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Reliable predictors of outcomes after treatment discontinuation in HBeAg-negative chronic hepatitis B (CHB) patients have not been established. We investigated the role of hepatitis B surface antigen (HBsAg), interferon-inducible protein-10 (IP10) and hepatitis B core-related antigen (HBcrAg) serum levels as predictors of HBsAg loss, relapse and retreatment in noncirrhotic HBeAg-negative CHB patients who discontinued long-term antiviral therapy. All HBsAg-positive (n = 57) patients of the prospective DARING-B study were included and followed monthly for 3 months, every 2/3 months until month-12 and every 3/6 months thereafter. HBsAg, IP10 and HBcrAg levels were measured by enzyme immunoassays, and SCALE-B score was calculated. Twelve patients achieved HBsAg loss before retreatment with 18-month cumulative incidence of 25%. Independent predictors of HBsAg loss were baseline HBsAg and month-1 IP10 levels. Of 10 patients with baseline HBsAg ≤100 IU/mL, 70% cleared HBsAg and 10% required retreatment. Of 23 patients with baseline HBsAg >1000 IU/mL, 4% cleared HBsAg and 43% required retreatment. Of 24 patients with intermediate baseline HBsAg (100-1000 IU/mL), 17% cleared HBsAg and 21% required retreatment; in this subgroup, month-1 IP10 was significantly associated with HBsAg loss, which occurred in 30% and 7% of cases with IP10 >150 and ≤150 pg/mL, respectively. Baseline HBcrAg was undetectable in all patients who cleared HBsAg and was associated with retreatment. SCALE-B was associated with HBsAg loss but not with relapse or retreatment. In conclusion, HBsAg, IP10 and HBcrAg serum levels can be useful for the decisions and management of treatment discontinuation in noncirrhotic Caucasian patients with HBeAg-negative CHB., (© 2019 John Wiley & Sons Ltd.)

Background: Liver disease severity must be determined before treatment of chronic hepatitis C (CHC). We evaluated the diagnostic performance of the APRI and FIB-4 scores compared to transient elastography liver stiffness (TE-LS) in detecting significant fibrosis (F3) or cirrhosis (F4)., Methods: We retrospectively enrolled 575 patients with CHC who underwent TE-LS between May 2014 and September 2018: 365 (63.5%) male, mean age 51.54±12.4 years. APRI and FIB-4 scores were compared to TE-LS., Results: One hundred patients (17.5%) had TE-LS values between 9 and 11.9 kPa, and were classified as F3, while 265 (46%) were classified as F4 (TE-LS ≥12 kPa). APRI and FIB-4 scores predicted F4 patients adequately using cutoff values of 0.65 (sensitivity 85.5%, specificity 77%) and 1.63 (sensitivity 91%, specificity 77%), respectively. Cutoff values of 0.64 for APRI and 1.46 for FIB-4 predicted F3/F4 patients (sensitivity 72% and 81.5%; specificity 83% and 79%, respectively). The use of these cutoff values with APRI and FIB-4 in combination adequately predicted patients with significant fibrosis or cirrhosis (positive predictive value 91.5%), while cutoff values of 0.3 and 0.98, respectively, predicted F1/F2 patients with specificity 94.5% and sensitivity 26.5%, suggesting that in 58.5% of patients TE-LS could possibly be avoided., Conclusions: The APRI/FIB-4 combination performed well in predicting significant fibrosis, while FIB-4 performed well in predicting cirrhosis. These noninvasive biochemical markers could be used as screening tools instead of LS measurement, which is not widely available. Further prospective validation studies are required to confirm this finding., Competing Interests: Conflict of Interest: None

There are estimated to be 74,000-134,000 patients living with chronic hepatitis C in Greece, but only 20-30% of them are aware of their disease status. In July 2017, the Hellenic National Plan for Hepatitis C was announced in alignment with the World Health Organization goals for the eradication of hepatitis C virus (HCV) by the year 2030. This article discusses the epidemiology and current treatment of chronic hepatitis C in Greece. Additionally the authors propose actions on how to bring back to care diagnosed patients lost to follow up, optimize access to care for HCV-infected people who inject drugs, and increase HCV screening in the general population. The medical community in Greece can play a pivotal role in the implementation of the HCV National Plan and in the efforts to reach the goal of HCV elimination., Competing Interests: Conflict of Interest: The article includes opinions expressed during a Gilead-sponsored scientific meeting held at the end of June 2017. Data have been updated to reflect the current HCV landscape in Greece. No compensation has been provided to any of the authors for the preparation of this manuscript.

The optimal duration of treatment with nucleos(t)ide analogues (NAs) for patients with HBeAg-negative chronic hepatitis B (CHB) is unknown. The aim of this study was to identify an immune signature associated with off-treatment remission to NA therapy. We performed microarray analysis of peripheral blood mononuclear cell (PBMCs) from six patients with chronic hepatitis B who stopped NA therapy (three with off-treatment remission, three with relapse) and five patients with chronic HBV infection (previously termed 'inactive carriers') served as controls. Results were validated using qRT-PCR on a second group of 21 individuals (17 patients who stopped treatment and four controls). PBMCs from 38 patients on long-term NA treatment were analysed for potential to stop treatment. Microarray analysis indicated that patients with off-treatment remission segregated as a distinct out-group. Twenty-one genes were selected for subsequent validation. Ten of these were expressed at significantly lower levels in the patients with off-treatment remission compared to the patients with relapse and predicted remission with AUC of 0.78-0.92. IFNγ, IL-8, FASLG and CCL4 were the most significant by logistic regression. Twelve (31.6%) of 38 patients on long-term NA therapy had expression levels of all these four genes below cut-off values and hence were candidates for stopping treatment. Our data suggest that patients with HBeAg-negative CHB who remain in off-treatment remission 3 years after NA cessation have a distinct immune signature and that PBMC RNA levels of IFNγ, IL-8, FASLG and CCL4 may serve as potential biomarkers for stopping NA therapy., (© 2019 John Wiley & Sons Ltd.)

Several polymorphisms in the vitamin D receptor (VDR) are associated with the occurrence of chronic liver disease. Here, we investigated the association between BsmI, ApaI, TaqI and FokI VDR polymorphisms and the severity of liver cirrhosis in relation to serum cytokine and lipopolysaccharide binding protein (LBP) levels and their role on survival in cirrhotic patients. We found that patients harboring the BB genotype had higher MELD score, and they were mainly at CP stage C; patients harboring the AA genotype had increased LBP, IL-1β and IL-8 levels, and they were mostly at CP stage C; TT genotype carriers had higher MELD score and they were mainly at CP stage C and FF genotype carriers had lower IL-1β levels when compared to Bb/bb, Aa/aa, Tt/tt and Ff/ff genotypes respectively. In the multivariate analysis ApaI, BsmI and TaqI polymorphisms were independently associated with liver cirrhosis severity. In the survival analysis, the independent prognostic factors were CP score, MELD and the FF genotype. Our results indicate that the ApaI, TaqI and BsmI polymorphisms are associated with the severity of liver cirrhosis, through the immunoregulatory process. Survival is related to the FF genotype of FokI polymorphism, imparting a possible protective role in liver cirrhosis.

Background: It is estimated that 17,000 people who inject drugs (PWID) in Greece have hepatitis C virus (HCV) viremia. The aim of our study was to explore the characteristics of the HCV-infected, direct acting antiviral (DAA)-naïve PWID., Methods: This is a retrospective analysis of PWID with HCV infection. We selected data from six liver clinics during the period from 1 st May 2014 to 31 st May 2017 in order to record the characteristics of infected PWID., Results: We included 800 PWID with HCV infection (78.5% male, mean age 42±10 years) who had not received DAAs before 1 st June 2017. One third of the patients had comorbidities (diabetes mellitus, arterial hypertension and psychological disorders); 70% were smokers, 27% alcohol users, 67% unemployed, 29% married, and 34% had education >12 years; 65% were attending addiction programs; 57% were receiving methadone and 36% buprenorphine. Sporadic or systemic drug use was reported by 37% while 1.4% and 2.9% had HIV and HBV coinfection, respectively. The genotype distribution was 20.5%, 4.6%, 3.3%, 61% and 10% for genotypes 1a, 1b, 2, 3 and 4, respectively. Mean (±SD) liver stiffness was 9±7 kPa and 21% of the patients had cirrhosis. Half of the patients were in the F0-F1 stage of liver disease, defined as stiffness ≤7 kPa., Conclusions: Our real-life data suggest that HCV genotype 3 remains the predominant genotype among PWID. One third of PWID had comorbidities and one-fifth cirrhosis. Half of PWID had early-stage liver disease and remained without access to DAAs according to the Greek prioritization criteria., Competing Interests: Conflict of Interest: Gilead Sciences

Relapses are observed in most hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients who discontinue treatment with nucleos(t)ide analogues (NAs); however, the rates of relapse vary widely among studies, and whether all patients with relapse need retreatment is unclear. The aim of this study was to assess the impact of different definitions on the rates of posttreatment relapse and therefore on the probability of retreatment in patients who have discontinued effective long-term NA therapy. In total, 130 HBeAg-negative chronic hepatitis B patients without cirrhosis and before NA treatment were included. All had on-therapy virological remission for ≥24 months and close follow-up for ≥12 months after stopping NA treatment or until retreatment, which started on stringent predefined criteria. Relapses rates based on several predetermined definitions of virological and perhaps biochemical criteria were assessed. The median duration of therapy was 60 months and the median duration of on-therapy virological remission was 43 months. During a median off-NAs follow-up of 15 months, no patient experienced liver decompensation or died. Cumulative relapse rates were 2%-49%, 4%-73%, 11%-82%, and 16%-90% at 3, 6, 12, and 24 months, respectively, whereas cumulative retreatment rates were 15%, 22%, and 40% at 6, 12, and 24 months, respectively, after discontinuation of NA therapy. No patient characteristic was independently associated with the probability of relapse based on at least two definitions or of retreatment., Conclusion: In HBeAg-negative chronic hepatitis B patients who discontinue NA therapy, the definition of relapse has a great impact on off-NAs relapse rates and potentially on the probability of retreatment. Regardless of definition, off-NAs relapses cannot be easily predicted by patient characteristics. A substantial proportion of such patients may not require retreatment if stringent criteria are adopted. (Hepatology 2017)., (© 2017 by the American Association for the Study of Liver Diseases.)

Aim: To summarize and critically examine the role of band ligation in secondary prophylaxis of variceal bleeding in patients with cirrhosis., Methods: A literature review was performed using the MEDLINE and PubMed databases. The search terms consisted of the words "endoscopic band ligation" OR "variceal band ligation" OR "ligation" AND "secondary prophylaxis" OR "secondary prevention" AND "variceal bleeding" OR "variceal hemorrhage" AND "liver cirrhosis". The data collected from relevant meta-analyses and from the most recent randomized studies that were not included in these meta-analyses were used to evaluate the role of endoscopic band ligation in an effort to demonstrate the most recent advances in the treatment of esophageal varices., Results: This study included 11 meta-analyses published from 2002 to 2017 and 10 randomized trials published from 2010 to 2017 that evaluated the efficacy of band ligation in the secondary prophylaxis of variceal bleeding. Overall, the results proved that band ligation was superior to endoscopic sclerotherapy. Moreover, the use of β-blockers in combination with band ligation increased the treatment effectiveness, supporting the current recommendations for secondary prophylaxis of variceal bleeding. The use of transjugular intrahepatic portosystemic shunt was superior to combination therapy regarding rebleeding prophylaxis, with no difference in the survival rates; however, the results concerning the hepatic encephalopathy incidence were conflicting. Recent advances in the management of secondary prophylaxis of variceal bleeding have targeted a decrease in portal pressure based on the pathophysiological mechanisms of portal hypertension., Conclusion: This review suggests that future research should be conducted to enhance current interventions and/or to develop innovative treatment options with improved clinical endpoints., Competing Interests: Conflict-of-interest statement: Spilios Manolakopoulos has received research grants from Gilead Sciences, Regulus and Bristol-Myers Squibb and fees for lectures and advisory board from Gilead Sciences, Roche, Bristol-Myers Squibb, GSK, AbbVie and MSD; Christos Triantos has received fees as a speaker/advisory board member and research/travel grants from MSD, Roche, AbbVie, Janssen, Bristol-Myers Squibb, Bayer and Gilead Sciences.

Background & Aims: The effects of long-term antiviral therapy on survival have not been adequately assessed in chronic hepatitis B (CHB). In this 10-centre, ongoing cohort study, we evaluated the probability of survival and factors affecting survival in Caucasian CHB patients who received long-term entecavir/tenofovir therapy., Methods: We included 1,951 adult Caucasians with CHB, with or without compensated cirrhosis and without hepatocellular carcinoma (HCC) at baseline, who received entecavir/tenofovir for ≥12 months (median, six years). Kaplan-Meier estimates of cumulative survival over time were obtained. Standardized mortality ratios (SMRs) were calculated by comparing death rates with those in the Human Mortality Database., Results: The one-, five-, and eight-year cumulative probabilities were 99.7, 95.9, and 94.1% for overall survival, 99.9, 98.3, and 97.4% for liver-related survival, and 99.9, 97.8, and 95.8% for transplantation-free liver-related survival, respectively. Overall mortality was independently associated with older age and HCC development, liver-related mortality was associated with HCC development only, and transplantation-free liver-related mortality was independently associated with HCC development and lower platelet levels at baseline. Baseline cirrhosis was not independently associated with any type of mortality. Compared with the general population, in all CHB patients mortality was not significantly different (SMR 0.82), whereas it was lower in patients without HCC regardless of baseline cirrhosis (SMR 0.58) and was higher in patients who developed HCC (SMR 3.09)., Conclusion: Caucasian patients with CHB and compensated liver disease who receive long-term entecavir/tenofovir therapy have excellent overall and liver-related eight-year survival, which is similar to that of the general population. HCC is the main factor affecting their overall mortality, and is the only factor affecting their liver-related mortality., Lay Summary: Caucasian patients with chronic hepatitis B with or without compensated cirrhosis who receive long-term entecavir or tenofovir therapy have excellent overall eight-year survival, which is similar to that of the general population. Hepatocellular carcinoma is the main factor affecting their overall mortality, and is the only factor affecting liver-related mortality in this setting., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Only limited data concerning hepatitis B (HBV) and C viruses (HCV) coinfection are available. Direct-acting antivirals (DAAs) may be more effective for HCV clearance than interferon (IFN)-based regimens with a risk of HBV reactivation., Methods: We retrospectively enrolled 40 HBV/HCV-coinfected patients to evaluate their clinical profile and treatment outcomes., Results: Chronic dual infection was present in 25/40 (62.5%) patients, acute HCV superinfection in 5/40 (12.5%) patients and acute HBV superinfection in 10/40 (25%). Twenty-five patients (62.5%) were treated: 16/25 (64%) with IFN, 4/25 (16%) with nucleot(s)ide analogs (NUCs) and 5/25 (20%) with DAAs. Of the 16 patients treated with IFN-based therapy, 6 (37.5%) achieved both sustained virological response (SVR) and HBsAg clearance. Of the 4 patients treated with NUCs, one (25%) achieved both SVR and HBsAg clearance. All five patients treated with DAAs (100%) achieved SVR, while one case of HBV reactivation was recorded. Fifteen of the 40 patients (37.5%) did not receive any treatment. Eight of them (53.5%) presented with acute HBV superinfection: spontaneous HCV clearance was recorded in 5/8 (62.5%), while HBsAg clearance occurred in 6/8 (75%). Three of them (20%) presented with acute HCV superinfection; spontaneous HCV clearance was recorded in one of the three (33.5%). The other four patients (26.5%) presented with dual HBV/HCV infection., Conclusions: A significant proportion of patients presented with active HBV replication. Treatment with DAAs seems to be efficacious for HCV eradication. However, clinicians should be aware of HBV reactivation. HBV superinfection may lead to both HBsAg and HCV clearance., Competing Interests: Conflict of Interest: None

Background: The remission rates after stopping antivirals in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) vary among studies, while reliable predictors of relapse have not been identified. This prospective study assessed rates and predictors of relapse and retreatment in 57 non-cirrhotic hepatitis B surface antigen (HBsAg)-positive patients with HBeAg-negative CHB who discontinued effective ≥4-year entecavir or tenofovir disoproxil fumarate (TDF) therapy., Methods: A total of 57 patients discontinued therapy after median virological remission of 5.3 years and remained under close follow-up. They were retreated with entecavir/TDF if they fulfilled predetermined criteria., Results: During median follow-up of 18 months, no patient died, developed jaundice or liver decompensation. The cumulative relapse rates varied according to HBV DNA and alanine aminotransferase cutoffs; for HBV DNA >2,000 IU/ml, they were 56%, 70% and 72% at 3, 12 and 18 months after stopping entecavir/TDF. The cumulative probability of retreatment was 18% and 26% at 3 and 12 months being significantly affected only by pretreatment fibrosis severity (adjusted relative hazard: 3.43; P=0.015). Cumulative rates of HBsAg loss were 5%, 16% and 25% at 6, 12 and 18 months being higher in patients with lower HBsAg levels at treatment discontinuation., Conclusions: Our prospective study shows that effective ≥4-year entecavir/TDF therapy can be safely discontinued in non-cirrhotic HBeAg-negative CHB patients. The probability of relapse decreased after month 6. Despite common virological relapses, most patients, particularly those with mild-moderate pretreatment fibrosis, remain without retreatment, at least in the first 18 months, as a substantial proportion of them clear HBsAg and the majority eventually enters into an inactive carrier state.

