Publications by authors named "Anouk Dev"

43 Publications

Safety of RAPid INJECTion of Undiluted Ferric Carboxymaltose to Patients with Iron Deficiency Anaemia (RAPINJECT): A Phase II Single Arm study.

Intern Med J 2021 Jan 18. Epub 2021 Jan 18.

Department of Haematology, Monash Health, Clayton, VIC, 3168, Australia.

Background: Ferric carboxymaltose is increasingly utilised to treat iron deficiency and is usually diluted in saline and administered as an intravenous infusion over 15 minutes. Whilst this is highly convenient compared with older formulations, we hypothesised the drug could be administered safely given as a rapid bolus injection.

Aims: To define the risk of serious adverse events following administration of an undiluted, rapid, high dose ferric carboxymaltose injection. Secondary aims included all other adverse events, as well as longitudinal effects on haemoglobin, iron stores, phosphate, and hepcidin.

Methods: In a single arm, Phase II study in 121 patients with iron deficiency anaemia, we administered up to 1000mg of ferric carboxymaltose as a rapid undiluted bolus injection, and recorded adverse events and collected blood samples over the first hour, and again at two and four weeks post-treatment.

Results: No patient experienced a serious adverse event. Flushing during the injection was common, as was a transient headache in the subsequent weeks. A single patient experienced Grade 3 chest tightness necessitating emergency department assessment but not admission or treatment. Treatment produced an average 12.3g/L improvement in haemoglobin within two weeks, but commonly caused reductions in serum phosphate (although none of these were clinically symptomatic). Parenteral iron caused elevations in hepcidin sustained to four weeks post injection. Patients stated they would be prepared to receive the treatment again.

Conclusion: Rapid injection of undiluted ferric carboxymaltose is well tolerated and could provide an approach to treat patients in the ambulatory setting. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15195DOI Listing
January 2021

SIRT Compared with DEB-TACE for Hepatocellular Carcinoma: a Real-world Study (the SITAR Study).

J Gastrointest Cancer 2020 Sep 9. Epub 2020 Sep 9.

Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia.

Background: Hepatocellular carcinoma (HCC) is responsible for 1% of deaths worldwide, and the incidence continues to increase. Despite surveillance programs, 70% of HCC patients are not suitable for curative options at diagnosis, and therefore, non-curative treatments are essential to modern clinical practice. There are many novel treatments, though their roles are not well defined. This study aimed to contrast Selective Internal Radiation Therapy (SIRT) and Drug Eluting Bead Transarterial Chemoembolisation (DEB-TACE) to further define their roles.

Methods: This was a retrospective multicentre cohort study. Factors included for analysis were type of HCC treatment, number of lesions, lesion size, multiple disease severity scores, cirrhosis and vascular invasion. The primary endpoint was transplant-free survival.

Results: Transplant-free survival was similar between the two cohorts (p = 0.654), despite a variation in median lesion size, SIRT: 54.5 mm, DEB-TACE: 34 mm (p ≤ 0.001). A univariate Cox proportional hazard model utilising treatment modality as the covariate showed no significant difference in survival (DEB-TACE HR 1.4 (95%CI 0.85-2.15 p = 0.207). The size of the largest lesion was the best predictor of 3-year survival (p = 0.035). Lesion size was inversely associated with survival (HR 1.01 (95%CI 1-1.02, p = 0.025)) on multivariate analysis.

Conclusion: This study is the first to catalogue the experience of using SIRT in HCC in a real-world Australian population. It has demonstrated no difference in survival outcomes between DEB-TACE and SIRT. Further, it has shown SIRT to be a reasonable alternative to DEB-TACE especially in larger lesions and has demonstrated that DEB-TACE has a role in select patients with advanced disease.
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http://dx.doi.org/10.1007/s12029-020-00502-zDOI Listing
September 2020

Prognostic role of alpha-fetoprotein in patients with hepatocellular carcinoma treated with repeat transarterial chemoembolisation.

BMC Cancer 2020 May 29;20(1):483. Epub 2020 May 29.

Department of Gastroenterology, The Alfred Hospital, 55 Commercial Rd, Melbourne, 3004, Australia.

Background: Repeat transarterial chemoembolisation (rTACE) is often required for hepatocellular carcinoma (HCC) to achieve disease control, however, current practice guidelines regarding treatment allocation vary significantly. This study aims to identify key factors associated with patient survival following rTACE to facilitate treatment allocation and prognostic discussion.

Method: Patients with HCC undergoing rTACE at six Australian tertiary centers from 2009 to 2014 were included. Variables encompassing clinical, tumour, treatment type and response factors were analysed against the primary outcome of overall survival. Univariate analysis and multivariate Cox regression modelling were used to identify factors pre- and post-TACE therapy significantly associated with survival.

Results: Total of 292 consecutive patients underwent rTACE with mainly Child Pugh A cirrhosis (61%) and BCLC stage A (57%) disease. Median overall survival (OS) was 30 months (IQR 15.2-50.2) from initial TACE. On multivariate analysis greater tumour number (p = 0.02), higher serum bilirubin (p = 0.007) post initial TACE, and hepatic decompensation (p = 0.001) post second TACE were associated with reduced survival. Patients with serum AFP ≥ 200 ng/ml following initial TACE had lower survival (p = 0.001), compared to patients with serum AFP level that remained < 200 ng/ml post-initial TACE, with an overall survival of 19.4 months versus 34.7 months (p = 0.0001) respectively.

Conclusion: Serum AFP level following initial treatment in patients undergoing repeat TACE for HCC is a simple and useful clinical prognostic marker. Moreover, it has the potential to facilitate appropriate patient selection for rTACE particularly when used in conjunction with baseline tumour burden and severity of hepatic dysfunction post-initial TACE.
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http://dx.doi.org/10.1186/s12885-020-06806-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257176PMC
May 2020

Adherence in chronic hepatitis B: associations between medication possession ratio and adverse viral outcomes.

BMC Gastroenterol 2020 May 7;20(1):140. Epub 2020 May 7.

WHO Collaborating Centre for Viral Hepatitis, Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne Victoria, 3000, Australia.

Background: Antiviral therapy for chronic hepatitis B (CHB) is effective and can substantially reduce the risk of progressive liver disease and hepatocellular carcinoma but is often administered for an indefinite duration. Adherence has been shown in clinical trials to maximize the benefit of therapy and prevent the development of resistance, however the optimal threshold for predicting clinical outcomes has not been identified. The aim of this study was to analyse adherence using the medication possession ration (MPR) and its relation to virological outcomes in a large multi-centre hospital outpatient population, and guide development of an evidence-based threshold for optimal adherence.

