Incidence and associated risk factors of antituberculosis drug induced hepatotoxicity among TB patients

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Use of anti-TB drugs to treat TB is associated with high prevalence of side effects and unpredictable clinical hepatotoxicity that include anti-TB drug induced liver injury (ATDILI). The aim of this study was to determine the incidence and associated clinical risk factors of ATDILI among South African patients with TB infections. Methods This was an exploratory, mixed prospective and retrospective case control study of patients with TB infections receiving drug sensitive and drug resistant treatment regimens. The retrospective and prospective studies were done from January 2021 to June 2024, involving a total of 616 patients with TB infections from whom 13 had ATDILI. From the retrospective and prospective cohorts, we extracted 13 ATDILI cases and 276 controls. Additionally, 44 extreme ATDILI cases were directly recruited from the hospital to enrich the number of cases in the study. All participants provided informed consent and had available DNA samples for genetic analysis. Results In the studied cohorts, the incidence of ATDILI was 2.1% (13/616). The ATDILI cases and controls consisted of 215 (64.56%) male patients; 57 patients were diagnosed with hepatotoxicity, 44 from the hospitalized cohort,12 from the retrospective cohort and 1 patient from the prospective cohort. The median time from the initiation of treatment to the onset of hepatotoxicity was approximately 30 days. Univariate logistic regression revealed significant differences (p < 0.05) in gender (p = 0.001), HIV status (p = 0.004), BMI (p = 0.036), Hypertension (p = 0.047) smoking (p = 0.010), and alcohol consumption (p = 0.003) in relation to ATDILI. Multivariate analysis further demonstrated that female gender (p = 0.041) had a cumulative risk factor for ATDILI. Conclusions The incidence of ATDILI of 2.1% is on the lower end of the reported literature values of 5–35% indicative of potentially less rigorous ATDILI phenotype assignment in previous studies reporting much higher values. Female gender, HIV status, BMI, Hypertension, smoking, and alcohol consumption were identified as risk factors associated with ATDILI. Among these, the cumulative effect of gender significantly increased the risk of developing ATDILI. The DNA from the case and control samples is undergoing further genomic analysis in search of potential genetic biomarkers for ATDILI. Tuberculosis anti-tuberculosis regimens risk factors and drug induced liver injury Figures Figure 1 Figure 2 BACKGROUND Tuberculosis (TB) is a global health challenge with ~ 10 million people with TB disease in 2020, and 1.5 million TB deaths ( 1 ); South Africa contributes 3.6% to this global burden with a prevalence of 737/100,000 ( 2 ). According to the current recommendations by the World Health Organization (WHO), the first-line treatment of drug sensitive TB (TB sensitive to all first-line anti-TB drugs) is a combination chemotherapy of four anti-TB drugs consisting of an intensive 2-month phase of isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB) and a 4-month continuation phase of INH and RIF ( 3 ). Currently, treatment for drug resistance TB (TB resistant to at least two first-line anti-TB drugs) lasts between 9 and 24 months and involves multiple drugs ( 4 ). Despite the effectiveness against TB, this polychemotherapy may cause anti-TB drug-induced liver injury (ATDILI) that is estimated to occur in 5–33% of patients ( 3 ) leading to early treatment withdrawal, prolonged treatment duration, treatment failure, and emergence of drug resistance. ATDILI may result from direct toxicity of the primary compound, from a metabolite, or from an immunologically mediated response affecting hepatocytes, biliary epithelial cells and/or liver vasculature ( 5 ). The incidence of ATDILI when INH is combined with rifampicin appears higher than for INH alone, with addition of pyrazinamide the risk increases further by 3-fold ( 6 ). Because mechanisms by which anti-TB drugs causes DILI are poorly understood, ATDILI is difficult to predict and prevent. Therapeutic responses to ATDILI requires temporary cessation of all TB treatment for several weeks with re-introduction of TB treatment once liver enzymes have normalized. Re-introduction may result in re-escalation of liver enzymes warranting change in TB therapy. These changes in therapy are difficult as primary care clinics often do not stock alternatives to the routine four drug fixed dose combination tablet drug sensitive TB treatment. Should TB treatment be continued despite elevated liver enzymes, severe liver necrosis and death may result ( 7 ). Although it might be challenging to predict when hepatotoxicity will occur, it is known that certain patient characteristics put them at increased risk. These risk factors include co-infection with HIV, hepatitis B/C, high alcohol intake, smoking, advanced age, female sex, pre-existing chronic liver disease, malnutrition, and genetic factors ( 8 ). However, the risk factors that contribute to the development of ATDILI remain unclear and contentious. Several studies reported that advance age is a potential risk factor for ATDILI ( 8 , 9 ). But, a study in Nepal showed that the incidence of ATDILI was higher in younger patients ( 10 ). Some studies reported that the history of chronic alcohol intake is a predisposing factor for ATDILI ( 8 ). Some studies suggested that female gender is an independent predictor of ATDILI ( 11 , 12 ). However, a recent report suggested that males have a higher risk of developing ATDILI ( 5 ). Some studies from China, ( 8 ), and India ( 13 ), showed that pre-existing chronic liver disease and malnourishment had a significant association with the incidence of ATDILI. Differences in study design, study population, definition of hepatotoxicity and monitoring practices restricts understanding of ATDILI. It is estimated that ATDILI affects 5–33% of patients on TB treatment ( 14 , 15 ). In South Africa Cecilia et al reported ATDILI incidence of 12% by reviewing of patients managed for ATDILI from 2005 to 2013 at King Edward VIII Hospital in Durban ( 16 ). Mehta et al also reported that, among 129 South African TB patients, 36 (27.9%) of the total TB cases developed ATDILI ( 17 ). To date, no study has determined the incidence of ATDILI and assessed the clinical risk factors of ATDILI among TB patients in South Africa. We therefore aim to determine the incidence and associated clinical risk factors of ATDILI among South African TB patients. METHODS Study design This was an exploratory, mixed prospective and retrospective case control study of patients with TB infections receiving drug-sensitive and drug-resistant treatment regimens. We recruited participants from the following four retrospective studies. The India-South Africa collaboration on pharmacokinetics in drug resistant TB patients (ISA-DRPK) study investigated the pharmacokinetics of drug-resistant TB patients ( 18 ), while the Adjunctive Aspirin and Ibuprofen for tuberculosis assessed the efficacy and safety of aspirin and ibuprofen as adjunctive therapies for TB ( 19 ), and the Bedaquiline, Pretomanid and Linezolid Clinical Access Program (BPaL CAP) (B-Pa-L) study provided clinical access to a combination of bedaquiline, pretomanid, and linezolid for TB patients. Additionally, Statin Adjunctive Therapy for TB (STAT-TB) study explored dose-finding for pravastatin as an adjunctive therapy for TB. The PGx@DILI study consisting of both the hospitalized and prospective TB patients were recruited from Gauteng, North West, and Free State provinces in South Africa. Cases were defined as patients who developed biochemical evidence of liver injury during the patient follow up, attributable to TB drugs, after initiating TB therapy, with resolution upon drug withdrawal in severe cases. Controls were patients who did not develop biochemical liver injury during TB therapy during the patient follow up, despite undergoing repeated screening. The study was conducted in clinics and hospitals at existing research sites where well-established cohorts were already in place, facilitating participant recruitment and data collection (Fig. 1 ). Patient inclusion/exclusion criteria and ATDILI diagnosis Study participants were self-identified black South African adults with laboratory confirmed TB or had received TB treatment previously and have had monitoring of liver enzymes during their TB treatment; or admitted to hospital with ATDILI. The normal ranges for ALT are 7–35 IU/L ( 20 ). For the purposes of this study, patients were screened for elevated ALT using a definition of ATDILI defined as alanine transaminase (ALT) level > 120 IU/L and symptomatic (nausea, vomiting, abdominal pain, jaundice); or ALT level > 200 IU/L and asymptomatic ( 17 ). The dosages of anti-TB drugs were: 5mg/kg/day (maximum 300mg/day) of isoniazid (H); 10mg/kg/day (maximum 1200mg/day) of rifampicin (R), 15–30mg/kg/day (maximum 2000mg/day) of pyrazinamide (Z), 15 mg/kg/day or 25–30mg/kg/day (maximum 2500mg/day) of ethambutol (E). Key inclusion criteria: 1. ≥ 18 years ; 2. Laboratory confirmation of TB infection (Xpert Ultra or mycobacterial culture positive for Mycobacterium tuberculosis ); 3.Consent to test for HIV infection; 4. Agreement to the collection and storage of blood, urine, oral swab and sputum specimens for future use; 5. Consent for genomic analysis of DNA samples and data sharing (nationally and internationally) and 6. Baseline ALT within normal range. Key exclusion criteria: 1. Active psychiatric conditions, alcohol or drug dependence that might interfere with the ability to provide informed consent and/or adhere to study requirements; 2. For cases, patients with Hepatitis B virus (HBV) and hepatitis C virus (HCV) and other possible causes of liver injury were excluded. All participants provided written informed consent and the study was approved by the University of the Witwatersrand's Human Research Ethics Committee (Wits HREC: M240904). Statistical analysis The data were analyzed using STATA (version 18; Stata Corp, College Station, TX, USA) and R Statistical Software (version 3.4.3, https://www.r-project.org/ ). Categorical data were summarized using frequency counts and percentages while continuous variables were summarized with mean and standard deviation. Univariate and multivariate logistic regression model was used to assess the risk factors associated with anti-TB drugs induced hepatotoxicity (ATDILI). A variable with p-value of less than 20% at univariate logistic regression was considered for multivariate logistic regression. A backward elimination, with the help of likelihood ratio test at a p-value