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INTRODUCTION: Alcohol use is common in patients with chronic hepatitis C virus (HCV) infection. We examined the impact of alcohol use on direct-acting antiviral (DAA) therapy outcome and the clinical course of liver disease and 2-year survival for patients receiving HCV DAA therapy. METHODS: Adults (n = 2624) recruited from 26 Australian hospital liver clinics during 2016-2021 were followed up for 2 years. Risky alcohol use was defined by a combination of self-report (≥40 g/day of ethanol), physician-reported history of problematic alcohol use, and anti-craving medication prescription via population-based database linkage. We examined factors associated with advanced liver fibrosis and survival using multivariable logistic and Cox regression. RESULTS: Among 1634 patients (62.3%) with risky alcohol use, 24.6% reported consuming ≥40 g/day of alcohol, 98.3% physician-reported problematic alcohol use; only 4.1% were dispensed naltrexone/acamprosate. One hundred and forty-three patients with cirrhosis reported ≥40 g/day of alcohol, 6 (4.3%) were prescribed naltrexone/acamprosate. Risky alcohol use was associated with advanced fibrosis (adjusted-odds ratio 1.69, 95% confidence interval 1.32-2.17) and patients were over-represented for cirrhosis (45.1% vs. 25.6% in no-risky alcohol use [p < 0.001]) and hepatocellular carcinoma (5.7% vs. 2.5% [p < 0.001]). Sustained viral response (p = 0.319) and 2-year survival (adjusted-hazard ratio 1.98, 95% confidence interval 0.84-4.63) after DAA therapy were not associated with risky alcohol use. DISCUSSION AND CONCLUSIONS: Risky alcohol use in HCV patients was prevalent, but did not reduce HCV cure. Treatment for alcohol dependence was low. Risky alcohol use may be under-recognised in liver clinics. Better integration of addiction medicine into liver services and increased resourcing and addiction medicine training opportunities for hepatologists may help address this.
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BACKGROUND: Therapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking. METHODS: Trans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses. DISCUSSION: The SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research. TRIAL REGISTRATION: anzctr.org.au, ACTRN12621001444875, registered 21 October 2021.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Radiocirugia , Nivel de Atención , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/cirugía , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/cirugía , Radiocirugia/métodos , Estudios Prospectivos , Masculino , Femenino , Estadificación de Neoplasias , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Anciano , AdultoRESUMEN
Background: Hepatitis C virus (HCV) infection can now be cured with well-tolerated direct-acting antiviral (DAA) therapy. However, a potential barrier to HCV elimination is the emergence of resistance-associated substitutions (RASs) that reduce the efficacy of antiviral drugs, but real-world studies assessing the clinical impact of RASs are limited. Here, an analysis of the impact of RASs on retreatment outcomes for different salvage regimens in patients nationally who failed first-line DAA therapy is reported. Methods: We collected data from 363 Australian patients who failed first-line DAA therapy, including: age, sex, fibrosis stage, HCV genotype, NS3/NS5A/NS5B RASs, details of failed first-line regimen, subsequent salvage regimens, and treatment outcome. Results: Of 240 patients who were initially retreated as per protocol, 210 (87.5%) achieved sustained virologic response (SVR) and 30 (12.5%) relapsed or did not respond. The SVR rate for salvage regimens that included sofosbuvir/velpatasvir/voxilaprevir was 94.3% (n = 140), sofosbuvir/velpatasvir 75.0% (n = 52), elbasvir/grazoprevir 81.6% (n = 38), and glecaprevir/pibrentasvir 84.6% (n = 13). NS5A RASs were present in 71.0% (n = 210) of patients who achieved SVR and in 66.7% (n = 30) of patients who subsequently relapsed. NS3 RASs were detected in 20 patients (20%) in the SVR group and 1 patient in the relapse group. NS5B RASs were observed in only 3 patients. Cirrhosis was a predictor of relapse after retreatment, as was previous treatment with sofosbuvir/velpatasvir. Conclusions: In our cohort, the SVR rate for sofosbuvir/velpatasvir/voxilaprevir was higher than with other salvage regimens. The presence of NS5A, NS5B, or NS3 RASs did not appear to negatively influence retreatment outcomes.
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Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator-activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.
