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Background: Recent prospective studies suggest combination therapy with immunomodulators improves efficacy, but long-term data is limited. Aim(s): 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. Method(s): 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. Result(s): 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(s): 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.Copyright © 2018 Royal Australasian College of Physicians

Item does not contain fulltext, Diminished colonic health is associated with various age-related pathologies. Calorie restriction (CR) is an effective strategy to increase healthy lifespan, although underlying mechanisms are not fully elucidated. Here, we report the effects of lifelong CR on indicators of colonic health in aging C57Bl/6J mice. Compared to an ad libitum control and moderate-fat diet, 30% energy reduction was associated with attenuated immune- and inflammation-related gene expression in the colon. Furthermore, expression of genes involved in lipid metabolism was higher upon CR, which may point towards efficient regulation of energy metabolism. The relative abundance of bacteria considered beneficial to colonic health, such as Bifidobacterium and Lactobacillus, increased in the mice exposed to CR for 28 months as compared to the other diet groups. We found lower plasma levels of interleukin-6 and lower levels of various metabolites, among which are bile acids, in the colonic luminal content of CR-exposed mice as compared to the other diet groups. Switching from CR to an ad libitum moderate-fat diet at old age (24 months) revealed remarkable phenotypic plasticity in terms of gene expression, microbiota composition and metabolite levels, although expression of a subset of genes remained CR-associated. This study demonstrated in a comprehensive way that CR affects indicators of colonic health in aging mice. Our findings provide unique leads for further studies that need to address optimal and feasible strategies for prolonged energy deprivation, which may contribute to healthy aging.

Calorie restriction (CR) has been shown to extend life- and health-span in model species. For most humans, a life-long CR diet is too arduous to adhere to. The aim of this study was to explore whether weekly intermittent CR can 1) provide long-term beneficial effects and 2) counteract diet-induced obesity in male aging mice. In this study, we have exposed C57Bl/6J mice for 24 months to an intermittent (INT) diet, alternating weekly between CR of a control diet and ad libitum moderate-fat (MF) feeding. This weekly intermittent CR significantly counteracted the adverse effects of the MF diet on mortality, body weight and liver health markers in male 24-month-old mice. Hepatic gene expression profiles of INT-exposed animals appeared much more comparable to CR than to MF-exposed mice. At 12 months of age, a subgroup of MF-exposed mice was transferred to the INT diet. Gene expression profiles in the liver of the 24-month-old diet switch mice were highly similar to the INT-exposed mice. However, a small subset of genes was consistently changed by the MF diet during the first phase of life. Weekly intermittent CR largely, but not completely, reversed adverse effects caused by a MF diet.

Aims: In inflammatory bowel disease (IBD), large studies have suggested a benefit with using immunomodulator (IM) co-therapy with anti-tumour necrosis factor alpha (anti-TNF) agents over anti-TNF monotherapy to prevent loss of response (LOR). We recently showed similar rates of LOR and outcomes, regardless of IM use, at both short-term and extended follow-up in a real-world cohort of anti-TNF treated patients. There is limited existing data on outcomes after anti-TNF LOR. Our aims were to assess rates of clinical response recapture post first LOR. Method(s): A retrospective audit was conducted of all patients with IBD receiving anti-TNF therapy in a tertiary centre and specialist private practices. All patients on anti-TNF therapy with an accurate date for TNF commencement and adequate correspondence to determine end-points were included. LOR was defined by an admission or surgery post-induction, escalation of anti-TNF dose or concurrent IMs for clinical LOR or emergence of a new fistula. Patients <18 years of age, and those with prior exposure to any anti-TNF agent were excluded. Outcomes measured included biochemical parameters, IM co-therapy, cause of first LOR and days to second LOR. Statistical analysis was performed with GraphPad Prism v6. Result(s): A total of 211 IBD (Crohn's disease (CD) n = 188, ulcerative colitis (UC) n = 23) patients on anti-TNF therapy were identified, of which 94 experienced LOR (CD n = 85, (45% of CD patients), UC n = 9, (39% of UC patients) [p = 0.660]). Of patients with LOR, 54 (57%) were on combination therapy and 40 (43%) on monotherapy at anti-TNF induction. Thirty-nine (41%) were treated with infliximab and 55 (59%) with adalimumab. Mean days to first LOR was 449 +/- 398.7 in the combination group and 620 +/- 553.4 in the monotherapy group (p = 0.165). Causes for LOR included clinical LOR (n = 60, 64%), hospital admission (n = 21, 22%), surgery (n = 10, 11%) or new fistula (n = 3, 3%). First LOR was managed with corticosteroids