of 5%, was used to keep the variable in the final model. The dependent variable was the occurrence of anti-TB drugs induced hepatotoxicity (ATDILI). RESULTS Table 1 summarizes the participants with ATDILI recruited across the studies. In total, 57 participants were identified: 4/52 from India-South Africa collaboration on pharmacokinetics in drug resistant TB patients (ISA DRPK) study, 5/217 from Adjunctive Aspirin and Ibuprofen for Tuberculosis (SMA TB): Phase 2b Randomized double-blind, placebo controlled trial to estimate the potential efficacy and safety of two repurposed drugs, acetyl salicylic acid and ibuprofen, for use as adjunct therapy added to, and compared with, the standard WHO recommended TB regimen (SMA-TB) study, 1/90 from Bedaquiline, Pretomanid and Linezolid Clinical Access Program (BPaL CAP) in South Africa (BPAL) study, 2/16 participants were recruited from Statin Adjunctive Therapy for TB (STAT-TB) A Phase 2b Dose- finding Study of Pravastatin in Adults with Tuberculosis and 44 cases from retrospective arm of the Pharmacogenomics of Hepatotoxicity in the treatment of drug sensitive and drug-resistant TB in Africans (PGx@DILI Study) and 1 participant was included from prospective arm of PGx@DILI Study cohort. Table 2 presents a comparison of the clinical and demographic characteristics among participants without ATDILI, those with standard ATDILI, and hospitalized individuals with extreme ATDILI. A total of 333 patients with tuberculosis (TB) infections were enrolled, of whom 215 (64.56%) were male. The overall mean age was 38.97 years (IQR: 30.00–46.00); however, patients in the extreme ATDILI group were older on average (42.10 years) than those in the standard ATDILI (41.46 years) and non-ATDILI (39.60 years) groups. ALT levels varied significantly across the groups. Participants with extreme ATDILI exhibited a median ALT of 478.88 U/L (IQR: 265.00–626.00), markedly higher than the standard ATDILI group (389.06 U/L; IQR: 189.00–729.00) and the non-ATDILI group (21.53 U/L; IQR: 12.00–28.00). Body mass index (BMI) distributions also differed. Underweight status was more prevalent among participants without ATDILI (34.06%, n=94), whereas overweight individuals were more frequently observed in the standard (38.46%, n=5) and extreme (34.09%, n=15) ATDILI groups. Correspondingly, the mean BMI was slightly higher in the ATDILI groups, 22.98 kg/m² in standard and 23.02 kg/m² in extreme compared to 22.60 kg/m² in the non-ATDILI group. In terms of gender distribution, the standard ATDILI group had a greater proportion of female participants (61.54%, n=8) than the non-ATDILI group (19.22%, n=64), while the extreme ATDILI group had a more balanced gender composition (52.27%, n=23). Unemployment was common across all groups (ranging from 63.64% to 66.37%), potentially reflecting the impact of socioeconomic or health-related factors, especially among those with severe liver injury. Although the overall prevalence of diabetes was low (1.80%), it was considerably higher in the extreme ATDILI group (9.09%), suggesting a possible link between diabetes and increased susceptibility to severe hepatotoxicity. A similar trend was observed with hypertension, which was more common in the standard (23.08%) and extreme (13.64%) ATDILI groups compared to the non-ATDILI group (5.07%). HIV infection was a major comorbidity, affecting 59.16% of the entire cohort. The proportion of HIV-positive individuals increased with ATDILI severity—56.52% in non-ATDILI, 69.23% in standard ATDILI, and 84.09% in extreme ATDILI—highlighting a potential correlation. Smoking (current and former use) was also prevalent (71.47% overall), with current smoking particularly common in the standard ATDILI group (53.85%) compared to the non-ATDILI group (42.75%). Alcohol use was widespread (67.57%) but showed a declining trend with increasing ATDILI severity: 80.80% among non-ATDILI participants, 69.23% in the standard ATDILI group, and 52.27% in the extreme ATDILI group. Clinical symptoms were more pronounced in patients with extreme ATDILI. Jaundice was observed in 36.36% (n=16) of patients in this group (N=44), compared to 7.69% (n=1, N=13) in the standard ATDILI group and 7.61% (n=21, N=276) in the non-ATDILI group. Similarly, abdominal pain and dark urine were most frequent in the extreme ATDILI group (43.18% and 52.27%, respectively), followed by the standard (30.77% for both symptoms) and non-ATDILI groups (31.16% and 21.01%, respectively). All patients diagnosed with tuberculosis (TB) were treated with standard combination chemotherapy, consisting of an intensive two-month phase with four first-line anti-TB drugs: isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB) followed by a four-month continuation phase with INH and RIF. Patients who were not responsive to first-line therapy were initiated on second-line regimens, including bedaquiline, pretomanid, and linezolid. Moreover, all TB patients who developed anti tuberculosis drug-induced liver injury (ATDILI) had documented adherence to their prescribed anti-TB treatment regimens throughout therapy. Similarly, all HIV-positive patients were initiated on the standard fixed-dose combination therapy comprising Tenofovir disoproxil fumarate (TDF), Lamivudine (3TC), and Dolutegravir (DTG) (TLD regimen), in line with international treatment guidelines. Table 3 summarizes the univariate and multivariate logistic regression analyses of factors associated with anti-tuberculosis drug-induced liver injury (ATDILI). In the univariate analysis, female gender (reference: male) was significantly associated with an increased risk of ATDILI (HR = 3.29, SE = 1.19, p = 0.001, 95% CI: 1.62–6.67). Similarly, individuals living with HIV (reference: HIV-negative) had more than a threefold higher risk of developing ATDILI (HR = 3.19, SE = 1.30, p = 0.004, 95% CI: 1.43–7.07). An incremental increase in BMI (reference: normal weight) was also associated with elevated ATDILI risk (HR = 1.08 per unit, SE = 0.04, p = 0.036, 95% CI: 1.01–1.16). Hypertension (reference: no hypertension) showed a borderline association (HR = 1.53, SE = 1.06, p = 0.047, 95% CI: 0.40–5.93), indicating a potential role in risk stratification. Current or former smokers (reference: non-smokers) and alcohol consumption (reference: non-drinkers) were both associated with ATDILI risk. Smoking had a hazard ratio of 2.30 (SE = 0.14, p = 0.010, 95% CI: 0.12–0.75), while alcohol had hazard ratio of 1.35 (SE = 0.12, p = 0.003, 95% CI: 0.17–0.70). In the multivariate model, only gender remained a significant independent predictor, with females having a markedly higher risk of ATDILI (HR = 11.21, SE = 13.27, p = 0.041, 95% CI: 1.10–114.06), underscoring the need for targeted clinical surveillance in this subgroup. While these findings may suggest potential risk or confounding effects, they underscore the complexity of ATDILI pathogenesis and the need for further investigation to elucidate underlying mechanisms. Figure 2 presents the distribution of natural log-transformed alanine aminotransferase (ln[ALT]) levels stratified by age, gender, smoking status, and alcohol use among participants with and without anti-tuberculosis drug-induced liver injury (ATDILI). Figure 2. (a) illustrates the relationship between age and ln(ALT) levels. Among individuals who developed ATDILI, those aged below 36 years exhibited the highest ALT levels, followed by participants in the 36–65 years group. The oldest age group (≥65 years) showed the lowest ALT elevation among those with DILI. In contrast, among participants without ATDILI, ALT levels remained uniformly low across all age categories, with minimal variability. In figure 2. (b), ALT levels are compared between male and female participants. Both sexes showed elevated enzyme levels in the DILI group, with slightly higher median values in females. However, in the non-DILI group, ALT levels were significantly lower and showed little difference between males and females, suggesting that gender-related differences in ALT elevation are more pronounced in the context of liver injury. Figure 2. (c) explores the effect of smoking on ALT levels. Current and former smokers with ATDILI exhibited higher ALT concentrations compared to never-smokers. Among participants without ATDILI, the differences were negligible, as ALT levels remained consistently low regardless of smoking history. This pattern may indicate a possible interaction between smoking and liver injury susceptibility. Figure 2. (d) evaluates ALT levels in relation to alcohol use. Both current drinkers and non-drinkers who developed ATDILI had similarly elevated ALT values, indicating that alcohol use alone may not fully account for enzyme elevation in this group. However, in the non-DILI group, ALT values were notably lower in both alcohol users and non-users, highlighting a clear distinction between individuals with and without liver injury irrespective of alcohol intake. DISCUSSION The reported incidence of ATDILI varies significantly across different ethnicities, ranging from approximately 1–36%. In the United States of America (USA), it is 3%, in the United Kingdom (UK) 4%, in Germany 11%, in Argentina 9.9%, in Hong Kong 13%, in Japan 36%, in Taiwan 26%, and in India between 8% and 36%( 8 ). The incidence of ATDILI in our study was 2.1%, which is close to the values reported across in the USA and UK. The variation in the incidence of ATDILI worldwide may be attributed to the differences in patients’ characteristics, indiscriminate use of drugs and the definition criteria of drug induced liver injury ( 14 ). In our study we defined anti-tuberculosis drug-induced liver injury (ATDILI) according to the criteria established by the Drug Induced Liver Injury Network (DILIN),( 17 ) which classifies ATDILI cases as ALT > 120 IU/L or ALT > 3 × upper limit of normal (ULN) with symptoms like vomiting, nausea, abdominal pain. A study in France reported an annual ATDILI incidence rate of 13.9 ( 21 ), while a two-year study in Iceland found an incidence of 19.1( 22 ) and a similar study in Delaware, US, reported 2.7 cases per 100,000 ( 23 ). In this study a higher cut off for alanine aminotransferase (ALT) values (> 5 × upper limit of normal (ULN) was used for case definition than in the French (> 2 × ULN) and Icelandic (> 3 × ULN) studies, and could account at least in part for the lower incidence of ATDILI. Our adherence to the DILIN( 17 ) definition is therefore an important contribution towards a well-defined case-control cohort that can be used to investigate the clinical and molecular genetic risk factors for ATDILI. The clinical presentation of anti-tuberculosis drug-induced liver injury is varied and non-specific, ranging from asymptomatic liver dysfunction to severe acute hepatitis or even acute liver failure. The mechanism of ATDILI primarily involves hypersensitivity reactions, which can present with symptoms such as dark urine, jaundice, fever, fatigue, and abdominal pain. In our study, the most common clinical manifestations were dark urine, jaundice and abdominal pain similar results were observed in a study carried out by Cavaco et al ( 24 ) and Lei et al ( 25 ). Although some patients presented with clinical symptoms about 65% of patients presented with asymptomatic transaminase elevation with standard anti-TB drug therapy. ATDILI can sometimes be fatal if not diagnosed and managed promptly ( 26 ). Therefore, it is advisable to routinely monitor liver function in patients receiving anti-TB drugs. In our study, the average time from the initiation of anti-TB treatment to the development of ATDILI was approximately 30 days. This was similar to previous reports of 24–30 days reported by ( 27 – 29 ). According to the literature, several factors influence the severity of ATDILI, including advanced age, gender, smoking, alcohol consumption, HIV/AIDS, and body mass index ( 14 , 30 ). We found significant association between gender of patients and ATDILI. It has been reported that women are at increased risk of developing hepatotoxicity when receiving anti-tuberculosis treatment ( 24 , 25 ). In our study, the proportion of women with ATDILI was higher than that of men, suggesting that women receiving anti-tuberculosis drugs may be more prone to liver damage or even liver failure. Kumar et al .