Clinical trial NCT00976040: Optimal Time to Start Antiretroviral Therapy in HIV-infected Adults With Cryptococcal Meningitis
Official title: A Randomized Clinical Trial of Immediate Versus Standard Antiretroviral Therapy for HIV-infected Adults Presenting With Cryptococcal Meningitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cryptococcal Meningitis
HIV Infections
Keywords: HIV-1
Africa
Botswana
Highly active antiretroviral therapy
treatment naive
Lead sponsor: Botswana-UPenn Partnership
Sponsor class: OTHER
Collaborators: name: Doris Duke Charitable Foundation
name: University of Pennsylvania
First posted: 2009-09-14
Enrollment: 28
Sex: ALL
Minimum age (years): 21
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this randomized clinical trial is to compare early versus standard timing of initiation of antiretroviral therapy (ART) with respect to clearance of Cryptococcus neoformans from cerebrospinal fluid (CSF) among HIV-infected adults with Cryptococcal Meningitis.

The investigators hypothesize that early ART mediates more rapid clearance of C. neoformans from CSF, as manifested by a greater rate of decrease in C. neoformans colony forming units (CFUs) during the first 28 days after initiating antifungal treatment.

Secondary hypotheses are that recovery of pathogen specific cellular immunity directed at C. neoformans, as manifested by increases in the number and function of C. neoformans-specific peripheral blood mononuclear cells is associated with 1) ART and 2) pathogen clearance. In addition, patients randomized to the intervention arm will have more rapid clearance of antigen levels in CSF and serum and will have a lower incidence of grade 3 and 4 Adverse events.


Eligibility criteria: Inclusion Criteria:

* HIV 1 infection confirmed by licensed ELISA kit and/or detectable Viral load.
* Confirmed Cryptococcal meningitis on the current admission by India ink or CSF cryptococcal antigen
* ART naive at the time of enrollment
* 21 years old and above
* Ability and willingness to give written informed consent to participate in the study
* Able (as assessed by the patient's medical team)to initiate amphotericin B for cryptococcal meningitis
* Initiated amphotericin B 72 hours or less prior to assessment for enrollment or not on amphotericin B at the time of assessment for enrollment
* Agrees to obtain outpatient care after discharge within 50 kilometers from Princess Marina Hospital,Scottish Livingstone Hospital and Bamalete Lutheran Hospital

Exclusion Criteria:

* Recent (within the past 4 weeks) antifungal use
* Pregnant or breastfeeding
* Initiated anti-tubercular therapy 2 weeks or less prior to assessment for enrollment.
* Bacterial meningitis at the time of assessment for enrollment.
* Recent (within the past 1 month) use of the following:systemic cancer chemotherapy,oral or intravenous corticosteroids or other immunomodulators.
* Judged by study coordinator to be likely to initiate chemotherapy or any other immunomodulatory therapy prior to the 4 week LP.
* Imprisoned.

Primary outcomes:
measure: Change in the CSF CFUs between the immediate and standard ART initiation groups
timeFrame: 4 weeks
Secondary outcomes:
measure: Grade 3 or 4 adverse events
timeFrame: 6 months
measure: Clearance of C. neoformans antigen from CSF and blood.
timeFrame: 6 months
measure: Change in the number of peripheral blood mononuclear cells responding to C. neoformans
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Gaborone,Ramotswa,Molepolole
country: Botswana
facility: Princess Marina Hospital,Bamalete Lutheran Hospital and Scottish Livingstone Hospital
Study officials:
affiliation: Botswana-UPenn Partnership, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
name: Gregory P Bisson, MD,MSCE
role: PRINCIPAL_INVESTIGATOR
affiliation: Botswana-UPenn Partnership, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
name: Pablo Tebas, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bisson GP, Molefi M, Bellamy S, Thakur R, Steenhoff A, Tamuhla N, Rantleru T, Tsimako I, Gluckman S, Ravimohan S, Weissman D, Tebas P. Early versus delayed antiretroviral therapy and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitis. Clin Infect Dis. 2013 Apr;56(8):1165-73. doi: 10.1093/cid/cit019. Epub 2013 Jan 29.