Aims: In inflammatory bowel disease (IBD), studies have not shown a significant difference in patients treated with anti-tumour necrosis factor alpha (anti-TNF) monotherapy versus with immunomodulator co-therapy; however, recent data proposed a benefit with combination therapy to reduce immunogenicity to anti-TNFs. We recently showed similar rates of loss of response (LOR) and outcomes, despite immunomodulator use, at both short and long-term follow-up in a small cohort of patients on anti-TNF therapy. This is an expanded analysis of a larger real-world cohort including private outpatients, to better assess whether anti-TNF monotherapy was associated with earlier LOR versus combination therapy. Method(s): A retrospective audit was conducted of all patients with IBD receiving anti-TNF therapy in a tertiary centre and specialist private practices. All patients on anti-TNF therapy with an accurate date for TNF commencement and adequate correspondence to determine end-points were included. Patients <18 years of age, and those with prior exposure to any anti-TNF agent were excluded. Outcomes measured included biochemical parameters and immunomodulator therapy pre and post anti-TNF and days to first loss of response; defined by an admission or surgery post-induction, escalation of TNF dose or concurrent immunomodulators for clinical LOR or emergence of a new fistula. Statistical analysis was performed with GraphPad Prism v6. Result(s): A total of 211 patients were included for analysis: 188 patients treated for Crohn's disease and 23 for ulcerative colitis. Baseline characteristics are highlighted in Table 1. One hundred twenty-eight (61%) patients received combination therapy, whereas 83 (39%) had monotherapy. Ninety-nine (47%) patients had loss of response during follow-up; 58 (59%) on combination therapy and 41 (41%) on monotherapy (p =0.433). Causes for LOR included clinical LOR (n = 62, 63%), hospital admission (n = 22, 22%), surgery (n = 12, 12%) or new fistula (n =

Fibroblast growth factor 21 (Fgf21) has emerged as a potential plasma marker to diagnose non-alcoholic fatty liver disease (NAFLD). To study the molecular processes underlying the association of plasma Fgf21 with NAFLD, we explored the liver transcriptome data of a mild NAFLD model of aging C57BL/6J mice at 12, 24, and 28 months of age. The plasma Fgf21 level significantly correlated with intrahepatic triglyceride content. At the molecular level, elevated plasma Fgf21 levels were associated with dysregulated metabolic and cancer-related pathways. The up-regulated Fgf21 levels in NAFLD were implied to be a protective response against the NAFLD-induced adverse effects, e.g. lipotoxicity, oxidative stress and endoplasmic reticulum stress. An in vivo PPARalpha challenge demonstrated the dysregulation of PPARalpha signalling in the presence of NAFLD, which resulted in a stochastically increasing hepatic expression of Fgf21. Notably, elevated plasma Fgf21 was associated with declining expression of Klb, Fgf21’s crucial co-receptor, which suggests a resistance to Fgf21. Therefore, although liver fat accumulation is a benign stage of NAFLD, the elevated plasma Fgf21 likely indicated vulnerability to metabolic stressors that may contribute towards progression to end-stage NAFLD. In conclusion, plasma levels of Fgf21 reflect liver fat accumulation and dysregulation of metabolic pathways in the liver.

Background and Aims: Natural killer (NK) cells have been shown to attenuate hepatic fibrosis in transgenic HBV murine models. There is a paucity of data regarding the role of human NK and NKT cells in hepatitis B virus associated fibrogenesis. The aim of this study was to investigate the potential anti-fibrotic effects of human NK and or NKT cells from immune active HBV patients on HSC. Method(s): Immune active (IA) HBV was defined as ALT >=5 ULN and Immune control (IC) was defined as normal ALT. Human NK (90-96% purity) and NKT cells (75-85% purity) were magnetically isolated from peripheral blood mononuclear cells and cultured with LX2 human hepatic stellate cells (HSC). NK and NKT cells were further phenotyped by Tim-3, NKG2A, NKG2D, NKp46, FasL and TRAIL expression. Induction of LX2 apoptosis was analysed by caspase-3 activation. Intracellular cytokine production (IFN-alpha and TNF-alpha) and CD107a degranulation were used to determine NK and NKT cell functional activity. HSC collagen production was determined by the Sircol assay. Result(s): 15 patients were recruited: 6 IA HBV, 4 IC HBV and 5 healthy controls (HC) [serum ALT (IU/ml): 260.83+/-232 vs 24.25+/-8.93 and 24+/-5.42 respectively, p = 0.007]. Median HBVDNA viral load was higher in IA compared to IC (6.29 log10 IU/ml, IQR: 4.8-7.49 vs 2.26 log10 IU/ml, IQR: 1.73-2.88; p = 0.019). NK and NKT cells from IA HBV were significantly more effective in HSC apoptosis induction than similar cells from IC HBV or HC (16.15% +/- 13.8 vs 5.17% +/- 2.31 and 2.67% +/- 0.85, respectively; p < 0.0001). HSC caspase-3 expression correlated with serum ALT [Spearman's rho (rho) = 0.66, p < 0.0001], reduced proline incorporation (rho = -0.62, p < 0.0001) and increased NKp46 expression on NKBright cells (rho = 0.56, p = 0.04) and NKG2D expression on NKT cells (rho = 0.54, p = 0.03). There was no significant difference in cytokine production, TRAIL or FasL expression. Conclusion(s): NK and NKT cells from immune active HBeAg neg