( 27 ) conducted a study in India, reporting that approximately 70% of anti-TB drug-associated liver failure cases occurred in female patients. In contrast, among hospitalized patients with extreme ATDILI, the proportion of females 23 (52.27%) was slightly higher than that of males. Moreover, in the standard ATDILI group, females were also more prevalent accounting for 61.54% of cases, while males comprised only 38.46%. We found no significant difference in age of patients and risk for ATDILI. There are few studies that have reported an association between age and ATDILI ( 7 , 15 , 31 ), although some studies have reported an association between advanced age and ATDILI ( 26 , 29 , 32 ). Hypertension, alcohol consumption, and smoking were also identified as risk factors for anti-tuberculosis drug-induced liver injury (ATDILI). Overall, the findings suggest that female sex, higher body mass index (BMI), HIV infection, hypertension, smoking, and alcohol use may contribute to elevated liver enzyme levels and should be considered potential risk factors for ATDILI. All HIV-positive individuals in the cohort were initiated on the standard fixed-dose combination therapy of Tenofovir disoproxil fumarate (TDF), Lamivudine (3TC), and Dolutegravir (DTG) commonly referred to as the TLD regimen in accordance with international treatment guidelines ( 33 ). Given that TLD is typically well tolerated and associated with a low incidence of hepatotoxicity, it is likely that the observed risk of ATDILI in this cohort was primarily driven by the anti-TB drug regimens rather than the TLD therapy. Additionally, we consistently observed that all patients adhered well to their anti-TB therapy, which could have contributed to an increased risk of ATDILI due to higher cumulative drug exposure. Although our study found no significant association between the presence of diabetes and the occurrence of anti-tuberculosis drug-induced liver injury (ATDILI), findings from other studies have been inconsistent. For instance, other studies have reported a significantly higher incidence of ATDILI among patients with hypertension and diabetes compared to those without these comorbidities ( 34 – 36 ). In contrast, several other studies have similarly reported no significant association between these comorbid conditions and ATDILI risk ( 37 – 39 ). These conflicting findings underscore the need for further well-designed studies to clarify the role of hypertension and diabetes in the development of ATDILI. CONCLUSION This mixed retrospective and prospective study found an incidence of ATDILI at 2.1%. The study indicated a higher incidence of ATDILI in female patients. Identified risk factors associated with ATDILI included female gender, HIV status, BMI, hypertension, smoking, and alcohol use. The risk of developing ATDILI appears to be higher in females within our study population, indicating the need for closer monitoring of gender in high-risk patients to reduce the incidence of ATDILI. Abbreviations · Adjunctive Aspirin and Ibuprofen for Tuberculosis – SMA TB · Alanine transaminase – ALT · ALT – Alanine aminotransferase · Anti-tuberculosis drug induced liver injury – ATDILI · Bedaquiline, Pretomanid and Linezolid – BPAL · Body Mass Index – BMI · Confidence Interval – CI · Dolutegravir – DTG · Drug Induced Liver Injury Network – DILIN · DTG – Dolutegravir · Ethambutol – EMB · Hazard Ratio – HR · Hepatitis B virus – HBV · Hepatitis C virus – HCV · HIV – Human Immunodeficiency Virus · India-South Africa collaboration on pharmacokinetics in drug resistant TB patients – ISA DRPK · Interquartile Range – IQR · Isoniazid – INH · Lamivudine – 3TC · Natural log-transformed ALT – ln[ALT] · Pharmacogenomics of drug induced liver injury – PGx@DILI · Pyrazinamide – PZA · Rifampicin – RIF · Standard Error – SE · Statin Adjunctive Therapy for TB – STAT-TB · Tenofovir disoproxil fumarate – TDF · TDF – Tenofovir disoproxil fumarate · United Kingdom – UK · United States of America – USA · University of Witwatersrand Human Research Ethics Commission – Wits HRE · World Health Organization – WHO Declarations Ethics Approval and Consent to Participate This study received ethical approval from the Human Research Ethics Committee of the University of the Witwatersrand (Wits HREC: M240904). All study procedures were conducted in accordance with the Declaration of Helsinki and adhered to applicable national regulations and ethical guidelines governing research in South Africa. Written informed consent was obtained from all participants prior to their enrolment in the study. Consent for Publication All participants provided written informed consent for the publication of findings derived from this study Data availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Competing interest All authors declare no conflict of interest. Funding Research reported in this publication was supported by the South African Medical Research Council (SAMRC) with funds received from Novartis and GSK R&D for Project Africa GRADIENT Grant number SAMRC-RFA-GSK/NVS 01-2021. The study was also supported by the GATES Foundation INV-036801 Calestous Juma Fellowship to Collen Masimirembwa. Authors contribution Collen Masimirembwa, Neil Martinson, Ananyo Choudhury, Roslyn Thelingwani, Tom Boyles, and Vincent Nyangwara were involved in the conceptualization of the study.Vincent Nyangwara, Ziyaad Waja, Collen Masimirembwa, and Neil Martinson contributed to the methodology.Formal analysis was conducted by Vincent Nyangwara, Ziyaad Waja, Raadhiya Osman, Ziska Pretorius, Keitumetse Majoro, and Bekiwe Ncwana.Vincent Nyangwara and Ziyaad Waja prepared the original draft of the manuscript.Writing – review and editing were performed by Vincent Nyangwara, Ziyaad Waja, Collen Masimirembwa, and Neil Martinson. All authors read and approved the final manuscript. Clinical trial number Not applicable. Acknowledgements Thank you to patients who agreed to be part of this study. Enormous gratitude to Mr. Blessing Sitabule and Jocelyn Gayenga for their assistance during the study. References Johnston JC, Cooper R, Menzies D. Chapter 5: Treatment of tuberculosis disease. 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An analysis on the clinical features and risk factors associated with the prognosis of patients with drug-induced liver injury. Exploration of Digestive Diseases. 2023 Jun 30;100–17. Su Q, Liu Q, Liu J, Fu L, Liu T, Liang J, et al. Study on the associations between liver damage and antituberculosis drug rifampicin and relative metabolic enzyme gene polymorphisms. Bioengineered. 2021;12(2):11700–8. Costiniuk CT, Gosnell BI, Manzini TC, Du Plessis CN, Moosa MYS. Tuberculous drug-induced liver injury and treatment re-challenge in Human Immunodeficiency Virus co-infection. J Glob Infect Dis. 2015 Oct 1;7(4):151–6. Mehta R, Ive P, Evans D, Menezes CN. Treatment outcomes among patients admitted to hospital with antiretroviral and/or antituberculosis drug-induced liver injury. Vol. 111, South African Medical Journal. South African Medical Association; 2021. p. 474–81. Kengo A, Nabeemeeah F, Denti P, Sabet R, Okyere-Manu G, Abraham P, et al. Assessing potential drug-drug interactions between clofazimine and other frequently used agents to treat drug-resistant tuberculosis. Antimicrob Agents Chemother. 2024 May 1;68(5). Arias L, Otwombe K, Waja Z, Tukvadze N, Korinteli T, Moloantoa T, et al. SMA-TB: study protocol for the phase 2b randomized double-blind, placebo-controlled trial to estimate the potential efficacy and safety of two repurposed drugs, acetylsalicylic acid and ibuprofen, for use as adjunct therapy added to, and compared with, the standard WHO recommended TB regimen. Trials. 2023 Dec 1;24(1). Kolahdoozan S, Mirminachi B, Sepanlou SG, Malekzadeh R, Merat S, Poustchi H. Upper normal limits of serum alanine aminotransferase in healthy population: A systematic review. Vol. 12, Middle East Journal of Digestive Diseases. Shiraz University of Medical Sciences; 2020. p. 194–205. Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al. Incidence of drug-induced hepatic injuries: A French population-based study. Hepatology. 2002;36(2):451–5. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of iceland. Gastroenterology. 2013;144(7). Vega M, Verma M, Beswick D, Bey S, Hossack J, Merriman N, et al. The Incidence of Drug- and Herbal and Dietary Supplement-Induced Liver Injury: Preliminary Findings from Gastroenterologist-Based Surveillance in the Population of the State of Delaware. Drug Saf. 2017 Sep 1;40(9):783–7. Cavaco MJ, Alcobia C, Oliveiros B, Mesquita LA, Carvalho A, Matos F, et al. Clinical and Genetic Risk Factors for Drug‐Induced Liver Injury Associated with Anti‐Tuberculosis Treatment—A Study from Patients of Portuguese Health Centers. J Pers Med. 2022 May 1;12(5). Lei S, Gu R, Ma X. Clinical perspectives of isoniazid-induced liver injury. Vol. 5, Liver Research. KeAi Communications Co.; 2021. p. 45–52. Zhong T, Fan Y, Dong XL, Guo X, Wong KH, Wong WT, et al. An Investigation of the Risk Factors Associated With Anti-Tuberculosis Drug-Induced Liver Injury or Abnormal Liver Functioning in 757 Patients With Pulmonary Tuberculosis. Front Pharmacol. 