months. Thereafter, all patients will received antiretrovirals.

Clinical monitoring: Patients will be assessed weekly as an inpatient for 3 months. Hospital outpatient review will occur monthly until 9 months. A final follow-up visit will take place at 12 months.

Laboratory monitoring: Routine laboratory tests will be monitored weekly as an inpatient and monthly as an outpatient. Blood samples for CD4 T-lymphocyte count and plasma HIV-1 RNA level will be monitored 3-monthly. CSF samples will be taken at 0, 1, 2, 3, 6 and 9 months.

Radiology: Patients will have a chest radiograph performed on admission. A CT or MRI brain scan may also be performed if clinically indicated.

Adverse events: All grade 3 and 4 adverse events will be reported immediately to the Data and Safety Monitoring Committee.

Outcome measures: The primary endpoint will be mortality at 9 months. The secondary endpoints will be: mortality at 12 months; fever clearance time; coma clearance time; neurological relapse; progression to new or recurrent AIDS defining illness; any grade 3 or 4 adverse event; CD4 count response; plasma HIV-1 RNA response; neurological disability.

Data analysis: Analysis will be based on intention to treat.

• Study Type: Interventional
• Enrollment (Actual): 253
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Vietnam
  • Ho Chi Minh City, Vietnam
    • Hospital for Tropical Diseases
  • Ho Chi Minh City, Vietnam
    • Pham Ngoc Thach Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age 15 years or older
• HIV antibody positive
• clinical diagnosis of TB meningitis

Exclusion Criteria:

• positive CSF Gram or India ink stain
• known or suspected pregnancy
• antituberculous treatment 8 - 30 days immediately prior to recruitment
• previous antiretroviral therapy
• laboratory contraindications to antiretroviral or antituberculous therapy
• lack of consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1; Combivir, efavirenz for 12 months	Drug: Combivir and efavirenz; Arm 1: Combivir and efavirenz for 12 months Arm 2: Placebo for 2 months then Combivir and efavirenz for 10 months
PLACEBO_COMPARATOR: 2; Placebo for 2 months followed by Combivir and efavirenz for 10 months	Drug: Combivir and efavirenz; Arm 1: Combivir and efavirenz for 12 months Arm 2: Placebo for 2 months then Combivir and efavirenz for 10 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mortality	9 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Fever clearance time
Mortality	12 months
Coma clearance time
CD4 count	12 months
plasma HIV RNA	12 months
Grade 3 or 4 adverse event	Any
Neurological disability	12 months

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Wellcome Trust
• Investigators: Principal Investigator: Estee Torok, University of Oxford

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (ANTICIPATED): December 1, 2008
• Study Completion (ANTICIPATED): December 1, 2008

Study Registration Dates

• First Submitted: January 25, 2007
• First Submitted That Met QC Criteria: February 9, 2007
• First Posted (ESTIMATE): February 12, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): August 7, 2008
• Last Update Submitted That Met QC Criteria: August 6, 2008
• Last Verified: June 1, 2008

More Information

Terms related to this study

• Keywords: Human immunodeficiency virus; Treatment Naive; Tuberculous meningitis
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Tuberculosis, Central Nervous System; Tuberculosis; Meningitis; Tuberculosis, Meningeal; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Efavirenz; Lamivudine, zidovudine drug combination
• Other Study ID Numbers: OXTREC 023-04; ISRCTN63659091