Isoniazid is primarily metabolized by the arylamine N-acetyltransferase 2 (NAT2) enzyme. Single nucleotide polymorphisms (SNPs) in the NAT2 gene could classify an individual into three distinct phenotypes: rapid, intermediate and slow acetylators. NAT2 SNPs and the slow acetylator phenotype have been implicated as risk factors for the development of antitubercular drug-induced liver injury (AT-DILI) in several tuberculosis (TB) populations.

We conducted a prospective observational study to characterize and compare the NAT2 SNPs, genotypes and phenotypes among patients with TB and AT-DILI from the Southern and Western regions of India. The NAT2 pharmacogenomic profile of patients from these regions was compared with the reports from several geographically diverse TB populations and participants of different genetic ancestries extracted from literature reviews and the 'All of Us' Research Program database, respectively.

The TB patients of Southern and Western regions of India and several other geographically closer regions exhibited near similar NAT2 MAF characteristics. However significant heterogeneity in NAT2 SNPs was observed within and between countries among AT-DILI populations and the participants of different genetic ancestry from the 'All of Us' Research Program database. The MAF of the NAT2 SNPs rs1041983, rs1801280, rs1799929, rs1799930 and rs1208 of the TB patients from Southern and Western Indian Sites were in near range to that of the South Asian genetic ancestry of 'All of Us' Research Program database. About one-third of the total TB patients from the Southern and Western regions of India were NAT2 slow acetylators, among whom a relatively higher proportion experienced AT-DILI.

Further studies exploring the risk of NAT2 SNPs in different AT-DILI patients with larger sample sizes and a population-specific approach are required to establish a policy for NAT2 genotyping as a pre-emptive biomarker for AT-DILI monitoring for personalized isoniazid therapy in clinics.

Tuberculosis remains a major global health concern, presenting as either active disease or latent infection, the latter carrying a risk of activation, particularly in immunocompromised individuals. Prolonged isoniazid monotherapy is the standard preventive treatment, often supplemented with pyridoxine to mitigate isoniazid-induced pyridoxine depletion, as recommended by the US Centers for Disease Control and Prevention. This present study investigates an alternative transdermal approach using hydrogel-forming microarray patches (MAPs) incorporating lyophilised isoniazid and pyridoxine wafers. The MAPs were formulated with a novel poly(vinylpyrrolidone) and poly(vinyl alcohol) hydrogel, supplemented with sorbitol and adipic acid. In vitro studies demonstrated that approximately 15 % of isoniazid (8 mg) and 10 % of pyridoxine HCl (5 mg) permeated neonatal porcine skin over 24 h. In Sprague Dawley rats, MAPs provided significantly greater systemic exposure to isoniazid compared to oral administration (11,485 ± 1297 ng·mL-1·day vs. 9538 ± 656 ng·mL-1·day). A similar trend was observed for pyridoxine HCl, with MAPs yielding higher systemic exposure than the oral control (6118 ± 1185 ng·mL-1·day vs. 823 ± 322 ng·mL-1·day). These findings suggest that hydrogel-forming MAPs, which bypass first-pass metabolism and reduce hepatic exposure, hold promise as an effective alternative for the long-term management of latent tuberculosis.

Tuberculosis (TB) is a severe respiratory infectious disease caused by Mycobacterium tuberculosis (M.tb), which puts enormous pressure on public health and economic systems worldwide. Therefore, accurate diagnosis and timely intervention of TB are critical for interrupting disease transmission and reducing mortality among TB patients. However, the low bioavailability, inadequate targeting, and significant adverse side effects of conventional antibiotics and the emergence of the multidrug-resistant M.tb strain result in limited TB treatment efficacy or even the development of multidrug-resistant TB. The development of nanomaterials provides new perspectives to improve the drawbacks of antibiotics for improved TB treatment, while enabling the diagnosis of TB. Herein, we review the conventional and nanotechnology-based diagnosis and intervention strategy of TB and the currently developed novel methods to solve the TB dilemma.

Previous studies found that sodium alginate (SA) was protective against several liver diseases. However, the effect of SA on drug-induced liver injury is not clear. This study investigated the effect and mechanism of SA on isoniazid (INH)-induced liver injury in mice. Twenty-one male BALB/c mice were randomly divided into three groups: the control (AIN-93 M diet), the INH (AIN-93 M diet with 0.66 g INH/kg diet) and the SA group (AIN-93 M diet with 0.66 g INH/kg diet and 0.8 g SA/kg diet). After 10 weeks, the liver function indices, histopathological changes, fecal metabolites, and gut microbiota compositions were measured. Compared with the INH group, the SA group had significantly reduced alanine aminotransferase (ALT) and histopathological liver injury. Also, the SA treatment significantly reduced the content of several fecal metabolites including the indole, phenylalanine, and tyrosine derivatives. In addition, the SA treatment significantly increased the content of seven gut bacteria including Dorea, Eubacterium xylanophilum group, and Papillibacter and reduced the content of 11 gut bacteria including Alloprevotella. The changes in fecal metabolites and gut bacteria were associated with those in serum ALT and histopathological liver injury. In conclusion, SA alleviated INH-induced liver injury in mice by modulating fecal metabolites and gut bacteria.

Antituberculosis drug-induced hepatotoxicity (ATDH) is a common adverse drug reaction often requiring treatment interruption, complicating tuberculosis management. The slow acetylator phenotype, characterized by reduced N-acetyltransferase 2 (NAT2) enzyme activity, is associated with increased hepatotoxicity risk, while rapid acetylators are associated with a higher risk of therapeutic failure. This study investigates the association between the NAT2 acetylation phenotype and ATDH occurrence, with an emphasis on its predictive value in regard to a multiethnic population and its impact on the timing of ATDH onset. A retrospective observational study was conducted on tuberculosis patients treated at Luigi Sacco Hospital, Milan, Italy (July 2020-September 2023). The NAT2 genotyping identified slow and rapid/intermediate acetylators. Cumulative incidence analysis and Fine-Gray competing risks regression models were used to assess ATDH risk and onset timing. Among 102 patients, 21.6% developed ATDH, including 16.7% with slow and 4.9% with rapid/intermediate acetylators. ATDH onset was significantly earlier in regard to slow acetylators (median 0.5 vs. 2 months, interquartile range-IQR: 0.5-3 vs. 1.7-5.5). Slow acetylators were associated with a higher risk of developing ATDH (Sub-distribution hazard ratio, SHR = 3.05; 95% confidence interval-CI: 1.17-7.95; p = 0.02), even after adjusting for confounders. The NAT2 acetylation phenotype strongly influences ATDH risk and timing. Early acetylator status identification may enable dose adjustments, enhancing treatment safety. These findings highlight the role of pharmacogenetics in optimizing antituberculosis therapy by improving efficacy and minimizing toxicity.

