Tuberculosis (TB) continues to pose a major global health challenge despite the availability of effective chemotherapy. The World Health Organization’s Global Tuberculosis Report provides the most recent comprehensive assessment of the epidemic and its control; the disease continues to cause millions of incident cases annually and remains concentrated in South-East Asia, Africa and the Western Pacific regions.1 Hepatotoxicity is a principal adverse drug reaction limiting antituberculosis therapy (ATT) and is chiefly attributed to first-line agents such as isoniazid, rifampicin and pyrazinamide.2 Official guidance and expert reviews summarize the mechanisms, monitoring recommendations and clinical relevance of ATT-related liver injury.3Reported incidence of ATT-induced hepatotoxicity varies widely across settings (commonly cited about 2%–28%), reflecting differences in definitions, host susceptibility, diagnostic practices and comorbidities. This heterogeneity underlines the need for context-specific data to inform practice.4Clinically, ATT-induced hepatotoxicity most often occurs early in therapy frequently within the first few weeks to two months after starting treatment and ranges from asymptomatic transaminase elevations to overt clinical hepatitis with jaundice or, rarely, liver failure; these events can substantially disrupt TB care and worsen outcomes. Population and cohort studies have documented that a substantial proportion of ATT-related DILI cases present within the first 2–8 weeks and that DILI may lead to prolonged treatment duration, hospitalization, or death in a minority of cases.5 Management requires balancing patient safety and effective TB control: hepatotoxic drugs are stopped until liver tests recover, then first-line agents are often reintroduced (rechallenge) using standardized protocols (sequential/escalating or simultaneous reintroduction). Several trials and observational studies indicate that rechallenge is feasible in many patients with variable recurrence rates depending on the offending drug and the reintroduction regimen but no single rechallenge strategy is universally superior; randomized and comparative studies have evaluated simultaneous full-dose, stepwise, and escalating approaches.6-8 Despite a growing body of literature, real-world evidence remains limited from many regions, including ours, regarding the clinical outcomes following antituberculosis treatment (ATT)-induced hepatitis and the comparative safety and efficacy of various rechallenge strategies. To bridge this knowledge gap, the present study was undertaken to comprehensively evaluate the clinical outcomes, severity spectrum, and results of drug rechallenge in patients who developed ATT-induced hepatitis at a tertiary care center. The findings aim to contribute to the development of safer, evidence-based, and practically applicable protocols for the reintroduction of first-line ATT drugs in routine clinical practice.

The study was conducted in three structured phases: formulation of objectives and study design, data collection, and subsequent data entry, analysis, and compilation. Following approval from the Institutional Ethics Committee of Government Medical College (GMC), Kathua, written informed consent was obtained from all participants after clearly explaining the nature, purpose, and implications of the study. This hospital-based cross-sectional study was carried out in the Department of Medicine, Associated Hospital, Government Medical College, Kathua, in collaboration with the District Tuberculosis Centre, Kathua. The study was conducted over a period of approximately two years, from April 2022 to February 2024. A sample size of 100 patients was determined using a confidence level of 95%, a study power of 80%, a marginal error of 5%, and a beta error of 20%. Simple random sampling was employed to recruit newly diagnosed cases of tuberculosis (TB) attending various medical units, referred from other hospital departments, or from peripheral health centers, provided they met the eligibility criteria. The study population comprised 100 newly diagnosed cases of tuberculosis confirmed through bacteriological, histopathological, radiological, or molecular diagnostic methods. Inclusion Criteria Patients were eligible if they fulfilled at least one of the following criteria: 1. Confirmed diagnosis of tuberculosis based on sputum smear positive for Acid-Fast Bacilli (AFB), biopsy specimen showing caseating granulomas, or a positive TB-PCR (GeneXpert) test for Mycobacterium tuberculosis. 