Search

Background & Aims: The presence of baseline resistance‐associated substitutions (RASs) reduced sustained virologic response (SVR) rates in chronic hepatitis C virus (HCV) genotype 1a infected patients treated with Elbasvir/Grazoprevir (EBR/GZR). This study aimed to evaluate the frequency of NS5A RASs and treatment outcomes in patients for whom EBR/GZR was intended. Methods: We sequenced NS5A in 832 samples from German genotype1a‐infected DAA‐naïve patients population‐based, which were collected in the European Resistance Database. Treatment outcomes and clinical parameters were evaluated in 519 of such patients retrospectively. Results: Overall, 6.5% of patients harboured EBR‐specific NS5A RASs at baseline, including Q30H/R (3.3%), L31M (1.8%), Y93H (1.6%) and other individual variants. Antiviral treatment, including EBR/GZR, was initiated in 88% of the patients. In the absence of RASs, the majority of patients received EBR/GZR for 12 weeks (57%) and the SVR rate was 97% compared to 99% SVR achieved using other DAA regimens (LDV/SOF ± RBV, G/P, PrOD + RBV, VEL/SOF). Various regimens were used in the presence of RASs and SVR rates were high following treatment with LDV/SOF (100%), G/P (83%), PrOD/RBV (100%), VEL/SOF (100%), SMV/SOF (100%) and EBR/GZR + RBV for 16 weeks (100%). However, two patients received EBR/GZR for 16 weeks without RBV and one relapsed. Conclusions: EBR/GZR treatment with or without RBV for 12 or 16 weeks according to a baseline RAS analysis was highly effective with ≥97% SVR in patients with genotype 1a. EBR/GZR without RBV should be avoided in patients with RASs. High SVR rates were also achieved using other 8‐ or 12‐week DAA regimens. [ABSTRACT FROM AUTHOR]

Summary: Treatment decisions are based on extent of fibrosis in patients with chronic hepatitis C (HCV) infection. Noninvasive diagnostic tools may help to avoid liver biopsy. We investigated the diagnostic accuracy of noncommercial serum scores in comparison with transient elastography (TE). Data analysis was undertaken based on 2458 patients enrolled in the German Hepatitis C Registry, in a prospective, observational study. Aspartate aminotransferase‐to‐platelet ratio index (APRI), FORNS index and FIB‐4 score were calculated and the diagnostic accuracy was compared to TE. As estimated by TE, 955 (38.9%) patients had absence of significant fibrosis (SF), 736 (29.9%) patients had SF, and 767 (31.2%) patients were shown to have cirrhosis. Patients with absence of SF had a sustained virological response (SVR) rate of 97.9%, whereas SVR was attained in 96.2% and 92.2% in those with SF and cirrhosis, respectively (P < 0.0001). The area under the receiver operator characteristic curve (AUROC), sensitivity and specificity in discriminating of SF were 0.789, 0.596 and 0.939 by APRI; 0.838, 0.852 and 0.748 by FORNS index; and 0.828, 0.658 and 0.946 by FIB‐4 score. AUROCs for the prediction of cirrhosis, sensitivity and specificity were 0.881, 0.851 and 0.854 by APRI; 0.846, 0.948 and 0.628 by FORNS index; and 0.907, 0.907 and 0.848 by FIB‐4 score. In conclusion, in the present multicentre real‐world cohort, SF and cirrhosis were predicted with high accuracy with noncommercial serum markers using TE as reference. Further prospective long‐term follow‐up is necessary to compare biomarkers with TE concerning liver‐related outcome and overall mortality. [ABSTRACT FROM AUTHOR]

Aims Serelaxin is a recombinant form of human relaxin-2 in development for treatment of acute heart failure. This study aimed to evaluate the pharmacokinetics ( PK) of serelaxin in patients with hepatic impairment. Secondary objectives included evaluation of immunogenicity, safety and tolerability of serelaxin. Methods This was an open-label, parallel group study ( NCT01433458) comparing the PK of serelaxin following a single 24 h intravenous (i.v.) infusion (30 μg kg−1 day−1) between patients with mild, moderate or severe hepatic impairment ( Child- Pugh class A, B, C) and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration-time curve AUC(0-48 h) and AUC(0-∞) and serum concentration at 24 h post-dose ( C24h)] were compared between each hepatic impairment group and healthy controls. Results A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12-24 h and then declined following completion of infusion, with a mean terminal half-life of 7-8 h. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to adverse events or deaths were reported. No serelaxin treatment-related antibodies developed during this study. Conclusions The PK and safety profile of serelaxin were not affected by hepatic impairment. No dose adjustment is needed for serelaxin treatment of 48 h i.v. infusion in patients with hepatic impairment. [ABSTRACT FROM AUTHOR]