Background: The diagnosis of bacterial infection in cirrhotic patients may be difficult, because of the absence of classical signs such as fever and raised white blood cell count. The role of C-reactive protein (CRP) in this context has not been clearly defined., Methods: Clinical and laboratory characteristics of 210 consecutive cirrhotic patients with (n=100) or without (n=110) bacterial infection were compared with a control group of non-cirrhotic patients with infection (n=106)., Results: Significantly fewer patients with cirrhosis had a body temperature ≥37°C when presenting with bacterial infection (56% cirrhotic vs. 85.5% non-cirrhotic patients, P=0.01). Mean leukocyte count was 6.92 × 10 3 /mm 3 in patients with cirrhosis and infection, 5.75 × 10 3 /mm 3 (P=0.02) in cirrhotic patients without infection, and 11.28 × 10 3 /mm 3 in non-cirrhotic patients with infection (P<0.001). Multivariate analysis revealed that CRP level and model for end-stage liver disease score were significantly associated with the presence of infection in patients with cirrhosis. A cutoff level of CRP>10 mg/L indicated the presence of infection with a sensitivity of 68%, a specificity of 84.5% and an area under the receiver operating characteristic curve of 0.8197. CRP cutoff level differed according to the severity of the liver disease: Child-Pugh score (CPS) A: 21.3 mg/L, B: 17 mg/L, and C: 5.78 mg/L., Conclusions: CRP at admission could help diagnose infection in cirrhotic patients. Since the severity of liver disease seems to affect the CRP values, lower CRP levels might indicate infection. Clinical suspicion is necessary to avoid delay in diagnosis and initiate antibiotic treatment., Competing Interests: Conflict of Interest: None

Background/aims: Serum hepatitis B s antigen (HBsAg) levels might be used as a predictor of virological breakthrough or of sustained off-treatment virological response in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. We evaluated the changes of HBsAg in those patients under nucleos(t)ide analogue(s) [NA(s)] therapy for ≥12 months., Methods: We included 99 HBeAg-negative CHB patients treated with low-genetic barrier NA(s) for a mean of 66 months (lamivudine: 66, adefovir: 6, lamivudine plus adefovir: 11 and telbivudine: 16) and 86 HBeAg-negative CHB patients treated under entecavir or tenofovir for a mean of 30 months as the comparison group., Results: Compared to baseline, HBsAg levels decreased by a median of 162, 1525, 943, 1545, 2163 and 3859 IU/mL at 6, 12, 24, 36, 48 and 60 months of therapy with low-genetic barrier NA(s) respectively. The 6-, 12-, 24-, 36-, 48- and 60-month cumulative rates of HBsAg<100 IU/mL were 2%, 3%, 3%, 5%, 5% and 5%, and <1000 IU/mL 6%, 9%, 15%, 19%, 24% and 61% respectively. Baseline HBsAg levels were the only significant variable associated with the time to HBsAg drop <1000 IU/mL. HBsAg loss occurred in 3.0% of patients. The high-genetic barrier NAs were not found to offer a greater or faster HBsAg decline., Conclusions: In HBeAg-negative CHB patients, long-term therapy with low-genetic barrier NA(s) decreases serum HBsAg levels, but the rate of decline is slow. Lower baseline HBsAg levels are significantly associated with on-therapy HBsAg drop <1000 IU/mL. Serum HBsAg decline is similar during therapy with low- or high-genetic barrier NAs., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Whether there is a change of hepatocellular carcinoma (HCC) incidence in chronic hepatitis B patients under long-term therapy with potent nucleos(t)ide analogues is currently unclear. We therefore assessed the HCC incidence beyond year 5 of entecavir/tenofovir (ETV/TDF) therapy and tried to determine possible factors associated with late HCC occurrence. This European, 10-center, cohort study included 1,951 adult Caucasian chronic hepatitis B patients without HCC at baseline who received ETV/TDF for ≥1 year. Of them, 1,205 (62%) patients without HCC within the first 5 years of therapy have been followed for 5-10 (median, 6.8) years. HCCs have been diagnosed in 101/1,951 (5.2%) patients within the first 5 years and 17/1,205 (1.4%) patients within 5-10 years. The yearly HCC incidence rate was 1.22% within and 0.73% after the first 5 years (P = 0.050). The yearly HCC incidence rate did not differ within and after the first 5 years in patients without cirrhosis (0.49% versus 0.47%, P = 0.931), but it significantly declined in patients with cirrhosis (3.22% versus 1.57%, P = 0.039). All HCCs beyond year 5 developed in patients older than 50 years at ETV/TDF onset. Older age, lower platelets at baseline and year 5, and liver stiffness ≥12 kPa at year 5 were independently associated with more frequent HCC development beyond year 5 in multivariable analysis. No patient with low Platelets, Age, Gender-Hepatitis B score at baseline or year 5 developed HCC., Conclusion: The HCC risk decreases beyond year 5 of ETV/TDF therapy in Caucasian chronic hepatitis B patients, particularly in those with compensated cirrhosis; older age (especially ≥50 years), lower platelets, and liver stiffness ≥12 kPa at year 5 represent the main risk factors for late HCC development. (Hepatology 2017;66:1444-1453)., (© 2017 by the American Association for the Study of Liver Diseases.)

Background: Two models are mostly used to predict survival in cirrhosis: the Child-Pugh score (CP score) and the model for end-stage liver disease score (MELD score)., Aims: The aim of this study is to evaluate the CP score and the MELD score for short- and long-term prognosis in cirrhosis, as well as CP-creatinine score, MELD-Na score, and UKELD score., Methods: One thousand and forty-seven patients from five referral centers were included: men/women: 620/427, median age: 58 years (IQR 48-66), median follow-up: 33 months (IQR 12-74), CP (A/B/C): 493/357/147, CP score: 7 (IQR 5-9), MELD score: 12 (IQR 9-16). The performance of each score was evaluated by the Cox hazard model in terms of their: discrimination ability (C-index and Somer's D) and calibration (3, 12 months). Internal validation was done with bootstrapping (100 samples)., Results: Three hundred and fifty-two patients (33.6%) died. All scores were significantly associated with overall mortality, when assessed by univariate Cox analysis. CP-creatinine score performed significantly better than all other scores [bootstrap C-index 0.672, 95% CI 0.642-0.703, bootstrap Somer's D 0.344 (0.285-0.401)], apart from CP score, which showed similar performance. Inclusion in the multivariable Cox model of age together with CP-creatinine score improved the discriminative ability of the model [bootstrap C-index (95% CI) 0.700 (0.661-0.740)]. In terms of calibration, CP-creatinine score was the best for both 3- and 12-month survival in the total population., Conclusions: CP score and CP-creatinine score have better prognostic value compared to MELD score, MELD-Na score, and UKELD score for predicting short- and long-term mortality in patients with stable cirrhosis.

Transoral incisionless fundoplication (TIF) using the EsophyX device has been shown to be effective and safe in patients with Gastroesophageal reflux disease (GERD); however, the subset of patients that would mostly benefit from this technique remains unknown. The aim of this study was to evaluate the long-term efficacy and safety of the TIF procedure in patients with a history of esophagitis or proven chronic GERD who have achieved symptom control with the administration of proton pump inhibitors (PPIs) but did not wish to continue receiving medications for life. Forty-five patients with typical GERD symptoms (heartburn, regurgitation, chest pain) and a history of esophagitis grade A and B or proven GERD by esophageal pH monitoring underwent TIF using Esophyx. Patients with eosphagitis C and D or those with large hiatal hernias (>2 cm in length) were excluded. The primary clinical effectiveness measure was GERD symptom elimination at follow up based on normalization of the GERD health related quality of life (GERD-HRQL) questionnaire. After a median follow up period of 59 months (36-75) the median GERD-HRQL scores improved significantly from 27 (2-45) at baseline to 4 (0-26) (P < 0.001) in the 44 patients completing the study. Heartburn was eliminated in 12 out of the 21 patients included (57.1%), regurgitation was eliminated in 15 out of the 17 patients included (88.2%) and finally chest pain was eliminated in 5 patients out of the six patients included (83.3%). Overall, 32 patients out of the 44 patients (72.7%) that completed the study follow up reported elimination of their main symptom, without the need for PPI administration (none PPI usage). Furthermore, six more patients (13.6%), five with heartburn, and one with regurgitation reported half PPI dose taken for <50% of the preceding follow up period (occasional PPI usage), while six more patients (four with heartburn, one with regurgitation, and one with chest pain) reported full or half PPI dose taken for more than 50% of the preceding follow up period (daily PPI usage). Creation of an esophagogastric fundoplication using the EsophyX device abolished reflux symptoms in 72.7% of PPI-responsive GERD patients at a median 59 month follow-up., (© 2017 International Society for Diseases of the Esophagus.)

Background: We determined the proportions of patients with chronic hepatitis C (CHC) in association with possible prioritized indications for interferon-free regimens and the use of co-medications with potential drug-drug interactions (DDIs)., Methods: Five hundred consecutive mono-infected CHC patients seen in 2015 at 5 Greek centers were included. Priorities for interferon-free regimens were based on liver disease severity, contraindication(s) for interferon and prior interferon-treatment failure. All co-medications were classified into those with no DDIs/no clear data for DDIs, potential DDIs, and contraindication due to DDI for each agent, according to the HEP Drug Interaction Checker., Results: Of the 500 patients, 1% had undergone liver transplantation, whereas 6.6% had decompensated cirrhosis, 21.8% F4, 17.1% F3, 10.4% F2, and 34.8% F0-1 fibrosis. Contraindications for interferon were present in 38.5% of non-transplant patients with compensated liver disease. The probability of contraindications/potential DDIs was greater for boceprevir/telaprevir and ombitasvir/paritaprevir/ritonavir±dasabuvir, compared to all other agents (P<0.001), and least for sofosbuvir (P<0.05). Contraindications/potential DDIs were more frequently present in patients ≥50 than <50 years old (P≤0.034), and more common in F3-4 than F0-2, and F4 than F0-3 fibrosis (P≤0.019) for all direct-acting antivirals (DAAs)., Conclusions: The expansion of the criteria for prioritization of interferon-free regimens from cirrhosis to F3 and perhaps F2 fibrosis will increase the proportion of patients with DAA access by only 10-15% and 10%, respectively. A potential for DDIs is frequently present with protease inhibitors, but also exists with other DAAs. The probability of DDIs is higher in patients with priority for DAAs, including those who have advanced liver disease and are usually of older age., Competing Interests: Conflict of Interest: Μargarita Papatheodoridi has nothing to declare. George N. Dalekos has served as an advisor/lecturer for AbbVie, Bayer, Bristol-Myers Squibb, Gilead, Janssen, Novartis, Roche and has received grant support from Bristol-Myers Squibb, Gilead, Roche. John Goulis has served as an advisor/lecturer for Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Roche and has received grant support from Bristol-Myers Squibb. Spilios Manolakopoulos has served as an advisor/lecturer for AbbVie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche and has received grant support from Bristol-Myers Squibb. Christos Triantos has served as an advisor/lecturer for Bristol-Myers Squibb, Gilead, Merck Sharp & Dohme. Kalliopi Zachou has nothing to declare. Argyro Koukoufiki has nothing to declare. Αnastasia Κourikou has nothing to declare. Κonstantinos Ζisimopoulos has nothing to declare. Christos Τsoulas is an employee of Gilead Science Hellas, Greece. George V. Papatheodoridis has served as an advisor/lecturer for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, Roche, has received grant support from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Roche, has served as consultant for Roche and has served as a member of Data Safety Management Board for Gilead.

Background: The aim of the study was to determine the efficacy and safety of triple therapy with a first-generation protease inhibitor (PI; boceprevir, telaprevir) plus peginterferon alfa-2a or -2b plus ribavirin, and dual therapy (peginterferon alfa-2a or -2b plus ribavirin) in patients with chronic hepatitis C (CHC) in routine clinical practice., Methods: PegBase was an international, prospective, observational study in which 4441 patients with CHC were enrolled in 27 countries. This analysis focuses on results in 4100 treatment-naïve and previously treated patients treated with PI-based triple therapy or dual therapy, according to the discretion of the investigator and local standards of practice. The primary efficacy outcome was sustained virological response after 12-week follow up (SVR12)., Results: SVR12 rates in treatment-naïve genotype (G) 1 patients were 56.6% and 62.9% for recipients of boceprevir plus peginterferon alfa-2a/ribavirin and boceprevir plus peginterferon alfa-2b/ribavirin, respectively, and 65.3% and 58.6% for recipients of telaprevir plus peginterferon alfa-2a/ribavirin and telaprevir plus peginterferon alfa-2b/ribavirin, respectively. In previously treated patients assigned to these four regimens, SVR12 rates were 43.6%, 48.3%, 60.3% and 56.1%, respectively. Among treatment-naïve patients assigned to peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin, respectively, SVR12 rates were 49.2% and 41.9% in G1 patients, 75.7% and 83.3% in G2 patients, 65.9% and 65.9% in G3 patients, and 49.7%, and 51.1% in G4 patients. The safety and tolerability of dual and triple therapy were consistent with previous reports., Conclusion: The efficacy and safety of first-generation PI-based triple-therapy and dual-therapy regimens in this real-world cohort were broadly comparable to those of previous studies., Competing Interests: Conflict of interest: Alessandra Mangia: Advisory board: BMS, MSD, Gilead; Research grants: Janssen, MSD; Speakers’ bureau: Gilead, BMS, Janssen. Graham R. Foster: Consultancy and speaker fees for F. Hoffmann-La Roche, Gilead, AbbVie, Merck, GSK, Janssen. Christoph P. Berg: Advisory board: AbbVie, BMS, Gilead, Janssen, MSD, F. Hoffmann-La Roche; Speaker honorarium: AbbVie, BMS, Gilead, Janssen, MSD, Roche. Manuela Curescu: None. Victor De Ledinghen: Advisory board: AbbVie, BMS, Gilead, MSD, Janssen; Speaker honorarium: AbbVie, BMS, Gilead, Janssen, MSD. François Habersetzer: Personal fees from F. Hoffmann-La Roche Ltd and Merck; Travel grants from Merck and Janssen. Spilios Manolakopoulos: Advisor/Lecturer: Gilead, BMS, Janssen, Abbvie, MSD, Novartis, Bayer; Research grants: BMS, Gilead. Elisa Negri: None. George Papatheodoridis: Grant/research support from AbbVie, Boehringer Ingelheim, BMS, Gilead, Janssen, MSD, and Regulus; Scientific consultant and/or advisory boards and/or lecturer for AbbVie, BMS, Gilead, GlaxoSmithKline, Janssen, MSD, Novartis, F. Hoffmann-La Roche; Safety Management Board member for Gilead. Silke Ahlers: Employee of PROMETRIS GmbH, the clinical research organization providing data management and statistical services to Roche. Marco Castillo: Employee of F. Hoffmann-La Roche Ltd, Basel, Switzerland. Georgios Bakalos: Employee of F. Hoffmann-La Roche Ltd, Basel, Switzerland. Stefan Mauss: Advisory board: AbbVie, BMS, Gilead, MSD; Speaker honorarium: AbbVie, BMS, Gilead, Janssen, MSD

Objective: The aim of this study is to evaluate the outcomes of hepatitis B surface antigen (HBsAg)-negative, anti-HBc-positive patients who received immunosuppressive therapies., Patients and Methods: We retrospectively evaluated the medical records of HBsAg-negative, anti-HBc-positive patients with hematological diseases or solid tumors who underwent immunosuppressive therapies and were referred because of positive baseline hepatitis B virus (HBV) serology or HBV reactivation. The referral date was according to the judgment of the treating physician at the time of identification of any signs of HBV infection., Results: We included 55 HBsAg-negative, anti-HBc-positive patients. Of these, 31 received antiviral prophylaxis (group 1), whereas 24 patients did not receive any anti-HBV agent (group 2). The majority of patients [49/55 (89%)] had hematological malignancies and most of them 39/55 (71%) received rituximab-containing regimens. Lamivudine was used as antiviral prophylaxis in 13/31 (42%) patients of group 1. One patient in this group experienced HBV reactivation and was treated successfully with tenofovir add-on therapy. All patients in the second group experienced HBV reactivation and most of them [19/24 (79%)] were treated with tenofovir or entecavir as rescue therapy. Two of these patients (one of the tenofovir/entecavir subgroup and one of the lamivudine subgroup) eventually died because of hepatic failure despite rescue treatment., Conclusion: Patients with serological markers of previous HBV infection are still at risk for HBV reactivation. Screening of both anti-HBs and anti-HBc is mandatory before chemotherapy. Pre-emptive antiviral prophylaxis, including lamivudine, is highly effective in all subgroups of such patients, whereas deferring treatment upon HBV reactivation is not enough to rescue all cases.

