Risk of drug-induced liver injury in chronic hepatitis C and tuberculosis co– infection: a systematic review and meta– analysis

Antituberculosis drug-induced liver injury (ATLI) is a common and serious adverse drug reaction associated with tuberculosis treatment. The impact of ATLI in patients with chronic hepatitis C remains unclear.

This study aimed to evaluate the prevalence of drug-induced liver injury (DILI) in patients with and without hepatitis C virus (HCV) and assess its impact on the prevalence of ATLI. The preferred reporting items for systematic reviews and meta-analyses standards were followed, and the protocol was registered in PROSPERO.

PubMed, Web of Sciences, EMBASE, and the Cochrane Library were searched from inception to May 21, 2024. A systematic review and meta-analysis of relevant studies were performed to compare the prevalence of anti-tuberculosis drug-induced liver injury in patients with and without chronic hepatitis C.

Thirteen studies, including a total of 3,174 patients, met the inclusion criteria. Of these, 727 patients had HCV-TB co-infection, while 2,447 presented with active TB infection without HCV.

The overall prevalence of DILI in patients with HCV-TB was 15.54%, compared to 8.54% in patients without HCV (OR = 3.50, 95% CI 2.48–4.94, I2= 20%), which indicated a significantly higher prevalence of DILI in those with HCV infection.

The meta-analysis showed that TB patients with hepatitis C virus (HCV) infection had a higher risk of mild DILI compared to those without HCV infection (Relative Risk [RR] = 3.13, 95% CI 1.77–5.52, I²=0%). Additionally, TB patients with HCV infection were at a greater risk of moderate DILI (RR = 3.71, 95% CI 1.58–8.75, I²=33%), and they also had a higher risk of severe DILI (RR = 2.33, 95% CI 0.82–6.61, I²=31%).

Subgroup analysis revealed that TB patients with HCV infection had a higher risk of anti-tuberculosis drug-induced liver injury (ATDILI) than those without HCV, using both a strict definition of DILI (alanine aminotransferase [ALT] > 5 times the upper limit of normal [ULN], Odds Ratio [OR] = 4.13, 95% CI: 2.76–6.17, I²=0%) and a loose definition of DILI (ALT > 3 ULN, OR = 3.16, 95% CI: 1.41–7.05, I²=58%). This was observed in patients receiving standard four-drug combination anti-TB therapy (OR = 3.38, 95% CI: 2.01–5.69, I²=47%) and three-drug combination anti-TB therapy (OR = 3.01, 95% CI: 1.50–6.05, I²=0%).

The definition of HCV infection was associated with the risk of DILI. When HCV infection was defined by a positive hepatitis C antibody, the OR was 3.35 (95% CI: 2.23–5.03, I²=30%). When HCV infection was defined by a positive HCV RNA, the OR increased to 4.59 (95% CI: 2.17–9.69, I²=0%). Furthermore, the risk was examined in retrospective studies (OR 3.31, 95% CI: 2.10–5.20, I²=36%) and in prospective studies (OR 4.39, 95% CI: 2.36–8.16, I²=0%).

This meta-analysis suggests that the prevalence of DILI in patients with HCV is higher than in those without HCV. Routine HCV screening before the initiation of TB therapy is critically important for the early identification of HCV-TB co-infection, enabling clinicians to modify TB and HCV treatment and management to mitigate the risks of DILI.

Close follow-up and regular liver test monitoring are indispensable for the treatment of TB in chronic hepatitis C carriers.

The study demonstrated the heightened risk of drug-induced liver injury (DILI) in HCV-TB co-infected patients compared to TB-only patients. The findings underscore the importance of routine HCV screening before initiating TB treatment to identify HCV-TB co-infection early.

These findings have significant implications for clinical practice, supporting the use of regular liver tests and close monitoring in resource-limited settings to effectively manage TB treatment in chronic hepatitis C patients. This can inform clinical practices to improve patient outcomes and reduce the burden of drug-induced liver injury in HCV-TB co-infected patients.

