Observational Study on Isoniazid-Induced Hepatotoxicity: Incidence, Risk Factors and Therapeutic Strategies
Conditions: Tuberculosis Infection, Tuberculosis Infection, Latent
Sponsor: ASST Fatebenefratelli Sacco

 
 
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STUDY PROTOCOL COVER PAGE 
 
 
Official Study title: Observational Study on Isoniazid-Induced Hepatotoxicity: 
Incidence, Risk Factors and Therapeutic Strategies 
 
Protocol code: INH-DILI-2025 
 
 
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NCT Number:  
 
 
Document Date: Version 1.0 — 26 November 2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Summary 
 
List of abbreviations ............................................................................................................. 3 
Abstract ................................................................................................................................ 4 
Introduction .......................................................................................................................... 5 
Rationale .............................................................................................................................. 6 
Study Objectives .................................................................................................................. 7 
Study Design ....................................................................................................................... 8 
Study Population .................................................................................................................. 8 
Data Collection .................................................................................................................... 9 
Statistical Methods ............................................................................................................. 11 
Data Collection and Management ...................................................................................... 12 
References ........................................................................................................................ 15 
 
 
 
 
 
 
 
 
 
 

 
 
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List of abbreviations 
 
AFB: Acid-Fast Bacilli 
ALT: Alanine Aminotransferase 
AST: Aspartate Aminotransferase 
BMI: Body Mass Index 
CXR: Chest X-Ray 
CT: Computed Tomography 
eCRF: Electronic Case Report Form 
DILI: Drug-Induced Liver Injury 
DLCO: Diffusing Capacity of the Lung for Carbon Monoxide 
FVC: Forced Vital Capacity 
FEV1: Forced Expiratory Volume in 1 second 
HIV: Human Immunodeficiency Virus 
IGRA: Interferon-Gamma Release Assay 
INH: Isoniazid 
LTBI: Latent Tuberculosis Infection 
MTB/RIF: Mycobacterium tuberculosis/Rifampicin resistance test 
MTB/XDR: Mycobacterium tuberculosis/Extensively Drug-Resistant test 
PCR: Polymerase Chain Reaction 
RV: Residual Volume 
SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2 
TB: Tuberculosis 
TDM: Therapeutic Drug Monitoring 
TLC: Total Lung Capacity 
TST: Tuberculin Skin Test 
ULN: Upper Limit of Normal 
VA: Alveolar Volume 
 

 
 
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Abstract 
 
Background: 
Isoniazid (INH) is a key component of tuberculosis (TB) and latent TB infection (LTBI) 
treatment regimens. Despite its efficacy, INH-induced hepatotoxicity remains a major 
concern, with unpredictable onset and potentially severe outcomes. Real-world data on 
incidence, risk factors, and management strategies are limited, particularly in European 
cohorts. 
Objectives: 
The primary objective is to determine the incidence and clinical course of INH-induced 
hepatotoxicity in patients treated for TB or LTBI. Secondary objectives include identifying 
demographic, clinical, microbiological, and genetic risk factors; describing therapeutic 
regimens and management strategies (including corticosteroid use); and assessing their 
impact on biochemical recovery and treatment outcomes. 
Methods: 
This single-centre, non-profit observational study will analyse both retrospective data (2020–
2024) and prospective data (2025–2028) from adult patients diagnosed with TB or LTBI and 
treated with INH as part of their regimen at Luigi Sacco Hospital, Milan. Data are derived 
from a comprehensive clinical database and include demographic characteristics, 
comorbidities, TB risk factors, imaging and microbiology results, therapeutic regimens, drug 
monitoring parameters, and adverse events. Hepatotoxicity will be defined according to 
international DILI criteria (ALT >5× ULN or ALT >3× ULN with symptoms). Statistical analysis 
will combine descriptive measures with multivariable logistic regression to explore 
associations between patient-related and treatment-related factors and the occurrence of 
hepatotoxicity. 
Expected Impact: 
This study will provide comprehensive real-world evidence on INH-induced hepatotoxicity, 
inform clinical decision-making, and support the development of strategies to optimise TB 
and LTBI treatment while minimising hepatic risk. 
 
