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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified January 2009 by University of Zimbabwe.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborator:
AIDS Care Research in Africa
Information provided by:
University of Zimbabwe
ClinicalTrials.gov Identifier:
NCT00830856
First received: January 27, 2009
Last updated: February 25, 2009
Last verified: January 2009
  Purpose

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.


Condition Intervention
Cryptococcal Meningitis
HIV Infections
Drug: Fluconazole
Drug: Fixed dose - Stavudine, lamivudine and Nevirapine
Drug: Fixed dose - Stavudine, Lamivudine, Nevirapine

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Caregiver)
Primary Purpose: Treatment
Official Title: Randomized Control Trial of Early vs Delayed ART in the Treatment of Cryptococcal Meningitis.

Resource links provided by NLM:


Further study details as provided by University of Zimbabwe:

Primary Outcome Measures:
  • Mortality [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Enrollment: 54
Study Start Date: October 2006
Estimated Study Completion Date: October 2009
Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
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.
Drug: Fluconazole
Fluconazole 800mg po qday
Drug: Fixed dose - Stavudine, lamivudine and Nevirapine
Initiation within 72 hours of diagnosis of Cryptococcal meningitis.
Experimental: 2
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.
Drug: Fluconazole
Fluconazole 800mg po qday
Drug: Fixed dose - Stavudine, Lamivudine, Nevirapine
Delayed initiation of ART defined as 10 weeks after initiation of high dose fluconazole therapy.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00830856

Locations
Zimbabwe
University of Zimbabwe, College of Health Sciences
Harare, Zimbabwe
Sponsors and Collaborators
University of Zimbabwe
AIDS Care Research in Africa
Investigators
Principal Investigator: Chiratidzo E Ndhlovu, MBChB, FRCP University of Zimbabwe, Department of Medicine
Principal Investigator: Azure T Makadzange, MD, DPhil University of Zimbabwe, Department of Immunology
Study Chair: James Hakim, MBChB, FRCP University of Zimbabwe, Department of Medicine
  More Information

No publications provided

Responsible Party: Dr. Chiratidzo Ellen Ndhlovu, Chairman Department of Medicine, University of Zimbabwe, College of Health Sciences
ClinicalTrials.gov Identifier: NCT00830856     History of Changes
Other Study ID Numbers: ZimCrypto03
Study First Received: January 27, 2009
Last Updated: February 25, 2009
Health Authority: Zimbabwe: Medical Research Council

Keywords provided by University of Zimbabwe:
Cryptococcal Meningitis
HIV
Fluconazole
Antiretroviral therapy
Africa
treatment naive

Additional relevant MeSH terms:
Meningitis
Meningitis, Cryptococcal
Meningitis, Fungal
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Central Nervous System Infections
Central Nervous System Diseases
Nervous System Diseases
Central Nervous System Fungal Infections
Mycoses
Cryptococcosis
Lamivudine
Stavudine
Nevirapine
Fluconazole
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents

ClinicalTrials.gov processed this record on September 22, 2014