This study examined the risk of liver damage caused by tuberculosis (TB) medications in patients who also have chronic hepatitis C (HCV). Researchers analyzed data from 13 studies, including over 3,000 patients, to compare the risk of liver injury in TB patients with and without HCV.

The results showed that TB patients with HCV were more likely to experience liver damage from TB medications than those without HCV. Specifically, the risk of mild, moderate, and severe liver injury was significantly higher in HCV patients. The study also found that the risk varied depending on how HCV infection was defined and the type of TB treatment used.

These findings highlight the importance of screening for HCV before starting TB treatment, as early detection can help doctors adjust treatment plans and reduce the risk of liver damage. Regular monitoring of liver function is also crucial for TB patients with HCV.

Peer Review reports

Tuberculosis (TB) remains a major health problem in both developing and developed countries. The annual prevalence of active tuberculosis in the world is close to 8 million, and about 2 million people die each year. Anti-tuberculosis drugs such as isoniazid (INH), rifampicin (RFP), ethambutol (EMB), pyrazinamide (PZA) are effective drugs for the treatment of tuberculosis. Drug-induced liver injury (DILI) associated with anti-TB treatment is one of the most common adverse reactions of drugs, which results in a low treatment success rate.

Some studies have reported that ATDILI is associated with an increased risk of adverse outcomes in patients with chronic liver disease.

Patients with Chronic liver disease(CLD), raises a higher risk of hepatotoxicity during treatment for TB, up to three to five times more than TB patients who do not have viral infection. However, very limited data on rates of HCV co-infection among patients with TB exists.

Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is a common cause of chronic liver disease and a common cause of tuberculosis in high-risk groups. The guidelines of Chinese guideline for diagnosis and management of drug-induced liver injury (2023 version) suggest there is no sufficient evidence that concomitant underlying liver disease can increase the risk of all-cause DILI. The increased risk of hepatotoxicity of some drugs may be related to impaired liver function caused by specific drugs or underlying liver diseases, especially the latter.

At present, meta-analyses have been conducted on the risk of drug-induced liver injury in patients co-infected with chronic hepatitis B and tuberculosis; however, no direct meta-analysis has been performed specifically on the risk of drug-induced liver injury in patients co-infected with chronic hepatitis C and tuberculosis.

The aim of this meta-analysis is to evaluate whether underlying chronic hepatitis C virus and TB co-infection are associated with a higher risk of TB therapy-related DILI.

This study was registered in the Prospero database with the registration number CRD42024562315.

A literature search was performed in four electronic databases including PubMed, EMBASE, Web of Science and Cochrane Library for full-length English language articles from inception to 21 May 2024 using a combination of key words for “Anti-Tuberculosis Agent”, “drug-induced liver injury or or hepatotoxicity” and “Hepatitis C”. Furthermore, the reference lists of all the retrieved articles were manually searched for any bibliographies of retrieved publications in order to increase the yield of potentially relevant articles.

Both prospective and retrospective studies, including cohorts, observational and case–control study designs, were included. Reference lists of all selected articles were independently screened to identify additional studies left out in the initial search. Two investigators independently extracted data from the included studies and assessed their eligibility for this study. Differences in opinion were resolved by discussion until consensus were reached or by consulting a third author.

The Inclusion criteria were: (1) patients with anti-TB treatment; (2) providing information on the proportion of patients experiencing ATDILI and the proportion of patients with HCV co-infection; (3) Studies providing a clear definition of ATDILI, which must be based on specific liver biochemistry thresholds. Definitions accepted included an elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) to more than [2, 3, or 5] times the upper limit of normal (ULN), with or without an elevation in total bilirubin.

The definition of HCV infection includes both active HCV infection and past exposure to HCV: patients who have either cleared the virus or been cured, as well as those who are only antibody-positive, indicating a potential chronic infection with the hepatitis C virus (HCV). Active HCV infection is defined as patients who test positive for HCV RNA. Past HCV exposure is defined as the presence of positive anti-HCV antibodies.(5)published as a full length article.

