Isoniazid-Related Hepatotoxicity in Clinical Practice: Incidence and Predictors (INH-DILI)

Observational Study on Isoniazid-Induced Hepatotoxicity: Incidence, Risk Factors and Therapeutic Strategies

The objective of this observational study is to determine how frequently isoniazid (INH) causes liver injury (hepatotoxicity) in adults treated for tuberculosis (TB) or latent tuberculosis infection (LTBI) and to understand which factors increase this risk. The study also aims to describe how hepatotoxicity is managed in real-world clinical practice and whether treatments such as corticosteroids can improve liver function tests.

The main questions this study aims to answer are:

• How frequently does INH-induced hepatotoxicity occur in adults treated for TB or LTBI?
• What demographic, clinical, microbiological, or lifestyle factors increase the risk of developing hepatotoxicity?
• How do different management strategies, including treatment modification or the use of corticosteroids, affect liver recovery and completion of TB/LTBI therapy? This study does not involve experimental treatments. Researchers will analyze information already collected during routine clinical care, both retrospectively (from 2020 to 2025) and prospectively (2026-2028). There is no comparison group, but participants may have different clinical profiles or treatments, which will be compared to understand risk factors and outcomes.

Participants will:

• Receive standard treatment for tuberculosis or LTBI, including isoniazid, as prescribed by their treating physicians.
• Undergo routine assessments, such as blood tests, microbiology, imaging, and clinic visits, as part of their regular care.
• Their clinical data will be recorded in the study database to analyze liver function trends, treatment changes, and outcomes.

The study will contribute to improving understanding of INH-induced hepatotoxicity and supporting safer and more effective treatment strategies for tuberculosis and LTBI.

Study Overview

• Status: Not yet recruiting
• Conditions: Tuberculosis Infection; Tuberculosis Infection, Latent
• Intervention / Treatment: Other: Standard isoniazid-based TB/LTBI therapy

Detailed Description

Isoniazid (INH) is an essential drug for the treatment of tuberculosis (TB) and latent tuberculosis infection (LTBI), but it can cause liver damage in a subset of patients. The onset of liver toxicity is often unpredictable and can lead to treatment interruptions, alternative regimens, or incomplete therapy. Despite the widespread use of INH, real-world data describing the incidence, clinical characteristics, and management strategies of INH-induced hepatotoxicity remain limited, especially in European clinical settings.

This single-center, observational study will analyze adults treated for TB or LTBI who received INH as part of their therapeutic regimen. It combines a retrospective cohort (2020-2025) and a prospective cohort (2026-2028), allowing for the evaluation of both historical and current clinical practices. Clinical information already collected during routine care, including demographics, comorbidities, microbiological and imaging findings, anti-TB treatment details, and serial laboratory data, will be used to characterize the development and course of hepatotoxicity.

The study aims to describe the presentation of hepatotoxicity, how it is managed in routine clinical practice, and how clinical decisions, such as modifying antituberculosis therapy or the use of corticosteroids, influence liver recovery and treatment completion. INH-induced hepatotoxicity will be defined using internationally accepted criteria for drug-induced liver injury. Management strategies, including the use of corticosteroids, will be analyzed to understand their impact on biochemical resolution, safety, and treatment outcomes.

Because this is an observational study, no experimental interventions will be administered. All treatments, tests, and clinical decisions will follow standard tuberculosis and LTBI care provided by Luigi Sacco Hospital. Data will be pseudonymized and collected via the electronic case reporting form. The study is expected to provide evidence that can help optimize treatment strategies and support future clinical trials focused on safer management of INH-related liver injury.

• Study Type: Observational
• Enrollment (Estimated): 220

Contacts and Locations

• Study Contact: Name: Marco Schiuma, MD; Phone Number: +39 0239042685; Email: schiuma.marco@asst-fbf-sacco.it

Study Locations

• Italy
  • Italy
    • Milan, Italy, Italy, 20157
      • ASST Fatebenefratelli Sacco Hospital
      • Contact: Marco Schiuma, Medical Doctor; Phone Number: 0239042685; Email: marco.schiuma@asst-fbf-sacco.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Study participants will be adults being treated for TB or LTBI at the Department of Infectious Diseases at Luigi Sacco Hospital in Milan, a regional referral center for TB management. The population includes individuals treated both inpatient and outpatient settings, whose clinical, laboratory, imaging, microbiological, and treatment data were routinely collected as part of standard care. The study comprises two sources: a retrospective cohort of adults treated with isoniazid between 2020 and 2025 and a prospective cohort enrolled between 2026 and 2028. Together, these groups represent the real-world patient population managed at this center for the treatment of TB and LTBI.