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BACKGROUND: Direct-acting antiviral (DAA) therapies for hepatitis C virus infection (HCV) lead to excellent rates of sustained virological response (SVR). However, loss to follow-up (LTFU) for SVR testing remains a challenge. We examine factors associated with LTFU in a real-world setting. METHODS: Adults who received DAA therapy for HCV in one of 26 centers across Australia during 2016-2021 were followed up for 2 years. Data sources included the patient medical records and the national Pharmaceutical and Medicare Benefits Schemes. Linkage to Medicare provided utilization data of other health-care providers and re-treatment with DAAs. LTFU was defined as no clinic attendance for SVR testing by at least 52 weeks after DAA treatment commencement. Multivariable logistic regression assessed factors associated with LTFU. RESULTS: In 3619 patients included in the study (mean age 52.0 years; SD = 10.5), 33.6% had cirrhosis (69.4% Child-Pugh class B/C), and 19.3% had HCV treatment prior to the DAA era. Five hundred and fifteen patients (14.2%) were LTFU. HCV treatment initiation in 2017 or later (adj-OR = 2.82, 95% confidence interval [CI] 2.25-3.54), younger age (adj-OR = 2.63, 95% CI 1.80-3.84), Indigenous identification (adj-OR = 1.99, 95% CI 1.23-3.21), current injection drug use or opioid replacement therapy (adj-OR = 1.66, 95% CI 1.25-2.20), depression treatment (adj-OR = 1.49, 95% CI 1.17-1.90), and male gender (adj-OR = 1.31, 95% CI 1.04-1.66) were associated with LTFU. CONCLUSIONS: These findings stress the importance of strengthening the network of providers caring for patients with HCV. In particular, services targeting vulnerable groups of patients such as First Nations Peoples, youth health, and those with addiction and mental health disorders should be equipped to treat HCV.
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Hepatitis C Crónica , Hepatitis C , Adulto , Humanos , Masculino , Anciano , Adolescente , Persona de Mediana Edad , Antivirales/uso terapéutico , Programas Nacionales de Salud , Hepatitis C/tratamiento farmacológico , Hepacivirus , Respuesta Virológica Sostenida , Atención al Paciente , Continuidad de la Atención al PacienteRESUMEN
BACKGROUND: Epithelioid haemangioendothelioma (EHE) is an ultra-rare malignant vascular tumour with a prevalence of 1 per 1,000,000. It is typically molecularly characterised by a WWTR1::CAMTA1 gene fusion in approximately 90% of cases, or a YAP1::TFE3 gene fusion in approximately 10% of cases. EHE cases are typically refractory to therapies, and no anticancer agents are reimbursed for EHE in Australia. METHODS: We report a cohort of nine EHE cases with comprehensive histologic and molecular profiling from the Walter and Eliza Hall Institute of Medical Research Stafford Fox Rare Cancer Program (WEHI-SFRCP) collated via nation-wide referral to the Australian Rare Cancer (ARC) Portal. The diagnoses of EHE were confirmed by histopathological and immunohistochemical (IHC) examination. Molecular profiling was performed using the TruSight Oncology 500 assay, the TruSight RNA fusion panel, whole genome sequencing (WGS), or whole exome sequencing (WES). RESULTS: Molecular analysis of RNA, DNA or both was possible in seven of nine cases. The WWTR1::CAMTA1 fusion was identified in five cases. The YAP1::TFE3 fusion was identified in one case, demonstrating unique morphology compared to cases with the more common WWTR1::CAMTA1 fusion. All tumours expressed typical endothelial markers CD31, ERG, and CD34 and were negative for pan-cytokeratin. Cases with a WWTR1::CAMTA1 fusion displayed high expression of CAMTA1 and the single case with a YAP1::TFE3 fusion displayed high expression of TFE3. Survival was highly variable and unrelated to molecular profile. CONCLUSIONS: This cohort of EHE cases provides molecular and histopathological characterisation and matching clinical information that emphasises the molecular patterns and variable clinical outcomes and adds to our knowledge of this ultra-rare cancer. Such information from multiple studies will advance our understanding, potentially improving treatment options.
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Lean patients with MAFLD have an initial adaptive metabolic response characterised by increased serum bile acids and Farnesoid X Receptor (FXR) activity. How this adaptive response wanes resulting in an equal or perhaps worse long-term adverse outcome compared to patients with obese MAFLD is not known. We show that patients with lean MAFLD have endotoxemia while their macrophages demonstrate excess production of inflammatory cytokines in response to activation by Toll-like receptor (TLR) ligands when compared to healthy subjects. Alterations of the lean MAFLD macrophage epigenome drives this response and suppresses bile acids signalling to drive inflammation. Our data suggests that selectively restoring bile acids signalling might restore adaptive metabolic responses in patients with MAFLD who are lean.