Studies with abnormal liver function before anti-tuberculosis treatment were excluded, along with studies that did not include a clear definition of DILI, studies that evaluated TB patients with co-infections other than hepatitis C, and studies with incomplete data on the number of cases and controls.

The assessment process particularly emphasized ruling out other causes, especially the activity of underlying liver disease (HCV infection), to distinguish whether it was caused by the investigational drug or by the underlying HCV disease activity.

The following data were extracted: first author, year of publication, country where the study was conducted, study design, study period, TB therapy, definition of DILI, number of DILI in HCV-TB coinfection and number of patients with only HCV-TB Coinfection.The included studies employed varying diagnostic criteria for HCV infection: ten studies required only anti-HCV antibody positivity, while three studies mandated confirmation through HCV RNA detection.

Aggregate data regarding the risk of DILI in HCV-TB co-infected patients treated with TB therapies in contrast to TB patients without HCV were evaluated through meta-analysis, and A random effects model was adopted to analyze the cumulative risk of DILI in HCV-TB co-infection as opposed to TB infection without HCV infection, and subgroup analysis was carried out.

In the included studies, six assessed the severity grading of DILI, while twelve clearly defined HCV infection. Specific criteria are detailed in Tables1and2. This study referenced the FDA Drug-Induced Liver Injury Guidance [9] and WHO Standards for Tuberculosis Drug Management [10] to establish a unified severity grading standard: Mild DILI: ALT 2–5×ULN (or 120–200 IU/L), Moderate DILI: ALT 5–10×ULN (or 200–500 IU/L), Severe DILI: ALT >10×ULN (or >500 IU/L) or accompanied by hepatic decompensation (e.g., TBIL ≥ 2×ULN + INR ≥ 1.5 or hepatic encephalopathy or ascites).

Heterogeneity was assessed by between-study variance using I2>50% indicating significant heterogeneity [11]. Potential publication bias was assessed visually using a funnel plot and formally tested using Egger’s linear regression test for funnel plot asymmetry. p-value < 0.10 was considered indicative of significant asymmetry.

The extent of publication bias was evaluated by funnel plot. The assessment of risk of bias was performed using the Newcastle-Ottawa Quality Assessment Scale. Review Manager 5.3 software was used to analyze data. All statistical analyses were performed using Review Manager version 5.3.5.

In this meta-analysis, the selection of effect measures was based on study design characteristics: For the two included case-control studies, odds ratios (ORs) were used as the effect measure since incidence rates could not be calculated. In the analysis of DILI severity grading, RRs were uniformly employed to compare the absolute risk of different DILI severity grades between HCV-positive and HCV-negative patients, as the data were derived from cohort studies (prospective/retrospective) where incidence rates could be calculated. To ensure the robustness of results, sensitivity analyses (recalculating RRs after excluding case-control studies) were performed to verify the consistency of main conclusions.”

A total of 756 studies were identified on the initial search, from which 11 studies were included for the meta-analysis (Fig.1). In addition, two studies were manually searched for any bibliographies of the retrieved publications. The baseline characteristics of the included studies are presented in Table1.

Out of the 13 studies, ten were retrospective studies, while the remaining three were prospective studies. Seven of the included studies adopted the strict criteria of DILI as serum alanine aminotransferase (ALT) more than five times the upper limit of normal value(ULN), while the other five studies defined DILI as having ALT more than three times the upper limit of normal (ULN) with symptoms.

Some heterogeneity was present among the included studies. Eight of the included studies undergoing the standard treatment of four-drug combination therapy while two studies undergoing the treatment of INH, RIP, PZA of three-drug combination therapy treatment. Six of the included studies have defined the severity of drug-induced liver injury. Eleven of the included studies have defined hepatitis C infection as positive for hepatitis C antibody, while the other two of those have defined hepatitis C infection as positive for HCV RNA.