Methods: Pharmacy and pathology records of patients dispensed CHB antiviral therapy from 4 major hospitals in Melbourne between 2010 and 2013 were extracted and analysed to determine their MPR and identify instances of unfavourable viral outcomes. Viral outcomes were classified categorically, with unfavourable outcomes including HBV DNA remaining detectable after 2 years treatment or experiencing viral breakthrough. The association between MPR and unfavourable outcomes was assessed according to various thresholds using ROC analysis and time-to-event regression.

Results: Six hundred forty-two individuals were included in the analysis. Median age was 46.6 years, 68% were male, 77% were born in Asia, and the median time on treatment was 27.5 months. The majority had favourable viral outcomes (91.06%), with most having undetectable HBV DNA at the end of the study period. The most common unfavourable outcome was a rise of < 1 log in HBV DNA (6.54% of the total), while 2.49% of participants experienced viral breakthrough. Adherence was linearly associated with favourable outcomes, with increasing risk of virological breakthrough as MPR fell. Decreasing the value of MPR, at which a cut-point was taken, was associated with a progressively larger reduction in the rate of unfavourable event; from a 60% reduction under a cut-point of 1.00 to a 79% reduction when the MPR cut-point was set at 0.8.

Conclusion: Lower adherence as measured using the MPR was strongly associated with unfavourable therapeutic outcomes, including virological failure. Optimising adherence is therefore important for preventing viral rebound and potential complications such as antiviral resistance. The evidence of dose-response highlights the need for nuanced interventions.
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http://dx.doi.org/10.1186/s12876-020-01219-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203797PMC
May 2020

Constitutive STAT3 Serine Phosphorylation Promotes Helicobacter-Mediated Gastric Disease.

Am J Pathol 2020 06 19;190(6):1256-1270. Epub 2020 Mar 19.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia. Electronic address:

Gastric cancer is associated with chronic inflammation (gastritis) triggered by persistent Helicobacter pylori (H. pylori) infection. Elevated tyrosine phosphorylation of the latent transcription factor STAT3 is a feature of gastric cancer, including H. pylori-infected tissues, and aligns with nuclear transcriptional activity. However, the transcriptional role of STAT3 serine phosphorylation, which promotes STAT3-driven mitochondrial activities, is unclear. Here, by coupling serine-phosphorylated (pS)-STAT3-deficient Stat3 mice with chronic H. felis infection, which mimics human H. pylori infection in mice, we reveal a key role for pS-STAT3 in promoting Helicobacter-induced gastric pathology. Immunohistochemical staining for infiltrating immune cells and expression analyses of inflammatory genes revealed that gastritis was markedly suppressed in infected Stat3 mice compared with wild-type mice. Stomach weight and gastric mucosal thickness were also reduced in infected Stat3 mice, which was associated with reduced proliferative potential of infected Stat3 gastric mucosa. The suppressed H. felis-induced gastric phenotype of Stat3 mice was phenocopied upon genetic ablation of signaling by the cytokine IL-11, which promotes gastric tumorigenesis via STAT3. pS-STAT3 dependency by Helicobacter coincided with transcriptional activity on STAT3-regulated genes, rather than mitochondrial and metabolic genes. In the gastric mucosa of mice and patients with gastritis, pS-STAT3 was constitutively expressed irrespective of Helicobacter infection. Collectively, these findings suggest an obligate requirement for IL-11 signaling via constitutive pS-STAT3 in Helicobacter-induced gastric carcinogenesis.
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http://dx.doi.org/10.1016/j.ajpath.2020.01.021DOI Listing
June 2020

Innate Immune Molecule NLRC5 Protects Mice From Helicobacter-induced Formation of Gastric Lymphoid Tissue.

Gastroenterology 2020 07 10;159(1):169-182.e8. Epub 2020 Mar 10.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Victoria, Australia; Biomedicine Discovery Institute, Department of Microbiology, Monash University, Victoria, Australia. Electronic address:

Background & Aims: Helicobacter pylori induces strong inflammatory responses that are directed at clearing the infection, but if not controlled, these responses can be harmful to the host. We investigated the immune-regulatory effects of the innate immune molecule, nucleotide-binding oligomerization domain-like receptors (NLR) family CARD domain-containing 5 (NLRC5), in patients and mice with Helicobacter infection.

Methods: We obtained gastric biopsies from 30 patients in Australia. We performed studies with mice that lack NLRC5 in the myeloid linage (Nlrc5) and mice without Nlrc5 gene disruption (controls). Some mice were gavaged with H pylori SS1 or Helicobacter felis; 3 months later, stomachs, spleens, and sera were collected, along with macrophages derived from bone marrow. Human and mouse gastric tissues and mouse macrophages were analyzed by histology, immunohistochemistry, immunoblots, and quantitative polymerase chain reaction. THP-1 cells (human macrophages, controls) and NLRC5 THP-1 cells (generated by CRISPR-Cas9 gene editing) were incubated with Helicobacter and gene expression and production of cytokines were analyzed.

Results: Levels of NLRC5 messenger RNA were significantly increased in gastric tissues from patients with H pylori infection, compared with patients without infection (P < .01), and correlated with gastritis severity (P < .05). H pylori bacteria induced significantly higher levels of chemokine and cytokine production by NLRC5 THP-1 macrophages than by control THP-1 cells (P < .05). After 3 months of infection with H felis, Nlrc5 mice developed gastric hyperplasia (P < .0001), splenomegaly (P < .0001), and increased serum antibody titers (P < .01), whereas control mice did not. Nlrc5 mice with chronic H felis infection had increased numbers of gastric B-cell follicles expressing CD19 (P < .0001); these follicles had features of mucosa-associated lymphoid tissue lymphoma. We identified B-cell-activating factor as a protein that promoted B-cell hyperproliferation in Nlrc5 mice.

Conclusions: NLRC5 is a negative regulator of gastric inflammation and mucosal lymphoid formation in response to Helicobacter infection. Aberrant NLRC5 signaling in macrophages can promote B-cell lymphomagenesis during chronic Helicobacter infection.
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http://dx.doi.org/10.1053/j.gastro.2020.03.009DOI Listing
July 2020

Diagnosis and treatment of lung disease associated with alpha one-antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand.

Respirology 2020 03 6;25(3):321-335. Epub 2020 Feb 6.

Department of Allergy, Immunology and Respiratory Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia.

AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD-associated pulmonary emphysema remain undiagnosed and therefore without access to care and counselling specific to the disease. AAT augmentation therapy is available and consists of i.v. infusions of exogenous AAT protein harvested from pooled blood products. Its clinical efficacy has been the subject of some debate and the use of AAT augmentation therapy was recently permitted by regulators in Australia and New Zealand, although treatment is not presently subsidized by the government in either country. The purpose of this position statement is to review the evidence for diagnosis and treatment of AATD-related lung disease with reference to the Australian and New Zealand population. The clinical efficacy and adverse events of AAT augmentation therapy were evaluated by a systematic review, and the GRADE process was employed to move from evidence to recommendation. Other sections address the wide range of issues to be considered in the care of the individual with AATD-related lung disease: when and how to test for AATD, changing diagnostic techniques, monitoring of progression, disease in heterozygous AATD and pharmacological and non-pharmacological therapy including surgical options for severe disease. Consideration is also given to broader issues in AATD that respiratory healthcare staff may encounter: genetic counselling, patient support groups, monitoring for liver disease and the need to establish national registries for people with AATD in Australia and New Zealand.
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http://dx.doi.org/10.1111/resp.13774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078913PMC
March 2020

Implementation of an Educational iPad Application for Patients With Chronic Hepatitis B.

Front Public Health 2019 10;7:372. Epub 2019 Dec 10.

Department of Gastroenterology and Hepatology, Monash Health, Melbourne, VIC, Australia.

Chronic Hepatitis B (CHB) contributes to a high public health burden in Australia from chronic liver disease and hepatocellular carcinoma. Health literacy impacts on multiple aspects of long term management, including surveillance and long term follow up. We designed and implemented a multilingual educational iPad application for outpatients to use while in the clinic waiting room. The application employed an interactive and multimodal approach to education. It utilized graphics, audio and text to convey practical information regarding transmission of disease, long term complications, treatment and surveillance. Participants were recruited from a tertiary liver clinic and assigned to either standard treatment (routine clinical consult only) or the iPad group (clinical consult and additional education with the iPad app). There were 54 participants (control = 29, iPad = 25). Knowledge was assessed at baseline, secondly after the clinician appointment and finally at 6 months. Median follow up time was 6.1 months (range 0-18 months) and 87% of participants completed the final survey. At baseline, there was no difference in age, gender, proportion of newly referred patients, or use of antivirals. Baseline knowledge was similar in the two groups (61.4 vs. 55.1%, = 0.33). The iPad group scored significantly higher after the first consult (79.5 vs. 61.5%, = 0.0005). This improvement remained significant by the end of follow up (72.6 vs. 61.0%, = 0.0472). To conclude, interactive education with iPads may be an effective way to improve patient knowledge.
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http://dx.doi.org/10.3389/fpubh.2019.00372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916629PMC
December 2019

Increasing prevalence of primary biliary cholangitis in Victoria, Australia.

J Gastroenterol Hepatol 2020 Apr 28;35(4):673-679. Epub 2019 Dec 28.

Department of Gastroenterology, Austin Hospital, Heidelberg, Victoria, Australia.

Background And Aim: The prevalence of primary biliary cholangitis (PBC) reported in different countries varies significantly and in some parts of the world appears to be increasing. The aim of this study was to determine the 2013 prevalence of PBC in Victoria, Australia, and to determine the time trend by comparing it with previous studies undertaken in 1991 and 2002.

Methods: Four case-finding methods were used to identify cases of PBC in Victoria: (1) physicians' survey; (2) tertiary hospital search; (3) liver transplant database search; and (4) private pathology antimitochondrial antibody search.

Results: The prevalence of PBC in Victoria, Australia, is 189.0 per million using all four methods. The average annual increase in prevalence from 1991 to 2013 was 7.7 per million per year. Using the same case-finding methods as the 1991 Victorian prevalence study (methods 1 and 2), the prevalence of PBC increased from 19.1 per million in 1991 to 49.4 per million in 2002 (P < 0.001) and to 80.7 per million in 2013 (P < 0.001).

Conclusions: The current prevalence of PBC in Victoria is significantly higher than previously reported. The use of private pathology-based case-finding methods is important in identifying the maximum number of PBC cases.
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http://dx.doi.org/10.1111/jgh.14924DOI Listing
April 2020

Treatment choice for early-stage hepatocellular carcinoma in real-world practice: impact of treatment stage migration to transarterial chemoembolization and treatment response on survival.

Scand J Gastroenterol 2018 Oct - Nov;53(10-11):1368-1375. Epub 2018 Nov 5.

a Department of Gastroenterology , Alfred Hospital, and Monash University , Melbourne , Australia.

Objective: The objectives of our study were firstly to characterize the treatment stage migration phenomenon in early (Barcelona Clinic Liver Cancer [BCLC]-0/A) stage hepatocellular carcinoma (HCC) by comparing the efficacy of curative therapies with trans-arterial chemoembolization [TACE] and secondly, determining baseline and on-treatment predictors of survival.

Methods: All patients within BCLC-0/A stage from six tertiary hospitals who received curative therapy with either resection, transplantation, or ablation or TACE as first-line treatment were included in the analyses. The primary endpoint was overall survival; secondary end-points were transplant-free survival and recurrence-free survival.

Results: Between January 2000 and December 2013, we identified 253 BCLC-0/A HCC patients of whom 148 (58.5%) received curative therapy and 105 (41.5%) migrated to TACE. Patients undergoing TACE had lower median survival (2.7 vs. 6.7 years; p < .0001), transplant-free survival (2.6 vs. 4.8 years; p < .0001) and recurrence-free survival (1.3 vs. 2.7 years; p < .001). On multivariate analysis treatment allocation to TACE was an independent prognostic predictor for both lower overall survival (HR 1.70, p = .04) and for HCC recurrence (HR 2.25, p < .001). The main prognostic determinant for each target outcome was Child-Pugh score.

Conclusions: Our study confirms that curative treatments should always be preferred when applicable in early-stage HCC, but that in cases where this is not possible, TACE is a reasonable albeit inferior treatment option. In addition, it provides unique prognostic information on a significant proportion of patients with early-stage disease in whom curative therapy is not applicable.
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http://dx.doi.org/10.1080/00365521.2018.1517277DOI Listing
April 2019

Immunomodulator use does not prevent first loss of response to anti-tumour necrosis factor alpha therapy in inflammatory bowel disease: long-term outcomes in a real-world cohort.

Intern Med J 2019 06;49(6):753-760

Department of Gastroenterology and Hepatology, Monash Medical Centre, Melbourne, Victoria, Australia.

Background: Recent prospective studies suggest combination therapy with immunomodulators improves efficacy, but long-term data is limited.

Aim: To assess whether anti-tumour necrosis factor alpha (anti-TNF) monotherapy was associated with earlier loss of response (LOR) than combination therapy in a real-world cohort with long-term follow up.

