Immediate Versus Deferred Antiretroviral Therapy for HIV-Associated Tuberculous Meningitis

Brief Title

Immediate Versus Deferred Antiretroviral Therapy for HIV-Associated Tuberculous Meningitis

Official Title

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

Brief Summary

      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.
    

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


Primary Outcome

Mortality

Secondary Outcome

 Mortality

Condition

HIV Infections

Intervention

Combivir and efavirenz

Study Arms / Comparison Groups

 1
Description:  Combivir, efavirenz for 12 months

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

253

Start Date

September 2005

Completion Date

December 2008

Primary Completion Date

December 2008

Eligibility Criteria

        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.
      

Gender

All

Ages

15 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Estee Torok, , 

Location Countries

Vietnam

Location Countries

Vietnam

Administrative Informations


NCT ID

NCT00433719

Organization ID

OXTREC 023-04

Secondary IDs

ISRCTN63659091


Study Sponsor

University of Oxford

Collaborators

 Wellcome Trust

Study Sponsor

Estee Torok, Principal Investigator, University of Oxford


Verification Date

June 2008