Tuberculosis (TB) remains a significant global health concern, especially in Nepal, where the incidence of anti-TB drug-induced liver injury (DILI) is substantial. The main aim of this study is to investigate the incidence, clinical characteristics, outcomes, and contributing factors related to intensive phase anti-TB DILI among TB patients.

This prospective cross-sectional study enrolled 78 TB patients. Patients received a weight-based fixed-dose Antitubercular therapy (ATT). Liver function tests (LFTs) were performed at baseline and periodically during treatment to monitor for anti-TB DILI. Patients with DILI received immediate ATT discontinuation, supportive care, and reintroduction of ATT upon LFT normalization. Outcomes were tracked up to 60 days post-DILI. Data were analyzed using SPSS v21. Statistical significance was set at p < 0.05.

The mean age of the patients was 49.87 years (SD = 18.61), and 57.7% were male. Anti-TB DILI was observed in 15.4% of patients during the intensive treatment phase, with moderate severity in 50% of these cases. Half of the patients with DILI presented with nausea, vomiting, and anorexia. Notably, 91.7% of DILI patients showed improvement upon treatment discontinuation. The recurrence rate of anti-TB DILI after ATT re-initiation was 8.3%. Anti-TB DILI developed at a median of 11 days (range: 7-60 days) after ATT initiation, with liver enzyme normalization after discontinuation of ATT averaging 10.9 ± 6.45 days. The mortality rate among DILI patients was 8.3% (1 out of 12 patients). Hepatotoxic drugs, low BMI, and low serum albumin were identified as independent predictors of anti-TB DILI.

Anti-TB DILI occurred in a significant proportion of TB patients, with moderate severity being most common. Early detection and management, including treatment discontinuation, led to high recovery rates, though mortality remained notable. Low BMI, low serum albumin, and hepatotoxic drugs were key independent risk factors, emphasizing the need for careful monitoring and tailored management during ATT.

Intracranial tuberculoma represents one of the most severe complications of central nervous system tuberculosis (TB), with an incidence that is relatively low. In cases of intracranial tuberculoma, patients may develop drug toxicity and/or immune reconstitution inflammatory syndrome (IRIS) while receiving anti-TB treatment. The current study presented the case of a seven-year-old female patient with intracranial tuberculoma who developed drug-induced hepatotoxicity and IRIS during the course of treatment. During the follow-up of the patient, anti-TB drug-induced hepatitis developed, which led to the discontinuation of the drug twice. In the seventh month of treatment, cranial MRI showed the progression of tuberculoma lesions. The possibility of IRIS or treatment failure was considered and the treatment was restarted with steroids and non-hepatotoxic anti-TB drugs. With steroid and anti-TB treatment, the lesions regressed almost completely and the neurological deficit regressed. Patients receiving treatment should be followed up closely due to the possible side effects of anti-TB drugs, especially IRIS, which develops as an immune restructuring response during the recovery of the immune system.

In the United States, older adults have elevated prevalence of latent tuberculosis infection (LTBI) and incidence of tuberculosis (TB).

To estimate the health benefits and cost-effectiveness of LTBI testing and treatment among the Medicare-eligible population.

Model-based cost-effectiveness analysis.

Nationally representative surveys and published evidence.

Medicare-eligible persons aged 65 years or older with at least 1 of 15 factors associated with elevated TB risk, as identified by guidelines from the U.S. Preventive Services Task Force (USPSTF) and other organizations.

Lifetime.

Societal.

One-time offer of LTBI testing and treatment versus no intervention.

Lifetime TB cases and deaths averted, quality-adjusted life-years (QALYs) gained, costs, and incremental cost-effectiveness ratios (ICERs).

In 2022, there were an estimated 29.9 million Medicare-eligible persons (95% uncertainty interval [UI], 28.4 to 31.6 million persons) aged 65 years or older with elevated TB risks, including 14.7 million (95% UI, 13.4 to 16.0 million) with USPSTF-recommended factors. In the target population, 4.9 million persons (95% UI, 4.0 to 5.8 million persons) (16.4% [95% UI, 13.9% to 19.1%]) were estimated to have LTBI. Testing and treatment of LTBI was estimated to prevent 10 946 TB cases (95% UI, 4684 to 20 579 cases) and 2579 TB deaths (95% UI, 1106 to 4882 deaths), with 13 234 lifetime QALYs (95% UI, 5343 to 25 519 lifetime QALYs) gained. For the overall target population and for persons with USPSTF-recommended factors, ICERs were $192 000 (95% UI, $92 000 to $503 000) and $155 000 (95% UI, $77 000 to $393 000) per QALY gained, respectively.

The ICER was $109 000 (95% UI, $49 000 to $285 000) per QALY gained for 65-year-olds newly eligible for Medicare.

Health benefits from averted post-TB sequelae were not estimated.

Medicare-eligible persons represent approximately one third of all U.S. persons with LTBI. Testing and treatment of LTBI in this population could lead to substantial reductions in TB and TB-related mortality, particularly among 65-year-olds newly eligible for Medicare.

Centers for Disease Control and Prevention.

Adverse events during tuberculosis treatment are common and are a major challenge for patients and front-line care providers. We did a systematic review of treatment guidelines for rifampicin-susceptible tuberculosis to evaluate the adequacy of recommendations for adverse event management.

