Optimal Time to Start Antiretroviral Therapy in HIV-infected Adults With Cryptococcal Meningitis

Sponsor

Botswana-UPenn Partnership (Other)

Overall Status

Completed

CT.gov ID

NCT00976040

Collaborator

Doris Duke Charitable Foundation (Other), University of Pennsylvania (Other)

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cryptococcal Meningitis HIV Infections	Other: Early antiretroviral therapy	Phase 4

Study Design

Study Type:

Interventional

Actual Enrollment :

28 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Clinical Trial of Immediate Versus Standard Antiretroviral Therapy for HIV-infected Adults Presenting With Cryptococcal Meningitis

Study Start Date :

Sep 1, 2009

Actual Primary Completion Date :

Nov 1, 2011

Actual Study Completion Date :

Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Early antiretroviral therapy Subjects randomized to this arm will initiate antiretroviral therapy within 7 days of enrollment.	Other: Early antiretroviral therapy The intervention is early initiation of antiretroviral therapy after diagnosis of Cryptococcal meningitis. In the intervention/experimental arm, triple-drug highly active antiretroviral therapy regimens will be initiated within 7 days of diagnosis of Cryptococcal meningitis.
No Intervention: Standard antiretroviral therapy Subjects randomized to this arm will initiate antiretroviral therapy approximately 4 weeks after enrollment.

Arm

Intervention/Treatment

Experimental: Early antiretroviral therapy

Subjects randomized to this arm will initiate antiretroviral therapy within 7 days of enrollment.

Other: Early antiretroviral therapy

The intervention is early initiation of antiretroviral therapy after diagnosis of Cryptococcal meningitis. In the intervention/experimental arm, triple-drug highly active antiretroviral therapy regimens will be initiated within 7 days of diagnosis of Cryptococcal meningitis.

No Intervention: Standard antiretroviral therapy

Subjects randomized to this arm will initiate antiretroviral therapy approximately 4 weeks after enrollment.

Outcome Measures

Primary Outcome Measures

Change in the CSF CFUs between the immediate and standard ART initiation groups [4 weeks]

Secondary Outcome Measures

Grade 3 or 4 adverse events [6 months]
each participant is followed up for 6 months after the initiation of HAART
Clearance of C. neoformans antigen from CSF and blood. [6 months]
Change in the number of peripheral blood mononuclear cells responding to C. neoformans [4 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Princess Marina Hospital,Bamalete Lutheran Hospital and Scottish Livingstone Hospital	Gaborone,Ramotswa,Molepolole		Botswana

Sponsors and Collaborators

Botswana-UPenn Partnership
Doris Duke Charitable Foundation
University of Pennsylvania

Investigators

Principal Investigator: Gregory P Bisson, MD,MSCE, Botswana-UPenn Partnership, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Principal Investigator: Pablo Tebas, MD, Botswana-UPenn Partnership, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania