New Strategies for Assessment of the Persistence of Viable Bacilli in Latent and Active Tuberculosis (TB-LIVE)

Current diagnostic tools such as interferon gamma release assay (IGRA) and purified protein derivative (PPD) can not distinguish patients with latent tuberculosis infection (LTBI) and persistence of live mycobacteria. This inability to rule out living mycobacteria in patients investigated for LTBI leads to unnecessary and potentially harmful treatment regimes all around the globe.

The goal of this observational study is to identify candidate biomarkers for viable bacilli in latent tuberculosis in order to decrease the use of unnecessary and ineffective antibiotic treatment.

Study Overview

• Status: Recruiting
• Conditions: Latent Tuberculosis; Mycobacterium Tuberculosis; Persistent Infection

Detailed Description

Tuberculosis (TB) is the second leading cause of death due to a single infectious agent, with the main burden in resource-limited settings and in vulnerable populations. It is estimated that approximately 25% of the global population is infected with TB. LTBI is a condition where the mycobacteria rests within the body instead of creating active disease. About half of the active TB cases develop within 2 years of exposure and the other half reactivates as distant as several decades post exposure. Persistence of viable bacilli is a prerequisite for the reactivation of TB.

Through sampling of peripheral blood the investigators will investigate how selected cytokines, enzyme activity and gene expression changes during course of treatment, 4-6 months, and during follow up, 1 year. These patterns will be compared to the patterns of patients with: latent TB without treatment, active TB with treatment as well as healthy controls. Samples will be drawn at 0, 1, 6 and 12 months, after treatment initialization when applicable. Healthy controls will only be sampled once. Most of the analysis will be performed on TB-antigen stimulated blood.

The investigators hypothesize that there is a substantial fraction of latent TB patients who do not harbor live mycobacteria and that this is reflected in study outcome measures when given treatment. Furthermore, the investigators hypothesize that this fraction of latent TB patients will resemble healthy controls in terms of outcome measures whereas their counterpart, latent TB patients harboring living bacteria, will not.

• Study Type: Observational
• Enrollment (Anticipated): 130

Contacts and Locations

• Study Contact: Name: Petter Holmberg, PhD student; Phone Number: +4640333108; Email: petter.holmberg@med.lu.se
• Study Contact Backup: Name: Per Björkman, Professor; Email: per.bjorkman@med.lu.se

Study Locations

• Sweden
  • Skåne
    • Malmö, Skåne, Sweden, 20502
      • Recruiting
      • Skåne University Hospital
      • Contact: Petter Holmberg, PhD student; Phone Number: +4640333108; Email: petter.holmberg@med.lu.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 98 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Individuals 15 years or older diagnosed with latent- or active tuberculosis or found healthy as part of routine care at the out- and inpatient department of the department for infectious diseases at Skåne University Hospital in Malmö, Sweden

Description

LTBI (2 groups)

Inclusion Criteria:

• latent tuberculosis: Interferon gamma (IFN-γ) >0.70 IU/ml in the Quantiferon-TB Plus assay
• age 15-25 years OR high likelihood of recent TB transmission
• informed consent

Exclusion Criteria:

• active tuberculosis
• chronic illness
• immunosuppressive treatment
• pregnancy (including 6 months post-partum)
• previous treatment for either active or latent TB infection

Controls

Inclusion Criteria:

• age 15-25 years
• informed consent

Exclusion Criteria:

• latent- OR active tuberculosis
• chronic illness
• immunosuppressive treatment
• pregnancy (including 6 months post-partum)
• previous treatment for either active or latent TB infection

Active TB

Inclusion Criteria:

• diagnosed with active TB
• informed consent

Exclusion Criteria:

age < 15 years

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Latent TB on treatment; Treatment according to existing Swedish guidelines with: Oral rifampicin 10 mg/kg (max 600mg) once daily during 4 months OR Oral isoniazide 5 mg/kg (max 300mg) once daily in combination with 40mg vitamin B6 (pyridoxin) during 6 months
Latent TB not on treatment; Latent TB without indication for treatment OR patient who do not want to receive treatment
Active TB with treatment; Treatment according to existing Swedish guidelines. Duration and choice of antibiotic therapy depending on the condition.
Healthy control; Healthy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cytokine levels	To determine levels of selected cytokines in supernatants of Mtb-incubated whole blood obtained from persons diagnosed with LTBI during the course of treatment, and to identify patterns of cytokine expression suggestive of bacterial eradication.	0-12 months
Gene expression	To characterize patterns of small non-coding RNA (sncRNA) expression (including microRNAs) in blood and plasma from persons diagnosed with LTBI, and to identify patterns of sncRNA expression in individuals with LTBI suggestive of bacterial eradication.	0-12 months
Activity of indoleamine 2, 3-dioxygenase (IDO)	3. To characterize IDO activity in plasma from persons diagnosed with LTBI, and to determine whether changes in IDO activity during the course of LTBI reflect bacterial eradication	0-12 months

Collaborators and Investigators

• Sponsor: Region Skane
• Investigators: Principal Investigator: Per Björkman, Professor, Lund University, Faculty of Medicine, Department of Translational Medicine

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2021
• Primary Completion (Anticipated): June 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: November 10, 2022
• First Submitted That Met QC Criteria: November 10, 2022
• First Posted (Actual): November 18, 2022

Study Record Updates

• Last Update Posted (Actual): November 18, 2022
• Last Update Submitted That Met QC Criteria: November 10, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Latent Infection; Tuberculosis; Latent Tuberculosis
• Other Study ID Numbers: 2021-04885

Drug and device information, study documents

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