Methods: A retrospective audit was conducted of inflammatory bowel disease patients receiving anti-TNF therapy in a tertiary centre and specialist private practices. All patients with accurate data for anti-TNF commencement and adequate correspondence to determine end-points were included. Outcomes measured included time to first LOR, causes and biochemical parameters.

Results: Two hundred and twenty-four patients were identified; 139 (62.1%) on combination therapy and 85 (37.9%) on monotherapy. Forty-five percent of patients had LOR during follow up until a maximum of 8.5 years; 59.4% on combination therapy and 40.6% on monotherapy (P = 0.533). The median time to LOR was not different between groups; 1069 days for combination therapy and 1489 days for monotherapy (P = 0.533). There was no difference in time to LOR between patients treated with different combination regimens or different anti-TNF agents.

Conclusion: In this large cohort of patients in a real-world setting, patients treated with anti-TNF monotherapy had similar rates of LOR as patients on anti-TNF combination therapy, at both short- and long-term follow up.
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http://dx.doi.org/10.1111/imj.14150DOI Listing
June 2019

Surveillance improves survival of patients with hepatocellular carcinoma: a prospective population-based study.

Med J Aust 2018 10;209(8):348-354

St Vincent's Hospital Melbourne, Melbourne, VIC.

Objectives: To determine the factors associated with survival of patients with hepatocellular carcinoma (HCC) and the effect of HCC surveillance on survival.

Design, Setting And Participants: Prospective population-based cohort study of patients newly diagnosed with HCC in seven tertiary hospitals in Melbourne, 1 July 2012 - 30 June 2013.

Main Outcome Measures: Overall survival (maximum follow-up, 24 months); factors associated with HCC surveillance participation and survival.

Results: 272 people were diagnosed with incident HCC during the study period; the most common risk factors were hepatitis C virus infection (41%), alcohol-related liver disease (39%), and hepatitis B virus infection (22%). Only 40% of patients participated in HCC surveillance at the time of diagnosis; participation was significantly higher among patients with smaller median tumour size (participants, 2.8 cm; non-participants, 6.0 cm; P < 0.001) and earlier Barcelona Clinic Liver Cancer (BCLC) stage disease (A/B, 59%; C/D, 25%; P < 0.001). Participation was higher among patients with compensated cirrhosis or hepatitis C infections; it was lower among those with alcohol-related liver disease or decompensated liver disease. Median overall survival time was 20.8 months; mean survival time was 18.1 months (95% CI, 16.6-19.6 months). Participation in HCC surveillance was associated with significantly lower mortality (adjusted hazard ratio [aHR], 0.60; 95% CI, 0.38-0.93; P = 0.021), as were curative therapies (aHR, 0.33; 95% CI, 0.19-0.58). Conversely, higher Child-Pugh class, alpha-fetoprotein levels over 400 kU/L, and later BCLC disease stages were each associated with higher mortality.

Conclusions: Survival for patients with HCC is poor, but may be improved by surveillance, associated with the identification of earlier stage tumours, enabling curative therapies to be initiated.
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http://dx.doi.org/10.5694/mja18.00373DOI Listing
October 2018

Engaging new refugee in Australian communities at risk for chronic hepatitis B infection into care: A peer-educator intervention.

Health Soc Care Community 2018 Jul 10. Epub 2018 Jul 10.

Department of Gastroenterology and Hepatology, Monash Health, Clayton, Victoria, Australia.

Chronic Hepatitis B (CHB) infection and subsequent liver complications are rising in prevalence in Australia due to increased migration from endemic regions. Nearly 50% of all those living with CHB in Australia are undiagnosed, leading to missed opportunities for liver cancer and cirrhosis prevention. Health literacy around CHB among refugee communities such as Afghan, Rohingyan, and Sudanese populations (all with a high prevalence of CHB) is low, partly due to a paucity of targeted health promotion programmes; despite the release of the Victorian Hepatitis B Strategy (2016-2020). We developed a peer-education intervention in these three communities to deliver CHB focused radio programmes and community forums in their own language, following a needs assessment consisting of semistructured interviews and surveys. Effectiveness of this intervention was measured through paired comparison of disease-knowledge assessment pre and post forum. Community forums were held between 2015 and 2016, with 25 attendees at the Rohingyan forum (68% male), 10 attendees at the Afghan forum (90% male) and 0 attendees at the Sudanese forum. Participants demonstrated a significant improvement in CHB knowledge between pre- and post-forum surveys (p-value < 0.05). A peer-educator approach was a cost-effective health promotion strategy in building CHB knowledge and dispelling misconceptions within the Afghan and Rohingya communities. There were significant barriers in the engagement of the South Sudanese community, which will inform future strategies for health promotion.
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http://dx.doi.org/10.1111/hsc.12602DOI Listing
July 2018

Liver stiffness measurement in the primary care setting detects high rates of advanced fibrosis and predicts liver-related events in hepatitis C.

J Hepatol 2018 09 28;69(3):575-583. Epub 2018 Apr 28.

Department of Gastroenterology, Eastern Health, Box Hill, Victoria, Australia; Eastern Health Clinical School, Monash University, Melbourne, Australia; CATCH Study Group (Community Approach Targeting Cirrhosis and Hepatocellular Carcinoma), Australia.

Background & Aims: As many as 70% of individuals with chronic hepatitis C (CHC) are managed solely in primary care. The aims of this study were to determine the prevalence of elevated liver stiffness measurement (LSM) in a cohort of community managed patients with CHC and to evaluate predictors of advanced liver disease and liver-related events.

Methods: A prospective cohort of adult patients with CHC were recruited from 21 primary care practices throughout Victoria, Australia. Inclusion criteria included the presence of CHC for >6 months, no recent (<18 months) specialist input and no history of hepatocellular carcinoma. Clinical assessment, LSM and phlebotomy were carried out in primary care. A hospital cohort was recruited for comparison. Participants were followed longitudinally and monitored for liver-related events.

Results: Over 26 months, 780 community patients were recruited and included in the analysis. The median LSM was 6.9 kPa in the community, with 16.5% of patients at risk of advanced fibrosis (LSM ≥12.5 kPa); of these 8.5% had no laboratory features of advanced liver disease. The proportion at risk of cirrhosis was no different between the community and hospital cohorts (p = 0.169). At-risk alcohol consumption, advancing age, elevated body mass index and alanine aminotransferase were independent predictors of elevated LSM. Over a median follow-up of 15.2 months, liver-related events occurred in 9.3% of those with an LSM ≥12.5 kPa. An LSM of 24 kPa had the highest predictive power for liver-related events (hazard ratio152; p <0.001).

Conclusion: The prevalence of advanced fibrosis, as determined by LSM, in primary care managed CHC is significant and comparable to a hospital cohort. Furthermore, this study supports the use of LSM as a community screening tool in a CHC population and indicates a possible role in predicting liver-related events.

Lay Summary: The prevalence of advanced liver disease in primary care managed hepatitis C is unknown. Our data suggests that rates of advanced fibrosis in the community are significant (16.5%), often underdiagnosed and comparable to rates seen in specialist referral centres. Liver stiffness measurement is a feasible community screening tool prior to hepatitis C therapy and can predict liver-related adverse events.
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http://dx.doi.org/10.1016/j.jhep.2018.04.013DOI Listing
September 2018

Increased prevalence of fracture and hypoglycaemia in young adults with concomitant type 1 diabetes mellitus and coeliac disease.

Clin Endocrinol (Oxf) 2018 Jan 23;88(1):37-43. Epub 2017 Oct 23.

Departments of Endocrinology and Diabetes, Monash Health, Clayton, Vic., Australia.

Background: Both Type 1 diabetes mellitus (T1DM) and coeliac disease (CD) are independently associated with reduced bone mineral density (BMD) and increased fracture risk. Whilst poorer glycaemic control and increased microvascular complications have been described, the literature examining bone health and fractures in adults with concomitant T1DM and CD (T1DM + CD) is limited.

Objective: To evaluate fracture prevalence and explore associations with glycaemic control, hypoglycaemia and microvascular disease in T1DM + CD compared with T1DM alone.

Methods: We conducted a retrospective cross-sectional study of young adults with T1DM, who attended diabetes clinics at a large tertiary referral centre between August 2016 and February 2017. Clinical information, radiological and biochemistry results were extracted from medical records. Patients with comorbid chronic kidney disease, glucocorticoid use, hypogonadism and untreated hyperthyroidism were excluded.

Results: A total of 346 patients with T1DM alone (median age 23 years) and 49 patients with T1DM + CD (median age 24 years) were included. Median age, gender distribution, BMI, haemoglobin A1c, daily insulin dose and serum 25-hydroxyvitamin D levels were similar between groups. Higher adjusted fracture risk was observed in T1DM + CD compared with T1DM (12.2% vs 3.5%; OR 3.50, 95% CI 1.01-12.12, P = .01), yet BMD was only measured in 6% of patients. The adjusted risk of hypoglycaemia ≥2/week was greater for T1DM + CD (55% vs 38%, OR 3.28, 95% CI 1.61-6.69, P = .001); however, this was not independently associated with fractures. Replete vitamin D (≥ 50 nmol/L) was associated with less hypoglycaemia (OR 0.48, 95% CI 0.29-0.80; P = .005), but not with fractures.

Conclusions: Coeliac disease status was independently associated with increased fracture prevalence in young adults with T1DM. Recurrent hypoglycaemia was also increased in T1DM + CD, although hypoglycaemia was not independently associated with fractures. Prospective studies are required to determine the long-term impacts of CD on bone health and glycaemic control in patients with T1DM.
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http://dx.doi.org/10.1111/cen.13488DOI Listing
January 2018

Antenatal maternal hepatitis B care is a predictor of timely perinatal administration of hepatitis B immunoglobulin.

Intern Med J 2017 Aug;47(8):915-922

Department of Gastroenterology and Hepatology, Monash Health, Melbourne, Victoria, Australia.

Background: Mother-to-child transmission of hepatitis B virus continues to occur despite universal recommendations for neonatal immune prophylaxis therapy (IPT) and infant vaccination.

Aim: To characterise the risk factors for failure to provide timely IPT and completion of the infant hepatitis B vaccination schedule for children born to mothers with chronic hepatitis B (CHB).

Methods: We conducted a retrospective cohort study to assess compliance with universal guidelines for neonatal IPT for children born to CHB mothers at Monash Health, Australia from 2008 to 2013. These mothers were invited to participate in a telephone interview regarding post-partum hepatitis B virus (HBV) care and infant vaccination status. Multivariate logistic regression analysis was utilised to identify the predictors for engagement with specialist HBV care, timely administration of IPT, completion of HBV vaccination schedule and serological testing of the baby.

Results: A total of 451 CHB mothers delivered 454 live births. HBV immunoglobulin (HBIg) was dispensed within 12 h in 79.52% of births. HBIg was not administered to eight neonates. Of the 451 women, 125 were interviewed: 88.8% of babies completed the vaccine schedule, and 19.2% of infants had post-vaccination testing. Antenatal HBV care was independently associated with a greater likelihood of timely HBIg administration (odds ratio 1.64, P = 0.04, 95% CI: 1.03-2.61). There were no significant predictors for engagement with specialist HBV care, vaccine coverage or serological testing of the baby.

Conclusion: Targeted interventions to improve timely HBIg and completion of the vaccine schedule are recommended. All pregnant women with CHB should be referred for HBV-specific antenatal care regardless of viral replicative status.
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http://dx.doi.org/10.1111/imj.13466DOI Listing
August 2017

Barriers to Accessing Testing and Treatment for Chronic Hepatitis B in Afghan, Rohingyan, and South Sudanese Populations in Australia.

J Immigr Minor Health 2018 02;20(1):140-146

Department of Gastroenterology and Hepatology, Monash Health, 246 Clayton Road, Clayton VIC, 3126, Australia.

The burden of chronic Hepatitis B (CHB) infection and associated complications such as hepatocellular carcinoma is growing significantly in Australia due to increased migration from countries with a high prevalence of CHB. Significant barriers to screening and engagement with healthcare persist due to stigma and perceptions associated with CHB within these communities. Our study was a pilot intervention aimed at engaging Afghan, Rohingyan, and Sudanese populations into CHB care through an initial needs assessment. Twenty six patients from Afghan, Rohingyan, and Sudanese communities, identified in the Monash Health CHB database, participated in a combination of survey questionnaires and semi-structured interviews. Language and cultural barriers, lack of HBV knowledge, housing and family reunification priorities associated with new settlement, as well as previous experiences of healthcare engagement were all identified as obstacles to accessing CHB care. Healthcare and health promotion workers should be sensitive to the additional health barriers associated with seeking asylum, as these barriers can take priority over the often asymptomatic and chronic nature of CHB. Communities with high prevalence of CHB require culturally relevant education tools delivered at a community level in order to improve their knowledge.
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http://dx.doi.org/10.1007/s10903-017-0546-zDOI Listing
February 2018

Sorafenib in the treatment of hepatocellular carcinoma: a multi-centre real-world study.