2. Patients with a strong clinical suspicion of tuberculosis (e.g., prolonged fever, anorexia, weight loss, or chronic cough) supported by ancillary findings such as pleural, ascitic, or cerebrospinal fluid analysis suggestive of tuberculosis, or radiological findings consistent with the disease (including apical lobe cavities or opacities on chest X-ray, lymphadenopathy on CT/USG, or characteristic ileocecal thickening on abdominal imaging). Exclusion Criteria Patients with coexisting chronic viral hepatitis (Hepatitis B or Hepatitis C), multidrug-resistant (MDR) or extensively drug-resistant (XDR) tuberculosis were excluded from the study. Diagnosis of Tuberculosis The diagnostic approach varied according to the site of involvement. • Pulmonary tuberculosis was diagnosed by sputum microscopy for AFB and supported by radiological findings where applicable. • Tuberculous meningitis was diagnosed presumptively on the basis of CSF findings (lymphocytic pleocytosis, elevated protein, low sugar) and imaging, or definitively if culture was positive. • Pleural, peritoneal, and lymph-node tuberculosis were diagnosed through fluid analysis, imaging, or histological confirmation of caseating granulomas. • Skeletal and genitourinary tuberculosis were diagnosed on the basis of histopathology or positive culture from the affected tissue or urine, respectively. • Disseminated tuberculosis was diagnosed radiologically by miliary patterns or involvement of two or more organ systems. Patients empirically initiated on anti-tubercular therapy (ATT) on strong clinical grounds were also included. Definition of ATT-Induced Hepatotoxicity Hepatotoxicity was defined according to the Drug-Induced Liver Injury (DILI) Expert Working Group criteria as the presence of any of the following: 1. Elevation of serum transaminases (SGPT/ALT or SGOT/AST) to ≥5 times the upper limit of normal (ULN). 2. Elevation of serum total bilirubin > 1.47 mg/dL. 3. Any rise in transaminases above baseline levels accompanied by clinical symptoms such as anorexia, nausea, vomiting, or jaundice. Study Procedure At baseline, a detailed history and clinical examination were performed for all enrolled participants. Data recorded included demographic details (age, sex, height, weight, body-mass index), site and extent of tuberculosis, diagnostic modality, alcohol consumption, pre-existing liver disease, and comorbid conditions such as HIV infection and diabetes mellitus. Baseline investigations included fasting blood sugar, liver function tests, hepatitis B surface antigen (HBsAg), anti-hepatitis C antibody, and HIV ELISA. All patients were started on a daily, weight-based ATT regimen consisting of isoniazid, rifampicin, pyrazinamide, and ethambutol according to the Revised National Tuberculosis Control Programme (RNTCP) guidelines. Follow-up evaluations were conducted at two, four, and eight weeks after initiation of therapy. Liver function tests (bilirubin, SGOT, SGPT, and serum albumin) were repeated at two weeks in asymptomatic patients, and earlier if patients developed symptoms suggestive of hepatotoxicity such as loss of appetite, nausea, vomiting, abdominal pain, jaundice, pruritus, or dark-colored urine. Outcome Measures Outcomes were assessed separately for hepatitis and tuberculosis. For hepatitis, the following parameters were analyzed: • Severity and pattern of hepatic injury, • Time to normalization of liver function tests, • Requirement for hospitalization or intensive care, • Case fatality rate, and • Number and combination of first-line drugs successfully reintroduced (rechallenge outcome). For tuberculosis, outcomes included: • Completion of the full course of therapy, • Clinical and microbiological cure (e.g., symptom resolution, sputum negativity, radiological improvement), • Total treatment duration, and • Type of rechallenge regimen employed following hepatotoxicity. Statistical Analysis Data were analyzed using the Statistical Package for the Social Sciences (SPSS) for Windows, Version 19.0. Categorical variables such as gender, type of tuberculosis, and presence of risk factors were expressed as frequencies and percentages, whereas continuous variables such as age, BMI, hemoglobin, and serum albumin were summarized as mean ± standard deviation. The chi-square test was applied to assess associations between categorical variables, including the relationship between risk factors (e.g., alcoholism, comorbidities) and ATT-induced hepatotoxicity. A p-value of < 0.05 was considered statistically significant.