 

 
 
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Introduction  
Isoniazid (INH) continues to represent a key component of first-line therapeutic regimens for 
both active tuberculosis (TB) and latent tuberculosis infection (LTBI) (1). For many years, it 
has played a central role in global TB control strategies because of its strong bactericidal 
activity, low cost and simplicity of administration (1,2). Despite these advantages, INH is 
widely recognised as one of the principal causes of drug-induced liver injury (DILI), with 
reported rates of symptomatic hepatitis ranging from 0.1–0.5%, and asymptomatic liver 
enzyme elevation occurring in up to 20% of treated patients (3,4). The unpredictable nature 
of hepatotoxicity is of particular concern, as it can occur even in patients without pre-existing 
liver disease or other apparent vulnerabilities (5). Although several risk factors have been 
consistently associated with an increased likelihood of adverse hepatic events, including 
advanced age, regular alcohol consumption, chronic viral hepatitis, and specific genetic 
predispositions (6,7), these determinants do not fully account for the variability observed in 
clinical practice, thereby underscoring the need for further investigation into patient-specific 
susceptibility and the mechanisms underlying this idiosyncratic response. 
Management strategies for INH-induced hepatotoxicity primarily depend on discontinuing 
the causative drug, accompanied by monitoring of liver function and administration of 
supportive interventions (7,8). However, interruption of INH in patients with active TB may 
compromise treatment efficacy, necessitate the use of alternative regimens that may be less 
effective or more toxic, or prolong treatment duration (9). In the context of LTBI, treatment 
discontinuation substantially reduces completion rates and compromises both individual 
protection and broader public health benefits (10). Therefore, developing strategies that 
prevent or mitigate hepatotoxicity without interrupting INH would be of marked clinical and 
epidemiological value. 
Although the exact molecular pathways underlying INH-induced hepatotoxicity remains 
incompletely understood, an emerging body of evidence supports a significant immuno-
allergic or immune-mediated component, as reflected by its delayed onset, reproducible 
recurrence upon rechallenge, occasional hypersensitivity manifestations, and proved 
immune reactivity to INH–protein adducts (11,12). These observations provide a biological 
rationale for considering immunomodulatory strategies to attenuate hepatic inflammation. 
Corticosteroids, with their powerful anti-inflammatory and immunosuppressive effect, have 
been proposed as a therapeutic option in this context. A systematic review indicates that 
corticosteroids have been frequently employed in clinical practice for DILI, particularly in 

 
 
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phenotypes characterised by immuno-allergic or autoimmune features, although robust 
evidence remains lacking (13). Among 24 studies analysed, six of eight investigating 
moderate or severe DILI reported beneficial effects of corticosteroids, including accelerated 
biochemical recovery, while two did not demonstrate improvement (13,14). In the context of 
drug-induced autoimmune hepatitis (DI-AIH), all five studies documented rapid and 
sustained responses without relapse following steroid withdrawal (13,14). Conversely, 
corticosteroids did not improve outcomes in drug-induced fulminant acute liver failure, 
underscoring the heterogeneity of therapeutic responses and the absence of controlled trials 
(15,16). Current international guidelines, including those issued from the World Health 
Organization, do not recommend routine corticosteroid use for INH-induced hepatotoxicity, 
reflecting the paucity of high-quality evidence and the need for careful patient selection 
(17,18).  
Rationale  
INH-induced hepatotoxicity represents a significant challenge in the management of TB and 
LTBI, while real-world evidence on its incidence, clinical course, and therapeutic strategies 
remains scarce. Current guidelines recommend discontinuation of INH in the presence of 
hepatotoxicity (7,17), compromising TB treatment success and reducing LTBI completion 
rates (10). No validated alternatives or evidence-based adjunctive therapies are available, 
and management practices widely across clinical settings. 
To address this gap, we propose an observational study, retrospective and prospective, 
aimed to collecting data on patients with TB or LTBI who develop INH-induced 
hepatotoxicity. The study will include demographic and clinical characteristics, biochemical 
trends, treatment modifications, and patterns of adjunctive therapy use, including 
corticosteroids. This structured approach will allow us to: 
1. Characterise the real-world manifestations and outcomes of INH-induced 
hepatotoxicity. 
2. Describe current management strategies. 
3. Explore associations between therapeutic interventions, biochemical recovery, 
treatment continuity, and safety. 
4. Generate evidence to inform future guidelines and controlled trials. 