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Endotoxemia , Enfermedad del Hígado Graso no Alcohólico , Humanos , Receptores Citoplasmáticos y Nucleares/genética , Endotoxemia/genética , Inflamación/genética , Ácidos y Sales Biliares , Epigénesis GenéticaRESUMEN
Prostate specific membrane antigen (PSMA) is expressed by hepatocellular carcinoma (HCC). PSMA PET/CT has potential as an imaging agent for the detection of HCC including early diagnosis and monitoring for recurrence following surgical resection. This study aims to compare PSMA PET to standard surveillance imaging in the detection of HCC. Patients with suspected or treated HCC were prospectively recruited from a tertiary hospital outpatient clinic. In addition to routine surveillance imaging as recommended by the multidisciplinary team, a PSMA PET/CT was performed. Imaging and clinical characteristics were compared over a follow-up period of up to 12 months. In a cohort of 19 patients with known HCC or suspected recurrent HCC, PSMA PET/CT had similar efficacy to MRI for the detection of HCC, with a sensitivity of 91% and a specificity of 70% and sensitivity of 87% and a specificity of 73% for PSMA PET/CT and MRI, respectively. PSMA PET/CT had a higher negative predictive value of 90%. In this relatively large single centre study, PSMA is shown to have promising equivalence in performance and its role should be further evaluated in multi-centre prospective trials.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias de la Próstata , Humanos , Masculino , Carcinoma Hepatocelular/diagnóstico por imagen , Radioisótopos de Galio , Neoplasias Hepáticas/diagnóstico por imagen , Imagen por Resonancia Magnética , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Estudios Prospectivos , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND AND AIMS: In 2016, direct-acting antiviral (DAA) treatment for hepatitis C (HCV) became available through Australia's universal health care system, with the aim of HCV elimination. We report real-world effectiveness of DAA HCV treatment in Australia from a clinically well-informed cohort, enriched for cirrhosis and prior HCV treatment. METHODS: 3413 patients were recruited from 26 hospital liver clinics across Australia from February 2016 to June 2020. Clinical history and sustained viral response (SVR) were obtained from medical records and data linkage to the Australian Pharmaceutical Benefits Scheme. Factors associated with SVR were assessed by multivariable logistic regression (MVR). RESULTS: At recruitment, 32.2% had cirrhosis (72.9% Child Pugh class B/C), and 19.9% were treatment experienced. Of the 2,939 with data, 93.3% confirmed SVR. 137 patients received second-line therapy. Patients with cirrhosis had lower SVR rate (88.4 vs. 95.8%; p < 0.001). On MVR, failure to achieve SVR was associated with Genotype 3 (adj-OR = 0.42, 95%CI 0.29-0.61), male gender (adj-OR = 0.49, 95%CI 0.31-0.77), fair/poor adherence (adj-OR = 0.52, 95%CI 0.28-0.94), cirrhosis (adj-OR = 0.57, 95%CI 0.36-0.88), FIB-4 > 3.25 (adj-OR = 0.52, 95%CI 0.33-0.83) and MELD score ≥ 20 (adj-OR = 0.25, 95%CI 0.08-0.80). Consistent results were seen in cirrhotic sub-analysis. CONCLUSIONS: Excellent SVR rates were achieved with DAAs in this real-world cohort of patients with chronic HCV infection. More advanced liver disease and clinician impression of poor adherence were associated with HCV treatment failure. Supports to improve liver fibrosis assessment skills for non-specialist DAA prescribers in the community and to optimize patient adherence are likely to enable more effective pursuit of HCV elimination in Australia.