Background Non-alcoholic fatty liver disease ( NAFLD) is the most common chronic liver disorder in industrialized countries, yet its pathophysiology is incompletely understood. Small-molecule metabolite screens may offer new insights into disease mechanisms and reveal new treatment targets. Methods Discovery ( N = 33) and replication ( N = 66) of liver biopsies spanning the range from normal liver histology to non-alcoholic steatohepatitis ( NASH) were ascertained ensuring rapid freezing under 30 s in patients. 252 metabolites were assessed using GC/ MS. Replicated metabolites were evaluated in a murine high-fat diet model of NAFLD. Results In a two-stage metabolic screening, hydroquinone ( HQ, pcombined = 3.0 × 10−4) and nicotinic acid ( NA, pcombined = 3.9 × 10−9) were inversely correlated with histological NAFLD severity. A murine high-fat diet model of NAFLD demonstrated a protective effect of these two substances against NAFLD: Supplementation with 1% HQ reduced only liver steatosis, whereas 0.6% NA reduced both liver fat content and serum transaminase levels and induced a complex regulatory network of genes linked to NALFD pathogenesis in a global expression pathway analysis. Human nutritional intake of NA equivalent was also consistent with a protective effect of NA against NASH progression. Conclusion This first small-molecular screen of human liver tissue identified two replicated protective metabolites. Either the use of NA or targeting its regulatory pathways might be explored to treat or prevent human NAFLD. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of teneligliptin was compared in 3 groups of 8 subjects assigned according to their degree of hepatic impairment (mild, moderate, or matched healthy subjects). Hepatic impairment was associated with an increase in maximal plasma concentration (Cmax) and overall exposure (AUC0-∞) to teneligliptin. Geometric least square mean ratios for Cmax in subjects with mild and moderate hepatic impairment were 25% and 38% higher than in healthy subjects, and those for AUC0-∞ were 46% and 59% higher than in healthy subjects, respectively. For both parameters, the upper limit of the 90% confidence intervals was outside the 80%-125% 'no effect' limit, but below the FDA-recommended 'dose-adjustment' boundary of 200%. The lower mean total clearance in subjects with mild (9.79 L/h) or moderate (8.57 L/h) hepatic impairment resulted in longer mean half-lives (27.9 and 30.9 hours, respectively) than in healthy subjects (clearance: 13.11 L/h, half life: 24.8 hours). Protein binding ranged between 36.9% and 47.5% in subjects with hepatic impairment and between 32.5% and 34.5% in healthy subjects. Overall, teneligliptin was well tolerated by subjects with hepatic impairment. These results may indicate that caution will be needed when administering teneligliptin to subjects with hepatic impairment. [ABSTRACT FROM AUTHOR]

Aim This study investigated the effects of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban (10 mg), an oral, direct Factor Xa inhibitor. Method This single centre, non-randomized, non-blinded study included subjects with mild ( n = 8) or moderate hepatic impairment ( n = 8), according to the Child- Pugh classification, and gender-matched healthy subjects ( n = 16). Results Rivaroxaban was well tolerated irrespective of hepatic function. Mild hepatic impairment did not significantly affect the pharmacokinetics or pharmacodynamics of rivaroxaban, compared with healthy subjects. However, in subjects with moderate hepatic impairment, total body clearance was decreased, leading to a significant increase in the area under the plasma concentration-time curve ( AUC). The least-squares ( LS)-mean values for AUC were 1.15-fold [90% confidence interval ( CI) 0.85, 1.57] and 2.27-fold (90% CI 1.68, 3.07) higher in subjects with mild and moderate hepatic impairment, respectively, than in healthy subjects. Consequently, the pharmacodynamic responses were significantly enhanced in subjects with moderate hepatic impairment. For inhibition of Factor Xa, increases in the area under the effect-time curve and the maximum effect were observed, with LS-mean ratios of 2.59 and 1.24, respectively, vs. healthy subjects. Prolongation of prothrombin time was similar in healthy subjects and those with mild hepatic impairment, but was significantly enhanced in those with moderate hepatic impairment. Conclusion Moderate (but not mild) hepatic impairment reduced total body clearance of rivaroxaban after a single 10 mg dose, leading to increased rivaroxaban exposure and pharmacodynamic effects. [ABSTRACT FROM AUTHOR]