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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Cryptococcal Meningitis
• Intervention / Treatment: Other: Early antiretroviral therapy

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 4

Contacts and Locations

Study Locations

• Botswana
  • Gaborone,Ramotswa,Molepolole, Botswana
    • Princess Marina Hospital,Bamalete Lutheran Hospital and Scottish Livingstone Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Botswana-UPenn Partnership
• Collaborators: University of Pennsylvania; Doris Duke Charitable Foundation
• 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

Publications and helpful links

General Publications

• 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. Erratum In: Clin Infect Dis. 2013 Oct;57(7):1067.

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): November 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: September 11, 2009
• First Submitted That Met QC Criteria: September 11, 2009
• First Posted (Estimate): September 14, 2009

Study Record Updates

• Last Update Posted (Estimate): February 7, 2012
• Last Update Submitted That Met QC Criteria: February 3, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: HIV-1; Africa; treatment naive; Botswana; Highly active antiretroviral therapy
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections and Mycoses; Mycoses; Meningitis, Fungal; Central Nervous System Fungal Infections; Cryptococcosis; Meningitis; Meningitis, Cryptococcal; Anti-Infective Agents; Antiviral Agents; Anti-Retroviral Agents
• Other Study ID Numbers: THE BOTSHELO STUDY