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Hepatitis C Crónica , Hepatitis C , Humanos , Masculino , Antivirales , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Respuesta Virológica Sostenida , Australia/epidemiología , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Cirrosis Hepática/complicaciones , Hepacivirus/genética , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Loss-of-function HSD17ß13 mutations protect against the development of chronic liver disease. HSD17ß13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17ß13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH. METHODS: The safety, tolerability, and pharmacodynamics of ARO-HSD were evaluated in 32 NHVs and 18 patients with confirmed/clinically suspected NASH. Double-blind NHV cohorts received single escalating doses of ARO-HSD (25, 50, 100, or 200 mg) or placebo subcutaneously on Day 1. Open-label patient cohorts received ARO-HSD (25, 100, or 200 mg) subcutaneously on Days 1 and 29. Liver biopsy was performed pre-dose and on Day 71 to evaluate expression levels of HSD17ß13 mRNA and protein. RESULTS: ARO-HSD treatment was well tolerated with no treatment-related serious adverse events or drug discontinuations. The most frequently reported treatment-emergent adverse events were mild injection site reactions, which were short in duration. Mean changes in hepatic HSD17ß13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17ß13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17ß13 protein levels were similarly reduced across doses. In patients, mean changes in alanine aminotransferase from baseline to Day 71 were -7.7% (25 mg), -39.3% (100 mg), and -42.3% (200 mg) (p <0.001 for pooled cohorts). CONCLUSIONS: ARO-HSD was well tolerated at doses ≤200 mg. This proof-of-concept study demonstrated that short-term treatment with ARO-HSD reduces hepatic HSD17ß13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase. GOV NUMBER: NCT04202354. IMPACTS AND IMPLICATIONS: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17ß13 expression and hence to phenocopy the protective effect seen in individuals with HSD17ß13 loss-of-function. The reductions in HSD17ß13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17ß13, a drug target with substantial genetic validation, as an important modulator of human liver disease.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Interferencia de ARN , Alanina Transaminasa , Hígado/patología , Pruebas de Función Hepática , Método Doble Ciego , Resultado del TratamientoRESUMEN
The breakdown of toll-like receptor (TLR) tolerance results in tissue damage, and hyperactivation of the TLRs and subsequent inflammatory consequences have been implicated as risk factors for more severe forms of disease and poor outcomes from various diseases including COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a negative regulator of TLR signalling. MBOAT7 deficiency in macrophages as observed in patients with MAFLD and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can potentially be explored as a therapeutic target for diseases associated with dysregulation of the TLR signalling cascade.
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COVID-19 , Hepatopatías , Humanos , Receptores Toll-Like , Aciltransferasas , Proteínas de la MembranaRESUMEN
BACKGROUND: The use of biologics poses a moderate to high risk for hepatitis B virus reactivation (HBVr) in chronic carriers. AIM: To determine the prevalence of HBVr with TNF alpha inhibitors, ustekinumab and vedolizumab METHOD: We followed the MOOSE guidelines and conducted a comprehensive literature search. We conducted a systematic search of EMBASE (Ovid), MEDLINE (Ovid) and PubMed. The studies included patients who were chronic and occult HBV carriers with various rheumatological, dermatological or gastroenterological conditions. We used a random effects model using pooled estimates (prevalence of HBVr with 95% confidence intervals (CI)). RESULTS: We included 29 studies with 1409 patients infected with HBV. The prevalence of HBVr in chronic carriers of HBV was 17.1% (95% CI: 7.0-35.9, n = 5), 16.6% (95% CI: 9.5-27.5%, n = 6), 40.5% (95% CI: 20.3-64.5%, n = 4) and 19.1% (95% CI: 7.3-41.2%, n = 2), respectively, for adalimumab, etanercept, infliximab and ustekinumab. The respective prevalence for reactivation in patients with occult HBV infection was 5.0% (95% CI: 2.8-8.7%, number of studies: n = 18), 2.6% (95% CI: 1.4-4.7%, n = 18), 4.4% (95% CI: 2.2-8.7%, n = 12) and 6.4% (95% CI: 2.2-16.8, n = 5). There were 39 HBVr (26 in chronic HBV and 13 in the occult group) without any hepatic failure or death. In the chronic HBVr group, only three of 24 patients received antiviral prophylaxis. CONCLUSIONS: HBVr prevalence rates differ between the chronic carrier state and the occult carrier state. The uptake of prophylactic antiviral therapy in high-risk groups was low, contrary to clinical practice guidelines.