A total of 13 studies (including case-control and cohort designs) were analyzed to evaluate the association between HCV infection and the risk of anti-tuberculosis drug-induced liver injury (DILI) using odds ratios (ORs). Overall, 727 patients had HCV-TB co-infection and 2447 patients had active TB disease without HCV. The prevalence of DILI in TB patients with HCV infection was 15.54%(n= 113) and 8.54% (n= 209) in patients without HCV(OR = 3.50.95% CI 2.48–4.94,I2 = 20%), which revealed that the prevalence of DILI was significantly higher in those with HCV infection than those without HCV infection (Fig.2). The pooled analysis demonstrated that HCV infection was significantly associated with an increased risk of DILI.

To strengthen causal inference, two case-control studies were excluded and the remaining 11 cohort studies were re-analyzed using risk ratios (RRs). The results remained consistent: Pooled RR = 2.71 (95% CI: 2.08–3.54, I²= 23%)(Fig.3), confirming that HCV infection significantly increased DILI risk.

A sensitivity analysis, excluding two case-control studies, yielded a consistent and significant pooled effect (RR = 2.71, 95% CI 2.08–3.54). A minimal increase in statistical heterogeneity (I² = 23%) was observed compared to the main analysis (I² = 20%). This reflects the increased relative influence of clinical diversity among the remaining cohort studies, rather than a decrease in result consistency, as the heterogeneity remained low and non-significant in both analyses. Six studies were included in which the severity of DILI was graded.

After the reference method unified the severity grading criteria, six studies were selected for subgroup analysis.(Table2). Mild heterogeneity was observed among the studies (I2= 20%,p= 0.24). The funnel plot showed a roughly symmetrical distribution (Fig.4). Egger’s regression test did not suggest significant publication bias (p= 0.229).

In a subgroup analysis of the six studies that assessed DILI severity, the analysis demonstrated that TB patients with HCV co-infection had a significantly elevated risk of mild DILI (RR = 3.13, 95% CI: 1.77–5.52; I² = 0%) and moderate DILI (RR = 3.71, 95% CI: 1.58–8.75; I²= 33%) compared to their HCV-negative counterparts. Although a trend was observed, the increased risk of severe DILI in co-infected patients did not reach statistical significance (RR = 2.33, 95% CI: 0.82–6.61; I²= 31%) (Figs.5,6and7).

Moreover, subgroup analysis revealed that tuberculosis (TB) patients with hepatitis C virus (HCV)infection were at a higher risk of anti-tuberculosis drug-induced liver injury (ATDILI)compared to those without HCV infection. This was observed under both a strict definition of drug-induced liver injury (DILI)(serum alanine aminotransferase [ALT] greater than 5 times the upper limit of normal [ULN], OR = 2.59, 95% CI: 1.58–4.25, I2= 0) and a more lenient definition (ALT greater than 3 ULN, OR = 4.34, 95% CI: 2.96–6.37, I2= 58, Fig.8).

The increased risk was evident in patients receiving standard four-drug combination anti-TB therapy (OR = 3.38, 95% CI: 2.01–5.69, I2= 47) and three-drug combination therapy (OR = 3.01, 95% CI: 2.31–4.95, I2= 30, Fig.9). The definition of HCV infection was based on a positive hepatitis C antibody test (OR = 3.35, 95% CI: 2.23–5.03, I2= 30) and on the presence of positive HCV RNA (OR = 4.59, 95% CI: 2.17–9.69, I2= 0, Fig.10). The elevated risk was also consistent in both retrospective studies (OR = 3.31, 95% CI: 2.10–5.20, I2= 36) and prospective studies (OR = 4.39, 95% CI: 2.36–8.16, I2= 0, Fig.11).