Background - In rodent models, caloric restriction (CR) with maintenance of adequate micronutrient supply has been reported to increase lifespan and to reduce age-induced muscle loss (sarcopenia) during ageing. In the present study, we further investigated effects of CR on the onset and severity of sarcopenia in ageing male C57BL/6¿J mice. The aim of this study was to investigate whether CR induces changes in behaviour of the animals that could contribute to the pronounced health-promoting effects of CR in rodents. In addition, we aimed to investigate in more detail the effects of CR on the onset and severity of sarcopenia. Methods - The mice received either an ad libitum diet (control) or a diet matching 70 E% of the control diet (C). Daily activity, body composition (dual energy X-ray absorptiometry), grip strength, insulin sensitivity, and general agility and balance were determined at different ages. Mice were killed at 4, 12, 24, and 28¿months. Skeletal muscles of the hind limb were dissected, and the muscle extensor digitorum longus muscle was used for force-frequency measurements. The musculus tibialis was used for real-time quantitative PCR analysis. Results - From the age of 12¿months, CR animals were nearly half the weight of the control animals, which was mainly related to a lower fat mass. In the control group, the hind limb muscles showed a decline in mass at 24 or 28¿months of age, which was not present in the CR group. Moreover, insulin sensitivity (oral glucose tolerance test) was higher in this group and the in vivo and ex vivo grip strength did not differ between the two groups. In the hours before food was provided, CR animals were far more active than control animals, while total daily activity was not increased. Moreover, agility test indicated that CR animals were better climbers and showed more climbing behaviours. Conclusions - Our study confirms earlier findings that in CR animals less sarcopenia is present. The mice on the CR diet, however

We present a case of a 20-year-old man referred to our service with iron overload and mildly deranged liver biochemistry. Although liver histopathology was consistent with haemochromatosis, iron studies were not consistent with this diagnosis. Serum ceruloplasmin levels were undetectable, leading to a diagnosis of aceruloplasminaemia. Unlike other iron overload disorders, neurological complications are a unique feature of this illness, and often irreversible, once established. The patient was treated with iron chelation prior to the onset of neurological injury, and experienced progressive normalisation of his ferritin and liver biochemistry. This is one of the youngest diagnosed cases in the published literature and, crucially, was a rare case of diagnosis and treatment prior to the onset of neurological sequelae. This is presented alongside a review of previously published cases of aceruloplasminaemia, including responses to iron chelation therapy.Copyright © 2015 BMJ Publishing Group. All rights reserved.

Scope : We aimed to investigate whether a novel dietary intervention consisting of an every-other-week calorie restricted diet could prevent non-alcoholic fatty liver disease (NAFLD) development induced by a medium-fat diet. Methods and results : Nine week-old male C57BL/6J mice received either a 1) control (C), 2) 30E% calorie restricted (CR), 3) medium-fat (MF; 25E% fat) or 4) intermittent (INT) diet, a diet alternating weekly between 40E% CR and an ad libitum MF diet until sacrifice at the age of 12 months. The metabolic, morphological, and molecular features of NAFLD were examined. The INT diet resulted in healthy metabolic and morphological features as displayed by the continuous CR diet: glucose tolerant, low hepatic triglyceride content, low plasma alanine aminotransferase. In contrast, the C- and MF-exposed mice with high body weight developed signs of NAFLD. However, the gene expression profiles of INT-exposed mice differed to those of CR-exposed mice and showed to be more similar with those of C- and MF-exposed mice with a comparable body weight. Conclusions : Our study reveals that the INT diet maintains metabolic health and reverses the adverse effects of the MF diet, thus effectively prevent the development of NAFLD in 12-month-old male C57BL/6J mice.

Background and aim: Entecavir is now a 1st line therapeutic option for chronic Hepatitis B (CHB). However, most of the evidence is reliant on controlled phase III trials or real world data in treatment naive populations. This may not reflect its true efficacy in the treatment experienced population. This study aims to document the real world experience of using ETV in an Australian cohort and compares nucleoside analogue naive patients to those exposed to other agents. Method(s): 175 CHB patients at a tertiary centre with annual viral loads treated with Entecavir for 6 months or more were identified retrospectively through pharmacy and clinic records. Baseline demographic data and progressive 6 monthly pathology, fibroscan and imaging reports in addition to clinic notes were reviewed. Treatment outcomes were defined as time to undetectable viral load, time to viral load under 360 IU, new advanced cirrhosis or HCC and time to eAg seroconversion. Interim results: HBeAg positive: 77 patients (70.1% male, 63.6% treatment naive, 76.6% Asian ethnicity, average age 45.8 years). Median ALT 42.5 IU/L, 23% advanced fibrosis. HBeAg negative: 95 patients (74.7% male, 84.2% treatment naive, 68.4% Asian ethnicity, median age 54.8 years). Median ALT 30.5 IU/L, 37.9% advanced fibrosis. Conclusion(s): This study demonstrates that treatment experienced patients can achieve high rates of viral suppression similar to those that are treatment naive. (Figure Presented).

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. Method(s): 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<2000IU/mL 24 weeks post-therapy (HBeAg-positive patients) and HBV-DNA<2000IU/mL 24 weeks after peg-IFN (HBeAg-negative patients). The association between IL28B genotype and peg-IFN outcomes was analyzed. Result(s): 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 CCIL28B 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. Conclusion(s): 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. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

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.