Scand J Gastroenterol 2016 Aug 10;51(8):979-85. Epub 2016 May 10.

a Department of Gastroenterology , Monash Health , Victoria , Australia ;

Objective: Sorafenib is an oral multikinase inhibitor that improves survival in advanced hepatocellular carcinoma (HCC). In the absence of alternative therapies, sorafenib is often continued despite advancing liver disease or tumour progression. Real world studies are important to better characterise outcomes in these populations. Our aim was to review patterns of sorafenib use across eight Australian tertiary hospitals, defining variables associated with clinical outcomes.

Material And Methods: Retrospective cohort study of medical records of 320 patients treated with sorafenib for HCC. Baseline clinical parameters, dosage, adverse effects, and survival from initiation of treatment were collected. Time to radiological progression and 3-month alpha-fetoprotein (AFP) levels were available for a subset of patients.

Results: Adverse effects occurred in 79% of patients, requiring dose reduction in 31% of patients. Multivariate analysis identified an increased rate of mortality with Child-Pugh C (HR 5.52, p = 0.012), ECOG performance status 2-3 (HR 2.84, p = 0.001), and extrahepatic metastases (HR 1.54, p = 0.04), and decreased rate of mortality with an AFP reduction of at least 20% at 3 months (HR 0.38, p = 0.001). An increased rate of radiological progression was associated with ECOG performance status 2-3 (HR 2.34, p = 0.041), whilst a decreased rate of radiological progression was associated with development of on-treatment diarrhoea (HR 0.55, p = 0.015).

Conclusions: Survival in patients with Child-Pugh C liver function or advanced functional impairment treated with sorafenib is poor and thus routine use of this agent in these patients does not appear justified, particularly given the high rate of adverse effects. AFP concentration on therapy may help identify favourable response to treatment.
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http://dx.doi.org/10.3109/00365521.2016.1166518DOI Listing
August 2016

Novel population-based study finding higher than reported hepatocellular carcinoma incidence suggests an updated approach is needed.

Hepatology 2016 Apr 19;63(4):1205-12. Epub 2016 Feb 19.

Department of Gastroenterology & Hepatology:, St Vincent's Hospital, Melbourne, Australia.

Unlabelled: Hepatocellular carcinoma (HCC) incidence is rising rapidly in many developed countries. Primary epidemiological data have invariably been derived from cancer registries that are heterogeneous in data quality and registration methodology; many registries have not adopted current clinical diagnostic criteria for HCC and still rely on histology for classification. We performed the first population-based study in Australia using current diagnostic criteria, hypothesizing that HCC incidence may be higher than reported. Incident cases of HCC (defined by American Association for the Study of Liver Diseases diagnostic criteria or histology) were prospectively identified over a 12-month period (2012-2013) from the population of Melbourne, Australia. Cases were captured from multiple sources: admissions to any of Melbourne's seven tertiary hospitals; attendances at outpatients; and radiology, pathology, and pharmacy services. Our cohort was compared to the Victorian Cancer Registry (VCR) cohort (mandatory notified cases) for the same population and period, and incidence rates were compared for both cohorts. There were 272 incident cases (79% male; median age: 65 years) identified. Cirrhosis was present in 83% of patients, with hepatitis C virus infection (41%), alcohol (39%), and hepatitis B virus infection (22%) the commonest etiologies present. Age-standardized HCC incidence (per 100,000, Australian Standard Population) was 10.3 (95% confidence interval [CI]: 9.0-11.7) for males and 2.3 (95% CI: 1.8 to 3.0) for females. The VCR reported significantly lower rates of HCC: 5.3 (95% CI: 4.4 to 6.4) and 1.0 (95% CI: 0.7 to 1.5) per 100,000 males and females respectively (P < 0.0001).

Conclusions: HCC incidence in Melbourne is 2-fold higher than reported by cancer registry data owing to under-reporting of clinical diagnoses. Adoption of current diagnostic criteria and additional capture sources will improve registry completeness. Chronic viral hepatitis and alcohol remain leading causes of cirrhosis and HCC.
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http://dx.doi.org/10.1002/hep.28267DOI Listing
April 2016

Radiofrequency ablation versus resection for the treatment of early stage hepatocellular carcinoma: a multicenter Australian study.

Scand J Gastroenterol 2015 May 23;50(5):567-76. Epub 2015 Jan 23.

The Alfred Hospital , Melbourne , Australia.

Objectives: It remains unclear whether radiofrequency ablation (RFA) provides comparable outcomes to surgical resection (SR). We, therefore, compared survival outcomes of RFA to SR in patients with early stage and very early stage hepatocellular carcinoma (HCC).

Methods: A multicenter retrospective analysis was performed in patients from five academic hospitals with Barcelona Cancer of the Liver Clinic (BCLC) stages 0-A HCC having RFA or SR as primary therapy.

Results: From 2000-2010, 146 patients who received treatment with RFA (n = 96) or SR (n = 52) were identified. In BCLC A patients with ≤5 cm HCC, there was a trend of lower overall survival after RFA compared with SR (3- and 5-year survival: 62% and 37% vs. 66% and 62% respectively; p = 0.11). By multivariate analysis, RFA was an independent predictor of poor survival (hazard ratio = 2.26; 95% confidence interval: 1.02-5.03; p = 0.04). In ≤3 cm HCC (n = 109), the 3- and 5-year survivals in RFA and SR groups were 66% and 39%, and 69% and 59%, respectively, with no difference in the median survival (p = 0.41). Local recurrence was significantly higher after RFA compared to SR in HCC ≤5 cm (p = 0.006) with a trend of lower recurrence-free survival (p = 0.06) after RFA in HCC ≤3 cm. There were fewer major complications after RFA (2% vs. 8%).

Conclusion: While SR is superior to RFA for the management of early stage BCLC A disease with ≤5 cm HCC, both appear effective as first-line treatment options for Western patients with small ≤3 cm tumors. Although safer than SR, RFA is associated with higher rates of tumor recurrence and local disease progression. Further prospective randomized controlled trials are warranted to compare these two modalities.
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http://dx.doi.org/10.3109/00365521.2014.953572DOI Listing
May 2015

Acute liver injury secondary to sertraline.

BMJ Case Rep 2013 Sep 26;2013. Epub 2013 Sep 26.

Department of Gastroenterology and Hepatology, Monash Medical Centre, Monash Health, Melbourne, Australia.

