Vietnam Cryptococcal Retention in Care Study - Version 2.1

Study Overview
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Brief Summary
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This is a multicenter prospective cohort evaluation of the implementation of a cryptococcal antigen (CrAg) screening program at selected outpatient HIV clinics (OPCs) and network laboratories in Vietnam.

Detailed Description
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The project will be implemented in 2 phases; Phase 1: From August 2015 to March 2017 [projected], HIV-infected patients who present for HIV care and undergo CD4 testing will be reviewed to determine the proportion of newly presenting patients with advanced disease (CD4 ≤100 cells/μL). Reflex CrAg screening will be performed using Lateral Flow Assay (LFA) for those with CD4≤100 cells/μL, per Vietnam national guidelines. Patients with CD4≤100 cells/μL who present for antiretroviral treatment (ART) at a study OPCs-CRICS Sites- will be recruited into the longitudinal study and followed up with assessments and the collection of routine and supplemental data for 12 months or through September 2017 (whichever comes sooner). Those who are CrAg-positive, but have no features of central nervous system (CNS) disease, will be treated with high-dose fluconazole. Those with symptoms of CNS disease will be treated according to national guidelines. Survival, retention in care, and other clinical outcomes will be documented for patients who test CrAg-positive and are treated with fluconazole and those who test CrAg-negative. Data from those tested at participating labs but not eligible for enrollment in the longitudinal study will contribute to the estimation of the prevalence of CrAg. Phase 2: From April 2017 to September 2017, a cost and cost-effectiveness analysis of CrAg screening will be conducted, a routine screening will be continued at existing sites and expanded to additional sites (preferentially to hospitals affiliated with Phase 1 OPCs and to other OPCs whose CD4 testing is conducted at laboratories already conducting CrAg screening as part of Phase 1). CrAg tests will also be made available to screen all patients with CD4≤100 cells/μL including those who are treatment-experienced. The test will also be made available for use among symptomatic patients for diagnostic purposes, including cerebral spinal fluid (CSF) and blood testing. Investigators will monitor prevalence at each testing site, but screened patients will not be enrolled in longitudinal follow-up. Phase 2 will last for at least 6 months based on the availability of funding and fluconazole for those who screen CrAg positive and the availability/stability of CD4 testing. [Note that follow up of patients enrolled in Phase 1 will continue during this time period, but is considered to be part of Phase 1 rather than Phase 2. Also, sites included in Phase 2 may change over time as a result of the instability of CD4 testing (e.g., if participating laboratories stop conducting CD4 testing, those sites might no longer be included; if participating laboratories begin CD4 testing for other sites, those sites might be included).]

Official Title
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Vietnam Cryptococcal Retention in Care Study (CRICS) - Version 2.1

Conditions
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HIV/AIDS, Cryptococcal Meningitis, Opportunistic Infections, HIV Related, Cryptococcosis, Mycosis; Opportunistic, Mycosis Fungoides

Intervention / Treatment
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* Other: Preemptive high-dose Fluconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥ 18 years (having passed 18th birthday using Western calendar) Confirmed HIV infection using National Testing Algorithm CD4 ≤100 cells/μL Able to provide written informed consent Enrolled at and plan to receive ongoing outpatient care at one of the selected study OPCs Exclusion Criteria: History of prior CM Receipt of systemic antifungal medication for more than 4 consecutive weeks within the past 6 months Receipt of ART for more than 4 consecutive weeks within the past year For CrAg-positive patients only: Known to be currently pregnant or planning to become pregnant during the study period

