Clinical trial NCT02624453: Pre-Antiretroviral Therapy (ART) Cryptococcal Antigen Screening in AIDS
Official title: Implementation and Evaluation of a Screening Strategy to Reduce Morbidity and Mortality Due to Cryptoccocal Meningo-encephalitis in ART Naive AIDS Patients With <100 CD4 Count at the Day Hospital of the Yaounde Central Hospital, Cameroon
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Cryptococcal Meningitis
Keywords: cryptococcus
IMMY LFA
meningitis
antigen
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Yaounde Central Hospital
name: St George's, University of London
First posted: 2015-12-08
Enrollment: 186
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SCREENING

Brief summary: The aim of the study is to evaluate systematic pre-antiretroviral cryptococcal antigen screening and pre-emptive fluconazole therapy in antigen positive patients, as a strategy to reduce morbidity and mortality due to AIDS associated cryptococcal meningitis in patients starting antiretroviral therapy at \<100 CD4 in Cameroon.

Detailed description: Cryptococcal meningitis (CM) is a leading cause of death in AIDS patients in much of the developing world, responsible for up to 500,000 deaths each year in sub-Saharan Africa alone. Introduction of antiretroviral therapy (ART) has reduced the number of cases of cryptococcal meningitis in the developed world. Unfortunately, in many low resource settings, patients continue to present late to ART treatment programs with advanced immunosuppression, and many die of HIV-related illness in the weeks just prior to, and months following, initiation of ART. Cryptococcal meningitis causes many of these deaths, and is also a heavy burden on healthcare facilities. Treatment of the disease remains inadequate, with an acute mortality of between 20 and 50%, even with the best current treatment.

Many of these cases of cryptococcal meningitis may be preventable. Recent research has shown that routine screening for sub-clinical infection, using a simple test (cryptococcal antigen or CRAG) in patients presenting to ART programmes, can identify which patients are at risk of developing cryptococcal meningitis. Once identified, these patients could then be given safe oral "pre-emptive" treatment to prevent them developing a severe form of the disease. This strategy has many advantages over the alternative preventative measure, called generalised primary prophylaxis, which involves giving all profoundly immune depressed HIV-infected patients preventative treatment. Using a primary prophylaxis strategy, large numbers of patients are given medication, many of whom don't need it, and there are problems of cost and development of drug resistance and drug interactions. In a targeted strategy, only patients who benefit most from the treatment will be given medication.

The investigators propose to study the feasibility and effectiveness of CRAG screening and targeted pre-emptive treatment in patients entering ART treatment programmes in Yaoundé, Cameroon using a newly approved, easier to use, lateral flow format dipstick test (LFA). In the planned study, 400 patients will be screened using the CRAG test prior to starting ART. Patients with a positive cryptococcal antigen will be consented for a lumbar puncture (LP) for cerebrospinal fluid (CSF) analysis, and, if found to have cryptococcal meningitis, and eligible, they will be randomised and included in the complementary clinical trial "Advancing Cryptococcal Treatment in Africa" (ACTA) \[ISRCTN45035509, ANRS12275\] and treated according to the study protocol. Positive cryptococcal antigen patients with no evidence of neurological disease following lumbar puncture, or who decline a diagnostic LP will receive a tapering course of fluconazole. Cryptococcal antigen negative patients will not receive any additional antifungal therapy. All CRAG screened patients will be started on standard ART 2 to 4 weeks after screening and followed for up to 1 year, depending on antigen status, to determine whether any patients go on to develop clinical cryptococcal meningitis.

General objective

- To implement and evaluate systematic cryptococcal antigen screening as a strategy to reduce cryptococcal meningoencephalitis morbidity and mortality among HIV-infected patients initiating antiretroviral therapy at less than 100 CD4 cell counts at the Day Hospital of the Yaoundé Central Hospital in Cameroon

Specific objectives

* To determine the prevalence of cryptococcal antigenaemia and/or antigenuria among HIV-infected patients presenting with less than 100 CD4 cell count
* To determine the prevalence of laboratory confirmed cryptococcal meningoencephalitis among patients found to be CRAG positive
* To determine the incidence of newly diagnosed, and relapsing, laboratory confirmed cryptococcal meningitis in the first year after starting ART in all screened patients.
* To determine mortality within the first year of ART among patients screened for CRAG

Study design and number of patients A prospective cohort study of 400 ART naive patients presenting at entry of ART programme with less than 100 CD4 cell count/ml will be screened for CRAG using LFA in serum and urine and followed up for one year.