2021 Nov 8;12. Kumar R, Shalimar, Bhatia V, Khanal S, Sreenivas V, Gupta SD, et al. Antituberculosis therapy-induced acute liver failure: Magnitude, profile, prognosis, and predictors of outcome. Hepatology. 2010 May;51(5):1665–74. Zhao H, Wang Y, Zhang T, Wang Q, Xie W. Drug-induced liver injury from anti-tuberculosis treatment: A retrospective cohort study. Medical Science Monitor. 2020 Mar 7;26. Tweed CD, Wills GH, Crook AM, Dawson R, Diacon AH, Louw CE, et al. Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study. BMC Med. 2018 Mar 28;16(1). Soremekun C, Machipisa T, Soremekun O, Pirie F, Oyekanmi N, Motala AA, et al. Multivariate GWAS analysis reveals loci associated with liver functions in continental African populations. PLoS One. 2023 Feb 1;18(2 February). Wang N, Chen X, Hao Z, Guo J, Wang X, Zhu X, et al. Incidence and Temporal Trend of Antituberculosis Drug-Induced Liver Injury: A Systematic Review and Meta-Analysis. Vol. 2022, Journal of Tropical Medicine. Hindawi Limited; 2022. Jiang F, Yan H, Liang L, Du J, Jin S, Yang S, et al. Incidence and risk factors of anti-tuberculosis drug induced liver injury (DILI): Large cohort study involving 4652 Chinese adult tuberculosis patients. Liver International. 2021 Jul 1;41(7):1565–75. Enoh JE, Cho FN, Manfo FP, Ako SE, Akum EA. Abnormal Levels of Liver Enzymes and Hepatotoxicity in HIV-Positive, TB, and HIV/TB-Coinfected Patients on Treatment in Fako Division, Southwest Region of Cameroon. Biomed Res Int. 2020;2020. Zhang M, Wang S, Wilffert B, Tong R, van Soolingen D, van den Hof S, et al. The association between the NAT2 genetic polymorphisms and risk of DILI during anti-TB treatment: a systematic review and meta-analysis. Vol. 84, British Journal of Clinical Pharmacology. Blackwell Publishing Ltd; 2018. p. 2747–60. Li X, Tang J, Mao Y. Incidence and risk factors of drug-induced liver injury. Vol. 42, Liver International. John Wiley and Sons Inc; 2022. p. 1999–2014. Abdalhabib EK, Alzahrani B, Alanazi F, Algarni A, Ibrahim IK, Mohamed HA, et al. Increased Risk of Acute Lymphoblastic Leukemia in Adult Patients with GSTM1 Null Genetic Polymorphism. Pharmgenomics Pers Med. 2022;15:227–34. Yu Z, Zhao Y, Jin J, Zhu J, Yu L, Han G. Prevalence and risk factors of tigecycline-induced liver injury: A multicenter retrospective study. International Journal of Infectious Diseases. 2022 Jul 1;120:59–64. Freire ID, Fielding KL, Moore DAJ. Does diabetes mellitus comorbidity increase the risk of drug-induced liver injury during tuberculosis treatment? PLoS One. 2023 May 1;18(5 May). Nicoletti P, Devarbhavi H, Goel A, Venkatesan R, Eapen CE, Grove JI, et al. Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens. Clin Pharmacol Ther. 2021 Apr 1;109(4):1125–35. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Waja","email":"","orcid":"","institution":"Perinatal HIV Research Unit (PHRU) Baragwanath Hospital, University of the Witwatersrand","correspondingAuthor":false,"prefix":"","firstName":"Ziyaad","middleName":"","lastName":"Waja","suffix":""},{"id":456176722,"identity":"ba950249-5a2b-49ed-b6f8-d4c3d237352f","order_by":2,"name":"Roslyn Thelingwani","email":"","orcid":"","institution":"African Institute of Biomedical Science and Technology, Department of Bioanalytics","correspondingAuthor":false,"prefix":"","firstName":"Roslyn","middleName":"","lastName":"Thelingwani","suffix":""},{"id":456176723,"identity":"f042ba51-59aa-4e8b-84ea-f6cee0ee7809","order_by":3,"name":"Raadhiya Osman","email":"","orcid":"","institution":"Perinatal HIV Research Unit (PHRU) Baragwanath Hospital, University of the 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Witwatersrand","correspondingAuthor":false,"prefix":"","firstName":"Neil","middleName":"","lastName":"Martinson","suffix":""}],"badges":[],"createdAt":"2025-05-05 18:38:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6596752/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6596752/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-025-11796-4","type":"published","date":"2025-10-24T16:16:37+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82798306,"identity":"4e1106de-acea-49ea-ba9b-e8f84e43142b","added_by":"auto","created_at":"2025-05-15 10:48:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":137574,"visible":true,"origin":"","legend":"\u003cp\u003eThe study comprised three arms: prospective, retrospective, and hospitalized cohorts. A total of 333 patients with tuberculosis (TB) infection were recruited, including 57 cases and 276 controls.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6596752/v1/815410f791c3d66567b53d93.png"},{"id":82799384,"identity":"21465a48-5983-4ac2-bc5a-b32ea8e21c2c","added_by":"auto","created_at":"2025-05-15 10:56:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":143741,"visible":true,"origin":"","legend":"\u003cp\u003eBox plots showing natural log-transformed ALT (ln[ALT]) levels stratified by key demographic and behavioral factors among individuals with and without anti-tuberculosis drug-induced liver injury (ATDILI).(a) Stratification by age group: \u0026lt;36 years (blue), 36–65 years (orange), ≥65 years (purple), b) Stratification by gender: male (blue) and female (orange), (c) Stratification by smoking status: never smokers (green), current smokers (brown), and former smokers (red) and (d) Stratification by alcohol use: never drinkers (green) and current drinkers (red).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6596752/v1/799baf9cf6353afbd03e2a18.png"},{"id":94490651,"identity":"9fc1f398-0407-4b16-92f8-cb0a0f317ba3","added_by":"auto","created_at":"2025-10-27 17:13:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":794966,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6596752/v1/a88ba45e-ca8b-4897-9988-e0d5c08c7d52.pdf"},{"id":82798298,"identity":"701612dc-72a4-4d2d-8e70-740f20f02dab","added_by":"auto","created_at":"2025-05-15 10:48:43","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":25356,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6596752/v1/653e157e6bd60eb9408f0bf0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Incidence and associated risk factors of antituberculosis drug induced hepatotoxicity among TB patients","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eTuberculosis (TB) is a global health challenge with ~\u0026thinsp;10\u0026nbsp;million people with TB disease in 2020, and 1.5\u0026nbsp;million TB deaths (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e); South Africa contributes 3.6% to this global burden with a prevalence of 737/100,000 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). According to the current recommendations by the World Health Organization (WHO), the first-line treatment of drug sensitive TB (TB sensitive to all first-line anti-TB drugs) is a combination chemotherapy of four anti-TB drugs consisting of an intensive 2-month phase of isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB) and a 4-month continuation phase of INH and RIF (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Currently, treatment for drug resistance TB (TB resistant to at least two first-line anti-TB drugs) lasts between 9 and 24 months and involves multiple drugs (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite the effectiveness against TB, this polychemotherapy may cause anti-TB drug-induced liver injury (ATDILI) that is estimated to occur in 5\u0026ndash;33% of patients (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) leading to early treatment withdrawal, prolonged treatment duration, treatment failure, and emergence of drug resistance. ATDILI may result from direct toxicity of the primary compound, from a metabolite, or from an immunologically mediated response affecting hepatocytes, biliary epithelial cells and/or liver vasculature (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The incidence of ATDILI when INH is combined with rifampicin appears higher than for INH alone, with addition of pyrazinamide the risk increases further by 3-fold (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBecause mechanisms by which anti-TB drugs causes DILI are poorly understood, ATDILI is difficult to predict and prevent. Therapeutic responses to ATDILI requires temporary cessation of all TB treatment for several weeks with re-introduction of TB treatment once liver enzymes have normalized. Re-introduction may result in re-escalation of liver enzymes warranting change in TB therapy. These changes in therapy are difficult as primary care clinics often do not stock alternatives to the routine four drug fixed dose combination tablet drug sensitive TB treatment. Should TB treatment be continued despite elevated liver enzymes, severe liver necrosis and death may result (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough it might be challenging to predict when hepatotoxicity will occur, it is known that certain patient characteristics put them at increased risk. These risk factors include co-infection with HIV, hepatitis B/C, high alcohol intake, smoking, advanced age, female sex, pre-existing chronic liver disease, malnutrition, and genetic factors (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). However, the risk factors that contribute to the development of ATDILI remain unclear and contentious. Several studies reported that advance age is a potential risk factor for ATDILI (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). But, a study in Nepal showed that the incidence of ATDILI was higher in younger patients (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Some studies reported that the history of chronic alcohol intake is a predisposing factor for ATDILI (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Some studies suggested that female gender is an independent predictor of ATDILI (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). However, a recent report suggested that males have a higher risk of developing ATDILI (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Some studies from China, (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), and India (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), showed that pre-existing chronic liver disease and malnourishment had a significant association with the incidence of ATDILI.\u003c/p\u003e \u003cp\u003eDifferences in study design, study population, definition of hepatotoxicity and monitoring practices restricts understanding of ATDILI. It is estimated that ATDILI affects 5\u0026ndash;33% of patients on TB treatment (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). In South Africa Cecilia \u003cem\u003eet al\u003c/em\u003e reported ATDILI incidence of 12% by reviewing of patients managed for ATDILI from 2005 to 2013 at King Edward VIII Hospital in Durban (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Mehta \u003cem\u003eet al\u003c/em\u003e also reported that, among 129 South African TB patients, 36 (27.9%) of the total TB cases developed ATDILI (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). To date, no study has determined the incidence of ATDILI and assessed the clinical risk factors of ATDILI among TB patients in South Africa. We therefore aim to determine the incidence and associated clinical risk factors of ATDILI among South African TB patients.