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

NCT02434172 | Completed DMC

• 1 other identifier: 1U01GH000737-01
• Study Type: observational
• Target: 1,333
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cryptococcal Meningitis

Keywords

HIV; Cryptococcus; Lateral Flow Assay; sub-Saharan Africa; Screening; treatment; cryptococcal meningitis

Outcome Measures

Primary Outcomes (1)

• 12- month survival in CrAg-positive persons vs. CrAg-negative persons screened

  12 months

Secondary Outcomes (11)

• 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

  24 months

Study Arms (1)

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

Interventions

Pre-emptive screening and treatment for cryptococcal disease OTHER

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.

Screening

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Zimbabwe: lead
• Centers for Disease Control and Prevention: collaborator

Study Sites (1)

Parirenyatwa Hospital

Harare, Zimbabwe

Location

Related Publications (2)

• Kouamou V, Gundidza P, Ndhlovu CE, Makadzange AT; CryptoART Study Team. Effects of Gender and Baseline CD4 Count on Post-Treatment CD4 Count Recovery and Outcomes in Patients with Advanced HIV Disease: A Retrospective Cohort Study. AIDS Res Hum Retroviruses. 2023 Jul;39(7):340-349. doi: 10.1089/AID.2022.0117. Epub 2023 Apr 26.

  PMID: 36924288 DERIVED

• 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.

  PMID: 35924841 DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

Plasma, and peripheral blood mononuclear cells

MeSH Terms

Conditions

Meningitis, Cryptococcal

Interventions

Therapeutics

Condition Hierarchy (Ancestors)

Meningitis, Fungal; Central Nervous System Fungal Infections; Mycoses; Bacterial Infections and Mycoses; Infections; Cryptococcosis; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases

Study Officials

• Chiratidzo E Ndhlovu, MBBS, MSc

  University of Zimbabwe College of Health Sciences

  PRINCIPAL INVESTIGATOR

• Azure T Makadzange, MD DPhil

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: April 24, 2015
• First Posted: May 5, 2015
• Study Start: April 1, 2015
• Primary Completion: June 1, 2017
• Study Completion: June 1, 2017
• Last Updated: October 12, 2018

Record last verified: 2018-10

Locations

ZI (1)