Sertraline is widely prescribed to treat depression and anxiety disorders. However, hepatitis secondary to its use is a rare entity. We report the case of a 26-year-old woman in her 20th week of pregnancy presented with nausea, vomiting, malaise and dark urine. This occurred 6 months after sertraline 50 mg daily was started for the treatment of depression. Three weeks prior to her presentation, the dose of sertraline was increased to 100 mg daily. The patient's liver biochemical profile demonstrated increased transaminases. The biopsy of the liver showed lobular hepatitis, with a mild prominence of eosinophils, suggestive of a drug-induced or toxin-induced aetiology. Extensive biochemical work-up failed to show any other pathology to account for her hepatitis. Liver function tests normalised after cessation of sertraline, indicating a probable association between sertraline use and acute hepatocellular injury in our patient.
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http://dx.doi.org/10.1136/bcr-2013-201022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794285PMC
September 2013

Nucleotide oligomerization domain 1 enhances IFN-γ signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease severity.

J Immunol 2013 Apr 4;190(7):3706-15. Epub 2013 Mar 4.

Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia.

Virulent Helicobacter pylori strains that specifically activate signaling in epithelial cells via the innate immune molecule, nucleotide oligomerization domain 1 (NOD1), are more frequently associated with IFN-γ-dependent inflammation and with severe clinical outcomes (i.e., gastric cancer and peptic ulceration). In cell culture models, we showed that H. pylori activation of the NOD1 pathway caused enhanced proinflammatory signaling in epithelial cells in response to IFN-γ stimulation through the direct effects of H. pylori on two components of the IFN-γ signaling pathway, STAT1 and IFN regulatory factor 1 (IRF1). Specifically, H. pylori activation of the NOD1 pathway was shown to increase the levels of STAT1-Tyr(701)/Ser(727) phosphorylation and IRF1 expression/synthesis in cells, resulting in enhanced production of the NOD1- and IFN-γ-regulated chemokines, IL-8- and IFN-γ-induced protein 10, respectively. Consistent with the notion that heightened proinflammatory signaling in epithelial cells may have an impact on disease severity, we observed significantly increased expression levels of NOD1, CXCL8, IRF1, and CXCL10 in human gastric biopsies displaying severe gastritis, when compared with those without gastritis (p < 0.05, p < 0.001, p < 0.01, and p < 0.05, respectively). Interestingly, NOD1, CXCL8, and IRF1 expression levels were also significantly upregulated in gastric tumor tissues, when compared with paired nontumor samples (p < 0.0001, p < 0.05, and p < 0.05, respectively). Thus, we propose that cross-talk between NOD1 and IFN-γ signaling pathways contribute to H. pylori-induced inflammatory responses, potentially revealing a novel mechanism whereby virulent H. pylori strains promote more severe disease.
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http://dx.doi.org/10.4049/jimmunol.1200591DOI Listing
April 2013

IL28B genotype is not useful for predicting treatment outcome in Asian chronic hepatitis B patients treated with pegylated interferon-α.

J Gastroenterol Hepatol 2013 May;28(5):861-6

Department of Gastroenterology, St Vincent's Hospital, University of Melbourne, Melbourne, Australia.

Background And Aim: IL28B genotype predicts response to pegylated interferon (peg-IFN)-based therapy in chronic hepatitis C. However, the utility of IL28B genotyping in chronic hepatitis B (CHB) cohorts treated with peg-IFN is unclear. It was investigated whether IL28B genotype is associated with peg-IFN treatment outcomes in a predominantly Asian CHB cohort.

Methods: This was a retrospective analysis of CHB patients treated with 48 weeks of peg-IFN monotherapy. IL28B genotype (rs12979860) was determined (TaqMan allelic discrimination kit). Baseline hepatitis B virus (HBV)-DNA, alanine aminotransferase, and liver histology were available. The primary end-points were HBV e antigen (HBeAg) seroconversion with HBV-DNA < 2000 IU/mL 24 weeks post-therapy (HBeAg-positive patients) and HBV-DNA < 2000 IU/mL 24 weeks after peg-IFN (HBeAg-negative patients). The association between IL28B genotype and peg-IFN outcomes was analyzed.

Results: IL28B genotype was determined for 96 patients. Eighty-eight percent were Asian, 62% were HBeAg positive, and 13% were METAVIR stage F3-4. Median follow-up time was 39.3 months. The majority of patients carried the CC IL28B genotype (84%). IL28B genotype did not differ according to HBeAg status. The primary end-points were achieved in 27% of HBeAg-positive and 61% of HBeAg-negative patients. There was no association between IL28B genotype and the primary end-point in either group. Furthermore, there was no difference in HBeAg loss alone, HBV surface antigen, alanine aminotransferase normalization, or on-treatment HBV-DNA levels according to IL28B genotype.

Conclusions: In the context of a small possible effect size and high frequency in Asian populations, IL28B genotyping is likely to have, at best, limited clinical utility for predicting peg-IFN treatment outcome for CHB patients in the Asia-Pacific region.
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http://dx.doi.org/10.1111/jgh.12110DOI Listing
May 2013

STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation.

Cancer Cell 2012 Oct;22(4):466-78

Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia.

Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium. Increased STAT3 pathway activation and TLR2 expression were also associated with poor GC patient survival. Collectively, our data reveal an unexpected role for TLR2 in the oncogenic function of STAT3 that may represent a therapeutic target in GC.
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http://dx.doi.org/10.1016/j.ccr.2012.08.010DOI Listing
October 2012

Efficacy and tolerability of pegylated interferon-α-2a in chronic hepatitis B: a multicenter clinical experience.

J Gastroenterol Hepatol 2012 Sep;27(9):1447-53

Gastroenterology and Hepatology Unit, Monash Medical Centre, Australia Department of Medicine, Monash University, Clayton, Australia.

Background And Aim: Pegylated interferon-α (PEG-IFN) provides potential advantages over nucleos(t)ide analogues in the treatment of chronic hepatitis B (CHB) given its finite course, durability and lack of drug resistance. Much of the evidence is derived from controlled studies and it is unclear whether these results can be replicated in an everyday, non-controlled setting. The aim of this study was to examine the efficacy and tolerability of PEG-IFN-α2A in CHB patients in a clinical setting.

Methods: Chronic hepatitis B patients treated with PEG-IFN-α2A (180µg/week, 48 weeks) at five tertiary hospitals were retrospectively identified. Baseline demographic and clinical data, on-treatment virological and serological responses and adverse events (AE) were recorded. Treatment outcomes were defined as alanine aminotransferase (ALT) normalization, hepatitis B virus DNA <351 IU/mL and hepatitis B e antigen (HBeAg) seroconversion.

Results: Sixty three HBeAg positive patients were identified (65% male, 80% born in Asia, 84% with viral loads > 6log IU/mL, 9.5% advanced fibrosis). Six months after therapy 46% achieved normalization of ALT, 16% had viral loads < 351 IU/mL and 32% achieved HBeAg seroconversion. 29 HBeAg negative patients were treated (75% male, 86% born in Asia, 48% had viral loads > 6log IU/mL, 24% advanced fibrosis). Six months post-treatment, 55% and 36% maintained a normalized ALT and HBV DNA < 351 IU/mL, respectively. Optimal viral suppression was maintained in 50-75% of patients over 2 years of follow up. 6.5% of all patients discontinued therapy due to AEs.