Hepatitis C is a global health issue and constitutes a major cause of chronic liver disease worldwide. In this article, a comprehensive literature search was conducted for the prevalence of hepatitis C virus (HCV) infection in Greece, since data on the HCV prevalence, viremia and genotypes are important for developing strategies to manage or eliminate HCV infection. In addition, the pattern of HCV infection was analyzed according to the geographic region and the risk factors. These differences reflect not only distinct epidemiological characteristics among populations, but also differences on the strategy of data acquisition and quantification. Although there are not enough data, the estimation of the current prevalence of Hepatitis C in Greece ranges from 0.5% to 2%. The most important risk factors for HCV infection include blood product transfusion, intravenous drug use, chronic hemodialysis, organ transplantation, occupational exposure, sexual transmission, and vertical transmission. Because of lack of vaccine or effective post-exposure prophylaxis for HCV, the main focus of prevention is to recognize and control these risk factors. HCV infection in Greece is closely associated with the development of chronic liver disease, cirrhosis, and primary hepatocellular carcinoma. As far as the genotype distribution is concerned genotype 1 estimated to be 45%-47% and it constitutes the prevalent genotype in Greece, followed by genotype 3., Competing Interests: Conflict-of-interest statement: Triantos Christos has received fees for serving as a speaker for Gilead Sciences and Bristol-Myers Squibb, and as an advisory board member for Gilead Sciences and for MSD.

Daclatasvir (Daklinza™), a new oral direct-acting antiviral, is an inhibitor of hepatitis C virus NS5A protein and has recently been approved in the United States, Europe and Japan in chronic hepatitis C. It shows potent pangenotypic activity and moderately high genetic barrier to resistance improving the sustained virological response (SVR) rates. In COMMAND phase 2 trials, daclatasvir demonstrated high SVR rates in HCV genotype 1-4 chronically infected patients treated with peginterferon-a (pegIFNα) plus ribavirin (RBV). Furthermore, it produced even higher response rates in all-oral combination with sofosbuvir, an interferon-free regimen, with or without ribavirin, in patients with advanced liver disease, HCV/HIV coinfection, liver transplantation in ALLY studies and other real-world studies. This narrative review provides information on the pharmacological properties, role, efficacy and safety of daclatasvir-containing regimens in chronic hepatitis C patients. Daclatasvir administered once-daily in combination with sofosbuvir is an effective 12-week treatment in adult patients with chronic hepatitis C and is generally safe and well tolerated.

Background & Aims: Risk scores for hepatocellular carcinoma (HCC) developed in Asians offer poor-moderate predictability in Caucasian patients with chronic hepatitis B (CHB). This nine center cohort study aimed to develop and validate an accurate HCC risk score in Caucasian CHB patients treated with the current oral antivirals, entecavir/tenofovir., Methods: We included 1815 adult Caucasians with CHB and no HCC at baseline who received entecavir/tenofovir for ⩾12 months. Using data from eight centers (derivation dataset, n=1325), a HCC risk score was developed based on multivariable Cox models and points system for simplification. Harrell's c-index was used as discrimination, bootstrap for internal validation and the data from the 9(th) and largest center (validation dataset, n=490) for external validation., Results: The 5-year cumulative HCC incidence rates were 5.7% and 8.4% in the derivation and validation dataset, respectively. In the derivation dataset, age, gender, platelets and cirrhosis were independently associated with HCC. The PAGE-B score was developed based on age, gender and platelets (c-index=0.82, 0.81 after bootstrap validation). The addition of cirrhosis did not substantially improve the discrimination (c-index=0.84). The predictability of PAGE-B score was similar (c-index=0.82) in the validation dataset. Patients with PAGE-B ⩽9, 10-17, ⩾18 had 5-year cumulative HCC incidence rates of 0%, 3%, 17% in the derivation and 0%, 4%, 16% in the validation dataset., Conclusion: PAGE-B, which is based only on baseline patients' age, gender and platelets, represents a simple and reliable score for prediction of the 5-year HCC risk in Caucasian CHB patients under entecavir/tenofovir., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The aim of our study was to evaluate the safety and efficacy of triple therapy using boceprevir (BOC) with pegylated interferon (pIFN)/ribavirin (RBV) in chronic hepatitis C (CHC) genotype 1 (G1) treatment-experienced patients with advanced fibrosis or compensated cirrhosis., Methods: We report the Greek experience on the first CHC patients who received BOC-based regimen. From September 2011 to June 2012, 26 treatment-experienced CHC patients and G1 with bridging fibrosis or compensated cirrhosis received 48 weeks of BOC+pIFN+RBV antiviral therapy. Data on complete blood counts and HCV RNA levels were obtained prior to therapy, at treatment weeks 4, 8, 12, 24, 36, 48 and 24 weeks after the end of treatment., Results: A full set analysis was performed in 25 of 26 patients. Nine patients (36%) achieved sustained viral response (SVR). Ten patients (40%) stopped the therapy because of futility rules and 3 (12%) due to adverse events. Four patients (16%) developed a virological breakthrough (3 of those presented futility rules as well) and 2 (8%) relapse. All patients who achieved SVR had G 1b, 6 (67%) were non-cirrhotic and 5 (55%) had >1 log decline in baseline HCV RNA levels at week 4 of the treatment. There were no deaths, while two patients were hospitalized due to side effects., Conclusion: The triple therapy with BOC+pIFN+RBV in this cohort of real-life treatment-experienced CHC G1 patients and advanced liver disease was safe offering cure in the majority of those who could tolerate and complete treatment under a close monitoring.

Background & Aims: The risk of hepatocellular carcinoma (HCC) in Caucasian patients with chronic hepatitis B (CHB), treated with entecavir (ETV) or tenofovir (TDF), is unclear. We evaluated the incidence and predictors of HCC and the accuracy of existing HCC risk scores in Caucasian CHB patients receiving ETV/TDF., Methods: This large, multicentre, retrospective cohort study included 1666 adult Caucasian CHB patients under ETV/TDF for 39 months. CHB without cirrhosis, compensated and decompensated cirrhosis were present in 67%, 39%, and 3% of patients, respectively. The predictability of baseline parameters and three risk scores (GAG-HCC, CU-HCC, and REACH-B), developed in Asian patients, was assessed., Results: The cumulative probability of HCC was 1.3%, 3.4%, and 8.7% at year-1, year-3, and year-5 after ETV/TDF onset. Older age and lower platelets were strong independent HCC predictors in the total population and in the subgroups of cirrhotic and non-cirrhotic patients, while liver disease severity was an independent HCC predictor in the total population and in the cirrhotics. GAG-HCC, CU-HCC, and REACH-B risk scores were associated with HCC development only in the univariable but not in the multivariable analyses and offered poor to modest predictability., Conclusions: HCC can still develop in Caucasian CHB patients treated with ETV/TDF. Besides the well-known predictors of HCC, such as older age, male gender and more advanced liver disease, lower platelets represent an independent factor of higher HCC risk. The applicability and predictability of HCC risk scores developed in Asian patients are poor or modest in Caucasian CHB patients, for whom different risk scores are required., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Serum HBsAg levels might represent an important predictor of sustained off-treatment response in HBeAg-negative chronic hepatitis B (CHB). We evaluated the changes of HBsAg and interferon-inducible protein 10 (IP10) serum levels in HBeAg-negative CHB patients treated with entecavir., Methods: 114 patients received entecavir for a median of 4.3 years. HBsAg levels were determined at baseline, 6 and 12 months and every year thereafter until year-4. IP10 levels were measured at baseline and annually until year-4 in 76 patients., Results: Virological remission rates were high (year-1: 94%, after year-2: 97-98%). Compared to baseline, HBsAg levels decreased by a median of 0.03, 0.13, 0.17, 0.22, and 0.32 log₁₀ IU/ml at 6 months and 1, 2, 3, and 4 years, respectively (p≤0.001 for all comparisons). The proportions of patients with HBsAg decline of ≥0.5 or ≥1 log₁₀ IU/ml were 9% or 6% at year-1 and 21% or 10% at the last visit. Median IP10 levels (pg/ml) did not change from baseline to year-1 or -2 (245 vs. 229 or 251), but increased at year-3 and -4 (275 and 323, p<0.030). HBsAg drop ≥0.5 log₁₀ was associated with baseline IP10 or IP10 >350 pg/ml (p≤0.002). HBsAg loss occurred in 4/114 (3.5%) patients or in 1/2, 3/21, and 0/91 patients with baseline HBsAg <100, 100-1000 and >1000 IU/ml, respectively (p<0.001)., Conclusions: In HBeAg-negative CHB patients, 4-year entecavir therapy decreases serum HBsAg levels, but the rate of decline is rather slow. Serum IP10 levels represent a promising predictor of HBsAg decline in this setting., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Resistance to antiviral treatment for chronic hepatitis B virus (HBV) has been associated with mutations in the HBV polymerase region. This study aimed at developing an ultrasensitive method for quantifying viral populations with all major HBV resistance-associated mutations, combining the amplification refractory mutation system real-time PCR (ARMS RT-PCR) with a molecular beacon using a LightCycler. The discriminatory ability of this method, the ARMS RT-PCR with molecular beacon assay, was 0.01 to 0.25% for the different HBV resistance-associated mutations, as determined by laboratory-synthesized wild-type (WT) and mutant (Mut) target sequences. The assay showed 100% sensitivity for the detection of mutant variants A181V, T184A, and N236T in samples from 41 chronically HBV-infected patients under antiviral therapy who had developed resistance-associated mutations detected by direct PCR Sanger sequencing. The ratio of mutant to wild-type viral populations (the Mut/WT ratio) was >1% in 38 (63.3%) of 60 samples from chronically HBV-infected nucleos(t)ide analogue-naive patients; combinations of mutations were also detected in half of these samples. The ARMS RT-PCR with molecular beacon assay achieved high sensitivity and discriminatory ability compared to the gold standard of direct PCR Sanger sequencing in identifying resistant viral populations in chronically HBV-infected patients receiving antiviral therapy. Apart from the dominant clones, other quasispecies were also quantified. In samples from chronically HBV-infected nucleos(t)ide analogue-naive patients, the assay proved to be a useful tool in detecting minor variant populations before the initiation of the treatment. These observations need further evaluation with prospective studies before they can be implemented in daily practice.