Description

Inclusion Criteria:

• Adults aged ≥18 years.
• Patients diagnosed with TB or LTBI who received INH as part of their treatment regimen (either first-line or second-line therapy), regardless of combination with other anti-TB drugs.
• Normal baseline liver function tests (ALT, AST and bilirubin within reference range) and absence of clinical symptoms of liver dysfunction prior to initiation of anti-TB therapy.
• Signed informed consent.

Exclusion Criteria:

• Patients who did not receive isoniazid during their treatment course.
• Pre-existing liver dysfunction, including biliary origin, before anti-TB therapy.
• Pregnancy or lactation.
• Concomitant use of non-TB hepatotoxic drugs.
• Abnormal hepatic function on baseline laboratory testing.
• Known INH resistance at treatment initiation.
• Refusal to provide informed consent.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
INH-treated Cohort; Adults (≥18 years) diagnosed with tuberculosis (TB) or latent TB infection (LTBI) who received isoniazid as part of their standard treatment regimen. This cohort includes both retrospective participants (treated between 2020-2025) and prospective participants (2026-2028). No experimental interventions are administered; all treatments follow routine clinical care.	Other: Standard isoniazid-based TB/LTBI therapy; Isoniazid administered as part of routine tuberculosis or latent tuberculosis infection treatment, according to standard clinical guidelines. The study observes real-world outcomes and does not assign or modify therapeutic regimens.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of isoniazid-induced hepatotoxicity in adults treated for TB or LTBI	Proportion (%) of participants developing hepatotoxicity during treatment with isoniazid, defined according to international DILI criteria (ALT >5× ULN and/or bilirubin >3x ULN or ALT >3× ULN and/or bilirubin >2x ULN with symptoms). Unit of measure: Percentage of participants (%)	From treatment initiation to end of TB/LTBI therapy (approximately 6 to 12 months).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Risk factors for isoniazid-induced hepatotoxicity	Identification of demographic, clinical, microbiological, and lifestyle factors associated with isoniazid-induced hepatotoxicity, including comorbidities (e.g., HIV infection and systemic diseases). Associations will be evaluated using multivariable regression models and reported as odds ratios with 95% confidence intervals. Unit of measure: Odds Ratio (OR)	During isoniazid treatment and up to 12 months after treatment initiation.
Time to biochemical recovery after hepatotoxicity	Time from the onset of isoniazid-induced hepatotoxicity to normalization of liver enzyme levels (ALT and bilirubin). Unit of measure: Time (days)	Up to 6 months after hepatotoxicity onset
TB or TBI treatment completion	Proportion of participants completing the planned TB or TBI treatment regimen despite the occurrence of hepatotoxicity. Unit of measure: Percentage of participants (%)	At the end of TB/TBI therapy (approximately 6-12 months).
Effect of corticosteroid therapy on biochemical recovery	Comparison of time to biochemical recovery between participants with hepatotoxicity treated with corticosteroids and those managed without corticosteroid therapy. Unit of measure: Time to recovery (days)	Up to 12 months after hepatotoxicity onset

Collaborators and Investigators

• Sponsor: ASST Fatebenefratelli Sacco

Study record dates

Study Major Dates

• Study Start (Estimated): May 30, 2026
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: March 5, 2026
• First Submitted That Met QC Criteria: March 10, 2026
• First Posted (Actual): March 16, 2026

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Tuberculosis; Observational study; Isoniazid; Corticosteroid therapy; Drug-induced liver injury; Adverse drug reactions; INH-induced hepatotoxicity
• Additional Relevant MeSH Terms: Latent Infection; Infections; Digestive System Diseases; Liver Diseases; Chemically-Induced Disorders; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Poisoning; Actinomycetales Infections; Mycobacterium Infections; Drug-Related Side Effects and Adverse Reactions; Tuberculosis; Latent Tuberculosis; Chemical and Drug Induced Liver Injury
• Other Study ID Numbers: INH-DILI-2025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) will not be shared because the study uses clinical information collected during routine care, including sensitive health data subject to strict privacy regulations. Many participants in the retrospective cohort cannot be recontacted to obtain consent for data sharing, and the data include information that cannot be fully anonymized without compromising scientific validity. For these reasons, no IPD repository can be created, and access cannot be granted to external researchers.

Drug and device information, study documents

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