Study interventions Main intervention of the study will be cryptococcal antigen (CRAG) screening. All eligible patients will be screened at baseline using an LFA, a point of care (POC) dipstick test, on serum and/or plasma, and urine. Aliquots will be saved for later titering of CRAG positive samples. All subsequent treatments and patient management will be according to local guidelines and/or internationally accepted best practice standards.

Subsequent management Cryptococcal antigen negative participants: All CRAG negative participants will commence ART once counselling and pre-ART work-up are complete within an estimated time of 2 weeks in accordance with current Cameroon National AIDS control programme guidelines. There will be no further interventions. The participant will be seen at the outpatient clinic on the 2nd and 4th weeks following screening, then routinely according to the day hospital roster, and finally, every three months up to one year after the date of screening.

Cryptococcal antigen positive participants: All CRAG positive participants will have a careful symptom screen (headache/altered mental status), and will be asked to consent for an LP for CSF analysis: If cryptococcal meningitis is diagnosed by Indian ink and/or culture, and the patients is eligible, the patient may be included in the clinical trial "Advancing Cryptococcal Treatment in Africa" (ACTA) and treated according to ACTA protocol. If a patient is ineligible, or declines to be included in the ACTA trial, they will be treated with short course amphotericin B (one week) combined with oral fluconazole 800mg/day for two weeks, then 8 weeks of fluconazole 40mg/day and 200mg/day thereafter.

If LP is negative for cryptococcal meningitis (or LP refused), patients will receive Fluconazole 800 mg/day for 2 weeks then 400 mg/day for 8 weeks then 200 mg/day (based on current best practice).

Patients will commence ART (efavirenz based) 2-4 weeks after starting antifungal therapy, in accordance with current Cameroon National AIDS control programme guidelines. Follow-up will be for one year. Patients will be seen at the outpatient clinic every two weeks for the first ten weeks, then at three month intervals. During the outpatient visits, in case of any opportunistic infection occurrence, they will be managed according to local current practice of the Day Hospital. Women of child-bearing age will be proposed contraception (preferably barrier methods) during the period of follow up.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18years
* HIV 1 and 2 infected but naïve to ART
* CD4 cell count less than 100 cells/ml
* No documented past history of cryptococcal meningoencephalitis
* Acceptance to participate in the study
* Ambulatory/out patients.

Exclusion Criteria:

* Patients on ART
* Pregnant patients
* Patients with other severe AIDS-associated opportunistic infections

Primary outcomes:
measure: Prevalence of cryptococcal antigenaemia and antigenuria
timeFrame: at inclusion
Secondary outcomes:
measure: Baseline prevalence of laboratory confirmed Cryptococcal Meningitis
timeFrame: at inclusion
Other outcomes:
measure: Incidence of laboratory confirmed cryptococcal meningitis in the first year
timeFrame: first year of antiretroviral therapy initial
measure: Incidence of newly diagnosed and relapsing in all patients in the first year
timeFrame: first year of antiretroviral therapy initiation
measure: Incidence of mortality within the first year
timeFrame: first year of antiretroviral therapy initiation
Locations:
city: Yaounde
country: Cameroon
facility: Day Hospital of the Yaounde Central Hospital
state: Central Region
Study officials:
affiliation: Hôpital Universitaire Necker-Enfants Malades, Molecular Mycology Unit, Institut Pasteur of Paris, and Paris Descartes University, Paris, France
name: Olivier Lortholary, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Douala General Hospital, Douala, Cameroon and Paris Descartes University, Paris, France
name: Elvis Temfack, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Infectious Disease Unit, St George's University of London, London, United Kingdom
name: Thomas Harrison, MD
role: STUDY_DIRECTOR
affiliation: Day Hospital, Yaoundé Central Hospital, Yaoundé, Cameroon
name: Charles Kouanfack, MD, PhD
role: STUDY_DIRECTOR
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