Sustained virologic response to treatment is associated with improved clinical outcomes, mainly prevention of liver failure, in patients with chronic hepatitis C and advanced fibrosis.

Recent studies suggest that diabetes mellitus increases the risk of developing hepatocellular carcinoma (HCC). The aim of this study is to quantify the risk of HCC among patients with both diabetes mellitus and hepatitis C in a large cohort of patients with chronic hepatitis C and advanced fibrosis. We included 541 patients of whom 85 (16%) had diabetes mellitus. The median age at inclusion was 50 years. The prevalence of diabetes mellitus was 10.5% for patients with Ishak fibrosis score 4, 12.5% for Ishak score 5, and 19.1% for Ishak score 6. Multiple logistic regression analysis showed an increased risk of diabetes mellitus for patients with an elevated body mass index (BMI) (odds ratio R ecent epidemiological studies suggest that the presence of diabetes mellitus increases the risk of hepatocellular carcinoma (HCC). 1,2 An explanation for this association may be that diabetes often occurs as part of the metabolic syndrome, which increases the risk of nonalcoholic steatohepatitis (NASH), and that HCC can be a late complication of NASH. 3 Diabetes mellitus is more prevalent among patients with chronic hepatitis C than in the general population. 4 Liver disease contributes to insulin resistance because it leads to a progressive impairment of insulin secretion and it induces hepatic insulin resistance. 5 Studies in transgenic mouse models that harbored the hepatitis C core gene have shown that hepatic insulin resistance may be caused by elevated levels of tumor necrosis factor-alpha, which disturbs the tyrosine phosphorylation of insulin receptor substrate-1. 6 Chronic hepatitis C virus (HCV) infection itself also increases the risk of HCC. It leads to chronic inflammation of the liver, to liver fibrosis, and it may eventually progress to cirrhosis. For patients with hepatitis C cirrhosis the risk for development of HCC is 0.54 to 2.0% per year. 7,8 Abbreviations: anti-HBc, anti-hepatitis B core antigen; BMI, body mass index; CI, confidence interval; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; IQR, interquartile range; NASH, nonalcoholic steatohepatitis; OR, odds ratio. From the 1 Erasmus MC University Medical Center, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands; 2 Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; 3 Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany;4 Research and Development (ZonMw) (to B.J.V.).[Stefan Zeuzem is currently affiliated with Johann Wolfgang

Entecavir (ETV) is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B (CHB) patients. The aim of this study was to investigate the long term efficacy and safety of ETV in NA-naïve CHB patients, particularly in those with detectable hepatitis B virus (HBV) DNA after 48 weeks, in whom treatment adaptation is suggested by current guidelines. In a multicenter cohort study, we investigated 333 CHB patients treated with entecavir monotherapy. The NA-naïve population consisted of 243 patients, whereas 90 were NA-experienced. Virological response (VR) (HBV DNA <80 IU/ mL) was achieved in 48%, 76%, and 90% of hepatitis B e antigen (HBeAg)-positive and in 89%, 98%, and 99% of HBeAg-negative NA-naïve patients at weeks 48, 96, and 144, respectively. Thirty-six of 175 (21%) NA-naïve patients with at least 48 weeks of follow-up had a detectable load at week 48 (partial virological response [PVR]). Twenty-nine (81%) patients with PVR reached VR during prolonged ETV monotherapy, and none of them developed ETV-resistance. Among 22 patients with HBV DNA <1,000 IU/mL at week 48, VR was achieved in 21 (95%) patients, compared with eight of 14 (57%) patients with HBV DNA !1,000 IU/mL. Continuous HBV DNA decline was observed in most patients without VR during follow-up, and in three patients adherence was suboptimal according to the treating physician. ETV was safe and did not affect renal function or cause lactic acidosis. Conclusion: ETV monotherapy can be continued in NA-naïve patients with detectable HBV DNA at week 48, particularly in those with a low viral load because long-term ETV leads to a virological response in the vast majority of patients. (HEPATOLOGY 2011;54:443-451) C urrent treatment guidelines consider nucleos(-t)ide analogues (NAs) and pegylated interferon as first-line treatment for chronic hepatitis B (CHB). The ultimate goal of treatment is prevention of cirrhosis, hepatic decompensation, and hepatocellular carcinoma.1 Entecavir (ETV) is a cyclopentyl guanosine analogue that has shown superior biochemical, virological, and histological efficacy compared with lamivudine (LAM) in large phase III trials.2,3 Moreover, genotypic resistance to ETV is rare in NA-naïve