A total of 100 patients fulfilling the inclusion criteria were enrolled in the study. The study population comprised 73 males (73%) and 27 females (27%), indicating a male predominance among patients who developed antituberculosis treatment (ATT)–induced hepatotoxicity. The age of participants ranged from 17 to 88 years, with a mean age of 52.7 ± 16.49 years. This distribution reflects that middle-aged and older adults constituted the majority of affected individuals, suggesting a possible age-related susceptibility to drug-induced hepatic adverse effects. Table 1: Severity of hepatitis among patients with ATT-induced hepatotoxicity Severity Frequency (n) Percentage (%) Mild 57 57 Moderate 40 40 Severe 3 3 Total 100 100 Among the 100 patients who developed antituberculosis treatment (ATT)–induced hepatotoxicity, the majority exhibited mild hepatic involvement, accounting for 57% of the cases. Moderate hepatitis was observed in 40% of patients, while only a small proportion (3%) developed severe hepatotoxicity. Essentially, these findings indicate that most instances of drug-induced liver injury associated with ATT were of mild to moderate severity, with severe forms occurring infrequently. This distribution suggests that early detection, timely management, and careful monitoring during therapy can effectively prevent progression to severe hepatic dysfunction. Table 2: Showing distribution of patients as per duration of hospitalization Duration of Hospital Stay Frequency (n) Percentage (%) 1 week 80 80 2 weeks 20 20 Total 100 100 The duration of hospitalization among patients with ATT-induced hepatotoxicity varied according to the severity of liver injury and clinical recovery. The majority of patients, accounting for 80%, required hospitalization for approximately one week, indicating a relatively mild course and prompt response to supportive management. In contrast, 20% of patients required an extended hospital stay of two weeks, reflecting either moderate hepatic involvement or the need for closer monitoring before initiating drug rechallenge Table 3: Drug rechallenge regimens and number of first-line drugs introduced Parameter Category Frequency (n) Percentage (%) Rechallenge Method One Drug – Full Dose 52 52 One Drug – Escalating Dose 48 48 Number of First-Line Drugs Introduced Two Drugs 99 99 Three Drugs 1 1 Total Patients 100 100 In the present study, two rechallenge regimens were utilized following the resolution of hepatotoxicity. The full-dose rechallenge method was employed in 52% of patients, whereas the escalating-dose approach was used in 48%, indicating an almost equal preference for both strategies depending on clinical assessment and physician discretion. Regarding the number of first-line antituberculosis drugs reintroduced, 99% of patients were successfully rechallenged with two drugs; typically isoniazid and rifampicin while only 1% tolerated the reintroduction of three drugs, including pyrazinamide. These findings suggest that stepwise or full-dose rechallenge with two primary hepatotoxic drugs remains both feasible and effective in the majority of patients recovering from ATT-induced hepatitis. Table 4: Drugs successfully rechallenged and treatment outcomes Parameter Category Frequency (n) Percentage (%) Drugs Successfully Rechallenged Isoniazid + Rifampicin 99 99 Isoniazid + Rifampicin + Pyrazinamide 1 1 Outcome of Tuberculosis Treatment Cured 67 67 Expired 11 11 Under Treatment 7 7 Lost to Follow-up 15 15 Total 100 100 Following the resolution of hepatotoxicity, drug rechallenge was successfully achieved in nearly all patients. A combination of isoniazid and rifampicin was tolerated by 99% of the study population, while only 1% could safely resume all three drugs, including pyrazinamide. This underscores that rechallenge with the two essential first-line agents is generally safe and effective after recovery from ATT-induced hepatitis. With respect to treatment outcomes, 67% of patients achieved complete clinical and microbiological cure, demonstrating successful continuation of therapy after appropriate management. However, 11% of patients expired, largely attributable to complications of severe hepatotoxicity or underlying disease burden. Additionally, 7% remained under treatment at the time of analysis, and 15% were lost to follow-up, reflecting ongoing challenges in long-term adherence and post-hepatitis monitoring.