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Terapia Biológica , Hepatitis B , Antivirales/efectos adversos , Terapia Biológica/efectos adversos , Hepatitis B/tratamiento farmacológico , Hepatitis B/epidemiología , Virus de la Hepatitis B , Humanos , Ustekinumab/efectos adversos , Activación ViralRESUMEN
BACKGROUND: First Nations Peoples of Australia are disproportionally affected by hepatitis C (HCV) infection. Through a prospective study we evaluated the outcome of direct-acting antiviral (DAA) therapy among First Nations Peoples with HCV infection. METHODS: Adults who initiated DAA therapy at one of 26 hospitals across Australia, 2016-2019 were included in the study. Clinical data were obtained from medical records and the Pharmaceutical and Medicare Benefits Schemes. Outcomes included sustained virologic response (SVR) and loss to follow-up (LTFU). A multivariable analysis assessed factors associated with LTFU. RESULTS: Compared to non-Indigenous Australians (n = 3206), First Nations Peoples (n = 89) were younger (p < 0.001), morel likely to reside in most disadvantaged (p = 0.002) and in regional/remote areas (p < 0.001), and had similar liver disease severity. Medicines for mental health conditions were most commonly dispensed among First Nations Peoples (55.2% vs. 42.8%; p = 0.022). Of 2910 patients with follow-up data, both groups had high SVR rates (95.3% of First Nations Peoples vs. 93.2% of non-Indigenous patients; p = 0.51) and 'good' adherence (90.0% vs. 86.9%, respectively; p = 0.43). However, 28.1% of First Nations Peoples were LTFU vs. 11.2% of non-Indigenous patients (p < 0.001). Among First Nations Peoples, younger age (adj-OR = 0.93, 95% CI 0.87-0.99) and treatment initiation in 2018-2019 vs. 2016 (adj-OR = 5.14, 95% CI 1.23-21.36) predicted LTFU, while higher fibrosis score was associated with better engagement in HCV care (adj-OR = 0.71, 95% CI 0.50-0.99). CONCLUSIONS: Our data showed that First Nations Peoples have an equivalent HCV cure rate, but higher rates of LTFU. Better strategies to increase engagement of First Nations Peoples with HCV care are needed.
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Hepatitis C Crónica , Hepatitis C , Adulto , Anciano , Antivirales/uso terapéutico , Australia/epidemiología , Estudios de Seguimiento , Hepacivirus , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Programas Nacionales de Salud , Estudios Prospectivos , Respuesta Virológica SostenidaRESUMEN
BACKGROUND: The outcomes and disease associations in pregnant women with primary biliary cholangitis (PBC) have not been largely explored. This study aimed to determine the level of evidence associated with maternal and fetal outcomes and other disease associations in female patients with PBC. DATA SOURCES: A comprehensive literature search was conducted. Maternal and fetal outcomes were obtained from patients with a previous, current or subsequent diagnosis of PBC. A random-effects model was employed, using odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Eleven studies, with 2179 female PBC patients were included. Pregnant women with PBC were significantly more likely to have a miscarriage (OR = 1.27, 95% CI: 1.02-1.58; P = 0.03), and a history of abortion (OR = 1.50, 95% CI: 1.09-2.07; P = 0.01), with absent heterogeneity (I2 = 0%). PBC pregnant women were significantly more likely to deliver via vaginal birth (OR = 1.69, 95% CI: 1.33-2.14; P < 0.001) with low level heterogeneity (I2 < 0.001%). Patients had a statistically significant increased likelihood of lifetime smoking (OR = 1.95, 95% CI: 1.17-3.23; P = 0.01). Egger's regression revealed no evidence of publication bias. CONCLUSIONS: This meta-analysis provides pooled evidence that a PBC pregnancy is associated with fetal morbidity and maternal lifestyle associations that may influence pregnancy outcomes. More studies are needed to establish disease associations that may directly affect pregnancy outcomes. These data are essential for clinicians managing these patients before, during or after pregnancy.
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Cirrosis Hepática Biliar , Complicaciones del Embarazo , Femenino , Humanos , Cirrosis Hepática Biliar/diagnóstico , Cirrosis Hepática Biliar/epidemiología , Masculino , Oportunidad Relativa , Embarazo , Complicaciones del Embarazo/epidemiología , Resultado del EmbarazoRESUMEN
OBJECTIVES: Metabolic dysfunction-associated fatty liver disease (MAFLD) can develop in any patient, including those with chronic hepatitis C (CHC). The recently proposed diagnostic criteria for MAFLD provide a unique opportunity to investigate the impact of concomitant fatty liver in patients with another established cause for their liver disease. The objective of our study was to assess the characteristics and outcomes of patients with a dual etiology liver disease. METHODS: We evaluated 1181 patients including 744 with CHC and 437 with MAFLD. All patients in both cohorts underwent liver biopsy indicating disease activity and fibrosis stage. RESULTS: Nearly half (43.1%) the patients with CHC had concomitant MAFLD. Comparing patients with CHC alone with those with a dual etiology disease, we found that the latter had more severe liver injury, hepatic inflammation and fibrosis (all P < 0.001). Interestingly, lean or normal-weight patients with CHC and MAFLD had a similar fibrosis stage compared to the two other subgroups of MAFLD (obesity and/or diabetes mellitus). There was no statistical significance in hepatic steatosis and fibrosis between genotype 3 CHC and MAFLD group compared to other genotypes. CONCLUSIONS: Patients with CHC and concomitant MAFLD had more severe liver disease than those with viral hepatitis alone. Recognizing coexisting MAFLD in patients with CHC is important for the delivery of holistic care.