Background & Aims: In this study, we investigated metabolic and molecular effects of weekly intervening 30% calorie restriction on long term natural progression of non-alcoholic fatty liver disease (NAFLD), which was induced by a medium fat diet. Methods: Male C57BL/6J mice of 9 weeks old received either (1) a control (C), (2) a calorie restricted (CR), (3) a medium fat (MF; 25%fat) or (4) an intermittent diet (ID), a weekly alternating diet consisting of calorie restriction and medium fat diet ad libitum until sacrifice at the age of 12 months. Various metabolic and molecular features of the liver were examined. Results: The ID regimen improved the status of a range of metabolic parameters and showed no progression to NAFLD: proper glucose tolerance, low hepatic triglyceride content, low plasma alanine aminotransferase and no abnormalities in its liver morphological features; similarly to that of CR. In contrast, the metabolic parameters in a number of the C and MF animals indicated development of NAFLD and hepatic fibrosis, which was positively correlated with body weight. Despite the metabolic phenotypes similarity, the liver gene expression profile of ID-fed mice did not reflect that of CR mice and resembled more to C and MF-fed mice with similar low body weight. Conclusions: Our study reveals that ID is beneficial for metabolic health and prevents the development of NAFLD in mice, with a gene expression profile similar to C and MF diet in a body weight-dependent manner. Overall design: Male C57BL/6J mice were divided to 4 dietary intervention groups: Control (AIN-93W), 30% calorie restriction (CR; AIN-93W-CR), medium fat (MF; AIN-93W-MF; 25% energy from fat) and intermittent diet (ID; weekly alternating diet between AIN-93W-MF ad lib and 40% CR of AIN-93W). We treated the mice with either solvent (mock treatment) or PPARa agonist, Wy-14,643 (Wy treatment), 6 hours prior to sacrifice. The mock- and Wy-treatment were applied to body weight-matched mice within eac, Background & Aims: In this study, we investigated metabolic and molecular effects of weekly intervening 30% calorie restriction on long term natural progression of non-alcoholic fatty liver disease (NAFLD), which was induced by a medium fat diet. Methods: Male C57BL/6J mice of 9 weeks old received either (1) a control (C), (2) a calorie restricted (CR), (3) a medium fat (MF; 25%fat) or (4) an intermittent diet (ID), a weekly alternating diet consisting of calorie restriction and medium fat diet ad libitum until sacrifice at the age of 12 months. Various metabolic and molecular features of the liver were examined. Results: The ID regimen improved the status of a range of metabolic parameters and showed no progression to NAFLD: proper glucose tolerance, low hepatic triglyceride content, low plasma alanine aminotransferase and no abnormalities in its liver morphological features; similarly to that of CR. In contrast, the metabolic parameters in a number of the C and MF animals indicated development of NAFLD and hepatic fibrosis, which was positively correlated with body weight. Despite the metabolic phenotypes similarity, the liver gene expression profile of ID-fed mice did not reflect that of CR mice and resembled more to C and MF-fed mice with similar low body weight. Conclusions: Our study reveals that ID is beneficial for metabolic health and prevents the development of NAFLD in mice, with a gene expression profile similar to C and MF diet in a body weight-dependent manner. Overall design: Male C57BL/6J mice were divided to 4 dietary intervention groups: Control (AIN-93W), 30% calorie restriction (CR; AIN-93W-CR), medium fat (MF; AIN-93W-MF; 25% energy from fat) and intermittent diet (ID; weekly alternating diet between AIN-93W-MF ad lib and 40% CR of AIN-93W). We treated the mice with either solvent (mock treatment) or PPARa agonist, Wy-14,643 (Wy treatment), 6 hours prior to sacrifice. The mock- and Wy-treatment were applied to body weight-matched mice within eac

Background and Aim: Host IL28B genotype predicts response to pIFN in hepatitis C patients and was associated with HBeAg and HBsAg clearance in a European study of HBeAg-positive CHB patients treated with pIFN (Sonneveld, J Hepatol, 2011). The utility of IL28B genotyping in pIFN treated Asian CHB cohorts is not clear. We investigated whether IL28B genotype is associated with pIFN treatment outcomes in a predominantly Asian CHB cohort. Table: Treatment outcomes at 6 months post-pIFN HBeAg pre-treatment Positive HBeAg pre-treatment Negative IL28B genotype HBeAg seroclearance + HBVDNA <20,000 IU/mL P-value IL28B genotype HBVDNA <2,000 IU/mL P-value HBVDNA <400 IU/mL P-value Overall (n = 60) 19 (31%) Overall (n = 36) 22 (61%) 12 (33%) CC (n=51) 216(31%) 0.615 CC (n = 30) 19 (63%) 0.431 11 (37%) 0.331 Non-CC (n=9) 3 (33%) Non-CC (n=6) 3 (50%) 1 (17%) Methods: Retrospective analysis of CHB patients treated with pIFN (48 weeks) from two Australian centres. IL28B genotype (rs12979860) was determined (TaqMan allelic discrimination kit). Baseline HBV DNA, ALT, and liver histology were available. Baseline HBsAg were determined from stored sera. Treatment efficacy endpoint in HBeAg-positive patients was HBeAg seroclearanceseroconversion and HBV DNA <20,000 IU/mL 6 months postpIFN. In HBeAg-negative patients HBV DNA <2,000 IU/mL (VR) 6 months post-pIFN was the primary efficacy endpoint. We analysed associations between baseline, including IL28B genotype, and on-therapy factors associated with treatment outcome. Result(s): IL28B genotype was determined for 96 patients. 84 (88%) were Asian. Most patients carried the CC IL28B genotype, 81 (84%), CT in 14 (15%), TT in 1 (1%). 62% were HBeAg-positive. 13% were METAVIR F3-4. Median follow-up was 33 months. IL28B was not associated with treatment outcome in HBeAg-positive or HBeAgnegative CHB. In HBeAg-positive patients baseline HBV DNA level was the only baseline predictor of the primary outcome, and lower HBV DNA level and higher HBV