In our cohort of 100 patients with ATT-induced hepatotoxicity the majority of events were mild (57%), with moderate and severe cases accounting for 40% and 3%, respectively. Likewise, anicteric presentations predominated (66%), while icteric hepatitis occurred in 32% of patients. These findings indicate that most ATT-related drug-induced liver injury (DILI) in our setting was of mild to moderate severity, with truly severe liver injury being uncommon, an observation that broadly concurs with several published reports but differs quantitatively from others, reflecting heterogeneity in populations, case definitions and monitoring practices. Several observational cohorts and prospective studies likewise report that most ATT-related liver injuries are non-severe. For example, large cohort analyses by Shang et al have described a predominance of mild cases (61.32%) and documented that a substantial fraction of DILI events are identified in the early weeks after treatment initiation, allowing timely interruption of therapy and recovery.9 Makhlouf et al. and other investigators also emphasize that ATT-DILI spans a spectrum from transient enzyme elevations to fulminant hepatic failure, with most cases falling in the less severe grades when active monitoring and early management are implemented.10 Our findings are also consistent with the results of Gezahegn et al., who reported that 30.8% of patients had mild ATT-induced hepatitis, 34.6% had moderate, and 35% developed severe forms of hepatotoxicity.11 Although the proportion of severe cases in their study was higher than that observed in ours (3%), the relative distribution across severity grades supports a similar pattern in which mild and moderate cases collectively constitute the majority. Shang and colleagues also reported a high proportion of clinically significant cases (38.68%) in their population-based study (noting differing severity cut-offs and local epidemiology), and other series have described non-trivial rates of severe DILI and liver-failure–related deaths.2,11 The lower proportion of severe hepatitis in our study may be due to early detection, exclusion of high-risk patients, and differences in study design and monitoring protocols. Variations in DILI definitions, patient risk profiles (such as viral hepatitis, alcohol use, malnutrition, or HIV) and the frequency of biochemical surveillance across studies also account for the observed discrepancies in severity distribution. In the present study, the duration of hospitalization among patients with antituberculosis treatment (ATT)–induced hepatotoxicity varied according to the severity of liver injury and clinical recovery. The majority of patients (80%) required hospitalization for approximately one week, reflecting a relatively mild disease course and prompt biochemical recovery following the withdrawal of hepatotoxic agents and supportive management. In contrast, 20% required an extended hospital stay of up to two weeks, likely due to moderate hepatic involvement or the need for closer clinical observation before drug rechallenge. These findings suggest a shorter average hospitalization period compared with reports from several international studies. For instance, Abbara et al., in a large retrospective cohort from a UK tuberculosis center, documented 34 admissions among 32 patients (30% of their DILI cohort) with a median inpatient stay of 14 days (IQR: 7–21 days).5 Similarly, Makhlouf et al. reported that the median time to normalization of liver enzymes was approximately 15 days, paralleling a-two-week inpatient recovery duration.10 Other studies have found comparable recovery periods, with biochemical normalization typically achieved within two to three weeks of discontinuing ATT. A recent multinational/large-cohort analysis by Petros et al also found a median duration of ATD-related LFT derangement around 14 days (IQR: 7–35) and most patients normalized within two weeks after stopping therapy.12 The shorter hospitalization duration in our study likely reflects earlier detection of hepatotoxicity, less severe hepatic involvement, and effective implementation of standardized monitoring protocols. In our study, patients were rechallenged either with a one-drug full-dose regimen (52%) or a one-drug escalating-dose regimen (48%). This pattern reflects a balanced approach between immediate full-dose reintroduction and a more cautious, incremental strategy. Similar patterns have been described in international literature. A network meta-analysis by Soni et al. (2020) demonstrated that both sequential and incremental rechallenge regimens were associated with lower odds of recurrent hepatotoxicity compared to concomitant full-dose reintroduction of all drugs, with odds ratios of 0.33 and 0.24 respectively.13 Our findings align with this evidence, suggesting that a sequential or graded reintroduction remains a safer and practical approach. Furthermore, a cross-sectional survey of 197 physicians managing anti-TB drug¬–induced hepatotoxicity found that among those who opted for rechallenge, 16.6 % used a full dosage from the start and 71.4 % used an increasing (escalating) dose regimen (while only 0.6 % attempted simultaneous full-dose reintroduction of all drugs).14This suggests that globally, there is a strong preference for an escalating-dose approach rather than immediate full-dose rechallenge. Our nearly equal split thus may reflect institutional preference for individualisation based on clinical assessment, rather than a dominant one-size-fits-all strategy. In the current study, two drugs usually isoniazid and rifampicin were reintroduced in 99% of patients, while