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Hígado Graso , Hepatitis C Crónica , Enfermedad del Hígado Graso no Alcohólico , Genotipo , Hepatitis C Crónica/complicaciones , Humanos , Cirrosis Hepática/etiología , Enfermedad del Hígado Graso no Alcohólico/complicacionesRESUMEN
BACKGROUND/AIMS: Maternal and fetal outcomes in pregnant patients with Non-alcoholic fatty liver disease (NAFLD) have been largely unexplored. To determine the level of evidence associated with maternal and fetal outcomes in pregnant women with NAFLD. METHODS: We conducted a comprehensive literature search. The studies included pregnant patients with a previous, current or subsequent diagnosis of NAFLD. We used a random-effects model using odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Twenty-two studies, with 13,641 female NAFLD patients were reviewed. The results highlight that NAFLD patients had a statistically significant increased likelihood of baseline diabetes mellitus (OR, 6.00; 95% CI, 2.21-16.31; P<0.001; n=7), baseline Hypertension (OR, 3.75; 95% CI, 2.13-6.59; P<0.001; n=4), gestational hypertension (OR, 1.83; 95% CI, 1.03-3.26; P=0.041; n=2), and pre-eclampsia (OR, 2.43; 95% CI, 1.46-4.04; P=0.001; n=3). The odds for a past and current history of gestational diabetes mellitus were OR, 3.78; 95% CI, 2.21-6.44; P<0.001; n=5 and OR, 3.23; 95% CI, 1.97- 5.31; P<0.001; n=6, respectively. As for fetal outcomes, pregnant NAFLD patients were significantly more likely to have a premature birth (OR, 2.02; 95% CI, 1.44-2.85; P<0.001; n=4), large for gestational age birth (OR, 2.01; 95% CI, 1.72-2.37; P<0.001; n=2) or a history of prior miscarriage or abortion (OR, 1.15; 95% CI, 1.02-1.30; P=0.02; n=2). Egger's regression revealed no evidence of publication bias (P>0.05). CONCLUSION: This meta-analysis provides pooled evidence that NAFLD is associated with a substantial increase in maternal diabetic and hypertensive complications and multiple adverse fetal outcomes. This data is important for clinicians managing these patients before, during and after pregnancy.
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Diabetes Gestacional , Enfermedad del Hígado Graso no Alcohólico , Complicaciones del Embarazo , Nacimiento Prematuro , Diabetes Gestacional/diagnóstico , Femenino , Humanos , Masculino , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Embarazo , Resultado del EmbarazoRESUMEN
BACKGROUND & AIMS: Functional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S). Safety, antiviral activity, and immunogenicity of BRII-179 admixed with co-adjuvant interferon (IFN)-α were assessed in patients with CHB. METHOD: This randomized, open-label, controlled phase Ib/IIa study included 2 dose levels, 20 µg BRII-179 (Part 1, n = 25) and 40 µg BRII-179 (Part 2, n = 24). Patients, virally suppressed under nucleos(t)ide analogue (NA) therapy were randomized 1:2:2 into 3 cohorts in Part 1 and 1:1 into 2 cohorts in Part 2 to receive 4 monthly intramuscular injections of BRII-179 admixed with/without 3 MIU IFN-α. Antibody and cellular responses to HBsAg, as well as evolution of circulating HBsAg were monitored. RESULTS: Both 20 µg and 40 µg BRII-179 with/without IFN-α were well tolerated with no severe adverse events. BRII-179 induced anti-HBs responses in >30% patients in all treatment cohorts, however, moderate anti-Pre-S1 or anti-Pre-S2 antibody responses were only observed in patients receiving BRII-179 with IFN-α. BRII-179 also restored S-, Pre-S1-, Pre-S2-specific IFN-γ-producing T-cells in the majority of treated patients. Overall, no notable reduction of HBsAg was observed after BRII-179 treatment. CONCLUSION: In patients with CHB under NA therapy, BRII-179 with/without IFN-α exhibited a good safety profile and induced HBV-specific B- and T-cell immune responses. These data support further clinical evaluation of BRII-179 in combination with other therapies. CLINICAL TRIAL NUMBER: ACTRN12619001210167. LAY SUMMARY: BRII-179 is a therapeutic vaccine designed to improve the immune response in patients with chronic hepatitis B. In this study, BRII-179 alone or with a low dose of interferon-α was safe, well tolerated, and induced enhanced HBV-specific antibody and T-cell responses in patients with chronic hepatitis B. However, BRII-179 treatment alone had minimal effect on patient's virological status. The potential of BRII-179 to achieve a functional cure in conjunction with other agents is being evaluated in the clinic.