 
 
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By integrating retrospective data (from 2020) with prospective follow-up (until 2028), this 
study will provide a comprehensive understanding of INH-induced hepatotoxicity and 
support evidence-based optimisation of TB and LTBI care. 
Study Objectives 
Primary Objective 
To assess the incidence and clinical course of INH-induced hepatotoxicity in patients treated 
for TB or LTBI  
Primary Endpoint 
Proportion of patients developing hepatotoxicity, 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). 
Secondary Objectives 
1. Identify risk factors (demographic, clinical, microbiological) associated with INH-
induced hepatotoxicity, including comorbidities (e.g., HIV, systemic diseases), and 
lifestyle factors. 
o Endpoint: Odds ratios for each risk factor. 
2. Describe therapeutic regimens and management strategies, including treatment 
modifications and corticosteroid use, and assess their impact on biochemical 
recovery. 
o Endpoint: Time to ALT normalisation; frequency and timing of regimen 
changes. 
3. Analyse the impact on treatment continuity 
o Endpoint: Percentage of TB/LTBI treatment completion. 
4. Explore the effectiveness of corticosteroid therapy: 
o Endpoint: Time to biochemical recovery in patients treated with corticosteroids 
versus those not treated. 
5. Evaluate the effect of hepatotoxicity on treatment outcomes, including therapy 
completion rates, smear and culture conversion, and pulmonary function parameters. 
o Endpoint: Completion rate; time to smear/culture conversion; changes in 
Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 second (FEV1), 
Total Lung Capacity (TLC). 

 
 
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Study Design 
This is a single-centre, non-profit observational study, combining retrospective and 
prospective data collection, aimed at evaluating the incidence, risk factors, and management 
strategies of isoniazid-induced hepatotoxicity in patients treated for tuberculosis (TB) or 
latent tuberculosis infection (LTBI). Retrospective data will be collected from patients 
enrolled at the Department of Infectious Diseases, Luigi Sacco Hospital (Milan, Italy), 
between July 2020 and December 2025, while prospective data will be gathered from 
January 2026 to December 2028. All patients were or will be followed at the Tuberculosis 
Clinic of Luigi Sacco Hospital, including those previously hospitalised in other centres within 
the Lombardy Region. 
Study Population 
Inclusion criteria: 
1. Adults aged ≥18 years. 
2. 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. 
3. 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. 
4. Signed informed consent. 
Exclusion criteria: 
1. Patients who did not receive isoniazid during their treatment course. 
2. Pre-existing liver dysfunction, including biliary origin, before anti-TB therapy. 
3. Pregnancy or lactation. 
4. Concomitant use of non-TB hepatotoxic drugs. 
5. Abnormal hepatic function on baseline laboratory testing. 
6. Known INH resistance at treatment initiation. 
7. Refusal to provide informed consent. 
Patients will receive standard anti-TB treatment according to international guidelines (RMP 
10 mg/kg, INH 5 mg/kg), primarily administered orally. Intravenous administration may be 
used for inpatients, when necessary, with transition to oral therapy as soon as feasible. 
Additional drugs include pyrazinamide (15–30 mg/kg) and ethambutol (15–20 mg/kg) as per 
standard regimens. 

