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Early Versus Delayed Antiretroviral Therapy (ART) in the Treatment of Cryptococcal Meningitis in Africa

Primary Purpose

Cryptococcal Meningitis, HIV Infections

Status
Completed
Phase
Not Applicable
Locations
Zimbabwe
Study Type
Interventional
Intervention
Fluconazole
Fixed dose - Stavudine, lamivudine and Nevirapine
Fixed dose - Stavudine, Lamivudine, Nevirapine
Sponsored by
University of Zimbabwe
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cryptococcal Meningitis focused on measuring Cryptococcal Meningitis, HIV, Fluconazole, Antiretroviral therapy, Africa, treatment naive

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • HIV infection documented by a positive HIV antibody test at enrollment;
  • Adult men and women (age>18);
  • Cryptococcal meningitis infection documented by a positive CSF CRAG or CSF identification of C. neoformans.
  • Place of residence is located within a 50km radius of Harare.

Exclusion Criteria:

  • Previous diagnosis (>1 week) of and treatment for cryptococcal meningitis
  • Currently on ARVs, or have been intermittently on and off ART in the past.
  • Concurrent use of medications that affect the metabolism of fluconazole e.g., antiseizure medications, oral hypoglycaemic agents.
  • History of cardiac failure and or predisposition to arrhythmias will be excluded.
  • They are pregnant or active lactation women
  • History of active hepatitis or hepatic or renal dysfunction will be excluded.

Sites / Locations

  • University of Zimbabwe, College of Health Sciences

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

1

2

Arm Description

Early initiation of antiretroviral therapy. Patients in this treatment group were started on Fluconazole 800mg by mouth every day for Cryptococcal Meningitis, and within 72hrs of diagnosis were started on First line antiretroviral therapy per Zimbabwe treatment guidelines which is Stavudine, Lamivudine and Nevirapine.

Delayed initiation of antiretroviral therapy. Patients in this treatment group were started on Fluconazole 800mg by mouth every day for Cryptococcal Meningitis, and after completion of high dose fluconazole for 10 weeks, the patients in this group were started on First line antiretroviral therapy per Zimbabwe treatment guidelines which is Stavudine, Lamivudine and Nevirapine.

Outcomes

Primary Outcome Measures

Mortality

Secondary Outcome Measures

Full Information

First Posted
January 27, 2009
Last Updated
July 14, 2016
Sponsor
University of Zimbabwe
Collaborators
AIDS Care Research in Africa
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1. Study Identification

Unique Protocol Identification Number
NCT00830856
Brief Title
Early Versus Delayed Antiretroviral Therapy (ART) in the Treatment of Cryptococcal Meningitis in Africa
Official Title
Randomized Control Trial of Early vs Delayed ART in the Treatment of Cryptococcal Meningitis.
Study Type
Interventional

2. Study Status

Record Verification Date
July 2016
Overall Recruitment Status
Completed
Study Start Date
October 2006 (undefined)
Primary Completion Date
October 2008 (Actual)
Study Completion Date
October 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Zimbabwe
Collaborators
AIDS Care Research in Africa