Upon dividing the studies into subgroups based on the definition of hepatotoxicity, no significant heterogeneity was observed (I2= 0%). When focusing solely on studies that defined HCV using HCV-RNA, no significant heterogeneity was present (I²= 0%). Sub-analyses were conducted, dividing the studies into subgroups of prospective and retrospective studies. The results indicated no significant heterogeneity (I² = 0%) among the prospective studies.

According to the Newcastle-Ottawa Scale (NOS) criteria, studies with scores of 7–9 were defined as high-quality studies. Subsequently, the meta-analysis was re-conducted using only these high-quality studies (a total of 5 studies). The sensitivity analysis results showed: The pooled result including only high-quality studies “OR = 4.82, 95% CI: 2.95–7.87” was consistent with the preliminary analysis results (Fig.12).

Currently, there is no compelling evidence to indicate that underlying liver disease elevates the risk of all-cause DILI. Some drugs might have augmented liver toxicity risk within this population, which could be associated with specific drugs or liver dysfunction induced by underlying liver disease, particularly the latter. The association between DILI and adverse outcomes in patients with chronic liver disease has been reported by several studies.

During the course of anti-tuberculosis therapy, various types of adverse drug reactions may arise, among which anti-tuberculosis drug-induced liver injury (ATB-DILI) is the most prevalent and has the most significant potential for harm. The prevalence of ATB-DILI exhibits a distinct upward trend globally, with a rate ranging from 9.5% to 14.1% in China, rendering it one of the common causes of DILI in China and one of the most common drugs causing DILI in Asia.

PENG et al. have demonstrated that the liver toxicity induced by anti-tuberculosis drugs is a serious issue for patients undergoing anti-tuberculosis treatment. In mild cases of ATB-DILI, it can cause asymptomatic elevation of liver enzymes, while in severe cases, it can result in acute hepatitis and fulminant hepatic failure, even posing a threat to life. Consequently, some patients have no alternative but to suspend anti-tuberculosis treatment, thereby influencing the overall therapeutic outcome of tuberculosis.

Patients with chronic liver disease exhibit increased susceptibility to ATDILI. It has been reported that hepatitis virus infection or the coexistence of other acute or chronic liver diseases constitutes one of the risk factors for ATB-DILI. For patients with chronic hepatitis B virus (HBV)co-infection, if they meet the indications for antiviral therapy, they should receive antiviral therapy as soon as possible, followed by or shortly after anti-tuberculosis treatment; antiviral therapy is beneficial in reducing the risk of DILI in HBeAg-positive patients with high HBV viral load.

In recent years, the prevalence of pulmonary tuberculosis co-infection with HCV has been increasing. There is still controversy over the impact of HCV infection on the liver injury caused by (AT-DILI). The impact of CHC infection on ATDILI remains a subject of ongoing debate. Recent investigations have indicated that HCV infection is likewise a significant risk factor for DILI during anti-tuberculosis treatment.

In this systematic review and meta-analysis, the prevalence of drug-induced liver injury (DILI) in patients co-infected with hepatitis C virus (HCV) and tuberculosis (TB), who were undergoing TB therapies, was found to be 15.54% % in this systematic review and meta-analysis, which was higher than TB patients without underlying HCV infection.

Six of the studies which concerning data on different severities of drug-induced liver injury were selected to assess the risk of mild, moderate, and severe DILI in HCV-TB co-infected patients compared to those with active TB disease without HCV. The results showed that the risk of DILI of different severity in HCV-TB co-infected patients were all higher than those with active TB disease without HCV. The definitions of DILI varied among some of the studies and might have contributed to heterogeneity. The definition of DILI varies among different guidelines and remains controversial. In EASL, the Clinical Practice Guidelines [30]: Drug-induced Liver Injury and the Chinese Guidelines for the Diagnosis and Treatment of Drug-Induced Liver Injury (2023 Edition) [6] define drug-induced liver injury as ALT ≥ 5xULN, with ALT ≥ 3xULN accompanied by TBil >2xULN.