We searched websites, guideline registries, PubMed, and mobile health Apps to identify treatment guidelines published from October 2004 to October 2024. We recorded the presence and evidence base for specific recommendations for management of nausea/vomiting, hepatotoxicity, skin reactions, neuropathy, visual changes, drug fever, and arthralgias.

We included 47 guidelines: 25 from high-burden countries, 12 international and prominent national guidelines, and 10 non-governmental guidelines. 37 guidelines (79%) included recommendations for managing adverse events: 24 (96%) of guidelines from high-burden countries, eight (80%) of those from non-governmental organizations, and four (33%) of international and prominent national guidelines. Four recommendations had formal ratings of supporting evidence.

International and prominent national guidelines frequently lack recommendations for adverse event management or had non-specific recommendations. Research on prevention and management of common and serious adverse events should be a priority for improving the patient's experience and the outcomes of tuberculosis treatment.

This research was supported by Wellcome Trust Clinical Grants.

Drug-induced liver injury (DILI) results from the liver toxicity caused by drugs or their metabolites. Gallic acid (GA) is a naturally occurring secondary metabolite found in many fruits, plants, and nuts. Recently, GA has drawn increasing attention due to its potent pharmacological properties, particularly its anti-inflammatory and antioxidant capabilities. To the best of our knowledge, this is the first review to focus on the pharmacological properties of GA and related molecular activation mechanisms regarding protection against hepatotoxicity. We also provide a thorough explanation of the physicochemical properties, fruit sources, toxicity, and pharmacokinetics of GA after reviewing a substantial number of studies. Pharmacokinetic studies have shown that GA is quickly absorbed and eliminated when taken orally, which restricts its use in development. However, the bioavailability of GA can be increased by optimizing its structure or changing its form of administration. Notably, according to toxicology studies conducted on a range of animals and clinical trials, GA rarely exhibits toxicity or side effects. The antioxidation mechanisms mainly involved Nrf2, while anti-inflammatory mechanisms involved MAPKs and NF-κB signaling pathways. Owing to its marked pharmacological properties, GA is a prospective candidate for the management of diverse xenobiotic-induced hepatotoxicity. We also discuss the applications of cutting-edge technologies (nano-delivery systems, network pharmacology, and liver organoids) in DILI. In addition to guiding future research and development of GA as a medicine, this study offers a theoretical foundation for its clinical application.

Tuberculosis (TB), caused by Mycobacterium tuberculosis , is the most significant infectious cause of mortality across the globe. While TB disease can prey on immunocompetent individuals, it is more likely to occur in immunocompromised individuals. Immune-mediated inflammatory diseases (IMIDs) are a group of diseases (rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, psoriasis, hidradenitis suppurativa, autoimmune blistering diseases, and others) where there may be a need for systemic immunosuppression to control the disease manifestations, treat symptoms and improve long term outcomes. Immunosuppression may predispose them to active TB either from recent infection or reactivation of Latent TB (LTB). The major determinants of reactivation include the type of therapy (highest risk with TNF inhibitors and JAK inhibitors) and the underlying TB endemicity. The strategy to avoid TB reactivation includes the detection of LTB using tests that detect immunoreactivity to TB antigens (interferon-gamma release assays or tuberculin skin test) and treating LTB before or with initiation of IMID therapies. Available diagnostic tests have deficiencies in diagnostic sensitivity to detect LTB and even worse capability in predicting reactivation of TB. In addition to immunological tests, more stringent testing strategy utilizing one or many LTB equivalents may point towards subclinical TB. LTB equivalents include clinical (past history of TB, recent exposure to TB) and radiological criteria (use of chest roentgenogram, computed tomography, or, sometimes positron emission tomography - computed tomography). The present review summarizes the risk factors for TB reactivation in patients initiated on advanced therapies, geographically appropriate strategies for LTB testing, and treatment of LTB.

Anecdotal information suggests that clinical practice regarding the use of putative hepatoprotective agents in TB treatment varies across countries in the WHO European Region.

Between November 2023 and May 2024, we conducted a standardised questionnaire survey on the use of putative hepatoprotective agents in patients receiving TB treatment among Tuberculosis Network European Trials Group (TBnet) representatives in countries in the WHO European Region.

We received valid responses from 37 of 53 countries (69.8%), with 16 (43.2%) reporting regular use of putative hepatoprotective agents during anti-TB treatment. Half of these countries (n = 8) are part of the former Soviet Union. In five countries, these agents are recommended by national guidelines. The most commonly used hepatoprotective agents were silibin/silymarin (n = 9, 56.3%), ursodeoxycholic acid (n = 5, 31.3%), and soy phospholipids (n = 4, 25.0%). Treatment duration varied, with 56.3% (n = 9) using them for less than 1 month, 18.8% (n = 3) for 1-3 months, and 18.8% (n = 3) for 4-6 months.

Putative hepatoprotective agents are widely used as an adjunct to TB treatment in the WHO European Region, particularly in the countries of the former Soviet Union, some of which have included them in their national guidelines.

Data on childhood and adolescent multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in Indonesia are lacking. We aimed to assess clinical features, adverse events (AEs) and treatment outcomes of childhood and adolescent MDR/RR-TB.

A retrospective cohort study was performed in children and adolescents <18 years old treated for MDR/RR-TB at Hasan Sadikin General Hospital in Bandung, Indonesia, between June 2016 and March 2024. Multivariable logistic regression analyses were used to calculate adjusted odds ratios (aOR) for predictors of all-cause mortality.

Among 84 included patients, 69 (82%) were adolescents 10-17 years of age, 54 (64%) were female, 54 (64%) were malnourished and 55 (65%) had culture-confirmed disease. Among 69 (82%) patients with known outcomes, 48 (70%) were successfully treated, 14 (20%) died (including 5 pretreatment deaths) and 7 (10%) were lost to follow-up (LTFU) (including 5 pretreatment LTFU). Predictors of all-cause mortality included shortness of breath on admission [aOR: 6.4, 95% confidence interval (CI): 1.3-49.1], high bacillary burden on Xpert MTB/RIF assay (aOR: 17.0, 95% CI: 1.6-260.5) and the presence of lung cavities on chest radiograph (aOR: 4.8, 95% CI: 1.1-23.3). Among 74 patients who initiated treatment, 39 (53%) had at least one grade 1-2 AE, and 4 (5%) had one grade 3-4 AE each, including hepatotoxicity, QT prolongation, hearing loss and rash/hyperpigmentation.