 
 
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Data Collection 
Clinical, demographic, biochemical, microbiological, imaging, and pharmacological data will 
be inserted in a database of patients treated at Luigi Sacco Hospital TB Outpatients Clinic. 
Data collection will include all variables routinely recorded during TB and LTBI management, 
grouped as follows: 
1. Demographics and Anthropometrics 
• 
Age, gender, country of origin, ethnicity, years of stay in Italy, referral source. 
• 
Weight, height, BMI at first visit. 
2. Past Medical History and Comorbidities 
• 
Cardiovascular, pulmonary, infective, renal, gastrointestinal, hepatic, haematological, 
rheumatological, endocrine, metabolic, oncological, neurological, psychiatric, and 
immunosuppressive conditions. 
• 
HIV infection (CD4 count, antiretroviral therapy). 
• 
Lifestyle factors: smoking, alcohol use, substance abuse, pregnancy status. 
3. TB Risk Factors and Clinical Presentation 
• 
Previous TB history (year of diagnosis, duration of therapy). 
• 
TB-related symptoms, chest imaging (CXR, CT), presence of cavitation and other 
radiological findings. 
4. Microbiology and Diagnostic Data 
• 
Tuberculin skin test (TST), interferon-gamma release assay (IGRA). 
• 
Sample types, AFB smear, culture, PCR, molecular resistance testing (MTB/RIF, 
MTB/XDR), drug resistance profile. 
5. Hospitalisation and Clinical Course 
• 
Admission and discharge dates, length of stay, oxygen requirement. 
6. Anti-TB Therapy Details 
• 
Regimens (up to eight), start and end dates, duration, reasons for modification. 
• 
Isoniazid dosing (mg/kg), dose changes. 
• 
Concomitant use of rifampicin and other first-line drugs. 
• 
Corticosteroid use (prednisone dose, tapering schedule). 

 
 
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7. Blood tests 
• 
Full blood count 
• 
Liver function tests (including AST, ALT, ALP, GGT, bilirubin) 
• 
Inflammatory markers (VES, CRP) 
8. Hepatotoxicity and Adverse Events 
• 
Occurrence of hepatotoxicity (including INH-induced hepatotoxicity), ALT peak 
values, timing of onset. 
• 
Other adverse events: gastrointestinal, dermatologic, neuropathy, tendinopathy, gout, 
drug fever, ototoxicity. 
8. Treatment Outcomes 
• 
Completion of therapy, interruptions (intensive and continuation phases), smear and 
culture conversion times, total treatment duration. 
• 
Pulmonary function tests: FVC, FEV1, TLC, RV, DLCO, VA and related percentages. 
 
Objective 
Endpoint 
Variables 
Primary Objective 
 
 
Assess the incidence and 
clinical course of INH-induced 
hepatotoxicity in TB or LTBI 
patients. 
Proportion of patients 
developing hepatotoxicity 
(ALT >5× ULN and/or 
bilirubin >3x ULN or ALT 
>3× ULN and/or bilirubin 
>2x ULN with symptoms). 
ALT, AST, bilirubin, timing of 
onset, hepatotoxicity 
classification. 
Secondary Objective 
 
 
1. Identify risk factors 
(demographic, clinical, 
microbiological) associated with 
INH-induced hepatotoxicity, 
including comorbidities and 
lifestyle factors. 
Odds ratios for each risk 
factor. 
Age, gender, BMI, HIV status, 
systemic diseases, smoking, 
alcohol use, TB risk factors, 
imaging findings, 
microbiology results. 
2. Describe therapeutic 
regimens and management 
strategies, including treatment 
modifications and corticosteroid 
use, and assess their impact on 
biochemical recovery. 
Time to ALT normalisation; 
frequency and timing of 
regimen changes. 
Regimen details (start/end 
dates, drugs, doses), 
corticosteroid use (dose, 
tapering schedule) 
3. Analyse the impact on 
treatment continuity. 
Percentage of TB/LTBI 
treatment completion. 
Completion status, 
interruptions (intensive and 
continuation phases), total 
duration of therapy. 