In contrast, the Chinese Guidelines for Diagnosis and Treatment of Drug-Induced Liver Injury Caused by Antituberculosis Drugs (2024 Edition) [17] define drug-induced liver injury as follows: liver biochemical tests must meet one of the following two threshold criteria: (1) ALT ≥ 3 x ULN and/or TBil ≥ 2 x ULN; (2) AST, ALP, and TBil all rise simultaneously, with at least one value ≥ 2 x ULN.

In this research, when defining DILI as ALT > 3xULN, the odds ratio (OR) was 3.16 (95% CI: 1.41–7.05,P= 0.005).When using a stricter threshold (ALT > 5ULN), the OR was 3.50 (95% CI: 2.48–4.94,P< 0.00001).No significant subgroup differences were observed (P= 0.56, I²= 0%), indicating robustness across definitions.

In this meta-analysis, eight studies implemented the standard four-drug anti-tuberculosis treatment regimen, whereas two studies used the RIF three-drug anti-tuberculosis treatment regimen. There was no evidence that AT-DILI risk differed significantly between 3-drug and 4-drug regimens (P= 0.91 for subgroup difference), though this comparison was underpowered and based on between-study rather than within-study contrasts.

HCV coinfection consistently increased risk across all subgroups. The results indicated that the odds ratio (OR) for the RIPE four-drug anti-tuberculosis treatment regimen was slightly higher than that for the RIF three-drug regimen. This difference may be attributed to the frequency of drug-induced liver injury (DILI) associated with first-line anti-tuberculosis drugs such as isoniazid, rifamycin derivatives, pyrazinamide, and a lower frequency in ethambutol. It is reasonable that the odds ratio (OR) of anti-TB medications, including Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol(RIPE), indicates a higher potential for causing liver damage than that of the RIF three-drug anti-tuberculosis treatment regimen.

Eleven studies in this meta-analysis examined only serum anti-HCV antibodies and two examined HCV RNA. This subgroup analysis showed that the OR of studies using serum anti-HCV antibody testing was lower than that using HCV RNA testing. This may be because serum anti-HCV antibody testing only indicates past or current exposure to HCV, whereas HCV RNA detection directly identifies the presence of replicating virus, indicating the replication of the hepatitis C virus within the body.

It serves as a crucial marker to determine the stage of hepatitis C virus infectionand the effectiveness of treatment. Mo et al. confirmed the role of HCV-RNA in predisposing Chinese patients to ATDILI and emphasized that HCV-RNA is a better indicator of ATDILI than anti-HCV in HCV carriers. The subgroup analysis revealed a reduction in heterogeneity in the prospective studies compared to the retrospective studies.

Specifically, the level of heterogeneity was significantly lower in the prospective studies. This suggests that prospective studies may provide more consistent and reliable results when assessing the association between HCV-RNA and ATDILI. It can be attributed to the design of prospective studies, which systematically collect data in a controlled manner following the initiation of the study. This approach enables researchers to maintain rigorous standards for data collection, thereby enhancing the precision of measured relationships. In contrast, retrospective studies may suffer from limitations in data accuracy and completeness, as well as challenges in controlling for recall bias.

Previous studies have primarily examined the susceptibility to anti-tuberculosis drug-induced liver injury (ATB-DILI) in patients with chronic hepatitis C infection. In contrast, this study is the first to investigate the risk of ATB-DILI in patients co-infected with chronic hepatitis C and tuberculosis. This analysis indicates that HCV infection is significantly associated with an increased risk of ATB-DILI.

However, because of the variations in the methodologies employed by the included studies to adjust for confounding factors, it is not yet feasible to ascertain the complete independence of this association. These results underscore the importance of screening for viral hepatitis prior to initiating anti-tuberculosis treatment and administering timely antiviral therapy when necessary.

The study further analyzed the different severity risks of DILI in patients with HCV and tuberculosis co-infection compared to those with tuberculosis alone who were receiving anti-tuberculosis treatment. This detailed comparison highlights the specific risk profiles associated with each group, allowing for a more nuanced understanding of DILI in patients with and without HCV, regarding its prevalence and severity.

