Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study.

BACKGROUND & AIMS: There is currently no virological cure for chronic hepatitis B but successful nucleos(t)ide analogue (NA) therapy can suppress hepatitis B virus (HBV) DNA replication and, in some cases, result in HBsAg loss. Stopping NA therapy often leads to viral relapse and therefore life-long therapy is usually required. This study investigated the potential to discontinue tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. METHODS: Non-cirrhotic HBeAg-negative patients who had received TDF for ≥4years, with suppressed HBV DNA for ≥3.5years, were randomly assigned to either stop (n=21) or continue (n=21) TDF monotherapy. Standard laboratory tests including HBV DNA viral load, HBsAg and alanine aminotransferase (ALT) measurements, and adverse event reporting were carried out during treatment and post-treatment follow-up for 144weeks. RESULTS: Of the patients who stopped TDF therapy, 62% (n=13) remained off-therapy to Week 144. Median HBsAg change in this group was -0.59log10IU/ml (range -4.49 to 0.02log10IU/ml) vs. 0.21log10IU/ml in patients who continued TDF therapy. Four patients (19%) achieved HBsAg loss. Patients stopping therapy had initial fluctuations in viral load and ALT; however, at Week 144, 43% (n=9) had either achieved HBsAg loss or had HBV DNA <2,000IU/ml. There were no unexpected safety issues identified with stopping TDF therapy. CONCLUSIONS: This controlled study demonstrated the potential for HBsAg loss and/or sustained virological response in non-cirrhotic HBeAg-negative patients stopping long-term TDF therapy. Lay summary: Nucleos(t)ide analogue (NA) is usually a life-long therapy for HBV patients. This randomised controlled study investigated the discontinuation of tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. Of the patients who stopped TDF therapy, 62% remained off-therapy to Week 144, of which 43% of patients had achieved either HBsAg loss or HBV DNA <2,000IU/ml. This offers a potential for long-term HBV-suppressed patients without cirrhosis to stop NA therapy under strict surveillance. Clinical trial number: NCT01320943.

Interferon-free strategies without a nucleoside/nucleotide analogue.

The identification of viral and host factors involved in hepatitis C virus (HCV) replication was a key prerequisite for the discovery and further exploration of antiviral drug targets. As of today, numerous direct-acting antiviral agents (DAAs), as well as host-targeting agents (HTAs), have been developed and entered clinical testing. The goal to omit pegylated interferon due to its unfavorable side-effect profile from novel HCV therapeutic approaches led to an expedited design and competitive conduct of DAA combination trials striving for easily applicable, all-oral HCV treatments. Approval of several interferon-free regimens is awaited in the near future (2014/2015). Results of different DAA combination trials (without nucleos(t)ide polymerase inhibitors) and trials involving HTAs are reviewed herein.

Interferon-free antiviral combination therapies without nucleosidic polymerase inhibitors.

The establishment of robust HCV cell culture systems and characterization of the viral life cycle provided the molecular basis for highly innovative, successful years in HCV drug development. With the identification of direct-acting antiviral agents (DAAs), such as NS3/4A protease inhibitors, NS5A replication complex inhibitors, nucleotide and non-nucleoside polymerase inhibitors, as well as host cell targeting agents, novel therapeutic strategies were established and competitively entered clinical testing. The first-in-class NS3/4A protease inhibitors telaprevir and boceprevir, approved in 2011, were recently outpaced by the pan-genotypic nucleotide polymerase inhibitor sofosbuvir that in combination with pegylated interferon and ribavirin, further shortens therapy durations and also offers the first interferon-free HCV treatment option. In the challenging race towards the goal of interferon-free HCV therapies, however, several oral DAA regimens without nucleotide polymerase inhibitors that combine a NS3/4A protease inhibitor, a NS5A inhibitor and/or a non-nucleoside polymerase inhibitor yielded competitive results. Second generation NS3/4A protease and NS5A inhibitors promise an improved genotypic coverage and a high resistance barrier. Results of novel DAA combination therapies without the backbone of a nucleotide polymerase inhibitor, as well as treatment strategies involving host targeting agents are reviewed herein.

Hyponatremia influences the outcome of patients with acute-on-chronic liver failure: an analysis of the CANONIC study.

INTRODUCTION: Hyponatremia is a marker of poor prognosis in patients with cirrhosis. This analysis aimed to assess if hyponatremia also has prognostic value in patients with acute-on-chronic liver failure (ACLF), a syndrome characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. METHODS: We performed an analysis of the Chronic Liver Failure Consortium CANONIC database in 1,341 consecutive patients admitted to 29 European centers with acute decompensation of cirrhosis (including ascites, gastrointestinal bleeding, hepatic encephalopathy, or bacterial infections, or any combination of these), both with and without associated ACLF (301 and 1,040 respectively). RESULTS: Of the 301 patients with ACLF, 24.3% had hyponatremia at inclusion compared to 12.3% of 1,040 patients without ACLF (P <0.001). Model for end-stage liver disease, Child-Pugh and chronic liver failure-SOFA scores were significantly higher in patients with ACLF and hyponatremia compared to those without hyponatremia. The presence of hyponatremia (at inclusion or during hospitalization) was a predictive factor of survival both in patients with and without ACLF. The presence of hyponatremia and ACLF was found to have an independent effect on 90-day survival after adjusting for the potential confounders. Hyponatremia in non-ACLF patients nearly doubled the risk (hazard ratio (HR) 1.81 (1.33 to 2.47)) of dying at 90 days. However, when considering patients with both factors (ACLF and hyponatremia) the relative risk of dying at 90 days was significantly higher (HR 6.85 (3.85 to 12.19) than for patients without both factors. Patients with hyponatremia and ACLF had a three-month transplant-free survival of only 35.8% compared to 58.7% in those with ACLF without hyponatremia (P <0.001). CONCLUSIONS: The presence of hyponatremia is an independent predictive factor of survival in patients with ACLF. In cirrhosis, outcome of patients with ACLF is dependent on its association with hyponatremia.