all three first-line drugs were reintroduced in only 1%. This cautious approach corresponds with global practice, where reintroduction of two essential first-line drugs is preferred to minimize hepatotoxic risk. Singh et al. similarly reported that isoniazid and rifampicin could be safely reintroduced in 93% of patients after hepatotoxicity, while pyrazinamide was often omitted because of its high risk of recurrence.15 Likewise, Thongraung et al. noted that most patients were rechallenged with two drugs sequentially, reinforcing the safety and efficacy of this approach.14 Babalik et al and Durand et al documented that pyrazinamide may be permanently discontinued, with treatment extended to 9 months” in cases of severe hepatic injury, because “the benefit of a shorter treatment course likely does not outweigh the risk of severe hepatotoxicity from pyrazinamide rechallenge.16,17 In another study by Moosa et al on patients with AT-DILI from a high HIV-prevalence setting, of 79 participants who underwent rechallenge, 46 were rechallenged with PZA and the positive-rechallenge rate (i.e., recurrence of hepatotoxicity) was significantly higher among those receiving PZA (9/46) compared to none or very few among those receiving only rifampicin or isoniazid.7 Therefore, our observation of 99 % of patients reintroduced with two drugs (INH + RIF) and only 1 % with three drugs including PZA reflects a strategy grounded in the published risk-based approach. With respect to treatment outcomes, the present study demonstrated that 67% of patients achieved complete clinical and microbiological cure, highlighting the feasibility of successful continuation of anti-tuberculosis therapy following appropriate management of drug-induced hepatitis. This finding aligns with observations made by Sun et al., from a prospective cohort in China, where approximately 69.4% of patients with antituberculosis drug–induced liver injury (ATDILI) were able to resume and complete modified therapy after hepatic recovery.18 Similarly, Liu et al in a large cohort study reported an overall treatment success rate of 81.7% among patients who developed ATDILI, though this dropped to 73.9% among those with moderate or severe hepatic injury, which is compatible with our study.19 The mortality rate of 11% observed in this study is comparable to findings from other series that examined outcomes of ATT-induced hepatotoxicity. For instance, Devarbhavi et al. (2012), in a study of 269 patients with antituberculosis drug–related liver injury, reported a mortality of 22.7%, with most deaths occurring in those presenting with jaundice, ascites, or hepatic encephalopathy.20 Similarly, Sun et al noted that approximately 13% of patients with severe ATDILI had poor outcome and succumbed to liver failure or complications of underlying disease.18 The lower mortality in our cohort may reflect early recognition, timely withdrawal of offending agents, and structured rechallenge protocols under close hepatology supervision. Nonetheless, the 11% fatality emphasizes that ATT-induced hepatitis continues to pose a substantial risk, particularly among patients with advanced disease or co-morbid hepatic compromise. A proportion of patients (7%) remained under treatment at the time of analysis, a reflection of treatment prolongation due to hepatotoxicity-related interruptions and the cautious, stepwise re-introduction of essential drugs. This observation parallels reports by Sun et al., who demonstrated delayed sputum conversion and extended therapy duration among patients who experienced DILI during tuberculosis treatment.18 Such delays may be inevitable in the interest of patient safety but underscore the need for closer follow-up to ensure eventual treatment completion. In nutshell, the treatment outcomes in the present study are broadly consistent with international experiences but also highlight the multifactorial nature of morbidity and mortality associated with ATT-induced hepatitis. While most patients can achieve cure with careful rechallenge and monitoring, a subset continues to experience adverse outcomes either due to hepatotoxicity-related mortality or loss to follow-up. Strengthening early detection of hepatic injury, standardizing rechallenge protocols, and reinforcing post-hepatitis treatment support may further improve clinical outcomes in this vulnerable population.

The findings of this study demonstrated that most cases of ATT-induced hepatotoxicity were mild to moderate, with severe injury occurring infrequently, emphasizing the value of early detection and close biochemical monitoring in preventing further deterioration. Hospitalization patterns reflected this distribution, as the majority of patients required only short-term inpatient care, while a smaller subset needed prolonged observation due to slower clinical recovery or the need for careful planning before drug rechallenge. Rechallenge strategies were highly successful, with both full-dose and stepwise reintroduction approaches showing comparable utility. Nearly all patients tolerated the reintroduction of the two essential drugs, isoniazid and rifampicin, supporting their continued use even after hepatotoxicity, whereas rechallenge with pyrazinamide was rarely feasible. Treatment outcomes were generally favorable, although some patients experienced prolonged treatment courses, adverse outcomes, or were lost to follow-up. These findings underscore the importance of vigilant monitoring, individualized rechallenge strategies, and strengthened follow-up systems to optimize outcomes after ATT-induced hepatotoxicity.

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