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 |
| --- | --- |
| CrAg(+) and CM(-)<br>(1) Patients with CrAg positive without meningitis results will receive preemptive high-dose fluconazole to prevent developing meningitis. | Other: Preemptive high-dose Fluconazole<br>* Patients with advanced HIV diseases are screened for Cryptococcal Antigen using LFA CrAg tests. Then patients with CrAg positivity and without meningitis are given preemptive high-dose fluconazole to prevent the development of cryptococcal meningitis, which is one of the leading cause of death among immunocompromized patients.<br>* Other names: Preemptive Fluconazole;|
| CrAg(+) and CM(+)<br>(2) Patients with CrAg positive and meningitis results will receive standard treatment for cryptococcal meningitis, following national guidelines. | Other: Preemptive high-dose Fluconazole<br>* Patients with advanced HIV diseases are screened for Cryptococcal Antigen using LFA CrAg tests. Then patients with CrAg positivity and without meningitis are given preemptive high-dose fluconazole to prevent the development of cryptococcal meningitis, which is one of the leading cause of death among immunocompromized patients.<br>* Other names: Preemptive Fluconazole;|
| CrAg(-)<br>(3) Patients with CrAg negative results will be managed as other HIV infected patients with the standard of care, following national guidelines. | Other: Preemptive high-dose Fluconazole<br>* Patients with advanced HIV diseases are screened for Cryptococcal Antigen using LFA CrAg tests. Then patients with CrAg positivity and without meningitis are given preemptive high-dose fluconazole to prevent the development of cryptococcal meningitis, which is one of the leading cause of death among immunocompromized patients.<br>* Other names: Preemptive Fluconazole;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of HIV-infected adults who have CD4 count ≤ 100 cells/μL | The number of HIV-infected adults with CD4 count ≤ 100 cells/μL divided by the total number of HIV-infected patients. | August 2015 to March 2017 | 
| Prevalence of CrAg-positivity among HIV-infected patients with CD4 ≤100 cells/μL | The number of CrAg-positivity divided by the number HIV-infected patients with CD4 ≤100 cells/μL | August 2015 to March 2017 | 
| Clinical outcomes including common causes of mortality for people living with HIV (PLHIV) with CD4 ≤ 100 cells/μL who are enrolled in a programmatic rollout of screening for CrAg | Clinical outcomes include HIV-related hospitalization, causes of death, new AIDS defining opportunistic infections at 6 and 12 month. | August 2015 to March 2017 | 
| Twelve (12) month all-causes and cryptococcal meningitis (CM)-related mortality among patients who screen CrAg-positive and CrAg-negative | The 12-month mortality among two groups of HIV-infected patients with CD4 ≤ 100 cells/μL who are enrolled in care and treatment: Those who are CrAg-positive and are treated with high-dose fluconazole; Those who are CrAg-negative. | August 2015 to March 2017 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Twelve (12) month retention among patients who screen CrAg-positive and CrAg-negative | The 12-month retention in care among two groups of HIV-infected patients with CD4 ≤ 100 cells/μL who are newly enrolled in care and treatment. | August 2015 to March 2017 | 
| Challenges associated with implementation of routine plasma CrAg screening in clinics providing HIV care | The challenges associated with implementation may include lost to follow up, incomplete documentation, and poor retention in care. | August 2015 to March 2018 | 
| Lessons learned with participating sites | This will be delivered at reflection and transition workshops with participating sites. | August 2015 to March 2018 | 
| Total costs and unit cost per person screened, per CrAg+ treated by site, lab facility type, and cost component. | The costs of implementing CrAg screening based on data to be collected at 22 participating clinics participating in Phase 1 and provider costs associated with CM treatment. | August 2015 to March 2017 | 
| Incremental cost-effectiveness ratio (cost per CM death averted and cost per quality adjusted life year (QALY)) | The incremental cost-effectiveness analysis of CrAg screening compared with a standard of care (no CrAg screening, and treatment for symptomatic CM only). | August 2015 to March 2017 | 
| Total cost savings and amount of financial resources required to implement CrAg screening | Potential cost savings from implementing CrAg screening and financial resources required to implement CrAg screening under different scale-up scenarios and for national rollout | August 2015 to March 2017 | 
| Proportion of stored samples that test positive for TmAg | The prevalence of Talaromyces marneffei antigenemia (TmAg) in stored CRICS samples using the Mannose phosphate isomerase 1 (MP1) enzyme-linked immunosorbent assay (ELISA) | August 2015 to March 2017 | 
| Six (6) and twelve (12) month all-causes and Talaromyces marneffei-related mortality among patients who screen TmAg-positive and TmAg-negative | The impact of TmAg positivity on mortality | August 2015 to March 2017 |