Background Tenofovir (TDF) and Entecavir (ETV) are nucleos(t)ide (NUC) analogues which are potent inhibitors of hepatitis B virus. However, the long-term effect of TDF on renal function in CHB patients remains unclear. Aims To compare the incidence, severity and clinical significance of changes in renal function over 2 years amongst CHB patients treated with TDF 300 mg daily or ETV 0.5 mg or 1.0 mg daily versus an untreated cohort. Methods We retrospectively identified 124 patients treated with either ETV (n = 74) or TDF+/- LMV (n = 50) for a minimum of 2 years. 73 untreated CHB patients were used as controls. Renal function was assessed by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula (MDRD) at baseline, 6, 12 and 24 months. Exclusion criteria included concomitant use of potential nephrotoxins, decompensated cirrhosis and previous NUC exposure apart from lamivudine if renal function was normal upon commencement of TDF. Baseline demographics, MELD score, presence of cirrhosis and risk factors for renal impairment were recorded. Outcomes assessed included kidney function (decline in eGFR >=40% and change in eGFR over time) and dose adjustment or cessation of either therapy. Analysis was performed using a mixed linear model to incorporate repeated measures. Results Baseline characteristics were closely matched between the three cohorts (p = NS). Older age (p = 0.0043) and cirrhosis (p < 0.0001) were more prevalent in the ETV group. The proportion of patients with >=40% reduction in eGFR from baseline was 3.92% in the TDF +/- LMV group vs. 2.7% in the ETV group (p = NS). In the univariate mixed linear model, compared to control subjects at baseline, eGFR at 2 years declined in the ETV group by -7.6 ml/min (95% CI -15.8-+0.6, p = 0.07) and -8.7 ml/ min (CI -18.3-+1.0, p = 0.08) in the TDF +/- LMV group while in the control it remained stable at +7.4 ml/min (CI 0.78 - 14.1, p = 0.03). After adjustment for age, gender

Background Host IL28B genotype predicts response to peg-IFN in patients with chronic hepatitis C and was associated with HBeAg and HBsAg clearance in a European study of HBeAg-positive chronic hepatitis B (CHB) patients treated with peg-IFN. However, the utility of IL28B genotyping in Asian CHB cohorts who are treated with peg-IFN is not clear. Aims We investigated whether IL28B genotype is associated with treatment outcomes in a predominantly Asian CHB cohort treated with peg-IFN. Methods This was a retrospective analysis of consecutive CHB patients treated with 48 weeks of peg-IFN monotherapy from two large Australian centres. IL28B genotype (rs12979860) was determined retrospectively on stored sera using the TaqMan allelic discrimination kit. Baseline HBV DNA, ALT, and liver histology were available. The primary treatment outcome for HBeAg-positive patients was HBeAg seroconversion with HBV DNA <2,000 IU/mL 6 months after cessation of peg-IFN. In HBeAgnegative patients the primary treatment efficacy endpoint was HBV DNA < 2,000 IU/mL 6 months after completion of peg-IFN. We analysed the association between IL28B genotype (CC vs non-CC) and peg-IFN treatment outcomes. We also considered the association between IL28B genotype and the following secondary treatment outcomes: HBeAg seroclearance, normalisation of ALT and HBV DNA reduction on-treatment, and HBsAg seroclearance. Results 60 (62%) patients were HBeAg-positive and 36 (38%) were HBeAg-negative. 13% were METAVIR stage F3-4. Median follow-up time was 39.3 months (28.9-55.5); 31.4 months in HBeAg-positive patients and 42.5 months in HBeAg-negative patients. Overall, the majority of patients carried the CC IL28B genotype, 81/96 (84%) versus CT in 14 (15%) versus TT in 1 (1%). This distribution was similar in both HBeAg-positive and HBeAg-negative patients with 85% and 83% carrying the CC IL28B genotype, respectively. The primary endpoints were achieved in 27% and 61% of HBeAg-positive and HBeAg-negative patient