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Cryptococcal Meningitis continues to be one of the most devastating AIDS defining illness in sub-Saharan Africa. Despite the availability of azoles such as fluconazole for treatment, mortality remains high with some studies showing 100% mortality. The investigators designed a study to determine if timing of the initiation of antiretroviral therapy (ART) in patients with cryptococcal meningitis and HIV would improve survival. The investigators hypothesis was that early initiation of ART result in improved mortality for patients with HIV and cryptococcal meningitis.
Detailed Description
Cryptococcosis is an invasive fungal infection caused by an encapsulated yeast. Cryptococcosis in humans is almost always caused by Cryptococcus neoformans. The advent of the HIV epidemic has lead to a profound increase in the number of reported cases of cryptococcal meningoencephalitis throughout the world, particularly in sub-Saharan Africa. In Zimbabwe an analysis of the case reports at one of the major tertiary care hospitals showed an increase in the admission rate from meningitis between 1985-1995 from 78 to 523 cases per 100000 admissions with an increase in the number of those cases due to cryptococcosis from 5% to 46.2%. Cryptococcosis typically develops at a CD4 count of less than 50 cells/ mm3, and is the initial AIDS defining illness in up to 50-60% of patients. Prior to the introduction of amphotericin B, flucytosine and azoles, mortality from C neoformans meningoencephalitis was close to 100%. The introduction of amphotericin B led to a significant decrease in mortality with 60-70% of patients being successfully treated. The introduction of fluconazole prophylaxis in the 1990s lead to a significant decrease in the incidence of cryptococcosis. The use of antiretroviral therapy has also caused a significant decrease in the incidence of cryptococcal meningitis. Due to the prohibitive cost of amphotericin B and flucytosine, in many developing countries such as Zimbabwe, the mainstay of the treatment of CM is fluconazole. The current standard treatment is with fluconazole 400mg/day for 8-10 weeks, may be too low to result in adequate CNS concentration of the drug to achieve adequate killing of C. neoformans. Clinically some physicians in Zimbabwe have noted that patients are not responding adequately to this regimen and have started to treat patients with higher doses of fluconazole. Previous studies have shown that higher doses of fluconazole can be used for the treatment of CM and are well tolerated. In our proposed study, patients will be treated with high dose oral fluconazole at 800mg/day for a total 10 week period. The advent of the increased access to ART in sub-Saharan Africa provides an additional opportunity to improve morbidity and mortality in all AIDS patients. There are as yet no definitive studies to indicate if there is an advantage to immediate ART therapy in the setting of acute CM compared to deferring therapy after the first 10 weeks of intensive CM therapy. This study is designed to address this question and provide physicians in sub-Saharan Africa with evidence based guidelines for the appropriate management of HIV positive patients with acute presentation of CM.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cryptococcal Meningitis, HIV Infections
Keywords
Cryptococcal Meningitis, HIV, Fluconazole, Antiretroviral therapy, Africa, treatment naive

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
Care Provider
Allocation
Randomized
Enrollment
54 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
Early initiation of antiretroviral therapy. Patients in this treatment group were started on Fluconazole 800mg by mouth every day for Cryptococcal Meningitis, and within 72hrs of diagnosis were started on First line antiretroviral therapy per Zimbabwe treatment guidelines which is Stavudine, Lamivudine and Nevirapine.
Arm Title
2
Arm Type
Experimental
Arm Description
Delayed initiation of antiretroviral therapy. Patients in this treatment group were started on Fluconazole 800mg by mouth every day for Cryptococcal Meningitis, and after completion of high dose fluconazole for 10 weeks, the patients in this group were started on First line antiretroviral therapy per Zimbabwe treatment guidelines which is Stavudine, Lamivudine and Nevirapine.
Intervention Type
Drug
Intervention Name(s)
Fluconazole
Intervention Description
Fluconazole 800mg po qday
Intervention Type
Drug
Intervention Name(s)
Fixed dose - Stavudine, lamivudine and Nevirapine
Intervention Description
Initiation within 72 hours of diagnosis of Cryptococcal meningitis.
Intervention Type
Drug
Intervention Name(s)
Fixed dose - Stavudine, Lamivudine, Nevirapine
Intervention Description
Delayed initiation of ART defined as 10 weeks after initiation of high dose fluconazole therapy.
Primary Outcome Measure Information:
Title
Mortality
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: HIV infection documented by a positive HIV antibody test at enrollment; Adult men and women (age>18); Cryptococcal meningitis infection documented by a positive CSF CRAG or CSF identification of C. neoformans. Place of residence is located within a 50km radius of Harare. Exclusion Criteria: Previous diagnosis (>1 week) of and treatment for cryptococcal meningitis Currently on ARVs, or have been intermittently on and off ART in the past. Concurrent use of medications that affect the metabolism of fluconazole e.g., antiseizure medications, oral hypoglycaemic agents. History of cardiac failure and or predisposition to arrhythmias will be excluded. They are pregnant or active lactation women History of active hepatitis or hepatic or renal dysfunction will be excluded.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chiratidzo E Ndhlovu, MBChB, FRCP
Organizational Affiliation
University of Zimbabwe, Department of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Azure T Makadzange, MD, DPhil
Organizational Affiliation
University of Zimbabwe, Department of Immunology
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
James Hakim, MBChB, FRCP
Organizational Affiliation
University of Zimbabwe, Department of Medicine
Official's Role
Study Chair
Facility Information:
Facility Name
University of Zimbabwe, College of Health Sciences
City
Harare
Country
Zimbabwe

12. IPD Sharing Statement

Citations:
PubMed Identifier
20415574
Citation
Makadzange AT, Ndhlovu CE, Takarinda K, Reid M, Kurangwa M, Gona P, Hakim JG. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis. 2010 Jun 1;50(11):1532-8. doi: 10.1086/652652.
Results Reference
derived

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Early Versus Delayed Antiretroviral Therapy (ART) in the Treatment of Cryptococcal Meningitis in Africa

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