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis was an exploratory, mixed prospective and retrospective case control study of patients with TB infections receiving drug-sensitive and drug-resistant treatment regimens. We recruited participants from the following four retrospective studies. The India-South Africa collaboration on pharmacokinetics in drug resistant TB patients (ISA-DRPK) study investigated the pharmacokinetics of drug-resistant TB patients (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), while the Adjunctive Aspirin and Ibuprofen for tuberculosis assessed the efficacy and safety of aspirin and ibuprofen as adjunctive therapies for TB (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), and the Bedaquiline, Pretomanid and Linezolid Clinical Access Program (BPaL CAP) (B-Pa-L) study provided clinical access to a combination of bedaquiline, pretomanid, and linezolid for TB patients. Additionally, Statin Adjunctive Therapy for TB (STAT-TB) study explored dose-finding for pravastatin as an adjunctive therapy for TB. The PGx@DILI study consisting of both the hospitalized and prospective TB patients were recruited from Gauteng, North West, and Free State provinces in South Africa. Cases were defined as patients who developed biochemical evidence of liver injury during the patient follow up, attributable to TB drugs, after initiating TB therapy, with resolution upon drug withdrawal in severe cases. Controls were patients who did not develop biochemical liver injury during TB therapy during the patient follow up, despite undergoing repeated screening. The study was conducted in clinics and hospitals at existing research sites where well-established cohorts were already in place, facilitating participant recruitment and data collection (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient inclusion/exclusion criteria and ATDILI diagnosis\u003c/h3\u003e\n\u003cp\u003eStudy participants were self-identified black South African adults with laboratory confirmed TB or had received TB treatment previously and have had monitoring of liver enzymes during their TB treatment; or admitted to hospital with ATDILI. The normal ranges for ALT are 7\u0026ndash;35 IU/L (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). For the purposes of this study, patients were screened for elevated ALT using a definition of ATDILI defined as alanine transaminase (ALT) level\u0026thinsp;\u0026gt;\u0026thinsp;120 IU/L and symptomatic (nausea, vomiting, abdominal pain, jaundice); or ALT level\u0026thinsp;\u0026gt;\u0026thinsp;200 IU/L and asymptomatic (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The dosages of anti-TB drugs were: 5mg/kg/day (maximum 300mg/day) of isoniazid (H); 10mg/kg/day (maximum 1200mg/day) of rifampicin (R), 15\u0026ndash;30mg/kg/day (maximum 2000mg/day) of pyrazinamide (Z), 15 mg/kg/day or 25\u0026ndash;30mg/kg/day (maximum 2500mg/day) of ethambutol (E).\u003c/p\u003e \u003cp\u003eKey inclusion criteria: 1. \u0026ge; 18 years ; 2. Laboratory confirmation of TB infection (Xpert Ultra or mycobacterial culture positive for \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e); 3.Consent to test for HIV infection; 4. Agreement to the collection and storage of blood, urine, oral swab and sputum specimens for future use; 5. Consent for genomic analysis of DNA samples and data sharing (nationally and internationally) and 6. Baseline ALT within normal range.\u003c/p\u003e \u003cp\u003eKey exclusion criteria: 1. Active psychiatric conditions, alcohol or drug dependence that might interfere with the ability to provide informed consent and/or adhere to study requirements; 2. For cases, patients with Hepatitis B virus (HBV) and hepatitis C virus (HCV) and other possible causes of liver injury were excluded. All participants provided written informed consent and the study was approved by the University of the Witwatersrand's Human Research Ethics Committee (Wits HREC: M240904).\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe data were analyzed using STATA (version 18; Stata Corp, College Station, TX, USA) and R Statistical Software (version 3.4.3, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.r-project.org/\u003c/span\u003e\u003cspan address=\"https://www.r-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Categorical data were summarized using frequency counts and percentages while continuous variables were summarized with mean and standard deviation. Univariate and multivariate logistic regression model was used to assess the risk factors associated with anti-TB drugs induced hepatotoxicity (ATDILI). A variable with p-value of less than 20% at univariate logistic regression was considered for multivariate logistic regression. A backward elimination, with the help of likelihood ratio test at a p-value of 5%, was used to keep the variable in the final model. The dependent variable was the occurrence of anti-TB drugs induced hepatotoxicity (ATDILI).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eTable 1 summarizes the participants with ATDILI recruited across the studies. In total, 57 participants were identified: 4/52 from India-South Africa collaboration on pharmacokinetics in drug resistant TB patients (ISA DRPK) study, 5/217 from Adjunctive Aspirin and Ibuprofen for Tuberculosis (SMA TB): Phase 2b Randomized double-blind, placebo controlled trial to estimate the potential efficacy and safety of two repurposed drugs, acetyl salicylic acid and ibuprofen, for use as adjunct therapy added to, and compared with, the standard WHO recommended TB regimen (SMA-TB) study, 1/90 from Bedaquiline, Pretomanid and Linezolid Clinical Access Program (BPaL CAP) in South Africa \u0026nbsp;(BPAL) study, 2/16 participants were recruited from Statin Adjunctive Therapy for TB (STAT-TB) A Phase 2b Dose- finding Study of Pravastatin in Adults with Tuberculosis and 44 cases from retrospective arm of the Pharmacogenomics of Hepatotoxicity in the treatment of drug sensitive and drug-resistant TB in Africans (PGx@DILI Study) and 1 participant was included from prospective arm of PGx@DILI Study cohort.\u003c/p\u003e\n\u003cp\u003eTable 2 presents a comparison of the clinical and demographic characteristics among participants without ATDILI, those with standard ATDILI, and hospitalized individuals with extreme ATDILI. A total of 333 patients with tuberculosis (TB) infections were enrolled, of whom 215 (64.56%) were male. The overall mean age was 38.97 years (IQR: 30.00\u0026ndash;46.00); however, patients in the extreme ATDILI group were older on average (42.10 years) than those in the standard ATDILI (41.46 years) and non-ATDILI (39.60 years) groups. ALT levels varied significantly across the groups. Participants with extreme ATDILI exhibited a median ALT of 478.88 U/L (IQR: 265.00\u0026ndash;626.00), markedly higher than the standard ATDILI group (389.06 U/L; IQR: 189.00\u0026ndash;729.00) and the non-ATDILI group (21.53 U/L; IQR: 12.00\u0026ndash;28.00).\u003c/p\u003e\n\u003cp\u003eBody mass index (BMI) distributions also differed. Underweight status was more prevalent among participants without ATDILI (34.06%, n=94), whereas overweight individuals were more frequently observed in the standard (38.46%, n=5) and extreme (34.09%, n=15) ATDILI groups. Correspondingly, the mean BMI was slightly higher in the ATDILI groups, 22.98 kg/m\u0026sup2; in standard and 23.02 kg/m\u0026sup2; in extreme compared to 22.60 kg/m\u0026sup2; in the non-ATDILI group. In terms of gender distribution, the standard ATDILI group had a greater proportion of female participants (61.54%, n=8) than the non-ATDILI group (19.22%, n=64), while the extreme ATDILI group had a more balanced gender composition (52.27%, n=23). Unemployment was common across all groups (ranging from 63.64% to 66.37%), potentially reflecting the impact of socioeconomic or health-related factors, especially among those with severe liver injury.\u003c/p\u003e\n\u003cp\u003eAlthough the overall prevalence of diabetes was low (1.80%), it was considerably higher in the extreme ATDILI group (9.09%), suggesting a possible link between diabetes and increased susceptibility to severe hepatotoxicity. A similar trend was observed with hypertension, which was more common in the standard (23.08%) and extreme (13.64%) ATDILI groups compared to the non-ATDILI group (5.07%). HIV infection was a major comorbidity, affecting 59.16% of the entire cohort. The proportion of HIV-positive individuals increased with ATDILI severity\u0026mdash;56.52% in non-ATDILI, 69.23% in standard ATDILI, and 84.09% in extreme ATDILI\u0026mdash;highlighting a potential correlation. Smoking (current and former use) was also prevalent (71.47% overall), with current smoking particularly common in the standard ATDILI group (53.85%) compared to the non-ATDILI group (42.75%). Alcohol use was widespread (67.57%) but showed a declining trend with increasing ATDILI severity: 80.80% among non-ATDILI participants, 69.23% in the standard ATDILI group, and 52.27% in the extreme ATDILI group.\u003c/p\u003e\n\u003cp\u003eClinical symptoms were more pronounced in patients with extreme ATDILI. Jaundice was observed in 36.36% (n=16) of patients in this group (N=44), compared to 7.69% (n=1, N=13) in the standard ATDILI group and 7.61% (n=21, N=276) in the non-ATDILI group. Similarly, abdominal pain and dark urine were most frequent in the extreme ATDILI group (43.18% and 52.27%, respectively), followed by the standard (30.77% for both symptoms) and non-ATDILI groups (31.16% and 21.01%, respectively).\u003c/p\u003e\n\u003cp\u003eAll patients diagnosed with tuberculosis (TB) were treated with standard combination chemotherapy, consisting of an intensive two-month phase with four first-line anti-TB drugs: isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB) followed by a four-month continuation phase with INH and RIF. Patients who were not responsive to first-line therapy were initiated on second-line regimens, including bedaquiline, pretomanid, and linezolid. Moreover, all TB patients who developed anti tuberculosis drug-induced liver injury (ATDILI) had documented adherence to their prescribed anti-TB treatment regimens throughout therapy. Similarly, all HIV-positive patients were initiated on the standard fixed-dose combination therapy comprising Tenofovir disoproxil fumarate (TDF), Lamivudine (3TC), and Dolutegravir (DTG) (TLD regimen), in line with international treatment guidelines.