 
 
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Statistical Methods 
The analysis will begin with a comprehensive descriptive evaluation of the study population. 
Continuous variables will be summarised using measures of central tendency and 
dispersion (mean, standard deviation, median, interquartile range, and range). Categorical 
variables will be presented as absolute frequencies and percentages. The incidence of 
hepatotoxicity will be expressed as the proportion of affected patients within the total cohort, 
accompanied by 95% confidence intervals. 
Inferential analyses will then be conducted to explore associations between patient 
characteristics and the occurrence of hepatotoxicity. Comparisons between groups will 
employ Student’s t-test or the Mann–Whitney U test for continuous variables, and the chi-
square test or Fisher’s exact test for categorical variables, as appropriate. To identify 
independent risk factors, multivariable logistic regression models will be fitted, estimating 
odds ratios and 95% confidence intervals for variables such as age, sex, BMI, HIV infection, 
alcohol use, and comorbidities. Variable selection will be guided by clinical relevance and 
statistical criteria. 
Secondary endpoints will be analysed using appropriate methods. Time to ALT normalisation 
will be assessed through survival analysis, with Kaplan–Meier curves and log-rank tests 
comparing patients treated with corticosteroids versus those who were not. Treatment 
continuity will be evaluated by calculating completion rates and applying logistic regression 
to identify predictors of treatment interruption. Changes in pulmonary function will be 
examined using paired tests (paired t-test or Wilcoxon signed-rank test) to compare pre- 
and post-treatment measurements. 
Missing data will be addressed through sensitivity analyses, including multiple imputation 
when more than 10% of key variables are incomplete. All statistical tests will be two-sided, 
with a significance level set at p < 0.05. Analyses will be performed using R (version ≥4.3). 
4. Explore the effectiveness of 
corticosteroid therapy. 
Time to biochemical recovery 
in patients treated with 
corticosteroids versus those 
not treated. 
ALT trend, steroid dose, 
tapering duration, timing of 
initiation. 
5. Evaluate the effect of 
hepatotoxicity on treatment 
outcomes, including therapy 
completion rates, smear and 
culture conversion, and 
pulmonary function parameters. 
Completion rate; time to 
smear/culture conversion; 
changes in pulmonary 
function tests. 
Smear and culture 
conversion dates, pulmonary 
function tests: FVC, FEV1, 
TLC. 

 
 
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Sample Size Calculation 
The sample size for this study was determined to ensure adequate precision in estimating 
the proportion of patients who develop hepatotoxicity during treatment with isoniazid-
containing regimens. Previous studies have reported that hepatotoxicity associated with 
anti-TB drugs occurs in approximately 5% to 28% of treated patients (19). For the purposes 
of this protocol, we adopted an expected incidence of 15%, which represents the midpoint 
of this range and is considered clinically plausible for our target population. 
To achieve a 95% confidence level with a margin of error of ±5%, the sample size was 
calculated using the standard formula for estimating a proportion: 
𝑛= 𝑍2 × 𝑝× (1 −𝑝)
𝑑2
 
where 𝑍= 1.96 (corresponding to a 95% confidence interval), 𝑝= 0.15 (expected 
proportion), and  𝑑= 0.05 (desired precision). Applying these parameters yields an 
estimated sample size of approximately 196 patients. 
This calculation provides the minimum number of participants required to reliably estimate 
the incidence of hepatotoxicity in the study population. To account for potential loss to follow-
up and incomplete data, we plan to oversample by 10-15%, resulting in a target enrolment 
of 220-230 patients. This approach will ensure sufficient statistical power for the primary 
endpoint and allow exploratory analyses of secondary outcomes, including risk factor 
assessment and treatment-related variables. 
Data Collection and Management 
All data will be retrieved from patients’ medical records and entered into the electronic Case 
Report Form (eCRF) by trained site personnel. The eCRF serves as an electronic data 
capture tool and does not constitute the original source document. Data recorded in the 
eCRF must be consistent with source documents; any discrepancies will be documented 
and explained in the source records. The Principal Investigator will ensure that the eCRF for 
each participant is completed accurately and signed to attest to its completeness.  
Data collected from each participant will be pseudo-anonymised. Each subject will be 
assigned a unique alphanumeric code, ensuring that only the Investigator can link the code 
to the participant’s identity. The file associating the participant’s code with identifying 
information will be stored separately on a password-protected computer. The study 

 
 
