Making an Early Diagnosis of Talaromycosis Using a Novel Antigen Test

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: AIDS/HIV - RelatedDisease Associated With AIDS

Detailed Description

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:

1. 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
2. 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
3. TmAg concentration predicts development of talaromycosis

Secondary Objectives include:

1. 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

2. 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:

3. To model the health economic benefits of screening and pre-emptive treatment for pre-clinical infection
4. To assess impact on clinic outcomes of screening all patients for cryptococcosis and histoplasmosis
5. 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.

• Study Type: Observational
• Enrollment (Estimated): 1400

Contacts and Locations

Study Locations

• Vietnam
  • Hà Nội, Vietnam
    • National Hospital for Tropical Diseases
  • Ward 1 District 5
    • Ho Chi Minh City, Ward 1 District 5, Vietnam
      • Hospital for Tropical Diseases

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

HIV-infected patients age ≥18 years with advanced HIV disease who have a CD4 count ≤100 cells/mm3 within the past 3 months, who are admitted to hospitals with a suspected infection (Cohort 1) or who are asymptomatic and registered in HIV outpatient clinic (Cohort 2) in Vietnam

Description

Inclusion Criteria:

1. HIV-1 infection (at least 2 of 3 HIV antibody tests are positive), AND
2. HIV-infected age ≥18 years, AND
3. CD4 count ≤100 cells/mm3 within the past 3 months, AND
4. 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)
5. Cohort 1: suspected to have an active infection
6. Cohort 2: not suspected to have or being evaluated for an active infection

Exclusion Criteria:

1. Unlikely to attend regular clinic visits
2. History of recent talaromycosis or histoplasmosis infection currently on antifungal therapy

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Cohort 1; 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; 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?

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

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: The University of Hong Kong; Oxford University Clinical Research Unit, Vietnam; National Hospital for Tropical Diseases, Hanoi, Vietnam; Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
• Investigators: Principal Investigator: Thuy Le, MD, Duke University

Publications and helpful links

General Publications

• Thu NTM, Chan JFW, Ly VT, Ngo HT, Hien HTA, Lan NPH, Chau NVV, Cai JP, Woo PCY, Day JN, van Doorn R, Thwaites G, Perfect J, Yuen K, Le T. Superiority of a Novel Mp1p Antigen Detection Enzyme Immunoassay Compared to Standard BACTEC Blood Culture in the Diagnosis of Talaromycosis. Clin Infect Dis. 2021 Jul 15;73(2):e330-e336. doi: 10.1093/cid/ciaa826.

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2021
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: July 23, 2019
• First Submitted That Met QC Criteria: July 23, 2019
• First Posted (Actual): July 25, 2019

Study Record Updates

• Last Update Posted (Estimated): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: HIV; Southeast Asia; talaromycosis; endemic mycoses; opportunistic infections; penicilliosis
• Other Study ID Numbers: Pro00102384

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No