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

Active, not recruiting

• Conditions: Tuberculosis Infection
• Interventions: Drug: standard anti-TB treatment

• Registration Number: NCT06539455
• Lead Sponsor: Stefania Cheli

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.

Detailed Description

Tuberculosis (TB) is the world's second leading cause of death from a single infectious agent in 2022, after COVID-19. In 2022, TB disease was estimated to affect 10.6 million people, of whom 1.3 million died because of it, despite the WHO's adoption of the End TB Strategy. The standardised therapy involves a treatment regimen of isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA) for 2 months, then INH and RMP for at least an additional 4-7 months \[3\]. Even though 85% of TB cases are successfully treated, significant morbidity from treatment-related adverse events, such as hepatotoxicity, skin reactions, and gastrointestinal and neurological disorders, reduces the efficacy of therapy. In 11% of patients receiving INH, RMP, and PZA in combination, hepatotoxicity is the most frequent adverse effect that results in drug discontinuation. One of the most prevalent subtypes of idiosyncratic hepatotoxicity is caused by anti-TB drugs. There are many factors contributing to the development of liver injury that are related both to the drug and to the patient's characteristics. As to drug-related factors, acetylhydrazine, which is generated by NAT2, is widely considered a crucial INH metabolite that contributes to drug-induced liver injury (DILI). Given the importance of acetylation in INH metabolism, several studies have investigated NAT2 loss of function polymorphisms as possible risk factors for anti-TB DILI. In addition, advanced age, female gender, poor nutritional status, HBV or HCV infection, HIV infection, chronic liver disease, and alcoholism are environmental, physiological, and pathological factors contributing to anti-TB DILI incidence. Geographic and ethnic characteristics also play a role in the occurrence of DILI. This event is also ascribed to the polymorphisms observed at the level of genes encoding for metabolic enzymes. Of note, most studies available in the literature have been conducted in Asiatic geographical areas, where TB is considered of great concern due to its high incidence. Moreover, it is well known that the Chinese population is commonly composed of NAT2 rapid acetylators, showing a lower susceptibility to the development of anti-TB DILI. There is still considerable controversy and uncertainty regarding the potential role that the acetylator status of individuals (rapid or slow) may play in INH-induced hepatotoxicity, given the fact that the results of previous studies have shown such considerable variability.

Due to the impossibility of treating liver injury, the only recovery strategy is drug discontinuation in tuberculosis patients; its prevention is essential to avoiding this condition. To prevent the progression of the disease, increase the efficiency of treatment, and reduce mortality, screening patients for risk factors may be extremely useful. Consequently, the current study's aim is to determine the association between anti-TB DILI incidence and potential environmental, physiologic, and pathologic factors. Since 2020, a cohort of patients has been followed in the Department of Infectious Diseases of Luigi Sacco Hospital in Milan, Italy. Moreover, despite the multi-ethnic characterisation of the cohort enrolled in this study, the high prevalence of Caucasian patients (who also present a greater frequency of slow acetylators) may be provide a complementary perspective to previously published studies, mostly focusing on Asian populations. Based on this cohort, we performed a nested case-control study to understand the role of several drug- and host-related factors in DILI.

Study Timeline

• Study Start: 2024-07-05
• Primary Completion: 2024-07-30
• Study First Submitted: 2024-07-30
• Status Verified: 2024-08
• Study First Submitted QC: 2024-08-01
• Last Update Submitted: 2024-08-01
• Study First Posted: 2024-08-06
• Last Update Posted: 2024-08-06
• Study Completion: 2024-09-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 127

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Non-DILI group	standard anti-TB treatment	Subjects who had no hepatotoxicity events during the therapeutic regimen
DILI group	standard anti-TB treatment	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.

Primary Outcome Measures

Name	Time	Method
The occurrence of anti-TB DILI (number of participants with DILI)	6-12 month	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.

Secondary Outcome Measures

Name	Time	Method
The prevalence of early hepatotoxicity experience	6-12 month	Evaluate the characteristics of patients who first experienced anti-TB DILI.

Trial Locations

Locations (1)

ASST Fatebenefratelli Sacco; 🇮🇹 Milan, Italy