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

Study Overview
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Brief Summary
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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.

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

Conditions
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Cryptococcal Meningitis, HIV Infections

Intervention / Treatment
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* Other: Early antiretroviral therapy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early antiretroviral therapy<br>Subjects randomized to this arm will initiate antiretroviral therapy within 7 days of enrollment. | Other: Early antiretroviral therapy<br>* 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.<br>|
| No Intervention: Standard antiretroviral therapy<br>Subjects randomized to this arm will initiate antiretroviral therapy approximately 4 weeks after enrollment. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the CSF CFUs between the immediate and standard ART initiation groups |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3 or 4 adverse events | each participant is followed up for 6 months after the initiation of HAART | 6 months | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1, Africa, Botswana, Highly active antiretroviral therapy, treatment naive