Conclusion: In everyday clinical practice PEG-IFN therapy in CHB is well tolerated and can achieve a similar efficacy to that seen in large controlled trials.
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http://dx.doi.org/10.1111/j.1440-1746.2011.07051.xDOI Listing
September 2012

Chronic hepatitis B - a clinical audit of GP management.

Aust Fam Physician 2011 Jul;40(7):533-8

Monash Medical Centre, Clayton, Victoria, Australia.

Background: Hepatitis B virus (HBV) infection represents a growing health burden in Australia. This clinical audit aimed to enhance general practitioner awareness of the recommended management for patients with chronic hepatitis B.

Objective: This article describes a clinical two-phase audit of 119 Australian GPs who contributed records retrospectively of patients with chronic hepatitis B.

Discussion: Patient records were examined for compliance with prevailing guidelines and GPs received education on guidelines. At completion of the audit 29% of patients were monitored at recommended intervals and 47% were managed according to the current guidelines. Recording of hepatitis B virus DNA results increased from 24% in phase 1 to 63% in phase 2. General practitioners reported increased knowledge of appropriate management and referral. Twenty-five percent of patients audited in both phases had been referred to a specialist. Participating GPs improved their management of patients with chronic hepatitis B. However, there remains considerable scope for enhancing GP understanding of hepatitis B virus and applying current guidelines to clinical practice.
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July 2011

The molecular pathogenesis of STAT3-driven gastric tumourigenesis in mice is independent of IL-17.

J Pathol 2011 Oct 27;225(2):255-64. Epub 2011 Jun 27.

Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.

Chronic activation of the gastric mucosal adaptive immune response is a characteristic trait of gastric cancer. It has recently emerged that a new class of T helper (Th) cells, defined by their ability to produce interleukin (IL)-17A (Th17), is associated with a host of inflammatory responses, including gastritis. However, the role of these Th17 cells in the pathogenesis of gastric cancer is less clear. To formally address this, we employed gp130(F/F) mice, which spontaneously develop gastric inflammation-associated tumours akin to human intestinal-type gastric cancer. At the molecular level, these tumours demonstrate hyper-activation of the latent transcription factor signal transducer and activator of transcription (STAT)3 via the IL-6 cytokine family member, IL-11. In gp130(F/F) mice, the generation of Th17 cells, as well as the gastric expression of IL-17a and other Th17-related factors (Rorγt, IL-23), were augmented compared to wild-type gp130(+/+) mice. Consistent with a role for IL-6 and STAT3 in regulating IL-17A, increased Th17 generation and gastric expression of Th17-related factors in gp130(F/F) mice were reduced to wild-type levels in gp130(F/F) :Stat3(-/+) mice displaying normalized STAT3 activity, and also in gp130(F/F) :IL-6(-/-) mice. Importantly, genetic ablation of IL-17A in gp130(F/F) :IL-17a(-/-) mice did not suppress the initiation and growth of gastric tumours. Furthermore, IL-17A and RORC gene expression was strongly increased in human gastric biopsies from patients with gastritis, but not gastric cancer. Collectively, our data suggest that increased expression of Th17-related factors does not correlate with the molecular pathogenesis of gastric tumourigenesis.
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http://dx.doi.org/10.1002/path.2933DOI Listing
October 2011

Factors influencing the participation of gastroenterologists and hepatologists in clinical research.

BMC Health Serv Res 2008 Oct 8;8:208. Epub 2008 Oct 8.

Duke Clinical Research Institute, PO Box 17969, Durham, North Carolina, USA.

Background: Although clinical research is integral to the advancement of medical knowledge, physicians face a variety of obstacles to their participation as investigators in clinical trials. We examined factors that influence the participation of gastroenterologists and hepatologists in clinical research.

Methods: We surveyed 1050 members of the American Association for the Study of Liver Diseases regarding their participation in clinical research. We compared the survey responses by specialty and level of clinical trial experience.

Results: A majority of the respondents (71.6%) reported involvement in research activities. Factors most influential in clinical trial participation included funding and compensation (88.3%) and intellectual pursuit (87.8%). Barriers to participation were similar between gastroenterologists (n = 160) and hepatologists (n = 189) and between highly experienced (n = 62) and less experienced (n = 159) clinical researchers. These barriers included uncompensated research costs and lack of specialized support. Industry marketing was a greater influence among respondents with less trial experience, compared to those with extensive experience (15.7% vs 1.6%; P < .01). Hepatologists and respondents with extensive clinical trial experience tended to be more interested in phase 1 and 2 studies, whereas gastroenterologists and less experienced investigators were more interested in phase 4 studies.

Conclusion: This study suggests that the greatest barrier to participation in clinical research is lack of adequate resources. Respondents also favored industry-sponsored research with less complex trial protocols and studies of relatively short duration.
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http://dx.doi.org/10.1186/1472-6963-8-208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572062PMC
October 2008

Treatment responses in Asians and Caucasians with chronic hepatitis C infection.

World J Gastroenterol 2008 Jun;14(21):3416-20

Department of Medicine, St. George Hospital, Kogarah, Sydney 2217, NSW, Australia.

Aim: To conduct a multicentre retrospective review of virological response rates in Asians infected with genotype 1 chronic hepatitis C (CHC) treated with combination interferon and ribavirin and then to compare their responses to that among Caucasians.

Methods: Asian patients infected with genotype 1 CHC treated at 4 Australian centres between 2001 to 2005 were identified through hospital databases. Baseline demographic characteristics, biochemical, virological and histological data and details of treatment were collected. Sustained virological responses (SVR) in this cohort were then compared to that in Caucasian subjects, matched by genotype, age, gender and the stage of hepatic fibrosis.

Results: A total of 108 Asians with genotype 1 CHC were identified. The end of treatment response (ETR) for the cohort was 79% while the SVR was 67%. Due to the relatively advanced age of the Asian cohort, only sixty-four subjects could be matched with Caucasians. The ETR among matched Asians and Caucasians was 81% and 56% respectively (P = 0.003), while the SVR rates were 73% and 36% (P < 0.001) respectively. This difference remained significant after adjusting for other predictive variables.

Conclusion: Genotype 1 CHC in Asian subjects is associated with higher rates of virological response compared to that in Caucasians.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716597PMC
http://dx.doi.org/10.3748/wjg.14.3416DOI Listing
June 2008