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3 summarizes the univariate and multivariate logistic regression analyses of factors associated with anti-tuberculosis drug-induced liver injury (ATDILI). In the univariate analysis, female gender (reference: male) was significantly associated with an increased risk of ATDILI (HR = 3.29, SE = 1.19, p = 0.001, 95% CI: 1.62\u0026ndash;6.67). Similarly, individuals living with HIV (reference: HIV-negative) had more than a threefold higher risk of developing ATDILI (HR = 3.19, SE = 1.30, p = 0.004, 95% CI: 1.43\u0026ndash;7.07). An incremental increase in BMI (reference: normal weight) was also associated with elevated ATDILI risk (HR = 1.08 per unit, SE = 0.04, p = 0.036, 95% CI: 1.01\u0026ndash;1.16). Hypertension (reference: no hypertension) showed a borderline association (HR = 1.53, SE = 1.06, p = 0.047, 95% CI: 0.40\u0026ndash;5.93), indicating a potential role in risk stratification. Current or former smokers (reference: non-smokers) and alcohol consumption (reference: non-drinkers) were both associated with ATDILI risk. Smoking had a hazard ratio of 2.30 (SE = 0.14, p = 0.010, 95% CI: 0.12\u0026ndash;0.75), while alcohol had hazard ratio of 1.35 (SE = 0.12, p = 0.003, 95% CI: 0.17\u0026ndash;0.70). \u0026nbsp;In the multivariate model, only gender remained a significant independent predictor, with females having a markedly higher risk of ATDILI (HR = 11.21, SE = 13.27, p = 0.041, 95% CI: 1.10\u0026ndash;114.06), underscoring the need for targeted clinical surveillance in this subgroup. While these findings may suggest potential risk or confounding effects, they underscore the complexity of ATDILI pathogenesis and the need for further investigation to elucidate underlying mechanisms.\u003c/p\u003e\n\u003cp\u003eFigure 2 presents the distribution of natural log-transformed alanine aminotransferase (ln[ALT]) levels stratified by age, gender, smoking status, and alcohol use among participants with and without anti-tuberculosis drug-induced liver injury (ATDILI). Figure 2. (a) illustrates the relationship between age and ln(ALT) levels. Among individuals who developed ATDILI, those aged below 36 years exhibited the highest ALT levels, followed by participants in the 36\u0026ndash;65 years group. The oldest age group (\u0026ge;65 years) showed the lowest ALT elevation among those with DILI. In contrast, among participants without ATDILI, ALT levels remained uniformly low across all age categories, with minimal variability. In figure 2. (b), ALT levels are compared between male and female participants. Both sexes showed elevated enzyme levels in the DILI group, with slightly higher median values in females. However, in the non-DILI group, ALT levels were significantly lower and showed little difference between males and females, suggesting that gender-related differences in ALT elevation are more pronounced in the context of liver injury.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFigure 2. (c) explores the effect of smoking on ALT levels. Current and former smokers with ATDILI exhibited higher ALT concentrations compared to never-smokers. Among participants without ATDILI, the differences were negligible, as ALT levels remained consistently low regardless of smoking history. This pattern may indicate a possible interaction between smoking and liver injury susceptibility. Figure 2. (d) evaluates ALT levels in relation to alcohol use. Both current drinkers and non-drinkers who developed ATDILI had similarly elevated ALT values, indicating that alcohol use alone may not fully account for enzyme elevation in this group. However, in the non-DILI group, ALT values were notably lower in both alcohol users and non-users, highlighting a clear distinction between individuals with and without liver injury irrespective of alcohol intake.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe reported incidence of ATDILI varies significantly across different ethnicities, ranging from approximately 1\u0026ndash;36%. In the United States of America (USA), it is 3%, in the United Kingdom (UK) 4%, in Germany 11%, in Argentina 9.9%, in Hong Kong 13%, in Japan 36%, in Taiwan 26%, and in India between 8% and 36%(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The incidence of ATDILI in our study was 2.1%, which is close to the values reported across in the USA and UK. The variation in the incidence of ATDILI worldwide may be attributed to the differences in patients\u0026rsquo; characteristics, indiscriminate use of drugs and the definition criteria of drug induced liver injury (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In our study we defined anti-tuberculosis drug-induced liver injury (ATDILI) according to the criteria established by the Drug Induced Liver Injury Network (DILIN),(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) which classifies ATDILI cases as ALT\u0026thinsp;\u0026gt;\u0026thinsp;120 IU/L or ALT\u0026thinsp;\u0026gt;\u0026thinsp;3 \u0026times; upper limit of normal (ULN) with symptoms like vomiting, nausea, abdominal pain. A study in France reported an annual ATDILI incidence rate of 13.9 (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), while a two-year study in Iceland found an incidence of 19.1(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) and a similar study in Delaware, US, reported 2.7 cases per 100,000 (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). In this study a higher cut off for alanine aminotransferase (ALT) values (\u0026gt;\u0026thinsp;5 \u0026times; upper limit of normal (ULN) was used for case definition than in the French (\u0026gt;\u0026thinsp;2 \u0026times; ULN) and Icelandic (\u0026gt;\u0026thinsp;3 \u0026times; ULN) studies, and could account at least in part for the lower incidence of ATDILI. Our adherence to the DILIN(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) definition is therefore an important contribution towards a well-defined case-control cohort that can be used to investigate the clinical and molecular genetic risk factors for ATDILI.\u003c/p\u003e \u003cp\u003eThe clinical presentation of anti-tuberculosis drug-induced liver injury is varied and non-specific, ranging from asymptomatic liver dysfunction to severe acute hepatitis or even acute liver failure. The mechanism of ATDILI primarily involves hypersensitivity reactions, which can present with symptoms such as dark urine, jaundice, fever, fatigue, and abdominal pain. In our study, the most common clinical manifestations were dark urine, jaundice and abdominal pain similar results were observed in a study carried out by Cavaco \u003cem\u003eet al\u003c/em\u003e(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) and Lei \u003cem\u003eet al\u003c/em\u003e (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Although some patients presented with clinical symptoms about 65% of patients presented with asymptomatic transaminase elevation with standard anti-TB drug therapy. ATDILI can sometimes be fatal if not diagnosed and managed promptly (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Therefore, it is advisable to routinely monitor liver function in patients receiving anti-TB drugs.\u003c/p\u003e \u003cp\u003eIn our study, the average time from the initiation of anti-TB treatment to the development of ATDILI was approximately 30 days. This was similar to previous reports of 24\u0026ndash;30 days reported by (\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). According to the literature, several factors influence the severity of ATDILI, including advanced age, gender, smoking, alcohol consumption, HIV/AIDS, and body mass index (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). We found significant association between gender of patients and ATDILI. It has been reported that women are at increased risk of developing hepatotoxicity when receiving anti-tuberculosis treatment (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study, the proportion of women with ATDILI was higher than that of men, suggesting that women receiving anti-tuberculosis drugs may be more prone to liver damage or even liver failure. Kumar \u003cem\u003eet al\u003c/em\u003e.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) conducted a study in India, reporting that approximately 70% of anti-TB drug-associated liver failure cases occurred in female patients. In contrast, among hospitalized patients with extreme ATDILI, the proportion of females 23 (52.27%) was slightly higher than that of males. Moreover, in the standard ATDILI group, females were also more prevalent accounting for 61.54% of cases, while males comprised only 38.46%. We found no significant difference in age of patients and risk for ATDILI. There are few studies that have reported an association between age and ATDILI (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e), although some studies have reported an association between advanced age and ATDILI (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHypertension, alcohol consumption, and smoking were also identified as risk factors for anti-tuberculosis drug-induced liver injury (ATDILI). Overall, the findings suggest that female sex, higher body mass index (BMI), HIV infection, hypertension, smoking, and alcohol use may contribute to elevated liver enzyme levels and should be considered potential risk factors for ATDILI. All HIV-positive individuals in the cohort were initiated on the standard fixed-dose combination therapy of Tenofovir disoproxil fumarate (TDF), Lamivudine (3TC), and Dolutegravir (DTG) commonly referred to as the TLD regimen in accordance with international treatment guidelines (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Given that TLD is typically well tolerated and associated with a low incidence of hepatotoxicity, it is likely that the observed risk of ATDILI in this cohort was primarily driven by the anti-TB drug regimens rather than the TLD therapy. Additionally, we consistently observed that all patients adhered well to their anti-TB therapy, which could have contributed to an increased risk of ATDILI due to higher cumulative drug exposure.\u003c/p\u003e \u003cp\u003eAlthough our study found no significant association between the presence of diabetes and the occurrence of anti-tuberculosis drug-induced liver injury (ATDILI), findings from other studies have been inconsistent. For instance, other studies have reported a significantly higher incidence of ATDILI among patients with hypertension and diabetes compared to those without these comorbidities (\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). In contrast, several other studies have similarly reported no significant association between these comorbid conditions and ATDILI risk (\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). These conflicting findings underscore the need for further well-designed studies to clarify the role of hypertension and diabetes in the development of ATDILI.