Younger children were underrepresented among those treated for MDR/RR-TB, indicating reduced access to care. Severe AEs were uncommon during MDR/RR-TB treatment. Baseline indicators of extensive disease were associated with all-cause mortality. The high proportion of pre-treatment mortality and LTFU may reflect complex patient pathways limiting access to care.

Liver disease, responsible for two million annual deaths, causes Chronic Liver Disease (CLD) and cirrhosis, causing roughly a million deaths yearly. Treatment options for liver injury induced by hepatotoxicity vary, including medication (N-acetylcysteine, corticosteroids, and ursodeoxycholic acid), lifestyle changes, and sometimes liver transplant. However, effectiveness varies, and some treatments carry risks and side effects, highlighting the need for improved therapeutic approaches. Murraya koenigii (MK) is known for its hepatoprotective, antioxidant, anti-inflammatory, anti-microbial, nephroprotective, hepatoprotective, gastroprotective, cardioprotective, neuroprotective, wound-healing, anti-cancerous and immunomodulatory effects, etc. This review highlights the effectiveness of MK against liver damage induced by heavy metals, drug abuse, xenobiotics, etc. A comprehensive search across multiple databases like PubMed, Google Scholar, and others for articles on various hepatotoxicants and hepatoprotective activity of MK was conducted. The researchers applied specific search terms and limits, resulting in 149 eligible articles for final analysis, meeting predetermined inclusion criteria and excluding irrelevant studies. According to the available literature, the phytochemical components of MK, such as flavonoids, tannins, and alkaloids present in various extracts, play a crucial role in reversing the hepatotoxic effects by modifying oxidative and ER stresses, re-establishing the hepatic biochemical markers and enzymes involved in metabolism denoting ameliorative activity, and controlling the expression of pro-inflammatory cytokines. To conclude, this review highlights that MK has great potential as a natural hepatoprotective agent, providing a versatile defense against a range of injuries caused by heavy metals, xenobiotics, and common hepatotoxic agents.

Hesperidin and ascorbic acid (AA) enhance cellular antioxidant defense systems by neutralizing the free radicals which formed during oxidative stress that could offer protective effects against drug-induced liver injury. Hence, this study aims to investigate the effect of hesperidin, AA and their combination against antitubercular drug (ATDs)- induced hepatotoxicity in Wistar albino rats.

The rats were divided into six groups of 6 animals each. Isoniazid (H), Rifampicin (R), and pyrazinamide (Z) (27, 54, 135 mg/kg.b.wt) were co-administration for 50 days to induce hepatotoxicity. Hesperidin 200 mg/kg and AA 100 mg/kg p.o were administered 1 h before ATDs administration. At the end of the study, blood and liver tissues were collected and subjected to biochemical and histopathological examination. Biochemical parameters, serum marker enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acid phosphatase, Gamma glutamyltransferase, and lactate dehydrogenase), lipid peroxidation (LPO), antioxidant enzymes (superoxide dismutase, catalase, GSH, glutathione peroxidase, GR, Vitamin C, and Vitamin E), lipid profile, membrane bound ATPase, and histological changes of liver were assessed.

Our results revealed that HRZ-induced hepatotoxicity was evident by significant (P < 0.001) elevation in level of urea, creatinine, bilirubin, liver marker enzymes, lipid profile (P < 0.01), and LPO (P < 0.001) along with significant decline in the level of total protein, albumin (P > 0.05), ATPase (P < 0.001), and antioxidant enzymes (P < 0.001). Treatment with HDN and AA significantly reduced the changes induced by HRZ. However, compared to individual treatment, combined treatment with HDN and AA significantly (P < 0.001) ameliorated all the changes induced by ATDs and improved the hepatic architecture to near normal.

The combination of HDN and AA demonstrated a synergistic therapeutic effect against HRZ-induced liver injury; hence, this combination represents a potential novel strategy for the management of anti-TB drug-induced liver damage.

Idiosyncratic hepatotoxicity induced by prescribed drugs has been known since the early 20th century. Identifying risk factors, including genetic factors, that trigger this drug-induced liver injury (DILI) has been an important priority for many years, both to prevent drugs that cause liver injury being licensed and as a potential means of preventing at-risk patients being prescribed causative drugs. Improved methods for genomic analysis, particularly the development of genome-wide association studies, have facilitated the identification of genomic risk factors for DILI, but, to date, there are only two main examples, liver injury caused by amoxicillin-clavulanate (AC) and by flucloxacillin, where genetic risk factors causing the injury have been identified and replicated with understanding of the underlying mechanism. There has also been progress on identifying genetic risk factors for liver injury caused by other anti-infective agents, herbal remedies and nonsteroidal anti-inflammatory drugs. The majority of genetic risk factors identified to date are specific human leucocyte antigen (HLA) alleles and evidence that these alleles preferentially present self-peptides inappropriately to T cells in the liver has been obtained. Non-HLA genes also contribute to genetic susceptibility, both as co-factors in T-cell responses and, in the case of isoniazid-only, drug metabolism. Polygenic risk scores to predict DILI have been developed, both a simple score that predicts AC injury and complex scores that may be applied to DILI more generally and provide evidence that additional risk factors other than HLA genes exist.

Prevention of drug-resistant tuberculosis is a global health priority. However, trials evaluating the effectiveness of treating Mycobacterium tuberculosis infection among contacts of persons with drug-resistant tuberculosis are lacking.