Chronic hepatitis B is a major cause for liver cirrhosis and its complications hepatic decompensation and hepatocellular carcinoma (HCC), resulting in 500,000 to 1.2 million hepatitis B-related deaths annually. 1 Suppression of HBV DNA is a principal goal in treating chronic hepatitis B because this was shown to significantly improve liver histology and to decrease rates of hepatic complications and HCC. 2,3 Patients with chronic hepatitis B should be considered for antiviral treatment when HBV DNA levels are Ͼ2000 IU/mL, serum alanine aminotransferase levels are above the upper limit of normal, and liver histology shows at least moderate necroinflammation or fibrosis. Patients with liver cirrhosis are candidates for antiviral therapy even if alanine aminotransferase levels are normal or if HBV DNA levels are Ͻ2000 IU/mL. Current treatment options are pegylated interferonalfa and nucleoside or nucleotide inhibitors of the HBV polymerase/reverse transcriptase. For treating chronic hepatitis B, five polymerase inhibitors have been approved so far: the nucleoside analogues lamivudine, telbivudine, entecavir, and the nucleotide analogues adefovir dipivoxil and, most recently, tenofovir disoproxil.Entecavir is a potent cyclopentyl guanosine nucleoside inhibitor of the HBV polymerase which was approved for the treatment of patients with both hepatitis B envelope antigen (HBeAg)-positive and HbeAg-negative chronic hepatitis B and compensated liver disease. 4 Compared to lamivudine or adefovir, entecavir has a higher antiviral efficacy and superior resistance profile. 4

BACKGROUND & AIMS: Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given offlabel. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE. METHODS: We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n ¼ 59) or placebo (n ¼ 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity 2 on a scale of 0-10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label Gastroenterology 2019;157:74-86 CLINICAL AT treatment with BOT (1 mg twice daily). RESULTS: At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P < .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent. CONCLUSIONS: In a randomized trial of adults with active EoE, we found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029.

Therefore, beside the structural alterations (fibrosis, nodule formation), there is a complex dynamic component that contributes to increasing hepatic vascular resistance and splanchnic vasodilata-tion. Understanding this pathophysiology has revealed markers that are associated with the presence of PH and varices. On the other hand, variation of the genes that encode proteins involved in sys-temic and splanchnic vasodilatation have been found to be associated with the presence of esophageal varices. 8 Therefore, variation of these genes could play a role in addition to predicting the presence of esophageal varices, as well as their likelihood of bleeding. In this issue of the journal, Yang and colleagues have analyzed 951 patients with cirrhosis of various etiologies. The main aim was to evaluate additional blood markers and genetic risk for the prediction of the presence of esophageal varices in cirrhosis. Also, they performed a 2-year follow-up to evaluate predictors for esophageal varices (EV) bleeding. The authors also studied another 650 independent patients to confirm the association between genetic variants and presence of EVs, namely for validation cohort. 9 The factors analyzed in this study included plasma levels of soluble CD163 (sCD163), VEGF and HO-1, genetic polymorphisms of HO-1, VEGF, and vascular endothelial growth factor receptor 2 (VEGFR2). Soluble CD163 is a specific marker of activated macrophages, another potential biomarker for PH in cirrhosis. The activation of Kupffer cells may be involved in PH by the release of vasoconstrictor substances. Recently, Grønbaek et al. have shown that sCD163 plasma concentration in cirrhosis is almost three times higher than in controls, and sCD163 was an independent predictor of the hepatic venous pressure gradient. 10 Yang et al. 9 found that serum sCD163 level was elevated in patients with cirrhosis complicated by esophageal varices, and this marker could potentially be used to predict the presence of EVs in clinical practice. The genetic elements of the Yang study identified that patients with esophageal varices showed significantly higher frequencies of risk genotypes of HO-1, SS in (GT)n repeat, and AA in T(-413)A than corresponding wild-type genotypes. Further, cir-rhotic patients carrying C(+405)G GG and C(+936)T TT risk genotype of VEGF, and Val(-297)Ile Ile/Ile risk genotype of VEGFR2 had a higher likelihood of developing EVs than those carrying wild-type genotype. Therefore, in addition to traditional markers (platelet count and splenomegaly), the authors showed that high serum sCD163 level and these polymorphisms in the HO-1 and VEGF predict the presence of esophageal varices in patients with cirrhosis. Further, the combination of platelet count, serum sCD163 level, and those risk haplotypes of HO-1 and VEGF conferred higher predictive values for varices than platelet count alone. Finally, patients with these same risk haplotypes (HO-1 and VEGF) have a higher chance of esophageal variceal bleeding than those not carrying these haplotypes. In con...