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis mixed retrospective and prospective study found an incidence of ATDILI at 2.1%. The study indicated a higher incidence of ATDILI in female patients. Identified risk factors associated with ATDILI included female gender, HIV status, BMI, hypertension, smoking, and alcohol use. The risk of developing ATDILI appears to be higher in females within our study population, indicating the need for closer monitoring of gender in high-risk patients to reduce the incidence of ATDILI.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u0026middot;\u0026nbsp;Adjunctive Aspirin and Ibuprofen for Tuberculosis \u0026ndash; SMA TB\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Alanine transaminase \u0026ndash; ALT\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;ALT \u0026ndash; Alanine aminotransferase\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Anti-tuberculosis drug induced liver injury \u0026ndash; ATDILI\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Bedaquiline, Pretomanid and Linezolid \u0026ndash; BPAL\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Body Mass Index \u0026ndash; BMI\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Confidence Interval \u0026ndash; CI\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Dolutegravir \u0026ndash; DTG\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Drug Induced Liver Injury Network \u0026ndash; DILIN\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;DTG \u0026ndash; Dolutegravir\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Ethambutol \u0026ndash; EMB\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Hazard Ratio \u0026ndash; HR\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Hepatitis B virus \u0026ndash; HBV\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Hepatitis C virus \u0026ndash; HCV\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;HIV \u0026ndash; Human Immunodeficiency Virus\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;India-South Africa collaboration on pharmacokinetics in drug resistant TB patients \u0026ndash; ISA DRPK\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Interquartile Range \u0026ndash; IQR\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Isoniazid \u0026ndash; INH\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Lamivudine \u0026ndash; 3TC\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Natural log-transformed ALT \u0026ndash; ln[ALT]\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Pharmacogenomics of drug induced liver injury \u0026ndash; PGx@DILI\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Pyrazinamide \u0026ndash; PZA\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Rifampicin \u0026ndash; RIF\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Standard Error \u0026ndash; SE\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Statin Adjunctive Therapy for TB \u0026ndash; STAT-TB\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;Tenofovir disoproxil fumarate \u0026ndash; TDF\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;TDF \u0026ndash; Tenofovir disoproxil fumarate\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;United Kingdom \u0026ndash; UK\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;United States of America \u0026ndash; USA\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;University of Witwatersrand Human Research Ethics Commission \u0026ndash; Wits HRE\u003c/p\u003e\n\u003cp\u003e\u0026middot; World Health Organization \u0026ndash; WHO\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received ethical approval from the Human Research Ethics Committee of the University of the Witwatersrand (Wits HREC: M240904). All study procedures were conducted in accordance with the Declaration of Helsinki and adhered to applicable national regulations and ethical guidelines governing research in South Africa. Written informed consent was obtained from all participants prior to their enrolment in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants provided written informed consent for the publication of findings derived from this study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearch reported in this publication was supported by the South African Medical Research Council (SAMRC) with funds received from Novartis and GSK R\u0026amp;D for Project Africa GRADIENT Grant number SAMRC-RFA-GSK/NVS 01-2021. The study was also supported by the GATES Foundation INV-036801 Calestous Juma Fellowship to Collen Masimirembwa.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCollen Masimirembwa, Neil Martinson, Ananyo Choudhury, Roslyn Thelingwani, Tom Boyles, and Vincent Nyangwara were involved in the conceptualization of the study.Vincent Nyangwara, Ziyaad Waja, Collen Masimirembwa, and Neil Martinson contributed to the methodology.Formal analysis was conducted by Vincent Nyangwara, Ziyaad Waja, Raadhiya Osman, Ziska Pretorius, Keitumetse Majoro, and Bekiwe Ncwana.Vincent Nyangwara and Ziyaad Waja prepared the original draft of the manuscript.Writing – review and editing were performed by Vincent Nyangwara, Ziyaad Waja, Collen Masimirembwa, and Neil Martinson. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThank you to patients who agreed to be part of this study. Enormous gratitude to Mr. Blessing Sitabule and Jocelyn Gayenga for their assistance during the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eJohnston JC, Cooper R, Menzies D. Chapter 5: Treatment of tuberculosis disease. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. 2022;6(S1):66\u0026ndash;76. \u003c/li\u003e\n\u003cli\u003eChakaya J, Petersen E, Nantanda R, Mungai BN, Migliori GB, Amanullah F, et al. The WHO Global Tuberculosis 2021 Report \u0026ndash; not so good news and turning the tide back to End TB. International Journal of Infectious Diseases. 2022 Nov 1;124:S26\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003ePr\u0026scaron;o K, Židekov\u0026aacute; N, Porvazn\u0026iacute;k I, Solovič I, Mokr\u0026yacute; J, Kertys M. A high-throughput LC\u0026ndash;MS/MS method for simultaneous determination of isoniazid, ethambutol and pyrazinamide in human plasma. Rapid Communications in Mass Spectrometry. 2023 Jan 30;37(2). \u003c/li\u003e\n\u003cli\u003eConradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, et al. Bedaquiline\u0026ndash;Pretomanid\u0026ndash;Linezolid Regimens for Drug-Resistant Tuberculosis. New England Journal of Medicine. 2022 Sep 1;387(9):810\u0026ndash;23. \u003c/li\u003e\n\u003cli\u003eDevarbhavi H, Aithal G, Treeprasertsuk S, Takikawa H, Mao Y, Shasthry SM, et al. Drug-induced liver injury: Asia Pacific Association of Study of Liver consensus guidelines. Hepatol Int. 2021 Apr 1;15(2):258\u0026ndash;82. \u003c/li\u003e\n\u003cli\u003eMoosa MS, Maartens G, Gunter H, Allie S, Chughlay MF, Setshedi M, et al. Rechallenge after anti-tuberculosis drug-induced liver injury in a high HIV prevalence cohort. South Afr J HIV Med. 2022;23(1). \u003c/li\u003e\n\u003cli\u003eZhao H, Wang Y, Zhang T, Wang Q, Xie W. Drug-induced liver injury from anti-tuberculosis treatment: A retrospective cohort study. Medical Science Monitor. 2020 Mar 7;26. \u003c/li\u003e\n\u003cli\u003eXu N, Yang JX, Yang J. Incidence and associated risk factors of antituberculosis drug-induced hepatotoxicity among hospitalised patients in Wuhan, China. European Journal of Hospital Pharmacy. 2022 Jul 1;29(4):217\u0026ndash;21. \u003c/li\u003e\n\u003cli\u003eNicoletti P, Devarbhavi H, Goel A, Venkatesan R, Eapen CE, Grove JI, et al. Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens. Clin Pharmacol Ther. 2021 Apr 1;109(4):1125\u0026ndash;35. \u003c/li\u003e\n\u003cli\u003eMolla Y, Wubetu M, Dessie B. Anti-Tuberculosis Drug Induced Hepatotoxicity and Associated Factors among Tuberculosis Patients at Selected Hospitals, Ethiopia. Hepat Med. 2021 Jan;Volume 13:1\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eAbera W, Cheneke W, Abebe G. Incidence of antituberculosis-drug-induced hepatotoxicity and associated risk factors among tuberculosis patients in Dawro Zone, South Ethiopia: A cohort study. Int J Mycobacteriol. 2016 Mar 1;5(1):14\u0026ndash;20. \u003c/li\u003e\n\u003cli\u003eDhamnetiya D, Patel P, Jha RP, Shri N, Singh M, Bhattacharyya K. Trends in incidence and mortality of tuberculosis in India over past three decades: a joinpoint and age\u0026ndash;period\u0026ndash;cohort analysis. BMC Pulm Med. 2021 Dec 1;21(1). \u003c/li\u003e\n\u003cli\u003eAli N, Gupta N, Saravu K. Malnutrition as an important risk factor for drug-induced liver injury in patients on anti-tubercular therapy: an experience from a tertiary care center in South India. Drug Discov Ther. 2020 Jun 30;14(3):135\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eWei Q, Li L, Zeng X, Yin J, Guo J. An analysis on the clinical features and risk factors associated with the prognosis of patients with drug-induced liver injury. Exploration of Digestive Diseases. 2023 Jun 30;100\u0026ndash;17. \u003c/li\u003e\n\u003cli\u003eSu Q, Liu Q, Liu J, Fu L, Liu T, Liang J, et al. Study on the associations between liver damage and antituberculosis drug rifampicin and relative metabolic enzyme gene polymorphisms. Bioengineered. 2021;12(2):11700\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eCostiniuk CT, Gosnell BI, Manzini TC, Du Plessis CN, Moosa MYS. Tuberculous drug-induced liver injury and treatment re-challenge in Human Immunodeficiency Virus co-infection. J Glob Infect Dis. 2015 Oct 1;7(4):151\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eMehta R, Ive P, Evans D, Menezes CN. Treatment outcomes among patients admitted to hospital with antiretroviral and/or antituberculosis drug-induced liver injury. Vol. 111, South African Medical Journal. South African Medical Association; 2021. p. 474\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eKengo A, Nabeemeeah F, Denti P, Sabet R, Okyere-Manu G, Abraham P, et al. Assessing potential drug-drug interactions between clofazimine and other frequently used agents to treat drug-resistant tuberculosis. Antimicrob Agents Chemother. 2024 May 1;68(5). \u003c/li\u003e\n\u003cli\u003eArias L, Otwombe K, Waja Z, Tukvadze N, Korinteli T, Moloantoa T, et al. SMA-TB: study protocol for the phase 2b randomized double-blind, placebo-controlled trial to estimate the potential efficacy and safety of two repurposed drugs, acetylsalicylic acid and ibuprofen, for use as adjunct therapy added to, and compared with, the standard WHO recommended TB regimen. Trials. 