We conducted a double-blind, randomized, controlled trial comparing 6 months of daily levofloxacin (weight-based doses) with placebo to treat M. tuberculosis infection. The trial population comprised household contacts of persons with bacteriologically confirmed rifampicin-resistant or multidrug-resistant (MDR) tuberculosis in Vietnam. Contacts of any age with a positive tuberculin skin test or immunologic impairment were eligible. The primary end point was bacteriologically confirmed tuberculosis within 30 months. Secondary end points included grade 3 or 4 adverse events, death from any cause, and acquired drug resistance.

Of 3948 persons screened for eligibility, 61 (1.5%) had coprevalent tuberculosis (defined as active tuberculosis disease diagnosed before randomization) and 2041 underwent randomization. Of these 2041 participants, 1995 (97.7%) completed 30 months of follow-up, had a primary end-point event, or died. Confirmed tuberculosis occurred in 6 participants (0.6%) in the levofloxacin group and 11 (1.1%) in the placebo group (incidence rate ratio, 0.55; 95% confidence interval [CI], 0.19 to 1.62); this difference was not significant. There was little difference in grade 3 or 4 adverse events between the two groups (risk difference, 1.0 percentage point; 95% CI, -0.3 to 2.4). Adverse events of any grade were reported in 306 participants (31.9%) taking levofloxacin and 125 (13.0%) taking placebo (risk difference, 18.9 percentage points; 95% CI, 14.2 to 23.6). No acquired fluoroquinolone resistance was observed.

Although the incidence of tuberculosis was lower in the levofloxacin group than in the placebo group at 30 months, the difference was not significant. (Funded by the National Health and Medical Research Council of Australia; VQUIN MDR Australia New Zealand Clinical Trials Registry number, ACTRN12616000215426.).

The N-acetyltransferase 2 (NAT2) gene exhibits substantial genetic diversity, leading to distinct acetylator phenotypes among individuals. In this study, we determine NAT2 gene polymorphisms in tuberculosis (TB) patients and analyze serum isoniazid (INH) concentrations across the various genotypes. An observational prospective cohort study involving 217 patients with pulmonary or extrapulmonary TB was carried out. The NAT2 genotypes were identified using real-time polymerase chain reaction technology. INH concentrations at baseline and 2 hours post-dosing were estimated using high-performance liquid chromatography. The association between the acetylator status and INH concentrations was evaluated using odds ratios (OR) and the occurrence of adverse events across the different patient genotypes was also assessed. The genotype frequency of fast, intermediate, and slow acetylators was 7.37%, 39.17%, and 53.46%, respectively, while allele frequency was 27% for fast acetylators and 73% for slow acetylators. All the alleles followed the Hardy-Weinberg equilibrium. Patients with slow acetylator status had significantly increased serum INH concentrations 2 hours post-drug administration, followed by intermediate acetylators as compared to fast acetylators. 69 (31.8%) patients developed adverse drug reactions post-therapy. Patients with slow acetylator status had the highest (OR: 9.66) risk of developing drug-induced hepatoxicity, especially those with raised serum INH concentrations (OR: 1.34). Understanding the correlation between genetics and serum antitubercular drug levels in antitubercular drug-induced hepatotoxicity will provide valuable information to the medical community, minimizing the risk of adverse reactions and hospitalizations.

To prevent organ rejection, renal transplant (RT) recipients must take immunosuppressive medicines, which make them more susceptible to infections such as tuberculosis (TB). Hepatotoxicity, which can vary from asymptomatic increased liver enzymes to severe liver failure, is the most prevalent side effect of first-line antituberculosis (AT) drugs. Treating TB in RT patients involves unique concerns since AT medications might interact with immunosuppressive medications, potentially reducing efficacy or increasing toxicity. A 65-year-old RT recipient was diagnosed with active pulmonary TB 18 years after renal transplantation. He had drug-induced acute liver failure after initiating AT therapy, but his liver function improved after discontinuing AT medications and receiving supportive care.

Rationale: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/AIDS Clinical Trials Group A5349 represents the largest phase 3 randomized controlled therapeutic trial to date for such an investigation. Objectives: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure and efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits. Methods: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome. Measurements and Main Results: Among 2,255 participants with 6,978 plasma samples, pyrazinamide displayed sevenfold exposure variability (151-1,053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in therapeutic windows of 231-355 mg · h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1,000 mg would have permitted an additional 13.1% (n = 96) of participants allocated to the control and 9.2% (n = 70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared with the current weight-banded dosing. Conclusions: Flat dosing of pyrazinamide at 1,000 mg/d would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registered with www.clinicaltrials.gov (NCT02410772).

In Uganda, people with multi-drug resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) have been treated with a bedaquiline-based regimen since 2020. Still, their treatment outcomes have not been rigorously studied. We describe the treatment outcomes of people with MDR/RR-TB treated with a bedaquiline-based regimen and analyze the factors associated with their treatment success at three referral hospitals in Uganda.

We retrospectively reviewed medical records for people with MDR/RR-TB treated with a bedaquiline-based regimen between January 2020 and December 2021 at 3 referral hospitals. Treatment success was defined as cure or treatment completion on a binary scale at the end of the MDR/RR-TB treatment. Factors independently associated with treatment success were analyzed using the modified Poisson regression analysis with robust standard errors, reported as risk ratio (RR) and 95% confidence interval (CI). Analyses were performed at a 5% level of statistical significance.

Of 71 participants aged ≥ 15 years, 13 (18.3 %) completed treatment, 46 (64.8) were cured, 8 (11.3) died, and 4 were lost to follow-up. Overall, 59 (83.1) were successfully treated. Current alcohol consumption (adjusted RR [aRR] 0. 78, 95 % CI 0.60-0. 99) and high aspartate aminotransferase levels (aRR 0.77, 95 % CI 0.60-0.98) were associated with a lower treatment success.

The treatment success among people with MDR/RR-TB on a bedaquiline-based regimen was relatively high. High AST levels and alcohol consumption are associated with a lower treatment success. There is a need to strengthen psychosocial support regarding the harmful effects of alcohol consumption and its interaction with drugs, including routine monitoring of liver function to enhance the TB treatment success.Our study is the first to describe treatment success among people with MDR/RR-TB in three large hospitals in Uganda, this provides a good picture of treatment success among people with MDR/RR-TB on bedaquiline-based regimens in the country. The weaknesses are the smaller sample size, we analyzed data spanning a relatively shorter period, and alcohol use was measured by self-reporting, this might have underestimated its association with treatment success.