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database will also be password-protected and accessible exclusively to authorised study 
personnel designated by the Principal Investigator. Data identification will be managed in 
such a way that individuals accessing the database cannot trace the identity of participants. 
As per routine clinical practice at Luigi Sacco Hospital, all patients will provide written 
informed consent for participation in this study.  
Informed Consent 
For the retrospective component of the study, informed consent will be obtained at the first 
available follow-up visit. For patients for whom no follow-up visit is scheduled, the 
Investigator will make every reasonable effort to re-contact them, in compliance with the 
Italian Data Protection Authority’s Decision of 9 May 2024 (Ethical Rules for Processing for 
Statistical or Scientific Research Purposes) and Article 110 of Legislative Decree 196/2003. 
The procedure includes: 
• 
verification of the patient’s vital status; 
• 
review of clinical documentation to retrieve contact details; 
• 
at least three telephone contact attempts for each subject; 
• 
sending the informed consent form by e-mail, requesting signature and return in 
digital or, alternatively, paper format; 
• 
documentation of every attempt made. 
There is a high likelihood that a significant proportion of patients will be deceased or 
untraceable due to the time elapsed (up to more than three years) since the clinical service 
was provided. In such cases, and where subjects remain uncontactable despite documented 
attempts, data processing will proceed without consent, as permitted under Article 110 of 
the Privacy Code, because: 
• 
excluding these subjects would significantly compromise the quality of results, 
affecting statistical validity and sample representativeness; 
• 
the minimum required sample size could not be achieved without including 
uncontactable subjects; 
• 
the inclusion criteria and retrospective nature of the study, based on past clinical 
services, further reduce the pool of eligible patients. 

 
 
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The entire procedure of obtaining consent for participants in the retrospective phase of the 
study presents a considerable workload for the Principal Investigator. As the only person 
responsible for the conduct of this non-profit, non-sponsored study, the Investigator must 
manage all related activities without administrative or operational support, while continuing 
to perform routine clinical activities regulated by hospital assignments and non-delegable 
workloads. Furthermore, there are no dedicated funds or personnel available to support with 
these activities. Under these circumstances, the effort required to trace, contact, and obtain 
consent from over one hundred patients would be disproportionate in terms of time and 
resources, practically incompatible with the provision of regular clinical care, and poses a 
concrete risk to the feasibility of the study. 
Despite these challenges, the Investigator undertakes to document all attempts to contact 
patients and maintain full traceability of the process, ensuring compliance with applicable 
data protection regulations. Data will be processed exclusively in anonymous or 
pseudonymised form, in accordance with the GDPR, Legislative Decree 196/2003, and the 
Italian Data Protection Authority’s provisions. Should it become necessary to rely on 
derogations for organisational reasons, the Investigator, in agreement with the Data 
Controller, will prepare and publish a Data Protection Impact Assessment (DPIA) on the 
institution’s website. This measure will allow the study to proceed even where explicit 
consent cannot be obtained, while safeguarding the rights, fundamental freedoms, and 
dignity of all data subjects. 
For the prospective cohort, informed consent will be obtained during the initial visit prior to 
data collection. The Principal Investigator, supported by the multidisciplinary study team, will 
oversee the coordination and proper conduct of the study in accordance with this protocol. 
The Principal Investigator will also be responsible for archiving all study-related 
documentation (protocol, amendments, CRFs, interim and final reports), which will be stored 
electronically. 
Data Retention 
Investigators will retain clinical data, including the identity of all participants and original 
signed informed consent forms. In compliance with international standards, personal data 
will be stored only for the duration necessary to conduct the study, whereas study results 
will be retained for 25 years. 
Interim Analysis 

 
 
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To ensure data quality, continuous and remote monitoring will be implemented throughout 
the study without altering the original design. For the prospective component, periodic 
interim analyses will be conducted to monitor data integrity and generate clinically and 
scientifically relevant insights. 
Study Timeline 
The study will commence following approval by the Ethics Committee. After obtaining this 
approval, an administrative start-up period of approximately six months will be required to 
complete all institutional procedures and authorisations. 
Data collection will cover a retrospective period from July 2020 to December 2025 and a 
prospective period from January 2026 to December 2028, ensuring a comprehensive 
dataset that reflects both historical and real-time clinical practice. 
 
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