SUMMARY Chronic hepatitis C virus (HCV) infection affects more than 170 million persons worldwide and is responsible for the development of liver cirrhosis in many cases. Standard treatment with pegylated alpha interferon (IFN-α) in combination with the nucleoside analogue ribavirin leads to a sustained virologic response in approximately half of the patients. IFN-α is classified as an indirect treatment, as it interacts with the host's immune response. The mechanism of action of ribavirin is still unknown. The benefit of triple therapy by adding other antiviral agents, e.g., amantadine, is controversial. Currently, new direct antiviral drugs (HCV protease/polymerase inhibitors) are being evaluated in phase 1/phase 2 trials. Phenotypic resistance to antiviral therapy has been attributed to amino acid variations within distinct regions of the HCV polyprotein. While sensitivity to IFN-α-based antiviral therapy in vivo is clearly correlated with the number of mutations within the HCV NS5A protein, the underlying functional mechanisms for this association are unknown. In turn, in vitro, several mechanisms to circumvent the host immune defense or to block treatment-induced antiviral activities have been described for different HCV proteins. By the introduction of direct antiviral drugs, hepatitis C therapy now is entering a new era in which the development of resistance may become the most important parameter for treatment success or failure.

Present recommendations for the management of alpha interferon-based treatment in patients with chronic hepatitis C virus (HCV) infection are based on HCV RNA measurements before, during, and after antiviral therapy (6,22). Changes in HCV RNA serum concentrations during the early phase of interferon-based therapy have been analyzed based on complex models of viral kinetics and applied to the prediction of treatment outcomes (13,16,31). In different studies, a high predictive value for virologic nonresponse (98 to 100%) was observed for HCV genotype 1-and genotype 4-to 6-infected patients, with a decline in the HCV RNA serum concentration of less than 2 log steps between baseline and week 12 of (pegylated) alpha interferon-ribavirin combination therapy (3,5,8). Alternatively, an absolute HCV RNA concentration above 30,000 IU/ml may be used for decisions about early treatment discontinuation at week 12 (3). In addition, for genotype 1-and genotype 4-to 6-infected patients at week 24 of treatment, it is recommended that therapy be discontinued on the basis of detectable HCV RNA in serum by qualitative PCR-based assays (3,5,19). Recently, for patients infected with genotype 2 or 3, the HCV RNA concentration at baseline and viral decline at week 4 have been described as highly predictive for virologic response to pegylated alpha interferonribavirin combination therapy (4,18,30,32). Furthermore, for assessment of virologic response to currently developed direct antiviral drugs (i.e., protease and polymerase inhibitors), proper HCV RNA quantification for the different HCV genotypes is critical (1,14,25,26). WHO HCV international standard, 96/790 (2,7,11,17,23,24,27). However, continuing limitations are the lack of complete automation (22), the necessity for dilutions for quantification by standard PCR-based assays (6), the relatively low sensitivity of quantitative HCV RNA assays (31), and the need for different test systems for qualitative and quantitative HCV RNA measurements (31). Furthermore, standardization of results to IU are mainly based on HCV genotype 1 panels, and little is known about the variability of commercially available HCV RNA assays for quantification of different HCV genotypes.Real-time PCR methods for the quantification of HCV RNA have the advantage of linear amplification over a broad dynamic range, together with an integrated, automated detection system. With efficient HCV RNA extraction, they have the * Corresponding author. Mailing address: