Clinical characteristics and risk factors for antituberculosis drug-induced hypersensitivity.

AIMS: The aim of this study was to explore the clinical characteristics and risk factors for hypersensitivity reactions induced by antituberculosis drugs. METHODS: A retrospective analysis was conducted on the medical records of patients with active tuberculosis (TB) treated in the TB ward at West China Hospital, Sichuan University, from November 2010 to April 2020. RESULTS: Out of 7106 patients with active tuberculosis, 205 experienced hypersensitivity reactions to antituberculosis drugs; the incidence of hypersensitivity was 2.9%. The predominant clinical manifestation was a rash, observed in 57.1% (117/205) of these cases. Additionally, 19.0% (39/205) of patients presented with concurrent liver injury. The laboratory parameters white blood cell count, total lymphocyte count, monocyte count, eosinophil count, basophil count, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase were significantly elevated in patients with hypersensitivity compared to those without. In 38 patients who tested positive for oral antituberculosis drug provocation, 14 (36.8%) were allergic to more than two antituberculosis drugs. Significant risk factors included being female (odds ratio [OR] = 1.387, 95% confidence intervals [CI]: 1.016-1.894), under 65 years of age (OR = 1.826, 95% CI: 1.145-2.913), existing liver disease (OR = 2.464, 95% CI: 1.822-3.333) and a history of allergic diseases (OR = 6.633, 95% CI: 2.681-16.406) and were significantly correlated with hypersensitivity to antituberculosis drugs. CONCLUSIONS: Hypersensitivity reactions to antituberculosis drugs primarily affect the skin, with significant associations observed with liver injury. Females, individuals younger than 65 years, those with pre-existing liver disease and patients with a history of allergic diseases are at elevated risk for hypersensitivity.

SLCO1B1 variants and the risk of antituberculosis drug-induced hepatotoxicity: a systematic review and meta-analysis.

Aims: To evaluate the association between SLCO1B1 gene polymorphisms and susceptibility of antituberculosis drug-induced hepatotoxicity (ATDH). Methods: We searched the PubMed, Cochrane Library, Embase, Web of Science, Wan Fang and China National Knowledge Infrastructure database from inception to 2022. Results: Nine case-control studies with 1129 cases and 2203 controls were included. Among four SNPs reported in two or more studies, the final results indicated that SNP rs4149014 was significantly associated with decreased ATDH risk (dominant model, odds ratio: 0.73; 95% CI: 0.55-0.97; p = 0.03; allele model, odds ratio: 0.69; 95% CI: 0.55-0.86; p = 0.001), and the trial sequential analysis also confirmed this significant association. Conclusion: SLCO1B1 gene SNP rs4149014 was significantly associated with lower risk of ATDH susceptibility.

Glutamate dehydrogenase combined with ferrochelatase as a biomarker of liver injury induced by antituberculosis drugs.

AIMS: To explore the potential value of serum glutamate dehydrogenase (GLDH), ferrochelatase (FECH), heme oxygenase-1 (HO-1) and glutathione-S-transferase-α (GST-α) as diagnostic biomarkers for liver injury caused by antituberculosis drugs. METHODS: We established a rat model of isoniazide-induced liver injury and recruited 122 hospitalized tuberculosis patients taking antituberculosis drugs. We detected the concentration of GLDH, FECH, HO-1 and GST-α by enzyme-linked immunosorbent assay. GraphPad Prism8 and SPSS 26.0 were used for statistical analysis. RESULTS: In the rat model, serum GLDH concentration gradually increased during isoniazid (INH) administration, while serum FECH, HO-1 and GST-α concentrations significantly increased after INH administration was stopped. The receiver operating characteristic curve showed that the areas under the curve (AUCs) of serum GLDH and FECH for the diagnosis of anti-tuberculosis (TB) drug-induced liver injury (anti-TB-DILI) were 0.7692 (95% confidence interval [CI] 0.5442-0.9943) and 0.7284 (95% CI 0.4863-0.9705) and the diagnostic accuracies were 81.25% and 78.79%, respectively. In clinical research, the AUCs of GLDH and FECH were 0.9124 (95% CI 0.8380-0.9867) and 0.6634 (95% CI 0.5391-0.7877), and the optimal thresholds were 10.40 mIU/mL and 1.304 ng/mL, respectively. The diagnostic accuracy, specificity and positive predictive value (PPV) of GLDH were 82.61%, 79.38% and 47.22%. We performed a joint diagnostic test for GLDH and FECH. The diagnostic accuracy (90.43%), specificity (91.75%) and PPV (65.21%) of serial tests were better than for GLDH and FECH alone. CONCLUSIONS: GLDH in the diagnosis of liver injury induced by anti-TB drugs has high sensitivity, but low specificity and low PPV. The combination of GLDH and FECH could significantly improve the specificity, PPV and diagnostic accuracy, and reduce the false-positive rate of anti-TB-DILI.

Genetic variants of the nuclear factor erythroid 2-related factor 2/antioxidant reaction element pathway on the risk of antituberculosis drug-induced liver injury: a systematic review.

Aim: To evaluate the effects of genetic variants in the nuclear factor erythroid 2-related factor 2/antioxidant reaction element signaling pathway on antituberculosis drug-induced liver injury (AT-DILI) susceptibility. Methods: The PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure and Wanfang databases were searched from inception to April 2022. Results: Seven case-control studies with 4676 patients were included. Six genes with 35 SNPs in the pathway have been reported. Among 17 SNPs reported in two or more studies, the meta-analysis indicated that only one SNP (rs3735656 in MAFK) was significantly associated with a decreased risk for AT-DILI under the dominant model (odds ratio: 0.636; 95% CI: 0.519-0.780; p < 0.001). Conclusion: SNP rs3735656 in the MAFK gene was significantly associated with the risk of AT-DILI.

Relationship between common telomere length-related genetic variations, telomere length, and risk of antituberculosis drug-induced hepatotoxicity in Chinese Han population: As assessed for causality using the updated Roussel Uclaf Causality Assessment Method.

Antituberculosis drug-induced hepatotoxicity (ATDH) is a significant threat to tuberculosis control, and two recent studies indicated that leukocyte telomere length (LTL) might be a potential biomarker for ATDH. This study aimed to investigate the relationship between common telomere length-related genetic variations, LTL, and risk of ATDH in Eastern Chinese antituberculosis treatment patients. A 1:4 matched case-control study was conducted among 79 ATDH cases assessed for causality using the updated RUCAM and 316 controls. LTL was determined by quantitative real-time PCR, and nine SNPs involved in telomere biology reported by previous GWAS were assessed. Conditional logistic regression model was used to estimate the association between genotypes and risk of ATDH with odds ratios (ORs) and 95% confidence intervals (CIs). The average RUCAM score of cases was 7.1. The average LTL in cases was significantly shorter than that in controls (median = 1.239 vs. 1.481, P = 0.032). Differences in the distribution of LTL were statistically significant among three genotypes of SNP rs2736098 (CC vs. CT vs. TT, median = 1.544 vs. 1.356 vs. 1.337, P = 0.026) and rs2853677 (AA vs. AG vs. GG, median = 1.511 vs. 1.544 vs. 1.159, P = 0.005) in TERT. SNP rs7675998 in NAF1 was statistically associated with the risk of ATDH under the dominant model (adjusted OR = 1.725, 95% CI: 1.021-2.913, P = 0.042). This is the first study to investigate the relationship of LTL, common telomere length-related variations, and risk of ATDH. SNP rs2736098 and rs2853677 in TERT were significantly associated with LTL, and SNP rs7675998 in NAF1 may be associated with ATDH in Chinese population.

Antituberculosis Macozinone Extended-Release Tablets To Enhance Bioavailability: a Pilot Pharmacokinetic Study in Beagle Dogs.

Macozinone (MCZ; PBTZ169) is a first-in-class antituberculosis clinical-stage benzothiazinone-based drug candidate. Although its efficacy and safety have been strongly proven in several preclinical and clinical studies, the physicochemical and pharmacokinetic properties specific to MCZ required further optimization. Accordingly, this study aimed to evaluate the pharmacokinetics of MCZ administered as extended-release (ER) tablets F2 and F6 compared to immediate-release (IR) dispersible tablets for oral suspension. Oral absorption of MCZ from ER tablets was significantly different from that of IR tablets after a single oral dose in Beagle dogs in both fasted and fed states. In addition, food directly affects the bioavailability of MCZ from ER tablets but does not affect it from IR tablets. The high values of relative bioavailability of the prolonged-release tablets F2 and F6 compared to the IR tablets may indicate an indirect confirmation of their gastroretentive properties. Taken together, pharmacokinetic parameters have demonstrated that these MCZ oral formulations not just enhance drug bioavailability but may also improve regimen adherence by reducing MCZ dose frequency and reducing the development of drug resistance. IMPORTANCE Macozinone (MCZ) is the newest first-in-class clinical-stage benzothiazinone-based drug candidate for the treatment of tuberculosis. Yet, the extremely low oral bioavailability of MCZ, a major problem in clinical trials, needed to be addressed, and we are pleased to present our attempts to solve this issue. We report that extended-release tablets of MCZ significantly increased key pharmacokinetic parameters in the preclinical setting. We suggest that these MCZ oral formulations not just enhance drug bioavailability but may also improve regimen adherence by reducing MCZ dose frequency and reducing the development of drug resistance.

NADH alleviates anti-tuberculosis drug-induced liver injury and apoptosis in mice through SIRT1/Nrf2 pathway / 安徽医科大学学报

Objective To investigate the mechanism by which Nicotinamide adenine dinucleotide(NADH)regu-lates anti-tuberculosis drug-induced liver injury and apoptosis in mice through SIRT1/Nrf2 pathway.Methods Twenty-four six-week-old SPF male mice were randomly divided into four groups according to body weight,ADLI group[90 mg/(kg·d)Isoniazid,135 mg/(kg·d)Rifampicin,315 mg/(kg·d)Pyrazinamide were given by gavage],control group[thesame volume of saline was given by gavage as antituberculosis drug-induced liver injury(ADLI)group],NADH group(30 mg/kg NADH wasgiven by gavage on the basis of control group)and NADH intervention group(30 mg/kg NADH wasgiven by gavage on the basis of ADLI group),with sixmice in each group.They were gavaged continuously for seven days,and their seruand liver tissues were collected.The mRNA and protein expression of silence information regulator 1(SIRT1),nuclear factor erythroid 2-related factor 2(Nrf2)in SIRT1/Nrf2 pathway,apoptosis indicators B-cell lymphoma-2(Bcl-2),Bcl-2-associated X protein(Bax)and caspase-3 were detected by qRT-PCR and Western blot,respectively.HE staining was performed to observe the morphology of liver tissue.The liver was weighedandthe liver index was obtained by dividingweight by body weight.The levels of glutamate aminotransferase(ALT),aspartate aminotransferase(AST)and lactate dehydrogenase(LDH),which are indicators of liver injury,were detected by microplate method.Results Compared with control group,the protein and mRNA expression of SIRT1,Nrf2decreased significantly in ADLI group.Liver tissue struc-ture wasdisturbed,hepatocytes were obviously swollen,and their boundary was unclear.The weight of mice de-creased,but liver index increased.The mRNA and protein expression level of anti-apoptotic factor Bcl-2 decreased,while that of Bax and caspase-3 was raised.The level of ALT,AST and LDH were also elevated.The differences a-bove were statistically significant(P＜0.05).Compared with ADLI group,the protein and mRNA expression of SIRT1,Nrf2 were higher after NADH intervention.Liver tissue structure became clear,and hepatocytes were po-lygonal.The protein and mRNA expression of anti-apoptosis factor Bcl-2 was elevated and while that of Bax and caspase-3 was lower.The weight of mice increased and liver index decreased.The expression of ALT,AST and LDH decreased.The differences above were statistically significant(P＜0.05).Conclusion NADH may allevi-ate anti-tuberculosis drug-induced liver injury and apoptosis in mice by regulating SIRT1/Nrf2 pathway.

The first-line antituberculosis drugs, and their fixed-dose combination induced abnormal sperm morphology and histological lesions in the testicular cells of male mice.

Rifampicin (RIF), Isoniazid (INH), Ethambutol (EMB), Pyrazinamide (PZA), and/or their fixed-dose combination (FDC) are extensively prescribed in the cure of Tuberculosis (TB) globally. In spite of the beneficial effect, these drugs are capable of inducing cellular toxicity. Existing information on the genotoxic effects of the first-line anti-TB drugs is limited and contentious. Herein, we evaluated the reproductive genotoxicity of RIF, INH, EMB, PZA, and their FDC utilizing the mouse sperm morphology assay. Histological examination of the testes of exposed mice was also performed. Male Swiss albino mice (11-13 weeks old) were intraperitoneally exposed for 5 consecutive days to each of the anti-TB drugs at four different doses of 6.25, 12.5, 25, and 50 mg/kg bw of PZA; 2.5, 5.0, 10, and 20 mg/kg bw of RIF; 1.25, 2.5, 5.0 and 10 mg/kg bw of INH; 3.75, 7.5, 15 and 30 mg/kg bw of EMB; and 7, 14, 28 and 56 mg/kg bw of FDC corresponding respectively to ×0.25, ×0.5, ×1 and ×2.0 of the standard daily dose. In comparison with the negative control (normal saline), there was no significant difference in the testicular weight and organo-somatic index of exposed mice. There was an increase (p > 0.05) in the frequency of abnormal spermatozoa at most of the tested doses of each drug and a dose-dependent decrease with the FDC. Each of the anti-TB drugs except the FDC induced pathological lesions in the testes. These findings suggest that the individual first-line anti-TB drug unlike the FDC has the potential to provoke testicular anomalies in male mice.

Mitochondrial DNA content as a diagnostic marker for antituberculosis drug-induced liver injury.

OBJECTIVES: This study aimed to investigate whether mitochondrial DNA (mtDNA) content, an index of mitochondrial dysfunction, was associated with clinical parameters indicating anti-tuberculosis (TB) drug-induced liver injury (ATDILI) in TB patients and could emerge as an ATDILI biomarker. METHODS: Leukocyte mtDNA content in 102 TB patients (49 ATDILI cases and 53 non-ATDILI cases) and 100 age-matched healthy controls was measured using real-time polymerase chain reaction. RESULTS: Compared with healthy controls, both TB patients with and without ATDILI had significantly decreased mtDNA content. Compared with the patients without ATDILI, mtDNA content was significantly increased in those with ATDILI. Higher mtDNA content was observed to be independently associated with increased susceptibility to ATDILI. Increased mtDNA content measured within 1-7 days of treatment was independently associated with elevated levels of serum aminotransferases assessed within 8-60 days of treatment. After initiating treatment within 1-7 days, mtDNA content was detected to be more sensitive and selective for differentiating TB patients with ATDILI from those without ATDILI than serum aminotransferases. Kaplan-Meier analysis revealed a significant correlation between elevated mtDNA content and increased rate of ATDILI occurrence in TB patients, attested by Cox regression analysis, adjusting for confounders. CONCLUSION: Changes in leukocyte mtDNA content would reflect ATDILI progression and could be used as a potential stratification tool for identifying TB patients at risk of ATDILI.

Spectroscopic analysis to identify the binding site for Rifampicin on Bovine Serum Albumin.

This article reports the interaction of rifampicin, one of the important antituberculosis drugs, with Bovine Serum Albumin (BSA). Herein, we have monitored the fluorescence properties of tryptophan (Trp) residue in BSA to understand the interactions between protein and rifampicin. Fluorescence intensity of BSA was quenched tremendously upon interacting with the drug. Using steady state and time-resolved spectroscopic tools the static and dynamic nature of quenching have been characterised. Time correlated single photon counting technique confirmed that out of two lifetime components ∼6.2 ns and ∼2.8 ns of BSA, the rifampicin has affected only the shorter lifetime component a lot that was assigned to Trp-213 residue. Hence, it was thought that the drug must have been located near to the amino acid residue. Molecular docking studies have revealed the structural information of drug-protein complex which supported the above conjecture, confirming the nearest tryptophan as Trp-213 to the complexing rifampicin molecule.

Videoendoscopic Evaluation of Swallowing in Patients with Active Pulmonary Tuberculosis：A Retrospective Study / The Japanese Journal of Rehabilitation Medicine

Purpose：In recent years, the proportion of older people diagnosed with lung tuberculosis is increasing in Japan. There have been no previous reports on detailed evaluation of swallowing function in patients with pulmonary tuberculosis. This study aimed to retrospectively evaluate the severity and characteristics of dysphagia using videoendoscopic evaluation of swallowing (VE) in patients with lung tuberculosis.Methods：A total of 58 patients (average age, 85.2 years) were selected. They are diagnosed with active pulmonary tuberculosis and underwent VE (performed an average 23 days after admission) at our hospital between January 2017 and March 2020. The severity of dysphagia was assessed using the functional oral intake scale (FOIS)．Activities of daily living (ADL) of the patients was evaluated by using Barthel Index (BI).Results：The average body mass index of the patients was 17 kg/m2, average serum albumin was 2.3 mg/dl, and average BI score was 8.6. Approximately, 71％ of the patients showed severe dysphagia (FOIS 1-2), and BI score of the group was significantly lower than that of the moderate group (FOIS＞3). We observed residual thickened water in 76％ of the patients. Before the VE, 45％ patients were administered oral anti-tuberculosis drugs. Only 35％ of the patients continued those drugs after VE, and 45％ of the patients died in hospital.Conclusion：The results suggest that patients with pulmonary tuberculosis might have a high frequency of severe dysphagia. Appropriate method of anti-tuberculosis drug administration should be selected based on their swallowing functions.

Videoendoscopic Evaluation of Swallowing in Patients with Active Pulmonary Tuberculosis：A Retrospective Study / The Japanese Journal of Rehabilitation Medicine

Purpose：In recent years, the proportion of older people diagnosed with lung tuberculosis is increasing in Japan. There have been no previous reports on detailed evaluation of swallowing function in patients with pulmonary tuberculosis. This study aimed to retrospectively evaluate the severity and characteristics of dysphagia using videoendoscopic evaluation of swallowing (VE) in patients with lung tuberculosis.Methods：A total of 58 patients (average age, 85.2 years) were selected. They are diagnosed with active pulmonary tuberculosis and underwent VE (performed an average 23 days after admission) at our hospital between January 2017 and March 2020. The severity of dysphagia was assessed using the functional oral intake scale (FOIS)．Activities of daily living (ADL) of the patients was evaluated by using Barthel Index (BI).Results：The average body mass index of the patients was 17 kg/m2, average serum albumin was 2.3 mg/dl, and average BI score was 8.6. Approximately, 71％ of the patients showed severe dysphagia (FOIS 1-2), and BI score of the group was significantly lower than that of the moderate group (FOIS＞3). We observed residual thickened water in 76％ of the patients. Before the VE, 45％ patients were administered oral anti-tuberculosis drugs. Only 35％ of the patients continued those drugs after VE, and 45％ of the patients died in hospital.Conclusion：The results suggest that patients with pulmonary tuberculosis might have a high frequency of severe dysphagia. Appropriate method of anti-tuberculosis drug administration should be selected based on their swallowing functions.

Crystal Structure of Mycobacterium tuberculosis Elongation Factor G1.

Mycobacterium tuberculosis (Mtb) caused an estimated 10 million cases of tuberculosis and 1.2 million deaths in 2019 globally. The increasing emergence of multidrug-resistant and extensively drug-resistant Mtb is becoming a public health threat worldwide and makes the identification of anti-Mtb drug targets urgent. Elongation factor G (EF-G) is involved in tRNA translocation on ribosomes during protein translation. Therefore, EF-G is a major focus of structural analysis and a valuable drug target of antibiotics. However, the crystal structure of Mtb EF-G1 is not yet available, and this has limited the design of inhibitors. Here, we report the crystal structure of Mtb EF-G1 in complex with GDP. The unique crystal form of the Mtb EF-G1-GDP complex provides an excellent platform for fragment-based screening using a crystallographic approach. Our findings provide a structure-based explanation for GDP recognition, and facilitate the identification of EF-G1 inhibitors with potential interest in the context of drug discovery.

Ultrasound-Assisted Synthesis of 4-Alkoxy-2-methylquinolines: An Efficient Method toward Antitubercular Drug Candidates.

Tuberculosis (TB) has been described as a global health crisis since the second half of the 1990s. Mycobacterium tuberculosis (Mtb), the etiologic agent of TB in humans, is a very successful pathogen, being the main cause of death in the population among infectious agents. In 2019, it was estimated that around 10 million individuals were contaminated by this bacillus and about 1.2 million succumbed to the disease. In recent years, our research group has reported the design and synthesis of quinoline derivatives as drug candidates for the treatment of TB. These compounds have demonstrated potent and selective growth inhibition of drug-susceptible and drug-resistant Mtb strains. Herein, a new synthetic approach was established providing efficient and rapid access (15 min) to a series of 4-alkoxy-6-methoxy-2-methylquinolines using ultrasound energy. The new synthetic protocol provides a simple procedure utilizing an open vessel system that affords the target products at satisfactory yields (45-84%) and elevated purities (≥95%). The methodology allows the evaluation of a larger number of molecules in assays against the bacillus, facilitating the determination of the structure-activity relationship with a reduced environmental cost.

Prospective study of ALDH1A1 gene polymorphisms associated with antituberculosis drug-induced liver injury in western Chinese Han population.

Antituberculosis drug-induced liver injury (ATDILI) has received increasing attention globally, which may limit the effectiveness of antituberculosis (anti-TB) treatment. Many host genetic determinants of ATDILI have been identified recently. As little knowledge is currently available about the association between aldehyde dehydrogenase 1 family member A1 (ALDH1A1) polymorphisms and ATDILI, the association between their variants and the susceptibility to ATDILI was investigated. A total of 747 patients with TB treated by first-line anti-TB drugs were prospectively enrolled at West China Hospital. Genomic DNA was extracted from the peripheral blood sample of each patient and seven single-nucleotide polymorphisms (SNPs) of ALDH1A1 gene were screened and genotyped with a custom-designed 2×48-plex SNP Scan TM kit. The patients were followed up monthly to monitor the development of ATDILI. The C allele and the CA genotype of rs7852860 were significantly associated with an elevated risk for ATDILI (p = .006 and 0.005, respectively), which was consistent with the results in the dominant and additive models. No allele, genotype, or genetic model of the other six SNPs (rs3764435, rs348471, rs63319, rs610529, rs7027604, rs8187876) were found to be associated with susceptibility to ATDILI. The findings first demonstrate that rs7852860 variants in ALDH1A1 gene is associated with susceptibility to ATDILI in the Chinese Han population. Validation studies with larger sample sizes and other ethnic groups are needed to confirm the findings.

Patients with tuberculous meningitis and hepatitis B co-infection have increased risk for antituberculosis drug-induced liver injury and poor outcomes.

BACKGROUND: Tuberculous meningitis (TBM) is one of the most severe forms of tuberculosis. Previous studies reported that hepatitis B virus (HBV) infection could increase the risk of antituberculosis drug-induced liver injury (ATB-DILI) in pulmonary tuberculosis patients. To date, only a few studies exist on the effect of HBV on TBM. METHODS: This inpatient study retrospectively analyzed the medical records of patients who were diagnosed with TBM between June 2002 and June 2018. Statistical analysis was used to reveal the difference between the HBV and non-HBV groups. Univariate analysis and multivariate regression analysis were performed on data to determine the prognostic factors of TBM. RESULTS: A total of 386 patients were enrolled in our study, 57 of whom were included in the HBV group and 329 in the non-HBV group. The HBV group showed a higher frequency of ATB-DILI (HBV group: 14.0% versus non-HBV group: 3.3%, p < .001) and a higher risk of poor outcomes (i.e. death during inpatient period or neurological deficit at discharge, HBV group: 31.6% versus non-HBV group: 19.8%, p = .045) than the non-HBV group. The multivariate regression analysis identified ATB-DILI, scores of 3-8 on the Glasgow Coma Scale and hydrocephalus as independent predictors of poor outcomes in TBM patients. CONCLUSIONS: Our study demonstrated that HBV co-infection could increase the incidence of ATB-DILI and the risk of poor outcomes as identified by three predictors in TBM patients.

MmpL3 inhibitors as antituberculosis drugs.

The mycobacterial membrane protein Large 3 (MmpL3) is an inner membrane protein that transports trehalose-monomycolates, precursors for trehalose-dimycolates and mycolic acids that make up essential components of the mycobacterial outer membrane. Inhibition of MmpL3 weakens the mycobacterial cell wall and ultimately results in cell death in both in vitro and in vivo infection models. This highlights the therapeutic potential of MmpL3 as a drug target. High-throughput whole-cell screening along with whole genome sequencing of resistant mutants has identified numerous classes of compounds that can be classified as MmpL3 inhibitors. In this review, we provide insights into the current development of various MmpL3 inhibitors and discuss the potential challenges in this area.

Association of ABO blood group and antituberculosis drug-induced liver injury: A case-control study from a Chinese Han population.

WHAT IS KNOWN AND OBJECTIVE: Antituberculosis drug-induced liver injury (ATLI) is a serious adverse drug reaction, and its pathogenic mechanism is still largely unknown. Rifampin (RIF) has been reported to cause haemolysis due to the production of drug-dependent antibodies, and haemolysis results in an increased level of free haem, which affects the function of hepatocytes. Blood group determinants can act as specific receptor sites for drug-antibody complexes, causing erythrocyte destruction in the presence of RIF. RIF-induced immune haemolysis may be a potential mechanism for ATLI. Thus, the study aimed to explore the role of ABO blood group systems in Chinese ATLI patients. METHODS: A 1:4 matched case-control study was conducted among 146 ATLI cases and 584 controls. Multivariable conditional logistic regression and Cox proportional regression were used to estimate the association between ABO blood group and risk of ATLI by odds ratio (OR), hazards ratio (HR) and 95% confidence intervals (CIs), and liver disease history and taking hepatoprotectant were used as covariates. RESULTS AND DISCUSSION: Patients in the A, B, AB and non-O blood groups had a significantly higher risk of ATLI than those in the O blood group (OR = 1.832, 95% CI: 1.126-2.983, P = .015; OR = 1.751, 95% CI: 1.044-2.937, P = .034; OR = 2.059, 95% CI: 1.077-3.938, P = .029; OR = 1.822, 95% CI: 1.173-2.831, P = .007, respectively). After considering the time of ALTI occurrence, similar results were found in the A, B, AB and non-O blood groups (HR = 1.676, 95% CI: 1.072-2.620, P = .024; HR = 1.620, 95% CI: 1.016-2.584, P = .043; HR = 2.010, 95% CI: 1.130-3.576, P = .018; HR = 1.701, 95% CI: 1.138-2.542, P = .010, respectively). Furthermore, subgroup analysis also detected a significant association between ABO blood group and ATLI in patients taking RIF (P < .05). However, no significant difference was observed in patients not taking RIF (P > .05). WHAT IS NEW AND CONCLUSION: The present study is the first to evaluate the role of ABO blood group systems in Chinese ATLI cases. Based on the present matched case-control study, the ABO blood group may be associated with susceptibility to ATLI in the Chinese antituberculosis population, especially in patients with blood groups A, B and AB who are taking RIF.

Drug-induced liver injury in pregnancy.

Drug intake in pregnant women is common, including prescribed and over-the-counter medications, and herbal medicine and supplements. Drug-induced liver injury (DILI) has become the leading cause of acute liver failure in Western countries, and pregnancy is thought to be a risk factor, but only few anecdotal reports concerning pregnant women are found. These involved antihypertensive, antithyroid, antiretroviral, and antituberculosis medications, and antibiotics. Presentation was usually in the first 20 weeks of gestation following a latency of several weeks, because these drugs were usually prescribed before or in early pregnancy due to their fetal safety. The hepatotoxicity is usually of the idiosyncratic form, and most would resolve spontaneously although occasional liver transplantation and maternal death were reported. The scanty reports could have been related to under-reporting and missed diagnosis due to spontaneous resolution in most cases. DILI should remain one of the differential diagnoses in pregnant women with hepatitis.