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

NCT00976040 | Completed Phase 4 DMC

• 1 other identifier: THE BOTSHELO STUDY
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

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.

Conditions

Cryptococcal Meningitis; HIV Infections

Keywords

HIV-1; Africa; Botswana; Highly active antiretroviral therapy; treatment naive

Outcome Measures

Primary Outcomes (1)

• Change in the CSF CFUs between the immediate and standard ART initiation groups

  4 weeks

Secondary Outcomes (3)

• Grade 3 or 4 adverse events

  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

Study Arms (2)

Early antiretroviral therapy

EXPERIMENTAL

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

Other: Early antiretroviral therapy

Standard antiretroviral therapy

NO INTERVENTION

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

Interventions

Early antiretroviral therapy OTHER

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.

Early antiretroviral therapy

Eligibility Criteria

• Age: 21 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Botswana-UPenn Partnership: lead
• Doris Duke Charitable Foundation: collaborator
• University of Pennsylvania: collaborator

Study Sites (1)

Princess Marina Hospital,Bamalete Lutheran Hospital and Scottish Livingstone Hospital

Gaborone,Ramotswa,Molepolole, Botswana

Location

Related Publications (1)

• 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.

  PMID: 23362285 DERIVED

MeSH Terms

Conditions

Meningitis, Cryptococcal; HIV Infections

Condition Hierarchy (Ancestors)

Meningitis, Fungal; Central Nervous System Fungal Infections; Mycoses; Bacterial Infections and Mycoses; Infections; Cryptococcosis; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: September 11, 2009
• First Posted: September 14, 2009
• Study Start: September 1, 2009
• Primary Completion: November 1, 2011
• Study Completion: December 1, 2011
• Last Updated: February 7, 2012

Record last verified: 2012-02

Locations

BO (1)