Variants in interferon-alpha pathway genes and response to pegylated interferon-Alpha2a plus ribavirin for treatment of chronic hepatitis C virus infection in the hepatitis C antiviral long-term treatment against cirrhosis trial.

UNLABELLED: Combination treatment with pegylated-interferon-alpha (PEG IFN-alpha) and ribavirin, the current recommended therapy for chronic hepatitis C virus (HCV) infection, results in a sustained virological response (SVR) in only about half of patients. Because genes involved in the interferon-alpha pathway may affect antiviral responses, we analyzed the relationship between variants in these genes and SVR among participants in the Hepatitis C Antiviral Long-Term treatment Against Cirrhosis (HALT-C) trial. Patients had advanced chronic hepatitis C that had previously failed to respond to interferon-based treatment. Participants were treated with peginterferon-alpha2a and ribavirin during the trial. Subjects with undetectable HCV RNA at week 72 were considered to have had an SVR. Subjects with detectable HCV RNA at week 20 were considered nonresponders. We used TaqMan assays to genotype 56 polymorphisms found in 13 genes in the interferon-alpha pathway. This analysis compares genotypes for participants with an SVR to nonresponders. The primary analysis was restricted to European American participants because a priori statistical power was low among the small number (n = 131) of African American patients. We used logistic regression to control the effect of other variables that are associated with treatment response. Among 581 European American patients, SVR was associated with IFNAR1 IVS1-22G (adjusted odds ratio, 0.57; P = 0.02); IFNAR2 Ex2-33C (adjusted odds ratio, 2.09; P = 0.02); JAK1 IVS22+112T (adjusted odds ratio, 1.66; P = 0.04); and ADAR Ex9+14A (adjusted odds ratio, 1.67; P = 0.03). For the TYK2-2256A promoter region variant, a borderline association was present among European American participants (OR, 1.51; P = 0.05) and a strong relationship among African American patients; all 10 with SVR who were genotyped for TYK2 -2256 carried the A variant compared with 68 of 120 (57%) nonresponders (P = 0.006). CONCLUSION: Genetic polymorphisms in the interferon-alpha pathway may affect responses to antiviral therapy of chronic hepatitis C.

Anemia and Systemic Inflammation Rather than Arterial Circulatory Dysfunction Predict Decompensation of Liver Cirrhosis.

BACKGROUND: While systemic inflammation is recognized as playing a central role in the pathogenesis of organ failures in patients with liver cirrhosis, less is known about its relevance in the development of classical hepatic decompensation. AIM: To characterize the relationship between systemic inflammation, hemodynamics, and anemia with decompensation of liver cirrhosis. METHODS: This is a post-hoc analysis of a cohort study of outpatients with advanced liver fibrosis or cirrhosis. RESULTS: Analysis included 338 patients of whom 51 patients (15%) were hospitalized due to decompensation of liver cirrhosis during a median follow-up time of six months. In univariate analysis, active alcoholism (p = 0.002), model of end-stage liver disease (MELD) score (p = 0.00002), serum IL-6 concentration (p = 0.006), heart rate (p = 0.03), low arterial blood pressure (p < 0.05), maximal portal venous flow (p = 0.008), and low hemoglobin concentration (p < 0.00001) were associated with hospitalization during follow-up. Multivariate analysis revealed an independent association of low hemoglobin (OR = 0.62, 95% CI = 0.51-0.78, p = 0.001) and serum IL-6 concentration (OR = 1.02, 95% CI = 1.01-1.04, p = 0.03)-but not of hemodynamic parameters-with hepatic decompensation. An inverse correlation between hemoglobin concentration and portal venous flow (R = -0.362, p < 0.0001) was detected for the non-hospitalized patients. Accuracy of baseline hemoglobin levels for predicting hospitalization (AUC = 0.84, p < 0.000001) was high. CONCLUSION: Anemia and systemic inflammation, rather than arterial circulatory dysfunction, are strong and independent predictors of hepatic decompensation in outpatients with liver cirrhosis.

[New insights into epidemiology may promote screening in Cholangiocarcinoma]. / Das Gallengangskarzinom: Von neuen Erkenntnissen der Epidemiologie zur Früherkennung.

Cholangiocarcinoma is non-curable in many cases at establishing the diagnosis. New insights into epidemiology may promote screening of cholangiocarcinoma in a combination of risk scores, but today PSC is the only risk factor with an established screening recommendation.