CryptoART Study: Decreasing Mortality Associated With Initiation of Antiretroviral Therapy in Sub-Saharan Africa

Study Overview
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Brief Summary
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The study will determine if the initiation of a 'screen and treat' program for cryptococcal disease among HIV positive individuals decreases morbidity and mortality among individuals with CD4 count < 100 cells/mm3. The study will screen individuals who are asymptomatic for CM and are either ART naïve or ART experienced with CD4 count < 100 cells/mm3. The introduction of an cheap, easy to use point of care diagnostic test the lateral flow assay will facilitate rapid diagnosis of cryptococcal disease in resource limited settings. The investigators will determine the efficacy of the lateral flow assay in identifying latent and asymptomatic cryptococcal disease. The investigators will determine the efficacy of the test in detecting disease in readily available body fluids such as urine and whole blood obtained via finger-stick method. The investigators will also determine the cost effectiveness of a screen and treat approach for cryptococcal disease in Zimbabwe. The investigators also wish to understand why some individuals with low CD4 counts reactivate cryptococcal disease and screen positive for cryptococcal antigen (CrAg) while others with similar levels of immunocompromised do not.

Official Title
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The CryptoART Study: Decreasing Mortality Associated With Initiation of Antiretroviral Therapy in Sub-Saharan Africa Through Early Detection and Prevention of Cryptococcal Disease

Conditions
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Cryptococcal Meningitis

Intervention / Treatment
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* Other: Pre-emptive screening and treatment for cryptococcal disease


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented HIV positive test by standard national algorithm CD4 count ≤100 cells/mm3 Age > 18 years Residence within 50 km of Harare Able to provide written informed consent Exclusion Criteria: Presence of clinical symptoms suggestive of meningitis. Recent history of CM within 2 weeks of enrollment, i.e., participants within the induction phase of therapy. Individuals with severe hepatic injury, jaundice, alanine transferase (ALT) >5x upper limit of normal Individuals with renal failure, defined by an estimated Glomerular filtration rate (eGFR) ≤30 mL/min (using MDRD (Modification of Diet in Renal Disease) equation) Currently known to be pregnant A negative urine pregnancy test is required for study entry for women with childbearing potential. The use of contraception will be recommended to women with childbearing potential while on high dose fluconazole therapy. Referral to family planning services will be given as necessary. Previous allergy or other reaction to amphotericin B and/or fluconazole Currently enrolled in another clinical trial/study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Screening<br>There are no arms to the study. All participants will undergo screening. Preemptive treatment will only be provided to those who are CrAg positive. | Other: Pre-emptive screening and treatment for cryptococcal disease<br>* Preemptive screening for cryptococcal disease among individuals with CD4 counts below 100 cells/mm3 with anti fungal therapy for those what are Cryptococcus antigen positive. These participants will be followed longitudinally for 12 months to determine clinical outcome, with their outcome compared with similar patients who are cryptococcal antigen negative, who will also be followed longitudinally for 12 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 12- month survival in CrAg-positive persons vs. CrAg-negative persons screened |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seroprevalence of asymptomatic cryptococcal antigenemia among individuals with CD4≤100 cells/mm3 in an urban population in Zimbabwe |  | 24 months | 
| Sensitivity, specificity, positive and negative predictive values of point-of-care urine CrAg LFAs |  | 24 months | 
| Sensitivity, specificity, positive and negative predictive values of point-of-care whole blood CrAg LFAs |  | 24 months | 
| Proportion of individuals with CD4≤100 cells/mm3 and a positive CrAg assay who have disseminated cryptococcal infection with either blood infection or CSF involvement |  | 24 months | 
| 12-month survival among individuals with CD4≤100 cells/mm3 prior to implementation of CrAg screening program using historical controls | Retrospective analysis | 24 months | 
| Cost of implementation of CrAg screening among individuals with CD4≤100 cells/mm3 |  | 24 months | 
| Cryptococcus-associated mortality among individuals with CD4≤100 cells/mm3, |  | 24 months | 
| Incidence of cryptococcal and non-cryptococcal IRIS |  | 24 months | 
| Barriers to uptake of diagnostic LP by individuals with asymptomatic cryptococcal antigenemia. | Questionnaire will be administered to participants who are serum cryptococcal antigen positive who decline to undergo LP. | 24 months | 
| Inflammatory cytokines and functional impairments in antigen specific T cells that are associated with the development of cryptococcal antigenemia and meningitis. | Analysis will be done by ELISA and Luminex assays, cell culture and flow cytometry techniques, data collected will be entered into a database and analyzed by patient characteristics. | 24 months | 
| Impact of ART mediated immune reconstitution on the inflammatory cytokine profile and the cryptococcal antigen specific CD4+ T cell response in those with serum and CSF cryptococcal antigenemia compared with those without. | Analysis will be done by ELISA and Luminex assays, cell culture and flow cytometry techniques, data collected will be entered into a database and analyzed by patient characteristics. Data will be longitudinal including baseline characteristics and subsequent follow-up data at 6 months and 12 months. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Cryptococcus, Lateral Flow Assay, sub-Saharan Africa, Screening, treatment, cryptococcal meningitis