Background and Aim: Pegylated interferon-alpha (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-alpha2A in CHB patients in a clinical setting. Method(s): Chronic hepatitis B patients treated with PEG-IFN-alpha2A (180mug/week, 48weeks) 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. Result(s): 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 <351IU/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 <351IU/mL, respectively. Optimal viral suppression was maintained in 50-75% of patients over 2years of follow up. 6.5% of all patients discontinued therapy due to AEs. Conclusion(s): 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. © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Background: Tenofovir (TDF) and Entecavir (ETV) are nucleos(t)ide (NUC) analogues which are potent inhibitors of hepatitis B virus. However, the long-term effect of TDF on renal function in CHB patients remains unclear. Aim(s): To compare the incidence, severity and clinical significance of changes in renal function over 2 years amongst CHB patients treated with TDF 300mg daily or ETV 0.5mg or 1.0mg daily versus an untreated cohort. Method(s): We retrospectively identified 124 patients treated with either ETV (n=74) or TDF+/- LMV (n=50) for a minimum of 2 years. 73 untreated CHB patients were used as controls. Renal function was assessed by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula (MDRD) at baseline, 6, 12 and 24 months. Exclusion criteria included concomitant use of potential nephrotoxins, decompensated cirrhosis and previous NUC exposure apart from lamivudine if renal function was normal upon commencement of TDF. Baseline demographics, MELD score, presence of cirrhosis and risk factors for renal impairment were recorded. Outcomes assessed included kidney function (decline in eGFR >=40% and change in eGFR over time) and dose adjustment or cessation of either therapy. Analysis was performed using a mixed linear model to incorporate repeated measures. Result(s): Baseline characteristics were closely matched between the three cohorts (p=NS). Older age (p=0.0043) and cirrhosis (p<0.0001) were more prevalent in the ETV group. The proportion of patients with >=40% reduction in eGFR from baseline was 3.92% in the TDF +/- LMV group vs. 2.7% in the ETV group (p=NS). In the univariate mixed linear model, compared to control subjects at baseline, eGFR at 2 years declined in the ETV group by -7.6 ml/min (95% CI -15.8-+0.6, p=0.07) and -8.7 ml/min (CI -18.3-+1.0,p=0.08) in the TDF +/- LMV group while in the control it remained stable at +7.4 ml/min (CI 0.78-14.1, p=0.03). After adjustment for age, gender, hypertension

Background Rapid virological response (RVR) defined as undetectable viremia at 4 weeks of Interferon-based therapy for Hepatitis C virus (HCV) is a critical tool for predicting sustained virological response (SVR), which occurs in approximately 90% of patients following RVR. The aim of this study was to assess the impact of RVR compared with any detectable virus below 30 IU/mL at 4 weeks on SVR. Methods We retrospectively analysed the HCV treatment database in a large tertiary centre in Melbourne. We identified 133 of 272 patients who had week 4 viral load testing available from Interferon based therapy between 2008 and 2010. Viral loads were performed using the M2000 Abbott RealTime HCV assay which is able to accurately stratify between undetectable viral load and <30 IU/mL when using 200 uL aliquots of serum. Viral loads at weeks 4, 12 and 24 were documented as were ALT, patient age, ethnicity, sex, viral genotype and fibrosis score when available. Statistical analysis was performed using Fischer's exact test. Results 70.5% of patients were male and 20% were cirrhotic. Overall SVR for the 272 patients was 55% on an intention to treat (ITT) basis. SVR for the 133 patients with evaluable viral load data at week 4 was 67.2%. Of these, 67 patients were genotype 1, (SVR 61.2%) and 54 were genotype 2/3 (SVR 77.8%) and the remainder were genotype 4 and 6. 49 patients (36.8%) had an RVR (16 genotype 1) and all achieved SVR. 28 patients had viral load <30 IU/mL at 4 weeks; of these 4 relapsed and 2 were lost to follow-up. An SVR occurred in 22 (78.5% by ITT; 84.6% by per protocol analysis). Comparing these two groups, SVR was more likely to occur in patients with an RVR than those with VL <30 IU/mL (p = 0.012). 55 patients had viral loads >30 IU/mL at week 4. 21 were nonresponders, never fully suppressing viral load; 11 achieved an initial response then relapsed and 2 were lost to follow-up. 21 achieved SVR (38.2%). The difference in SVR between patients with VL >30 IU/mL

Background Patients with hepatitis C virus (HCV) related bridging fibrosis and cirrhosis represent a population at increased risk of developing liver failure and hepatocellular carcinoma (HCC). Historically these patients tolerate and respond poorly to therapy. However, achieving sustained virological response (SVR) following antiviral treatment reduces the likelihood of clinical decompensation and improves morbidity and mortality. Our aim was to identify factors predicting treatment response in patients with biopsy proven bridging fibrosis and cirrhosis. Methods We retrospectively analysed the HCV treatment database in a large tertiary centre in Melbourne. We identified 104 patients with biopsy proven bridging fibrosis (Metavir F3) and Child Pugh A cirrhosis (Metavir F4) who received pegylated interferon and ribavirin between 2003-2010. Patient age, weight, ethnicity, gender, albumin, bilirubin, INR, platelet count, viral genotype, baseline viral load and liver ultrasound examination were obtained. Statistical analysis was performed using Fischer's exact test. Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. Results 104 patients were included in this study with a total of 108 treatment episodes. The mean age of participants was 52 years (range 33-73 years), 60% were male, 52% were genotype 1 and 36% genotype 3. 62% had a viral load >=400,000 IU/ml. 55% were cirrhotic. Pre-treatment liver ultrasound was performed in 96 patients, 33 (34%) had ultrasound features of portal hypertension. SVR occurred in 41%, the mean age of these patients was 53 years, 64% were male, 27% were genotype 1, 48% were genotype 3, 47% had a viral load >=400,000 IU/ml, 50% were cirrhotic and 13% had ultrasound features of portal hypertension. Multivariate analysis identified genotype 3 (p = 0.002), the absence of ultrasound features of portal hypertension (p < 0.001) and a viral load <400,000 IU/ ml (p = 0.008) as independent predictors of SVR.