RESUMEN
BACKGROUND AND AIMS: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. METHODS: We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. RESULTS: 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 ± 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. CONCLUSIONS: Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangitis Esclerosante , Anciano , Australia/epidemiología , Neoplasias de los Conductos Biliares/diagnóstico , Conductos Biliares Intrahepáticos/patología , Colangitis Esclerosante/diagnóstico , Colangitis Esclerosante/tratamiento farmacológico , Colangitis Esclerosante/patología , Diagnóstico Diferencial , Humanos , Inmunoglobulina G , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Maternal and fetal outcomes in pregnant patients with autoimmune hepatitis (AIH) has been largely unexplored. AIM: This meta-analysis aims to determine the level of evidence associated with both maternal and fetal outcomes in patients with AIH. METHODS: We conducted a comprehensive literature search. The studies included AIH patients who had at least one pregnancy with a previously known or index presentation diagnosis of AIH. We used a random-effects model using odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Fourteen studies with 1452 AIH patients and with a total of 1556 gestations were included. Analysis revealed statistically significant increased likelihood of diabetes mellitus in the AIH group (OR: 5.73, 95% CI: 2.73-12.02; p < .001, n = 2) compared to controls. Fetal outcomes that indicated a statistically significant association with AIH included premature birth (OR: 2.20, 95% CI:1.66-2.91; p < .001, n = 3), small for gestational age (SGA) births (OR: 2.48, 95% CI:1.37-4.51; p = .003, n = 2) and low birth weight (LBW) (OR: 3.04, 95% CI:1.85-5.01; p < .001, n = 1). AIH pregnancies were significantly less likely to have a full-term birth (OR: 0.32, 95% CI:0.21-0.49; p < .001, n = 2). CONCLUSIONS: This meta-analysis provides the first pooled evidence that autoimmune hepatitis is associated with a substantial increase in maternal Pre-pregnancy and gestational diabetes mellitus, and that AIH females are more likely to have premature births, small for gestational age (SGA) births, and low birth weight (LBW) babies and a substantial decrease in full term birth compared to normal controls. This data is important for clinicians managing these patients before, during and after pregnancy.
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Hepatitis Autoinmune , Complicaciones del Embarazo , Nacimiento Prematuro , Femenino , Hepatitis Autoinmune/epidemiología , Humanos , Recién Nacido de Bajo Peso , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Embarazo , Complicaciones del Embarazo/epidemiología , Resultado del Embarazo , Nacimiento Prematuro/epidemiologíaRESUMEN
The gut microbiota is reported to modulate the immune response in hepatocellular carcinoma (HCC). Here, we employ metagenomic and metabolomic studies to characterise gut microbiota in patients with non-alcoholic fatty liver disease (NAFLD) related cirrhosis, with or without HCC, and evaluate its effect on the peripheral immune response in an ex vivo model. We find that dysbiosis characterises the microbiota of patients with NAFLD-cirrhosis, with compositional and functional shifts occurring with HCC development. Gene function of the microbiota in NAFLD-HCC supports short chain fatty acid production, and this is confirmed by metabolomic studies. Ex vivo studies show that bacterial extracts from the NAFLD-HCC microbiota, but not from the control groups, elicit a T cell immunosuppressive phenotype, characterised by expansion of regulatory T cells and attenuation of CD8 + T cells. Our study suggest that the gut microbiota in NAFLD-HCC is characterised by a distinctive microbiome/metabolomic profile, and can modulate the peripheral immune response.