Mycobacterium tuberculosis (TB) remains the leading cause of infection-related mortality worldwide. Drug resistance, need for multiple antimycobacterial agents, prolonged treatment courses, and medication-related side effects are complicating factors to TB cure. The introduction of treatment regimens containing the novel agents bedaquiline, pretomanid, and linezolid, with or without moxifloxacin (BPaL-M or BPaL, respectively) have substantially reduced TB-related morbidity and mortality and are associated with favorable rates of treatment completion and cure. This review summarizes key information on the pharmacology and treatment principles for moxifloxacin, bedaquiline, delamanid, pretomanid, linezolid, and tedizolid in the treatment of multi-drug resistant TB, with recommendations provided to address and attenuate common adverse effects during treatment.

Globally, nearly half of deaths from cirrhosis and chronic liver diseases (CLD) and three-quarters of deaths from hepatocellular carcinoma (HCC) occur in the Asia-Pacific region. Chronic hepatitis B is responsible for the vast majority of liver-related deaths in the region. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common form of CLD, affecting an estimated 30% of the adult population. Compared with people of European descent, people from the Asia-Pacific region carry more genetic variants associated with MASLD and its progression. Alcohol is a fast-growing cause of CLD and HCC in Asia as a result of the rising per-capita consumption of alcohol. Drug-induced liver injury is under-recognized and probably has a high prevalence in this region. The epidemiological and outcome data of acute-on-chronic liver failure are heterogeneous, and non-unified definitions across regions contribute to this heterogeneity. CLDs are severely underdiagnosed, and effective treatments and vaccinations are underutilized. In this Review, we highlight trends in the burden of CLD and HCC in the Asia-Pacific region and discuss the rapidly changing aetiologies of liver disease. We examine the multiple gaps in the care cascade and propose mitigating strategies and future directions.

Sepsis often causes severe liver injury and leads to poor patient outcomes. Early detection of sepsis-induced liver injury (SILI) and early treatment are key to improving outcomes.

To investigate the clinical characteristics of SILI patients and analyze the associated risk factors, to identify potential sensitive biomarkers.

Retrospective analysis of clinical data from 546 patients with sepsis treated in the intensive care unit of the 908th Hospital of Chinese People's Liberation Army Joint Logistic Support Force between May 2018 and December 2022. The patients were divided into the sepsis group (n = 373) and SILI group (n = 173) based on the presence of acute liver injury within 2 hours of admission. We used the random forest algorithm to analyze risk factors and assessed potential diagnostic markers of SILI using the area under the receiver operating characteristic curve, Kaplan-Meier survival curves, subgroup analysis and correlation analysis.

Compared with the sepsis group, tissue plasminogen activator-inhibitor complex (t-PAIC) levels in serum were significantly higher in the SILI group (P < 0.05). Random forest results showed that t-PAIC was an independent risk factor for SILI, with an area under the receiver operating characteristic curve of 0.862 (95% confidence interval: 0.832-0.892). Based on the optimal cut-off value of 11.9 ng/mL, patients at or above this threshold had significantly higher levels of lactate and Acute Physiology and Chronic Health Evaluation II score. The survival rate of these patients was also significantly worse (hazard ratio = 2.2, 95% confidence interval: 1.584-3.119, P < 0.001). Spearman's correlation coefficients were 0.42 between t-PAIC and lactate, and 0.41 between t-PAIC and aspartate transaminase. Subgroup analysis showed significant differences in t-PAIC levels between patients with different severity of liver dysfunction.

T-PAIC can serve as a diagnostic indicator for SILI, with its elevation correlated with the severity of SILI.

We studied the associations between 3'UTR genetic variants in ADME genes, clinical factors, and the risk of breast cancer chemotherapy toxicity. Those variants and factors were tested in relation to seven symptoms belonging to myelotoxicity (anemia, leukopenia, neutropenia), gastrointestinal side effects (vomiting, nausea), nephrotoxicity, and hepatotoxicity, occurring in overall, early, or recurrent settings. The cumulative risk of overall symptoms of anemia was connected with AKR1C3 rs3209896 AG, ERCC1 rs3212986 GT, and >6 cycles of chemotherapy; leukopenia was determined by ABCC1 rs129081 allele G and DPYD rs291593 allele T; neutropenia risk was correlated with accumulation of genetic variants of DPYD rs291583 allele G, ABCB1 rs17064 AT, and positive HER2 status. Risk of nephrotoxicity was determined by homozygote DPYD rs291593, homozygote AKR1C3 rs3209896, postmenopausal age, and negative ER status. Increased risk of hepatotoxicity was connected with NR1/2 rs3732359 allele G, postmenopausal age, and with present metastases. The risk of nausea and vomiting was linked to several genetic factors and premenopausal age. We concluded that chemotherapy tolerance emerges from the simultaneous interaction of many genetic and clinical factors.

Efforts to shorten rifampicin-resistant tuberculosis (RR-TB) treatment have led to concerns about hepatotoxicity in shorter regimens. We evaluated hepatotoxicity in two novel regimens against the standard shorter regimen recommended by the World Health Organization (WHO).

Participants from the TB-TRUST and TB-TRUST plus trials were assigned to the WHO shorter regimen, a levofloxacin (Lfx)-based regimen, or a bedaquiline (Bdq)-based regimen. Liver function was tested bi-weekly in the first month, then monthly until treatment ended. Eligibility required receiving at least one drug dose and undergoing at least two liver function tests.

Of 429 patients, hepatotoxicity was most prevalent in the WHO shorter group (26.7% of 169), compared to 4.7% in the Lfx group (172 patients), and 5.7% in the Bdq group (88 patients). The median peak alanine aminotransferase levels were 1.67 × upper limit of normal (ULN) for WHO, 0.82 × ULN for Lfx, and 0.88 × ULN for Bdq groups. The incidence of drug-induced liver injury was significantly higher in the WHO group (18.3%) than in the Lfx (3.5%) and Bdq (4.6%) groups. The time to significant alanine aminotransferase elevation was about 2.8 months, with no differences between groups.