A recent study highlighted that race influences survival in patients with hepatocellular carcinoma (HCC) with Asian patients having the best survival (Cancer 2010). Our aim was to determine if a difference in tumour characteristics, treatment and survival exists between Southeast Asian (SEA) and non-SE Asians presenting with HCC at our centre. Method(s): A prospective HCC database was used to identify all patients diagnosed with HCC between Jan 2000 and Dec 2009. Demographics, tumour characteristics, treatment and survival were compared in patients originating from SEA and non-SEA countries. Result(s): Over the 10 year study period 176 patients were diagnosed with HCC, of these 61 (35%) were from SE Asia; the remainder were from Australia, Europe, North Asia and South America. In the SEA and non-SEA groups, the majority of patients were male (77% and 79% respectively); the mean age was similar (61 and 63 years). The main risk factor for HCC in SE Asians was viral hepatitis in 96% [Hepatitis B (HBV) 51%, Hepatitis C (HCV) 45%]. In the non-SEA group, the commonest risk factor was alcohol (41%) followed by HCV (27%) and HBV (15%). Cirrhosis was present in 92% of SEA and 98% of non-SEA patients (p=ns). The majority of SEA patients had compensated cirrhosis (Childs Pugh Turcotte (CPT) A 82%, B 12%, C 6%); more non-SEA patients presented with decompensated disease (CPT A 50%, B 33%, C 27%). There was no difference in Afetoprotein values (normal in 33% SEA and 47% of non-SEA) or in tumour size between SEA and non-SEA groups (<5cm: 63% vs. 57%, 5-10cm: 20% vs. 27%, >10cm: 17% vs16%). SEA patients were less likely to present with multifocal disease than non-SE Asians (25% vs. 45%, p=0.02). SEA patients underwent significantly more potentially curative treatments (liver transplantation or resection, radiofrequency ablation) than non- SE Asians (28% vs. 10%, p=0.008). There was no difference in the number of patients offered TACE (41% vs 39%). Overall survival was superior in

A recent study highlighted that race influences survival in patients with hepatocellular carcinoma (HCC) with Asian patients having the best survival (Cancer 2010). Aim to determine if a difference exists between Southeast Asian (SEA) and non-SE Asians presenting with HCC at our centre. Method A prospective HCC database was used to identify all patients diagnosed with HCC between Jan 2000 and Dec 2009. Demographics, tumour characteristics, treatment and survival were compared in patients originating from SEA and non-SEA countries. Result(s): Over the 10-year study period 176 patients were diagnosed with HCC, of these 61 (35%) were from SE Asia; the remainder were from Australia, Europe, North Asia and South America. In the SEA and non-SEA groups, the majority of patients were male (77% and 79%); the mean age was similar (61 and 63 years). The main risk factor for HCC in SE Asians was viral hepatitis in 96% (Hepatitis B [HBV] 51%, Hepatitis C [HCV] 45%). In the non-SEA group, the commonest risk factor was alcohol excess (41%) followed by HCV (27%) and HBV (15%). Cirrhosis was present in 92% of SEA and 98% of non-SEA patients (p = ns). The majority of SEA patients had compensated cirrhosis (Childs Pugh Turcotte [CPT] A 82%, B 12%, C 6%); more non-SEA patients presented with decompensated disease (CPT A 50%, B 33%, C 27%). There was no difference in afetoprotein values (normal in 33% SEA and 47% of non-SEA) or in tumour size between SEA and non-SEA groups (<5 cm: 63% vs. 57%, 5-10 cm: 20% vs. 27%, <10 cm: 17% vs. 16%). SEA patients were less likely to present with multifocal disease than non-SE Asians (25% vs. 45%, p = 0.02). SEA patients underwent significantly more potentially curative treatments (liver transplantation or resection, radiofrequency ablation) than non-SE Asians (28% vs. 10%, p = 0.008). There was no difference in the number of patients offered TACE (41% vs 39%). Overall survival was superior in SEA compared to non-SEA patients (median 39 months vs. 16