Background/aims: Despite the improving efficacy of antiviral therapy, a significant proportion of chronic hepatitis C patients never start treatment. We determined the magnitude and reasons for no treatment in anti-hepatitis C virus (HCV)-positive patients visiting tertiary liver centers in Greece., Materials and Methods: We retrospectively enrolled 1146 consecutive anti-HCV-positive patients who visited four physicians at two tertiary liver centers between 2002 and 2010., Results: Treatment was initiated in 628 (55%) of the 1146 patients. In particular, 309 (27%) patients were lost to follow-up before HCV RNA testing. Independent predictors of no HCV RNA testing were first visit before 2007, parenteral drug use, and the treating physician. Of the 837 patients tested for HCV RNA, 768 (92%) were eligible for antiviral therapy, had detectable serum HCV RNA, and no contraindication to treatment. Among them, 140 (18%) patients were lost to follow-up before the initiation of treatment or refused antiviral therapy. Independent predictors of no treatment were the treating physician, absence of liver biopsy or transient elastography (odds ratio: 3.5, 95% confidence interval: 2.3-5.4, P<0.001), and normal compared with elevated alanine transaminase levels (odds ratio: 1.7, 95% confidence interval: 1.1-2.8, P=0.027)., Conclusion: A significant proportion (>40%) of anti-HCV-positive patients visiting Greek tertiary liver centers do not receive antiviral therapy. Most of them are lost during the initial evaluation process, whereas the majority (>80%) of eligible patients who complete the initial evaluation eventually start antiviral therapy. The probability of treatment seems to be significantly associated with the treating physician, the alanine transaminase levels, and whether liver biopsy or transient elastography was performed.

Background: Dendritic cells activated by hepatitis C virus (HCV) produce high amounts of interleukin (IL)-12, considered to be associated with HCV clearance. The aim of this study was to investigate the IL-12 levels in HCV-infected patients, before and after the application of combination therapy with Pegylated Interferon-α2β plus Ribavirin., Methods: Laboratory data of IL-12 levels and other clinical characteristics were selected from 26 HCV-infected patients. Comparisons of IL-12 serum levels before and after treatment or between responders and non-responders (including relapsers) were performed using non-parametric tests. The study moreover investigated the probable relationship of IL-12 concentrations with viral load, HCV genotypes, liver function tests (LFTs), histological activity and the response to combination treatment., Results: The baseline IL-12 levels were found significantly higher in patients who achieved sustained virological response (SVR), compared to patients who did not respond to the combination treatment (P=0.029). The IL-12 levels at the end of treatment were not statistically different from the IL-12 baseline levels, in both responders and non-responders. Baseline serum levels of IL-12 higher than 3 pg/mL (cut-off) were found to positively predict patients who successfully responded to treatment. No statistical correlation was found between the baseline serum IL-12 levels and viral load, HCV genotypes, histological activity or LFTs among the HCV patients., Conclusion: Pretreatment IL-12 levels seem to predict which patients will achieve SVR to treatment. Patients with increased IL-12 serum levels were more likely to achieve SVR.

Background & Aims: The adequacy of monitoring HBeAg-negative patients based on ALT activity is controversial and current guidelines favor liver biopsy in HBeAg-negative cases with normal ALT and HBV DNA >2000 IU/ml. We systematically reviewed all the available histological data on HBeAg-negative patients with persistently normal ALT (PNALT) to determine the prevalence of significant liver disease and its associating factors., Methods: Literature search to identify studies with adult HBeAg-negative patients who had PNALT as defined by the authors, a minimum follow-up of 1 year and histological data. Traditional cut-off values of normal ALT were used in all studies. The definitions of PNALT were considered as acceptable or good if there were ≥3 ALT determinations at unspecified intervals during 6-12 months or predefined intervals during ≥12-month periods, respectively., Results: Six studies including 335 patients met our inclusion criteria. Of these, four studies with 246 patients had good or acceptable definitions of PNALT. In the latter four studies, more than minimal (usually mild) necro-inflammatory activity was observed in 10% and more than mild fibrosis in 8% of all patients (moderate fibrosis: 7%, severe fibrosis: 1%, cirrhosis: 0%), and in 3% and 5% of patients with HBV DNA ≤20,000 IU/ml, respectively., Conclusions: Histologically significant liver disease is rare in HBeAg-negative patients with PNALT based on stringent criteria and serum HBV DNA ≤20,000 IU/ml. Such cases can be considered as true inactive HBV carriers, who require neither liver biopsy nor immediate therapy but continued follow-up., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Since therapeutic endoscopic retrograde cholangiopancreatography replaced surgery as the first approach in cases of choledocolithiasis, a plethora of endoscopic techniques and devices appeared in order to facilitate rapid, safe and effective bile duct stones extraction. Nowadays, endoscopic sphincterotomy combined with balloon catheters and/or baskets is the routine endoscopic technique for stone extraction in the great majority of patients. Large common bile duct stones are treated conventionally with mechanical lithotripsy, while the most serious complication of the procedure is "basket and stone impaction" that is predominately resolved surgically. In cases of difficult, impacted, multiple or intrahepatic stones, more sophisticated procedures have been used. Electrohydraulic lithotripsy and laser lithotripsy are performed using conventional mother-baby scope systems, ultra-thin cholangioscopes, thin endoscopes and ultimately using the novel single use, single operator SpyGlass Direct Visualization System, in order to deliver intracorporeal shock wave energy to fragment the targeted stone, with very good outcomes. Recently, large balloon dilation after endoscopic sphincterotomy confirmed its effectiveness in the extraction of large stones in a plethora of trials. When compared with mechanical lithotripsy or with balloon dilation alone, it proved to be superior. Moreover, dilation is an ideal alternative in cases of altered anatomy where access to the papilla is problematic. Endoscopic sphincterotomy followed by large balloon dilation represents the onset of a new era in large bile duct stone extraction and the management of "impaction" because it seems that is an effective, inexpensive, less traumatic, safe and easy method that does not require sophisticated apparatus and can be performed widely by skillful endoscopists. When complete extraction of large stones is unsuccessful, the drainage of the common bile duct is mandatory either for bridging to the final therapy or as a curative therapy for very elderly patients with short life expectancy. Placing of more than one plastic endoprostheses is better while the administration of Ursodiol is ineffective. The great majority of patients with large stones can be treated endoscopically. In cases of unsuccessful stone extraction using balloons, baskets, mechanical lithotripsy, electrohydraulic or laser lithotripsy and large balloon dilation, the patient should be referred for extracorporeal shock wave lithotripsy or a percutaneous approach and finally surgery.

Background: Although non-alcoholic fatty liver disease (NAFLD) is associated with obesity and metabolic syndrome (MS), it may also be present in lean individuals. We evaluated the characteristics of NAFLD patients, focusing on those with normal body mass index (BMI)., Methods: One hundred and sixty-two of 185 consecutive NAFLD patients were included (23 were excluded due to missing data). NAFLD diagnosis required elevated ALT and/or GGT, hepatic steatosis on ultrasonography and no other cause of liver disease. Demographic, clinical, somatometric and laboratory characteristics were recorded. BMI <25 kg/m2 was considered normal., Results: Normal BMI was present in 12% of patients. Patients with normal compared to those with increased BMI had numerically but not significantly lower prevalence of diabetes mellitus (6% vs. 15%, p=0.472), arterial hypertension (17% vs. 29%, p=0.276) and MS (20% vs. 41%, p=0.160). Normal BMI NAFLD patients met no criterion of MS more frequently (43% vs. 2%, p<0.0001) and had smaller waist circumference (94±6 vs. 108±10 cm, p<0.001), higher median levels of ALT (92 vs. 62 IU/L, p=0.032) and AST (45 vs. 37 IU/L, p=0.036) and relatively lower fasting glucose levels (98±22 vs. 106±29 mg/dL, p=0.052), but similar levels of HDL, LDL and triglycerides., Conclusion: Approximately 1 of 8 NAFLD patients coming to the tertiary liver center has normal BMI. These patients do not necessarily have insulin resistance associated metabolic disorders, but they have higher levels of ALT/AST than the overweight or obese NAFLD patients.

