Making an Early Diagnosis of Talaromycosis Using a Novel Antigen Test

Study Overview
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Brief Summary
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This is a research study to determine whether a new antigen detection test called Mp1p EIA can make an early diagnosis of talaromycosis from the blood and urine of patients. Talaromycosis is a life-threatening infection caused by a fungus endemic in Southeast Asia commonly found in patients with advanced HIV disease called Talaromyces marneffei.

Detailed Description
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This study aims to determine the diagnostic and prognostic values and the clinical impact of Talaromyces marneffei antigenemia (TmAg) in patients with advanced HIV disease using a novel enzyme immunoassay (EIA) detecting Tm-specific cell wall mannoprotein Mp1p. The data generated will be used to inform the design of future diagnostic clinical trials to test the utility of screening and providing pre-emptive antifungal therapy to prevent disease and reduce HIV mortality in Southeast Asia. The primary objective is to screen for TmAg and determine its diagnostic and prognostic performance in symptomatic and asymptomatic HIV-infected patients with a CD4 count ≤100 cells/mm3. We will test the following hypotheses: In symptomatic hospitalized patient Cohort 1, the sensitivity of the Mp1p EIA will be higher than conventional culture method while simultaneously specificity is higher than 95% for diagnosing culture-confirmed talaromycosis over a six-month follow up period In asymptomatic outpatient Cohort 2, there will be at least 30% difference in risk of talaromycosis development in TmAg-positive patients compared to TmAg-negative patients over a twelve-month follow up period TmAg concentration predicts development of talaromycosis Secondary Objectives include: To assess the impact of presence of TmAg on clinical outcomes, including development of culture-confirmed talaromycosis, incidence of state III and IV AIDS events, subsequent hospitalizations, and death over six- to twelve-month follow up periods To compare the diagnostic values of the Mp1p EIA when performed in plasma, sera, and urine samples and when performed in these matrices in combination We will test the following hypotheses: To model the health economic benefits of screening and pre-emptive treatment for pre-clinical infection To assess impact on clinic outcomes of screening all patients for cryptococcosis and histoplasmosis To collect additional blood samples and store left-over samples for future research to validate infectious disease diagnostics and research to understand genetic susceptibility to infectious diseases relevant to HIV population Participants in the study, will be asked questions about their medical and travel history. Participants will have blood and urine collected for the Mp1p EIA test to look for early talaromycosis infection and for other tests to look for common HIV-associated infections including tuberculosis, cryptococcosis, and histoplasmosis. They will be examined by a study doctor at least once weekly if they are in the hospital and will be followed in clinic monthly for between 6 and 12 months.

Official Title
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Making an Early Diagnosis of Talaromycosis - a Strategy to Reduce Morbidity and Mortality in Advanced HIV Disease in Southeast Asia

Conditions
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AIDS/HIV - RelatedDisease Associated With AIDS

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection (at least 2 of 3 HIV antibody tests are positive), AND HIV-infected age ≥18 years, AND CD4 count ≤100 cells/mm3 within the past 3 months, AND Antiretroviral therapy (ART) naïve OR recent ART ≤3 months OR suspected or confirmed treatment failure on ART ≥12 months (defined as poor treatment adherence, treatment interruption, or having a confirmed HIV RNA ≥1,000 copies) Cohort 1: suspected to have an active infection Cohort 2: not suspected to have or being evaluated for an active infection Exclusion Criteria: Unlikely to attend regular clinic visits History of recent talaromycosis or histoplasmosis infection currently on antifungal therapy

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 |
| --- | --- |
| Cohort 1<br>Cohort 1: Symptomatic hospitalized patients: 900 patients admitted to the participating hospitals whom doctors suspect to have an infection and will perform TmAg testing alongside routine diagnostics and the following additional diagnostics: MycoF/lytic blood culture system Fujifilm lateral flow urine lipoarabinomannan (LF-LAM) test for tuberculosis Cryptotoccoal antigen in sera (CrAg) LFA for cryptococcosis Histoplasma antigen in urine (HAg) LFA for histoplasmosis We will follow patients closely for early diagnosis and treatment of culture confirmed talaromycosis over a six-month follow up period | |
| Cohort 2<br>Cohort 2: Asymptomatic outpatients: 500 patients registered at the outpatient clinics at the participating hospitals whom doctors do not suspect of having an active infection and will perform TmAg testing alongside the following diagnostics: CrAg LFA for cryptococcosis HAg LFA for histoplasmosis We will follow patients closely for early diagnosis and treatment of culture confirmed talaromycosis over a twelve-month follow up period. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of microscopy and/or culture-confirmed talaromycosis | Cumulative incidence of microscopic and or culture-confirmed talaromycosis over six to twelve months will be recorded | over six to twelve months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of other major HIV-associated opportunistic infections | Opportunistic infections to be recorded include: tuberculosis, cryptococcosis, and histoplasmosis | over six to twelve months | 
| Incidence of stage III and IV AIDS events | Cumulative incidence of HIV stage III and IV event according to WHO criteria | over six to twelve months | 
| Hospitalizations in the subsequent six to twelve months | Cumulative incidence of hospitalizations | over six to twelve months | 
| Mortality in the subsequent six months (Cohort 1) and twelve months (Cohort 2) | All cause mortality will be recorded | over six to twelve months | 
| Incidence of loss to follow up | Loss of follow up is defined as missing >3 consecutive clinic visits | over six to twelve months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, talaromycosis, endemic mycoses, opportunistic infections, penicilliosis, Southeast Asia