2023 Dec 1;24(1). \u003c/li\u003e\n\u003cli\u003eKolahdoozan S, Mirminachi B, Sepanlou SG, Malekzadeh R, Merat S, Poustchi H. Upper normal limits of serum alanine aminotransferase in healthy population: A systematic review. Vol. 12, Middle East Journal of Digestive Diseases. Shiraz University of Medical Sciences; 2020. p. 194\u0026ndash;205. \u003c/li\u003e\n\u003cli\u003eSgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al. Incidence of drug-induced hepatic injuries: A French population-based study. Hepatology. 2002;36(2):451\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eBj\u0026ouml;rnsson ES, Bergmann OM, Bj\u0026ouml;rnsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of iceland. Gastroenterology. 2013;144(7). \u003c/li\u003e\n\u003cli\u003eVega M, Verma M, Beswick D, Bey S, Hossack J, Merriman N, et al. The Incidence of Drug- and Herbal and Dietary Supplement-Induced Liver Injury: Preliminary Findings from Gastroenterologist-Based Surveillance in the Population of the State of Delaware. Drug Saf. 2017 Sep 1;40(9):783\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eCavaco MJ, Alcobia C, Oliveiros B, Mesquita LA, Carvalho A, Matos F, et al. Clinical and Genetic Risk Factors for Drug‐Induced Liver Injury Associated with Anti‐Tuberculosis Treatment\u0026mdash;A Study from Patients of Portuguese Health Centers. J Pers Med. 2022 May 1;12(5). \u003c/li\u003e\n\u003cli\u003eLei S, Gu R, Ma X. Clinical perspectives of isoniazid-induced liver injury. Vol. 5, Liver Research. KeAi Communications Co.; 2021. p. 45\u0026ndash;52. \u003c/li\u003e\n\u003cli\u003eZhong T, Fan Y, Dong XL, Guo X, Wong KH, Wong WT, et al. An Investigation of the Risk Factors Associated With Anti-Tuberculosis Drug-Induced Liver Injury or Abnormal Liver Functioning in 757 Patients With Pulmonary Tuberculosis. Front Pharmacol. 2021 Nov 8;12. \u003c/li\u003e\n\u003cli\u003eKumar R, Shalimar, Bhatia V, Khanal S, Sreenivas V, Gupta SD, et al. Antituberculosis therapy-induced acute liver failure: Magnitude, profile, prognosis, and predictors of outcome. Hepatology. 2010 May;51(5):1665\u0026ndash;74. \u003c/li\u003e\n\u003cli\u003eZhao H, Wang Y, Zhang T, Wang Q, Xie W. Drug-induced liver injury from anti-tuberculosis treatment: A retrospective cohort study. Medical Science Monitor. 2020 Mar 7;26. \u003c/li\u003e\n\u003cli\u003eTweed CD, Wills GH, Crook AM, Dawson R, Diacon AH, Louw CE, et al. Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study. BMC Med. 2018 Mar 28;16(1). \u003c/li\u003e\n\u003cli\u003eSoremekun C, Machipisa T, Soremekun O, Pirie F, Oyekanmi N, Motala AA, et al. Multivariate GWAS analysis reveals loci associated with liver functions in continental African populations. PLoS One. 2023 Feb 1;18(2 February). \u003c/li\u003e\n\u003cli\u003eWang N, Chen X, Hao Z, Guo J, Wang X, Zhu X, et al. Incidence and Temporal Trend of Antituberculosis Drug-Induced Liver Injury: A Systematic Review and Meta-Analysis. Vol. 2022, Journal of Tropical Medicine. Hindawi Limited; 2022. \u003c/li\u003e\n\u003cli\u003eJiang F, Yan H, Liang L, Du J, Jin S, Yang S, et al. Incidence and risk factors of anti-tuberculosis drug induced liver injury (DILI): Large cohort study involving 4652 Chinese adult tuberculosis patients. Liver International. 2021 Jul 1;41(7):1565\u0026ndash;75. \u003c/li\u003e\n\u003cli\u003eEnoh JE, Cho FN, Manfo FP, Ako SE, Akum EA. Abnormal Levels of Liver Enzymes and Hepatotoxicity in HIV-Positive, TB, and HIV/TB-Coinfected Patients on Treatment in Fako Division, Southwest Region of Cameroon. Biomed Res Int. 2020;2020. \u003c/li\u003e\n\u003cli\u003eZhang M, Wang S, Wilffert B, Tong R, van Soolingen D, van den Hof S, et al. The association between the NAT2 genetic polymorphisms and risk of DILI during anti-TB treatment: a systematic review and meta-analysis. Vol. 84, British Journal of Clinical Pharmacology. Blackwell Publishing Ltd; 2018. p. 2747\u0026ndash;60. \u003c/li\u003e\n\u003cli\u003eLi X, Tang J, Mao Y. Incidence and risk factors of drug-induced liver injury. Vol. 42, Liver International. John Wiley and Sons Inc; 2022. p. 1999\u0026ndash;2014. \u003c/li\u003e\n\u003cli\u003eAbdalhabib EK, Alzahrani B, Alanazi F, Algarni A, Ibrahim IK, Mohamed HA, et al. Increased Risk of Acute Lymphoblastic Leukemia in Adult Patients with GSTM1 Null Genetic Polymorphism. Pharmgenomics Pers Med. 2022;15:227\u0026ndash;34. \u003c/li\u003e\n\u003cli\u003eYu Z, Zhao Y, Jin J, Zhu J, Yu L, Han G. Prevalence and risk factors of tigecycline-induced liver injury: A multicenter retrospective study. International Journal of Infectious Diseases. 2022 Jul 1;120:59\u0026ndash;64. \u003c/li\u003e\n\u003cli\u003eFreire ID, Fielding KL, Moore DAJ. Does diabetes mellitus comorbidity increase the risk of drug-induced liver injury during tuberculosis treatment? PLoS One. 2023 May 1;18(5 May). \u003c/li\u003e\n\u003cli\u003eNicoletti P, Devarbhavi H, Goel A, Venkatesan R, Eapen CE, Grove JI, et al. Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens. Clin Pharmacol Ther. 2021 Apr 1;109(4):1125\u0026ndash;35. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Tuberculosis, anti-tuberculosis regimens, risk factors and drug induced liver injury","lastPublishedDoi":"10.21203/rs.3.rs-6596752/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6596752/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTuberculosis (TB) is a global health challenge. Use of anti-TB drugs to treat TB is associated with high prevalence of side effects and unpredictable clinical hepatotoxicity that include anti-TB drug induced liver injury (ATDILI). The aim of this study was to determine the incidence and associated clinical risk factors of ATDILI among South African patients with TB infections.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis was an exploratory, mixed prospective and retrospective case control study of patients with TB infections receiving drug sensitive and drug resistant treatment regimens. The retrospective and prospective studies were done from January 2021 to June 2024, involving a total of 616 patients with TB infections from whom 13 had ATDILI. From the retrospective and prospective cohorts, we extracted 13 ATDILI cases and 276 controls. Additionally, 44 extreme ATDILI cases were directly recruited from the hospital to enrich the number of cases in the study. All participants provided informed consent and had available DNA samples for genetic analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the studied cohorts, the incidence of ATDILI was 2.1% (13/616). The ATDILI cases and controls consisted of 215 (64.56%) male patients; 57 patients were diagnosed with hepatotoxicity, 44 from the hospitalized cohort,12 from the retrospective cohort and 1 patient from the prospective cohort. The median time from the initiation of treatment to the onset of hepatotoxicity was approximately 30 days. Univariate logistic regression revealed significant differences (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in gender (p\u0026thinsp;=\u0026thinsp;0.001), HIV status (p\u0026thinsp;=\u0026thinsp;0.004), BMI (p\u0026thinsp;=\u0026thinsp;0.036), Hypertension (p\u0026thinsp;=\u0026thinsp;0.047) smoking (p\u0026thinsp;=\u0026thinsp;0.010), and alcohol consumption (p\u0026thinsp;=\u0026thinsp;0.003) in relation to ATDILI. Multivariate analysis further demonstrated that female gender (p\u0026thinsp;=\u0026thinsp;0.041) had a cumulative risk factor for ATDILI.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe incidence of ATDILI of 2.1% is on the lower end of the reported literature values of 5\u0026ndash;35% indicative of potentially less rigorous ATDILI phenotype assignment in previous studies reporting much higher values. Female gender, HIV status, BMI, Hypertension, smoking, and alcohol consumption were identified as risk factors associated with ATDILI. Among these, the cumulative effect of gender significantly increased the risk of developing ATDILI. The DNA from the case and control samples is undergoing further genomic analysis in search of potential genetic biomarkers for ATDILI.\u003c/p\u003e","manuscriptTitle":"Incidence and associated risk factors of antituberculosis drug induced hepatotoxicity among TB patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-15 10:48:39","doi":"10.21203/rs.3.rs-6596752/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-02T11:58:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-28T08:33:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-25T22:33:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-25T14:20:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-24T10:00:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"255189649668558082863836039088492447537","date":"2025-05-19T06:51:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-18T09:34:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"289975917790687480159747101269663197227","date":"2025-05-18T06:56:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-16T04:00:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"54732542838853196710808256490067027084","date":"2025-05-15T12:51:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"269140807580029900729758364057748780132","date":"2025-05-15T07:04:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"23639539675050672075129513208672968436","date":"2025-05-15T05:51:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"311996635770671233279701779974786004755","date":"2025-05-14T08:26:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223024630097335774120359295872514793482","date":"2025-05-13T12:29:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-13T05:36:54+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-05-12T05:03:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-08T05:37:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-08T05:36:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-05-05T18:24:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"21c91fff-7408-4e0d-a24a-ebd873e35fef","owner":[],"postedDate":"May 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-27T16:30:40+00:00","versionOfRecord":{"articleIdentity":"rs-6596752","link":"https://doi.org/10.1186/s12879-025-11796-4","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2025-10-24 16:16:37","publishedOnDateReadable":"October 24th, 2025"},"versionCreatedAt":"2025-05-15 10:48:39","video":"","vorDoi":"10.1186/s12879-025-11796-4","vorDoiUrl":"https://doi.org/10.1186/s12879-025-11796-4","workflowStages":[]},"version":"v1","identity":"rs-6596752","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6596752","identity":"rs-6596752","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}