Two novel regimens demonstrated lower hepatotoxicity compared to the WHO's shorter regimen. Entire course management monitoring is recommended in RR-TB treatment.

Drug-induced liver injury (DILI) continues to be a major concern in clinical practice, thus necessitating a need for novel therapeutic approaches to alleviate its impact on hepatic function. This review investigates the therapeutic potential of nutraceuticals against DILI, focusing on examining the underlying molecular mechanisms and cellular pathways. In preclinical and clinical studies, nutraceuticals, such as silymarin, curcumin, and N-acetylcysteine, have demonstrated remarkable efficacy in attenuating liver injury induced by diverse pharmaceutical agents. The molecular mechanisms underlying these hepatoprotective effects involve modulation of oxidative stress, inflammation, and apoptotic pathways. Furthermore, this review examines cellular routes affected by these nutritional components focusing on their influence on hepatocytes, Kupffer cells, and stellate cells. Key evidence highlights that autophagy modulation as well as unfolded protein response are essential cellular processes through which nutraceuticals exert their cytoprotective functions. In conclusion, nutraceuticals are emerging as promising therapeutic agents for mitigating DILI, by targeting different molecular pathways along with cell processes involved in it concurrently.

Pyrazinamide (PZA) is the standard first-line treatment for tuberculosis (TB); however, its safety in elderly patients has not been thoroughly investigated.

This retrospective study used data from the Japanese Diagnosis Procedure Combination inpatient database. We identified patients who were admitted for TB between July 2010 and March 2022. Patients were categorized into HRE (isoniazid, rifampicin and ethambutol) and HREZ (isoniazid, rifampicin, ethambutol and PZA) groups. Primary outcomes included in-hospital mortality and overall adverse events (characterized by a composite of hepatotoxicity, gout attack, allergic reactions and gastrointestinal intolerance). Secondary outcomes included the length of hospital stay, 90-day readmission and use of drugs related to the primary outcome adverse events. Data were analysed using propensity score matching; we also conducted a subgroup analysis for those aged ≥75 years.

Among 19,930 eligible patients, 8924 received HRE and 11,006 received HREZ. Propensity score matching created 3578 matched pairs with a mean age of approximately 80 years. Compared with the HRE group, the HREZ group demonstrated a higher proportion of overall adverse events (3.1% vs. 4.7%; p < 0.001), allergic reactions (1.4% vs. 2.5%; p < 0.001) and antihistamine use (21.9% vs. 27.6%; p < 0.001). No significant differences were observed regarding in-hospital mortality, hepatotoxicity or length of hospital stay between the groups. Subgroup analysis for those aged ≥75 years showed consistent results.

Medical practitioners may consider adding PZA to an initial treatment regimen even in elderly patients with TB.

We compared performance of the Roussel Uclaf Causality Assessment Method (RUCAM) with multidisciplinary expert panel review in identifying a drug-induced liver injury (DILI) due to antituberculosis therapy (ATT) and/or antiretroviral therapy (ART).

Cases were drawn from a prospective registry of hospitalised adults with suspected DILI due to ATT and/or ART in Cape Town, South Africa. Participants had to fulfil American Thoracic Society criteria for ATT interruption (alanine transaminase [ALT] ≥5 times upper limit of normal [ULN]/ALT ≥3 times [ULN] and symptomatic). Causality assessment by expert panel review served as reference standard. The panel ranked potentially implicated drugs as certain, probable, possible or unlikely causes guided by World Health Organization Uppsala Monitoring Centre criteria. The RUCAM was performed for each potentially implicated drug. We calculated sensitivity and specificity of the RUCAM in identifying a probable/certain drug cause for liver injury.

We included 48 participants. All were people with HIV (PWH). Twenty-seven were on concomitant ART and ATT, with a median of six potentially hepatotoxic drugs per case. Sensitivity and specificity of the RUCAM in identifying a probable/certain drug cause of liver injury compared with expert panel review was 7% and 100% respectively. Implicated drugs (times ranked probable/certain by panel) were isoniazid (18/0), pyrazinamide (17/0), rifampicin (15/1), efavirenz (6/4) and lopinavir/ritonavir (1/0).

PWH with liver injury received multiple potentially implicated drugs, which may increase liver injury risk and complicate causality assessment. Compared with expert panel review, the RUCAM had low sensitivity in detecting probable or certain drug causes of liver injury.

Detoxification is one of the most important liver functions. Therefore, liver is the front line of defense when the biosystem faces drug overdose, toxins, and anything that may cause harm. Some famous antibiotics are known for their side effects on liver; one of them is amoxicillin, AM. This work has investigated the toxic effect of amoxicillin on rat's liver with overdose (90 mg/kg) and has studied the ameliorative role of protective and therapeutic Ashwagandha seeds extract (ASE) at doses (100, 200, and 300 mg/kg) against this toxicity. To achieve this work, the authors used two modalities; the first is liver histopathology to figure out the amoxicillin and ASE effects and to detect the sensitivity of another modality; the electric modulus, and its related thermodynamic parameters of liver tissue. Histopathological examination showed that the role of therapeutic ASE in reducing amoxicillin (AM) toxicity was more effective than the protective one. Also, most dielectric and thermodynamic results achieved the same result. Histopathology confirmed the liver injury by amoxicillin and the partial repair by the biosystem using ASE. Moreover, electric modulus, related dielectric parameters, and their thermodynamic state functions showed different changes in their values under the effect of amoxicillin. Using ASE helped the biosystem to restore these changes near their control values.

Many biologic agents cause some degree of immunosuppression, which can increase the risk of reactivation of tuberculosis infection (TBI). This risk is variable between individual biologics. We aimed to assess current (and recommended) clinical practice of TBI screening and treatment among patients initiating treatment with biologic agents.

