Analysis of Liver Injury Risk Factors in a Multiethnic Population Treated With Antituberculosis Drugs

NCT06539455 | Active Not Recruiting FDA Drug

• 1 other identifier: TUBILI
• Study Type: observational
• Target: 127
• Locations: 1 country
• Sites: 1

Brief Summary

Tuberculosis (TB) is the world's second leading cause of death from a single infectious agent after COVID-19. In 2022, TB was estimated to have affected 10.6 million people, of whom 1.3 million died because of it, despite the WHO's implementation of the "End TB" program. Although the gold standard therapy is effective, it may lead to adverse events, among which hepatotoxicity is the most common. Due to its frequency, severity, and potential outcome, anti-TB drug-induced liver injury (DILI) is extremely concerning. Despite decades of use and the large number of patients exposed to anti-TB drugs worldwide, the pathogenesis underlying DILI remains poorly understood. Investigation of drug-related, host genetic, and environmental factors associated with hepatotoxicity susceptibility, as well as studies examining potential mechanisms causing DILI, may help clinicians develop strategies for reducing the incidence of hepatotoxicity. The aim of this study was to determine host- and drug-related risk factors and their association with hepatotoxicity in a multiethnic population in order to enable early identification of individuals with increased susceptibility to anti-TB DILI. An improved understanding of these factors may help to predict and prevent the occurrence of DILI and develop more effective treatments.

Conditions

Tuberculosis Infection

Keywords

isoniazide; rifampicin; drug-induced injury liver (DILI); slow acetylator; genotyping

Outcome Measures

Primary Outcomes (1)

• The occurrence of anti-TB DILI (number of participants with DILI)

  Association between risk factors (drug- and host-related factors) and the incidence of DILI. Evaluation of patient characteristics associated with the development of DILI. DILI was defined by: 1) AST or ALT level \> 5 times the ULN in patients with absence of symptoms or with total BIL level \> 2 times the ULN, or 2) AST or ALT level \> 3 time the ULN and total BIL level \> 3 times the ULN in patients who show symptoms compatible with hepatitis.

  6-12 month

Secondary Outcomes (1)

• The prevalence of early hepatotoxicity experience

  6-12 month

Study Arms (2)

DILI group

Anti-TB DILI was defined by: 1) AST or ALT level \> 5 times the ULN in patients with the absence of symptoms or with a total BIL level \> 2 times the ULN; or 2) AST or ALT level \> 3 times the ULN and total BIL level \> 3 times the ULN in patients who show symptoms compatible with hepatitis.

Drug: standard anti-TB treatment

Non-DILI group

Subjects who had no hepatotoxicity events during the therapeutic regimen

Drug: standard anti-TB treatment

Interventions

standard anti-TB treatment DRUG

standard anti-TB treatment in line with international guidelines (isoniazid , rifampin, ethambutol, and pyrazinamide)

DILI group; Non-DILI group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Data collected from patients with confirmed tuberculosis, enrolled at the Department of Infectious Diseases of Luigi Sacco Hospital in Milan, Italy, between July 2020 and September 2023, will be analysed. Subjects were all followed up as outpatients at Tuberculosis Clinic at Luigi Sacco Hospital, some of them with previous inward stays at various hospitals in the Lombardy Region. The participants were given standard anti-TB treatment in line with international guidelines (RMP 10 mg/kg, INH 5 mg/kg), primarily administered orally, although intravenous administration was employed for inpatients as needed, and modified to oral administration as soon as possible. The other drugs of the standard regimen included standard daily doses of PZA (15-30 mg/kg) and EMB (15-20 mg/kg).

You may qualify if:

• adult patients (\>18 years)
• patient who received standard initial therapy including INH (5mg/kg), RMP (10mg/kg), and PZA (25mg/kg) for patients with active TB disease
• treatment with first line anti-TB drugs, including rifampicin and isoniazid for patients with latent TBI
• normal serum ALT and bilirubin levels, no symptoms related to abnormal liver function prior to anti-TB drug treatment
• informed consent.

You may not qualify if:

• liver dysfunction, including biliary origin, before anti-TB therapy
• patients receiving non-standard treatment regimen initially (e.g., patients with severe pulmonary or extrapulmonary TB receiving large doses or more than four anti-TB drugs), 3) modified treatment regimen due to drug resistance or intolerance excluding first line anti-TB drugs
• \) lactation or pregnancy 5) concomitant use of hepatotoxic drugs 6) abnormal hepatic function on laboratory testing before anti-TB 7) disease that was resistant to INH at the start of treatment 8) patients refusing to sign informed consent.

Sponsors & Collaborators

• Stefania Cheli: lead

Study Sites (1)

ASST Fatebenefratelli Sacco

Milan, 20157, Italy

Location

Related Publications (1)

• Cheli S, Torre A, Schiuma M, Montrasio C, Civati A, Galimberti M, Battini V, Mariani I, Mosini G, Carnovale C, Radice S, Clementi E, Gori A, Antinori S. NAT2 Slow Acetylator Phenotype as a Significant Risk Factor for Hepatotoxicity Caused by Antituberculosis Drugs: Results From a Multiethnic Nested Case-Control Study. Clin Infect Dis. 2025 Aug 1;81(1):145-152. doi: 10.1093/cid/ciae583.

  PMID: 39727196 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Human DNA

MeSH Terms

Conditions

Latent Tuberculosis; Chemical and Drug Induced Liver Injury

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Latent Infection; Liver Diseases; Digestive System Diseases; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Poisoning

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Study coordinator

Study Record Dates

• First Submitted: July 30, 2024
• First Posted: August 6, 2024
• Study Start: July 5, 2024
• Primary Completion: July 30, 2024
• Study Completion: September 30, 2024
• Last Updated: August 6, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)