BACKGROUND: Patients with hepatitis C virus (HCV) related bridging fibrosis and cirrhosis represent a population at increased risk of developing liver failure and hepatocellular carcinoma (HCC). Historically these patients tolerate and respond poorly to therapy. However, achieving sustained virological response (SVR) following antiviral treatment reduces the likelihood of clinical decompensation and improves morbidity and mortality. Our aim was to identify factors predicting treatment response in patients with biopsy proven bridging fibrosis and cirrhosis. METHOD(S): We retrospectively analysed the HCV treatment database in a large tertiary centre in Melbourne. We identified 104 patients with biopsy proven bridging fibrosis (Metavir F3) and Child Pugh A cirrhosis (Metavir F4) who received pegylated interferon and ribavirin between 2003-2010. Patient age, weight, ethnicity, gender, albumin, bilirubin, INR, platelet count, viral genotype, baseline viral load and liver ultrasound examination were obtained. Statistical analysis was performed using Fischer's exact test. Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULT(S): 104 patients were included in this study with a total of 108 treatment episodes. The mean age of participants was 52 years (range 33-73 years), 60% were male, 52% were genotype 1 and 36% genotype 3. 62% had a viral load >/= 400,000IU/ml. 55% were cirrhotic. Pre-treatment liver ultrasound was performed in 96 patients, 33 (34%) had ultrasound features of portal hypertension. SVR occurred in 41%, the mean age of these patients was 53 years, 64% were male, 27% were genotype 1, 48% were genotype 3, 47% had a viral load >/= 400,000IU/ml, 50% were cirrhotic and 13% had ultrasound features of portal hypertension. Multivariate analysis identified genotype 3 (p=0.002), the absence of ultrasound features of portal hypertension (p<0.001) and a viral load < 400,000IU/ml (p=0.033) as independent predictors of SV

Background: Rapid virological response (RVR) defined as undetectable viremia at 4 weeks of Interferon-based therapy for Hepatitis C virus (HCV) is a critical tool for predicting sustained virological response (SVR), which occurs in approximately 90% of patients following RVR. . The aim of this study was to assess the impact of RVR compared with any detectable virus below 30 IU/mL at 4 weeks on SVR. Method(s): We retrospectively analysed the HCV treatment database in a large tertiary centre in Melbourne, Australia. We identified 133 of 272 patients who had week 4 viral load testing available from Interferon based therapy between 2008 and 2010. Viral loads were performed using the M2000 Abbott RealTime HCV assay which is able to accurately stratify between undetectable viral load and <30IU/mL when using 200ul aliquots of serum. Viral loads at weeks 4, 12 and 24 were documented as were ALT, patient age, ethnicity, sex, viral genotype and fibrosis score when available. Statistical analysis was performed using Fischer's exact test. Result(s): 70.5% of patients were male and 20% were cirrhotic. Overall SVR for the 272 patients was 55% on an intention to treat (ITT) basis. SVR for the 133 patients with evaluable viral load data at week 4 was 67.2%. Of these, 67 patients were genotype 1, (SVR 61.2%) and 54 were genotype 2/3 (SVR 77.8%) and the remainder were genotype 4 and 6. 49 patients (36.8%) had an RVR (16 genotype 1) and all achieved SVR. 28 patients had viral load <30IU/mL at 4 weeks; of these 4 relapsed and 2 were lost to follow-up. An SVR occurred in 22 (78.5% by ITT; 84.6% by per protocol analysis). Comparing these two groups, SVR was more likely to occur in patients with an RVR than those with VL <30 IU/mL (p = 0.012). 55 patients had viral loads >30IU/mL at week 4. 21 were non-responders, never fully suppressing viral load; 11 achieved an initial response then relapsed and 2 were lost to follow-up. 21 achieved SVR (38.2%). The difference in SVR between patients w

Background: The effect of serum ALT changes in the outcome of combination pegylated interferon alpha (PEG IFNalpha) and ribavirin therapy for chronic hepatitis C virus (HCV) infection is not well known. We evaluated changes in ALT during standard therapy for HCV to determine correlations with sustained virological response (SVR), non-response (NR) and relapse (R). Method(s): 179 patients with HCV infection who completed standard combination therapy in our institution from 2004 to 2008 were identified. Age, sex, pre-treatment ALT and viral load, fibrosis score, type of PEG IFNalpha, on treatment viral loads and ALT (weeks 2, 4, 8, 12, 16, 20, 24, 36, 48) and during follow-up at 6 months were retrospectively collected and evaluated. Patients were divided into SVR, NR and R. ALT and baseline characteristics were compared using Student's T-test and Chi squared analysis to determine correlations between ALT level and virological response. Result(s): Overall SVR (all genotypes) was 72.07%, with NR 16.76% and R 11.17%. There was no significant ALT rise after week 12 in any of the outcome groups, however the absolute ALT level was significantly higher in NR compared to SVR at weeks 2 to 24 (p < 0.001). The percentage decrease in ALT was also significantly reduced at weeks 8, 12, 36, 48 in NR compared to SVR (p < 0.03). ALT levels in the R group were significantly higher than the SVR group from weeks 12 to 36 (p < 0.01), and had a reduced percentage change in ALT at weeks 8 to 24 (p < 0.02). Comparing baseline demographics, clinical and virological factors, only males were significantly more likely to relapse after completing treatment (p = 0.027). Of patients with initial viral suppression continuing to week 24 (n = 170), we found that ALT <= 25 U/L was strongly associated with SVR compared to NR and R (p < 0.05). Conclusion(s): Higher ALT levels between weeks 2 to 24 and a smaller percentage drop in ALT compared to pre-treatment were associated with NR. Higher ALT levels a