An online questionnaire was distributed via email to members of the Global Tuberculosis Network and associated professional organisations to seek insights into the screening for and treatment of TBI in patients treated with biologics.

A total of 163 respondents in 27 countries answered at least one question. For all biologics described in the questionnaire, respondents advised increasing screening relative to current practice. Observed and supported TBI screening rates in patients treated with TNF-a inhibitors were high, especially for older TNF-a inhibitors. Most participants supported TBI screening in patients treated with B- or T-cell inhibitors but not in those treated with interleukin inhibitors. Guideline awareness was higher for TNF-a inhibitors than for other biologic classes (79% vs. 34%).

Although respondents stated that TBI screening rates are lower than what they consider ideal, there was a tendency to recommend TBI screening in patients treated with biologics not known to be associated with an increased risk of TBI. As a result, there is a potential risk of over-screening and over-treatment of TBI, potentially causing harm, in patients treated with biologics other than TNF-a inhibitors. There is a need to research the risk of TBI associated with biologics and for guidelines to address the spectrum of TBI risk across all types of biologics.

Many of the first line medications for the treatment of active and latent M. tuberculosis are hepatoxic and cause a spectrum of anti-tuberculosis drug induced liver injury (ATLI), including acute liver failure (ALF). Despite advances in recognition of and prevention of ATLI, isoniazid remains one of the leading causes of DILI as well as drug-induced ALF.

A literature search of the incidence, risk factors, current societal guidelines, monitoring, and prophylactic medication usage in ATLI was performed using PubMed and institutional websites. Relevant articles from 1972 to 2024 were included in this review.

Current societal guidelines regarding ATLI monitoring are mixed, but many recommend liver enzyme testing of high-risk populations. We recommend liver test monitoring for all patients on multi-drug therapy as well as those on isoniazid therapy. Precision medicine practices, such as N-acetyltransferase-2 polymorphism genotyping, are thought to be beneficial in reducing the incidence of ATLI in high-risk populations. However, broader implementation is currently cost prohibitive. Hepatoprotective drugs are not currently recommended, although we do recognize their potential. In patients who develop ATLI but require ongoing anti-TB treatment, strategies to restart the same or less hepatotoxic regimens are currently being followed.

Tuberculosis (TB) treatment is highly effective, but response to therapy can vary by geography, race, and ethnicity. We assessed for differences in TB treatment response in a representative and heterogeneous Brazilian population. We estimated genetic ancestry proportion according to major ancestry groups (African, European, and Amerindian ancestry) in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort. RePORT-Brazil is an observational prospective cohort study of individuals with newly-diagnosed, culture-confirmed, pulmonary TB. TB treatment outcomes that were attributed to TB treatment included Grade 2 or higher adverse drug reaction (ADR), Grade 3 or higher ADR, hepatic ADR, and failure/recurrence. Ancestry proportion was the main predictor in logistic regression for each outcome, with adjustments for candidate confounders. There were 941 pulmonary TB patients included in this study. We observed a decreased risk of Grade 2+ ADR when African ancestry proportion increased by 10% (Odds Ratio [OR] 0.41, 95% Confidence Interval [CI] 0.20 -0.85) and an increased risk for Grade 2+ ADR with increasing European ancestry (OR 2.84, 95% CI 1.47 - 5.48). We then performed the same analysis adding HIV status as an interaction term. The decreased risk for Grade 2+ ADR seen for African ancestry proportion did not hold for persons living with HIV; we observed increased risk for Grade 2+ ADR with increasing African ancestry proportion. There were no associations with Amerindian ancestry or for other treatment outcomes. In this Brazilian TB cohort, toxicity risk was associated with African and European ancestry, divergent, and affected by HIV. #RePORT-Brazil Consortium members include: Aline Benjamin and Flavia M. Sant'Anna Instituto Nacional de Infectologia Evandro Chagas, Fiocruz, Rio de Janeiro, Brazil Jamile Garcia de Oliveira and João Marine Clínica de Saúde Rinaldo Delmare, Rio de Janeiro, Brazil Adriana Rezende and Anna Cristina Carvalho Secretaria de Saúde de Duque de Caxias, Rio de Janeiro, Brazil Michael Rocha and Betânia Nogueira Instituto Brasileiro para Investigação da Tuberculose, Fundação José Silveira, Salvador, Brazil Alexandra Brito and Renata Spener Fundação Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil Megan Turner Vanderbilt University Medical Center, Nashville, USA.

Tuberculous meningitis (TBM) is a potentially life-threatening form of tuberculosis (TB) that affects the central nervous system. Its management in patients with concomitant chronic liver disease (CLD) presents unique challenges due to altered drug metabolism with potentially impaired spinal fluid drug penetration and hepatotoxicity. The standard regimen for TBM includes isoniazid (INH) and rifampin (RIF), and Pyrazinamide (PZA) which are metabolized by the liver and may cause hepatotoxicity, which can exacerbate preexisting liver disease. Thus, careful consideration is required to balance therapeutic efficacy with potential drug-induced hepatotoxicity. Regular monitoring of liver function tests and clinical response is essential to minimize adverse effects and optimize treatment outcomes. Further research is needed to establish evidence-based guidelines for the tailored management of TBM in this vulnerable patient subset. Overall, the treatment of TBM in patients with severe liver disease should be individualized and closely monitored.

Tuberculosis (TB) is a leading cause of mortality worldwide, and resistance to anti-tuberculosis drugs is a challenge to effective treatment. Multi-drug resistant TB (MDR-TB) can be difficult to treat, requiring long durations of therapy and the use of second line drugs, increasing a patient's risk for toxicities and treatment failure. Given the challenges treating MDR-TB, clinicians can improve the likelihood of successful outcomes by utilizing therapeutic drug monitoring (TDM). TDM is a clinical technique that utilizes measured drug concentrations from the patient to adjust therapy, increasing likelihood of therapeutic drug concentrations while minimizing the risk of toxic drug concentrations. This review paper provides an overview of the TDM process, pharmacokinetic parameters for MDR-TB drugs, and recommendations for dose adjustments following TDM.