The study also assessed the risk of drug-induced liver injury in individuals with chronic hepatitis C and tuberculosis co-infection through subgroup analysis, which was based on HCV infection-related detection indicators: Anti-HCV and HCV RNA.

The meta-analysis demonstrated a significant association between HCV co-infection and an increased risk of ATDILI. However, two included studies did not show a statistically significant association. This discrepancy is likely attributable to their limited statistical power, as both studies reported very few ATDILI events in their HCV co-infected cohorts, resulting in wide confidence intervals.

Additionally, heterogeneity in clinical practices and patient populations may have contributed to the variation in effect sizes across studies. Beyond these factors, regional and genetic backgrounds may offer another plausible explanation for the observed heterogeneity. Genetic polymorphisms in drug-metabolizing enzymes are known to influence ATDILI risk, and the prevalence of these polymorphisms varies by ethnicity and geography.

These findings suggest that while HCV is a clear risk factor at the population level, its observable impact in specific clinical settings may be modulated by local factors. Future prospective studies with standardized monitoring protocols and sufficient statistical power are warranted to better quantify this risk across diverse populations.

This meta-analysis has certain limitations. Several studies were over 20 years old. Consequently, the clinical management of both TB and HCV might have evolved during that period. It is not explicitly stated whether HIV infection is excluded in some of the studies included in this meta-analysis. We were unable to entirely eliminate the possibility of HIV hepatitis.

If the selected patients are infected with HIV, this may affect the risk of ATDILI. Generally, the presence and titer of serum HCV RNA can indicate the replicative activity of the HCV virus. However, most studies in this meta-analysis only detected serum anti-HCV antibodies and did not provide data on the viral load, which indicates the replicative activity of the virus. Due to the lack of HCV RNA data among some participants in the included studies, anti-HCV antibody positivity was used as a surrogate marker for HCV infection.

However, this may overestimate the actual burden of current infection with HCV, as it could include cases of past infection or cured individuals. A key limitation in interpreting the findings is the lack of reporting on HCV treatment status in most included studies. It was therefore not possible to discern whether the increased risk of ATDILI is driven solely by the underlying hepatic impairment from chronic hepatitis C, or whether concurrent pharmacological interventions for HCV contributed additively to the hepatotoxic risk.

Future studies should strive to document and analyze the impact of specific HCV treatments on ATDILI risk to clarify this important interaction. Another limitation of the review concerns the literature search strategy. While the searches were comprehensive within the selected databases, the scope of databases consulted and the selection of search terms may have been relatively narrow. It is possible that this approach did not capture all potentially relevant studies, which may introduce a degree of selection bias.

In conclusion, the comprehensive meta- analysis revealed that HCV co-infection significantly increases the risk of antituberculosis drug-induced liver injury (ATDILI). The finding carries immediate clinical implications, suggesting that clinicians should maintain a heightened vigilance when managing patients with TB/HCV co-infection. More intensive liver function monitoring and preemptive risk stratification based on the severity of underlying liver disease are strongly recommended.

Treatment strategies should be individualized, which may include selecting less hepatotoxic regimens or adjusting drug dosages. Future research should prioritize prospective studies that accurately document HCV treatment status and liver disease severity, with the aim of developing validated risk prediction tools for co-infected patients. Such tools would help guide personalized treatment and improve safety outcomes in this vulnerable population.

The findings confirm the significant association between HCV co-infection and an increased risk of antituberculosis drug-induced liver injury (ATDILI). The convergence of indirect evidence underscores the urgency of adopting proactive clinical management strategies.

The implementation of routine HCV screening in newly diagnosed tuberculosis cases is not only epidemiologically meaningful but also represents a critical risk mitigation measure. It enables preemptive interventions such as intensified monitoring and individualized treatment planning, thereby ultimately enhancing the safety and outcomes of tuberculosis therapy.

All data relevant to this study are included in the article.