Background/aims: As there are concerns about potential nephrotoxicity of nucleotide analogues, we evaluated renal function parameters during long-term adefovir and lamivudine combination therapy., Methods: Forty-six HBeAg-negative patients with lamivudine-resistance treated with adefovir and lamivudine for up to 90 months were included. Renal function was assessed by estimated creatinine clearance (eC(CR) ) and compared with a matched control group of untreated inactive hepatitis B virus carriers., Results: Serum HBV DNA became undetectable in 39 (85%) patients after a mean of 37 ± 21 months. Three (6.5%) patients developed virological breakthrough. Adefovir resistance was detected in two patients. At the end of follow up, there was a significant decrease in mean eC(CR) (95 ± 31-83 ± 30 ml/min, P = 0.003) in the treated patients with 16% presenting aeC(CR) decrease >30%. Similar changes in eC(CR) were observed in the control group (108 ± 28-96 ± 26 ml/min, P = 0.003). In multiple regression analysis, age and baseline eC(CR) were independent predictors of eC(CR) reduction., Conclusions: Adefovir and lamivudine combination therapy is not an independent factor for significant renal dysfunction in HBeAg-negative patients with lamivudine-resistance. Baseline age and creatinine clearance are the only independent predictors of worsening renal function., (© 2011 John Wiley & Sons A/S.)

Objective: To evaluate the risk and predictors of hepatocellular carcinoma (HCC) in HBeAg-negative chronic hepatitis B patients of the large HEPNET.Greece cohort study who received long-term oral antivirals starting with lamivudine monotherapy., Design: Retrospective analysis of HCC incidence in HBeAg-negative chronic hepatitis B patients from a retrospective-prospective cohort who were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy for ≥12 months., Setting: A nationwide network of liver centres., Patients: 818 patients were included: 517 with chronic hepatitis B only; 160 with compensated cirrhosis; 56 with decompensated cirrhosis; 85 with unclassified disease severity., Interventions: All patients were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy., Main Outcome Measures: Development of HCC., Results: During a median follow-up of 4.7 years, HCC developed in 49 (6.0%) patients. The 5-year cumulative incidence of HCC was higher in patients with cirrhosis than in those with chronic hepatitis B only (11.5% vs 3.2%, respectively; p<0.001). HCC developed in 0.7%, 6.7% and 11.7% of patients <50, 50-60 and >60 years old, respectively (p<0.001). Virological on-therapy remission did not significantly affect the incidence of HCC in all patients or those with cirrhosis, but it showed a trend for lower HCC incidence in patients with chronic hepatitis B only (p=0.076). In multivariate analysis, age, gender and cirrhosis were independently associated with HCC risk regardless of virological remission., Conclusions: Long-term therapy with nucleos(t)ide analogue(s) starting with lamivudine monotherapy does not eliminate HCC risk in HBeAg-negative chronic hepatitis B. The risk of HCC is particularly high in patients with cirrhosis, who should remain under HCC surveillance even during effective therapy. Older age and male gender remain independent risk factors for HCC, while virological on-therapy remission does not seem to significantly reduce the overall incidence of HCC.

Background and Aim: Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country-specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel., Methodology: Data references were identified through indexed journals and non-indexed sources. In this work, 13,000 articles were reviewed and 860 were selected based on their relevance., Results: Differences in prevalence were explained by local and regional variances in transmission routes or different public health measures. The lowest HCV prevalence (≤ 0.5%) estimates were from northern European countries and the highest (≥ 3%) were from Romania and rural areas in Greece, Italy and Russia. The main risk for HCV transmission in countries with well-established HCV screening programmes and lower HCV prevalence was injection drug use, which was associated with younger age at the time of infection and a higher infection rate among males. In other regions, contaminated glass syringes and nosocomial infections continue to play an important role in new infections. Immigration from endemic countries was another factor impacting the total number of infections and the genotype distribution. Approximately 70% of cases in Israel, 37% in Germany and 33% in Switzerland were not born in the country. In summary, HCV epidemiology shows a high variability across Europe, Canada and Israel., Conclusion: Despite the eradication of transmission by blood products, HCV infection continues to be one of the leading blood-borne infections in the region., (© 2011 John Wiley & Sons A/S.)

Background: Among the various methods of combined endoscopic therapy for high-risk bleeding peptic ulcers the use of adrenaline followed by injection of ethanolamine is minimally demanding in terms of the endoscopic skills and instrumentation but has not been adequately studied. The aim of the present study is to determine whether the injection of ethanolamine in combination with epinephrine compared to injection of epinephrine alone reduces rebleeding rates, need for surgery and overall mortality of patients with bleeding ulcers., Methods: Patients with ulcers and endoscopic features indicative of a high risk for spontaneous recurrent bleeding were included. High risk was defined by the Forrest classification. Patients were assigned to injection of epinephrine alone (n = 284) or epinephrine plus ethanolamine (n = 131)., Results: Initial hemostasis was achieved in 96% of patients in both groups. We detected significant difference in rates of recurrent bleeding, 16.4% vs. 8.7%, for epinephrine and epinephrine plus ethanolamine respectively (P<0.05). When patients were stratified according to Forrest criteria, no significant difference could be found, although there was a trend towards less recurrent bleeding in the case of dual injection therapy in all patient subgroups. There was no significant difference in the proportions of patients who required surgery, 7.7% vs. 7.6% respectively. Mortality was equal (3.2 vs. 3.1%) in the two groups. No major complications from endoscopic treatment were observed in either group., Conclusion: Adding ethanolamine to epinephrine for injection treatment of bleeding peptic ulcers decreases bleeding recurrence rates and represents a safe endoscopic treatment for high-risk bleeding ulcers.

Introduction and Aims: International guidelines and routine clinical practice express concerns about antiviral treatment in intravenous drug users (IDUs). We analysed the effect of IDU and/or substitution therapy on chronic hepatitis C (CHC) treatment adherence and response., Patients and Methods: Intravenous drug users with CHC were divided into three groups: (A) patients on a substitution programme; (B) active users; and (C) past IDUs. Patients were treated according to the standard of care and followed by a specialist team., Results: A total of 175 patients (mean age 39.4±8.8) were included. One hundred and forty-four (65%) were adherent to therapy (completing treatment and 6 months of follow-up). Twenty-two patients (36%) discontinued because of side effects, 28 (46%) discontinued on their own and 11 (18%) completed treatment but did not present at follow-up. Of 142 patients with available treatment outcome, 99 (69.7%) achieved a sustained virological response (SVR), with no differences among the study groups. Patients with genotypes 2-3 and those who completed the treatment schedule had 2.78-fold (95% CI: 1.3-5.8) and 6.4-fold (95% CI: 2.6-15.6) higher probability of achieving SVR., Conclusion: Active use of illicit drugs and/or drug substitution do not affect the treatment outcome in patients with CHC as long as they are closely followed and remain adherent to the treatment., (© 2010 John Wiley & Sons A/S.)

Background & Aims: Chronic hepatitis B patients are at increased risk for hepatocellular carcinoma (HCC). The effect of medium-term nucleos(t)ide analogue therapy on HCC incidence is unclear; therefore, we systematically reviewed all the data on HCC incidence from studies in chronic hepatitis B patients treated with nucleos(t)ide analogues., Methods: We performed a literature search to identify studies with chronic hepatitis B patients treated with nucleos(t)ide analogues for> or = 24 months., Results: Twenty-one studies including 3881 treated and 534 untreated patients met our inclusion criteria. HCC was diagnosed in 2.8% and 6.4% of treated and untreated patients, respectively, during a 46 (32-108) month period (p=0.003), in 10.8% and 0.5% of nucleos(t)ide naive patients with and without cirrhosis (p<0.001) and in 17.6% and 0% of lamivudine resistance patients with and without cirrhosis (p<0.001). HCC developed less frequently in nucleos(t)ide naive patients compared to those without virological remission (2.3% vs 7.5%, p<0.001), but there was no difference between lamivudine resistance patients with or without virological response to rescue therapy (5.9% vs 8.8%, p=0.466)., Conclusions: Chronic hepatitis B patients receiving medium-term nucleos(t)ide analogue therapy had a significantly lower incidence of HCC compared to untreated patients but treatment does not completely eliminate the risk of HCC. Among the treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC., (Copyright 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: The aim of this prospective study was to examine the safety of anti-tumour necrosis factor (TNF) therapy in patients with rheumatic disease and hepatitis B virus (HBV) infection., Methods: 14 patients with chronic HBV infection, 19 HBV-vaccinated patients and 19 patients with resolved HBV infection were included in the study. All HBV-infected patients received combination therapy with oral antivirals and anti-TNF agents. During treatment the levels of hepatitis B surface antibodies (anti-HBs) in HBV-vaccinated patients and of serum HBV DNA in patients with chronic or resolved HBV infection were monitored., Results: No viral reactivation was observed in patients with resolved HBV infection while anti-HBs titres decreased during anti-TNF treatment in vaccinated patients, similarly to patients treated with methotrexate alone. None of the HBV-infected patients developed liver decompensation or a significant increase in alanine aminotransferase levels. One patient (7%) treated with lamivudine and etanercept showed viral reactivation due to the emergence of a lamivudine-resistant mutant strain., Conclusions: Anti-TNF agents represent a safe option for patients with chronic HBV infection when combined with antiviral therapy, as well as in patients previously exposed to HBV receiving no HBV prophylaxis. Resistant HBV strains may arise in patients with chronic hepatitis B, necessitating the initial use of anti-HBV agents with a low risk of resistance.

