Clinical trial NCT02434172: CryptoART Study: Decreasing Mortality Associated With Initiation of Antiretroviral Therapy in Sub-Saharan Africa
Official title: The CryptoART Study: Decreasing Mortality Associated With Initiation of Antiretroviral Therapy in Sub-Saharan Africa Through Early Detection and Prevention of Cryptococcal Disease
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Cryptococcal Meningitis
Keywords: HIV
Cryptococcus
Lateral Flow Assay
sub-Saharan Africa
Screening
treatment
cryptococcal meningitis
Lead sponsor: University of Zimbabwe
Sponsor class: OTHER
Collaborators: name: Centers for Disease Control and Prevention
First posted: 2015-05-05
Enrollment: 1333
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.


Eligibility criteria: 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

Primary outcomes:
measure: 12- month survival in CrAg-positive persons vs. CrAg-negative persons screened
timeFrame: 12 months
Secondary outcomes:
measure: Seroprevalence of asymptomatic cryptococcal antigenemia among individuals with CD4≤100 cells/mm3 in an urban population in Zimbabwe
timeFrame: 24 months
measure: Sensitivity, specificity, positive and negative predictive values of point-of-care urine CrAg LFAs
timeFrame: 24 months
measure: Sensitivity, specificity, positive and negative predictive values of point-of-care whole blood CrAg LFAs
timeFrame: 24 months
measure: 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
timeFrame: 24 months
measure: 12-month survival among individuals with CD4≤100 cells/mm3 prior to implementation of CrAg screening program using historical controls
timeFrame: 24 months
measure: Cost of implementation of CrAg screening among individuals with CD4≤100 cells/mm3
timeFrame: 24 months
measure: Cryptococcus-associated mortality among individuals with CD4≤100 cells/mm3,
timeFrame: 24 months
measure: Incidence of cryptococcal and non-cryptococcal IRIS
timeFrame: 24 months
measure: Barriers to uptake of diagnostic LP by individuals with asymptomatic cryptococcal antigenemia.
timeFrame: 24 months
measure: Inflammatory cytokines and functional impairments in antigen specific T cells that are associated with the development of cryptococcal antigenemia and meningitis.
timeFrame: 24 months
measure: 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.
timeFrame: 24 months
Other outcomes:
Locations:
city: Harare
country: Zimbabwe
facility: Parirenyatwa Hospital
Study officials:
affiliation: University of Zimbabwe College of Health Sciences
name: Chiratidzo E Ndhlovu, MBBS, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Azure T Makadzange, MD DPhil
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.