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

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

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.

Study Overview

• Status: Completed
• Conditions: Cryptococcal Meningitis
• Intervention / Treatment: Other: Pre-emptive screening and treatment for cryptococcal disease

• Study Type: Observational
• Enrollment (Actual): 1333

Contacts and Locations

Study Locations

• Zimbabwe
  • Harare, Zimbabwe
    • Parirenyatwa Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The study will recruit Asymptomatic participants with severe immunosuppression at risk of cryptococcal disease. The individuals will have a CD4 count <100cells/mm3 and can be ART naive or ART experienced with no symptoms of active Cryptococcal disease.

They will be recruited from outpatient HIV/ART clinics.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Screening; 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Zimbabwe
• Collaborators: Centers for Disease Control and Prevention
• Investigators: Principal Investigator: Chiratidzo E Ndhlovu, MBBS, MSc, University of Zimbabwe College of Health Sciences; Principal Investigator: Azure T Makadzange, MD DPhil, Massachusetts General Hospital

Publications and helpful links

General Publications

• Boyd K, Kouamou V, Hlupeni A, Tangwena Z, Ndhlovu CE, Makadzange AT; CryptoART Study Team. Diagnostic Accuracy of Point of Care Cryptococcal Antigen Lateral Flow Assay in Fingerprick Whole Blood and Urine Samples for the Detection of Asymptomatic Cryptococcal Disease in Patients with Advanced HIV Disease. Microbiol Spectr. 2022 Aug 31;10(4):e0107522. doi: 10.1128/spectrum.01075-22. Epub 2022 Aug 4.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (ACTUAL): June 1, 2017
• Study Completion (ACTUAL): June 1, 2017

Study Registration Dates

• First Submitted: April 24, 2015
• First Submitted That Met QC Criteria: April 29, 2015
• First Posted (ESTIMATE): May 5, 2015

Study Record Updates

• Last Update Posted (ACTUAL): October 12, 2018
• Last Update Submitted That Met QC Criteria: October 11, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: treatment; HIV; Screening; sub-Saharan Africa; cryptococcal meningitis; Cryptococcus; Lateral Flow Assay
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections and Mycoses; Mycoses; Meningitis, Fungal; Central Nervous System Fungal Infections; Cryptococcosis; Meningitis; Meningitis, Cryptococcal
• Other Study ID Numbers: 1U01GH000737-01 (NIH)