Background: Apoptotic caspases are substantially activated in liver and serum caspase activity has been suggested as a marker of early liver injury., Aim: To investigate whether serum levels of caspase-generated fragments of cytokeratin-18 are associated with the severity of histologic lesions in chronic hepatitis C virus (HCV) infection and nonalcoholic fatty liver disease (NAFLD)., Methods: We included 134 patients with chronic HCV infection and 58 patients with NAFLD, who consecutively underwent liver biopsy, and 40 healthy controls. Caspase-generated cytokeratin-18 fragment levels were blindly measured in stored serum samples., Results: Median cytokeratin-18 fragment levels were lower in HCV-positive patients with minimal/mild than patients with moderate/severe histologic lesions (174 U/L vs. 223 U/L, P<0.001) offering moderate accuracy for differentiation between the 2 groups (c-statistic: 0.74). Cytokeratin-18 fragments levels were lower in healthy subjects (148 U/L) than patients with simple fatty liver (174 U/L, P=0.013) than patients with nonalcoholic steatohepatitis (355 U/L, P<0.001) offering excellent diagnostic accuracy for differentiation between the 2 latter groups (c-statistic: 0.87)., Conclusions: Serum apoptotic caspase activity is associated with the severity of liver histologic lesions in both chronic HCV infection and NAFLD, but it has excellent diagnostic accuracy in NAFLD and moderate accuracy in chronic HCV patients.

Background: Chronic hepatitis C (CHC) induces insulin resistance (IR) and subsequently diabetes., Aim: To examine viral, metabolic and histological predictors of IR in 275 CHC patients to test the hypothesis that IR differs among HCV genotypes and that viral replication directly affects IR., Methods: We studied 275 nondiabetic treatment-naïve CHC patients. Histological lesions were evaluated according to Ishak. IR was assessed using homeostasis model assessment for insulin resistance (HOMA-IR)., Results: HOMA > 3.0 was found in 37% of patients, independently associated with higher BMI and GGT. In genotype non-3 patients, HOMA > 3.0 was associated with higher BMI and GGT values, while no significant association was noted in genotype 3 patients. In non-obese patients with minimal fibrosis, HOMA > 3.0 was found in 20% of cases without significant differences among genotypes. No association between HOMA > 3.0 and HCV-RNA levels was found. Severe fibrosis (stage 5-6) related to older age (OR:1.048), HOMA-IR (OR:1.177), necroinflammation (OR: 2.990) and higher ALT (OR: 1.009) and GGT (OR:1.006)., Conclusions: IR develops at early stages of CHC without significant differences among genotypes. It is more frequent in obese patients with steatosis and contributes to fibrosis progression. However, IR does not seem to be associated with viraemia and therefore its exact pathogenetic mechanism in CHC remains elusive.

Background/aims: Lamivudine improves liver histology in patients with chronic hepatitis B (CHB), but its effects on portal pressure remain unknown. We evaluated the effect of lamivudine monotherapy on hepatic venous pressure gradient (HVPG) in CHB-related cirrhosis with significant portal hypertension., Methods: We studied 19 patients with cirrhosis due to HBeAg-negative CHB and HVPG >or=10 mm Hg treated with oral lamivudine (100mg daily). Liver biochemistry, Child-Pugh and MELD score were determined every 3 months, alpha-fetoprotein and HBV DNA every 6 months and HVPG at baseline and at 12 months after lamivudine initiation. Diuretics, beta-blockers, antibiotics and/or endoscopic therapy were used for routine indications., Results: At 12 months, a significant reduction was observed in ALT (p=0.001), HBV DNA (p=0.002), Child-Pugh (p=0.012) and MELD score (p=0.006). Four patients developed virological breakthrough during treatment. At 12 months, HVPG decreased in all but one patient [baseline: 14.4+/-3.9 and 12 months: 12.4+/-3.3 mm Hg (p=0.007)]. HVPG decreased >20% or below the 12 mm Hg threshold in 10 of 13 patients with baseline HVPG >or=12 mm Hg. HVPG increased in a patient with hepatic flare after virological breakthrough., Conclusion: In conclusion, in patients with cirrhosis due to HBeAg-negative CHB, lamivudine monotherapy reduces HVPG, especially when virological suppression and biochemical remission is achieved.

Mutations in the highly conserved tyrosine-methionine-aspartate-aspartate (YMDD) motif are frequently associated with resistance to antivirals and represent a major concern in the treatment of hepatitis B virus (HBV) infection. Conventional methods fail to detect minority populations of drug-resistant viral quasispecies if they represent less than 25% of the total sample virus population. The amplification refractory mutation system real-time PCR (ARMS RT-PCR) was combined with molecular beacon technology using the LightCycler system. The samples from HBV patients selected for assay evaluation included (i) 57 samples from treatment-naïve patients for biological discriminatory ability (cutoff) estimation, (ii) 12 samples from patients with treatment failure that were M204V positive by sequencing, and (iii) 13 samples from patients with treatment failure that were negative for mutation at codon 204 by sequencing. The discriminatory ability of the assay was 0.25% when tested with laboratory-synthesized DNA target sequences. The median mutant-to-wild-type ratio for samples from naive patients tested positive for the wild type and for mutant variants was 0.01% (5th and 95th percentiles = 0.0001 and 0.04%, respectively). A value of 0.04% was selected as the biological cutoff of the assay of clinical samples. In all samples M204V positive by sequencing (12/12), the mutant variant was detected as the predominant population (range, 82.76 to 99.43%). Interestingly, in 5 (38%) of 13 samples negative by sequencing, the M204V variant was detected at a ratio above the biological cutoff (0.05 to 28%). The assay represents an efficient technique for the early detection and quantification of M204V variants before mutant strains emerge to dominate the population.

Background: Endotoxaemia is commonly seen in cirrhotic patients with ascites and this may be associated with increased portal pressure., Aim: To investigate the effect of intestinal decontamination on liver haemodynamics in alcohol-related cirrhotic patients with ascites., Methods: We included 30 patients. At day 0, systemic and splanchnic circulation endotoxin levels were determined and HVPG measurement performed. Patients received rifaximin (1200 mg/day) for 28 days. At day 29, systemic and splanchnic circulation endotoxin levels were determined and HVPG measurement performed again., Results: Median (range) plasma endotoxin levels decreased significantly after rifaximin administration both in systemic [1.45(0-3.1) vs. 0.7(0-2.7), P < 0.0001] and splanchnic circulation [1.8(0-3.4) vs. 0.8(0-2.1), P < 0.0001]. Meanwhile, the difference seen in endotoxin levels between the splanchnic and systemic circulation at day 0 (P = 0.001) was not noted at day 29 (P = 0.137). HVPG measurement was possible in 28 patients. Median (range) HVPG values were 18 mmHg (12.7-26.3) on day 0 vs. 14.7 mmHg (7-20) on day 29 (P < 0.0001). HVPG decreased after rifaximin in 23, remained stable in two and increased in three patients., Conclusion: Hepatic venous pressure gradient values decreased significantly after intestinal decontamination with rifaximin in patients with alcohol-related decompensated cirrhosis and this might have been achieved through significant reduction of plasma endotoxin levels.

Insulin resistance (IR) and metabolic syndrome have recently been implicated in the pathogenesis and progression of chronic liver diseases, especially chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD). In this review, we provide current information on their deleterious effect on the liver, with particular interest in those two entities. In NAFLD, IR causes both the accumulation of fat in hepatocytes and the progression to non-alcoholic steatohepatitis (NASH). Moreover, the presence of metabolic syndrome seems to be associated with severe fibrosis in NASH patients. In CHC, IR develops early in the course of the disease and precedes steatosis. It is also independently associated with histological severity and negatively affects treatment response, irrespective of genotype. Consequently, therapies targeting IR and metabolic syndrome could indirectly ameliorate the prognosis of both NAFLD and CHC. As specific therapies do not exist, patients with metabolic syndrome and CHC and NAFLD should be counseled to lose weight and ameliorate their glycemic control and lipid profile.