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CompletedNCT02434172CryptoARTUpdated Oct 12, 2018

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

An observational study in Cryptococcal Meningitis, sponsored by University of Zimbabwe. Completed at 1 site in Zimbabwe. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2018-10-12.

Sponsored by University of Zimbabwe · Observational

Study type
Observational
Model
Cohort
Time perspective
Prospective
Enrollment
1,333
Ages
18 Years and older
Sex
All
01

Study 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.

02

Conditions studied

  • Cryptococcal Meningitis

Keywords

  • HIV
  • Cryptococcus
  • Lateral Flow Assay
  • sub-Saharan Africa
  • Screening
  • treatment
  • cryptococcal meningitis
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No
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.

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

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
04

Study design

Observational model
Cohort
Time perspective
Prospective
Enrollment
1,333 participants (actual)
Patient registry
No
Biospecimen retention
Samples without dna

Groups and cohorts

  • 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

  • OtherPre-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.

05

What researchers measure

Primary outcomes

  1. 12- month survival in CrAg-positive persons vs. CrAg-negative persons screened

    Time frame: 12 months

Secondary outcomes

  1. Seroprevalence of asymptomatic cryptococcal antigenemia among individuals with CD4≤100 cells/mm3 in an urban population in Zimbabwe

    Time frame: 24 months

  2. Sensitivity, specificity, positive and negative predictive values of point-of-care urine CrAg LFAs

    Time frame: 24 months

  3. Sensitivity, specificity, positive and negative predictive values of point-of-care whole blood CrAg LFAs

    Time frame: 24 months

  4. 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

    Time frame: 24 months

  5. 12-month survival among individuals with CD4≤100 cells/mm3 prior to implementation of CrAg screening program using historical controls

    Retrospective analysis

    Time frame: 24 months

  6. Cost of implementation of CrAg screening among individuals with CD4≤100 cells/mm3

    Time frame: 24 months

  7. Cryptococcus-associated mortality among individuals with CD4≤100 cells/mm3,

    Time frame: 24 months

  8. Incidence of cryptococcal and non-cryptococcal IRIS

    Time frame: 24 months

  9. 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.

    Time frame: 24 months

  10. 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.

    Time frame: 24 months

  11. 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.

    Time frame: 24 months

06

Study locations

1 site
  • Parirenyatwa Hospital
    Harare, Zimbabwe
07

References and documents

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. PubMed 35924841 ↗
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Registry details

Key details

Study ID
NCT02434172
Lead sponsor
University of Zimbabwe
Collaborators
Centers for Disease Control and Prevention
Responsible party
Chiratidzo Ndhlovu (Associate Professor of Medicine, University of Zimbabwe) — Principal investigator
First posted
May 5, 2015
Start date
Apr 2015
Primary completion
Jun 2017
Completion
Jun 2017
Last update
Oct 12, 2018

Study contacts

Chiratidzo E Ndhlovu, MBBS, MSc
principal investigator · University of Zimbabwe College of Health Sciences
Azure T Makadzange, MD DPhil
principal investigator · Massachusetts General Hospital

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Oct 2018. You cannot join it, but the record below documents what was studied.

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