Hepatitis C Clearance by Direct-Acting Antivirals Impacts Glucose and Lipid Homeostasis.

BACKGROUND: Chronic hepatitis C virus (HCV) infections are causally linked with metabolic comorbidities such as insulin resistance, hepatic steatosis, and dyslipidemia. However, the clinical impact of HCV eradication achieved by direct-acting antivirals (DAAs) on glucose and lipid homeostasis is still controversial. The study aimed to prospectively investigate whether antiviral therapy of HCV with DAAs alters glucose and lipid parameters. METHODS: 50 patients with chronic HCV who were treated with DAAs were screened, and 49 were enrolled in the study. Biochemical and virological data, as well as noninvasive liver fibrosis parameters, were prospectively collected at baseline, at the end of treatment (EOT) and 12 and 24 weeks post-treatment. RESULTS: 45 of 46 patients achieved sustained virologic response (SVR). The prevalence of insulin resistance (HOMA-IR) after HCV clearance was significantly lower, compared to baseline (5.3 ± 6.1 to 2.5 ± 1.9, p < 0.001), which is primarily attributable to a significant decrease of fasting insulin levels (18.9 ± 17.3 to 11.7 ± 8.7; p = 0.002). In contrast to that, HCV eradication resulted in a significant increase in cholesterol levels (total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL-C) levels) and Controlled Attenuated Score (CAP), although BMI did not significantly change over time (p = 0.95). Moreover, HOMA-IR correlated significantly with noninvasive liver fibrosis measurements at baseline und during follow-up (TE: r = 0.45; p = 0.003, pSWE: r = 0.35; p = 0.02, APRI: r = 0.44; p = 0.003, FIB-4: r = 0.41; p < 0.001). CONCLUSION: Viral eradication following DAA therapy may have beneficial effects on glucose homeostasis, whereas lipid profile seems to be worsened.

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.

Efficacy of Albumin Treatment for Patients with Cirrhosis and Infections Unrelated to Spontaneous Bacterial Peritonitis.

BACKGROUND & AIMS: We performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP). METHODS: We performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course. RESULTS: There were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007). CONCLUSIONS: In a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279.

Adherence to pan-genotypic glecaprevir/pibrentasvir and efficacy in HCV-infected patients: A pooled analysis of clinical trials.

BACKGROUND & AIMS: Adequate adherence to hepatitis C virus (HCV) treatment is believed to be a key component of treatment success because non-adherence can potentially result in treatment failure and the emergence of resistant viral variants. This analysis assessed factors associated with non-adherence to glecaprevir/pibrentasvir (G/P) therapy and the impact of non-adherence on sustained virological response at post-treatment week 12 (SVR12) rates in HCV genotype (GT) 1-6-infected patients. METHODS: Adherence was calculated by pill counts at study visits during treatment, and defined as having a lowest treatment adherence of ≥80% and ≤120% at each study visit. Exploratory logistic regression modelling assessed predictors of non-adherence to G/P therapy. SVR12 rates by treatment adherence were assessed in the intent-to-treat (ITT) population and modified ITT (mITT) population, which excludes non-virological failures. RESULTS: Overall, 97% (2024/2091) of patients were adherent to G/P therapy at all consecutive study visits. Alcohol use was the only baseline characteristic independently associated with non-adherence to G/P therapy (OR: 2.38; 95% CI: 1.13-5.01; P = .022). In the mITT population, overall SVR12 rates were high both in patients who were adherent to G/P therapy and those who were not (99% [1983/2008] and 95% [58/61] respectively; P = .047). Corresponding SVR12 rates in the ITT population were 98% (1983/2024) and 87% (58/67) respectively. CONCLUSIONS: Most patients adhered to G/P therapy. SVR12 rates were high both in patients who were adherent to G/P treatment and those who were not. Patient education on treatment adherence should remain an important part of HCV treatment. CLINICAL TRIALS REGISTRATION: NCT02604017, NCT02640482, NCT02640157, NCT02636595, NCT02642432, NCT02651194, NCT02243293, NCT02446717.

Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF. METHODS: We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals. RESULTS: Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid ß-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins. CONCLUSIONS: In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures. LAY SUMMARY: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures.

Assessing Patient Preferences for Treatment Decisions for New Direct Acting Antiviral (DAA) Therapies for Chronic Hepatitis C Virus Infections.

INTRODUCTION: The new direct acting antiviral (DAA) therapies are able to effectively treat chronic hepatitis C (CHC). This study elicited the preferences of CHC patients for treatment attributes of new DAAs. METHODS: An online discrete choice experiment survey was designed to collect data from adult CHC patients in the USA, UK, France, Germany, Spain, and Italy. Patients were asked to choose from alternative hypothetical DAA options, defined by differing levels of nine attributes [i.e., treatment duration, tablet count and packaging, cure rate, required office visits when on treatment, modifications to statins or to proton pump inhibitors (PPIs), and risks of diarrhea, headache and nausea]. Logistic regression was used to assess preference for the treatment options. RESULTS: A total of 328 patients with CHC completed the survey (USA, n = 227; European countries, n = 101), with a mean age of 47.7 years (SD = 14.4) and an average 11.2 years since CHC diagnosis; 51% of patients were female. More than half (60%) of the patients had treatment for CHC. Patients significantly preferred a DAA regimen with higher cure rate, shorter treatment duration, lower risks of diarrhea, headache, and nausea (all p < 0.001), reduced need for office visits when on treatment (p = 0.044), and without requiring dose reduction or timing change in PPIs (p = 0.032). Tablet counts were not found to be statistically significant. CONCLUSION: Given the overall high cure rates of new DAAs, CHC patients' preferences for therapy may be influenced by treatment attributes other than cure rates and tolerability. Treatments that are more convenient and require less disruption to their daily life (e.g., shorter treatment duration, no modification in PPI use, and fewer office visits when on treatment) are important to patients with CHC and should be considered when making treatment decisions. FUNDING: AbbVie.

miRNA-26b downregulation in peripheral blood mononuclear cells of patients with hepatitis C associated lymphomas is restored by successful interferon-free antiviral therapy.

BACKGROUND: Patients with chronic HCV infection are at increased risk of developing B-cell non-Hodgkin lymphoma (B-NHL). Regression of HCV-associated B-NHL (HCV-NHL) can be achieved through HCV eradication using interferon (IFN). However, only about two-thirds of patients with sustained virological response (SVR) also had a consecutive lymphoma response. miRNA-26b is associated with HCV-NHL response to antiviral therapy. Recent data suggest that IFN-free direct-acting antiviral (DAA) regimens also have anti-lymphoma activity in this patient population. METHODS: We report four patients with HCV-NHL who were treated with different IFN-free DAA regimens as oncological monotherapy in our centre between 2015 and 2016. We analysed the virological and lymphoproliferative disease response. Moreover, we analysed miRNA-26b expression in peripheral blood mononuclear cells at different time points during antiviral therapy for all included patients as well as for a total of 10 controls with (n=5) and without (n=5) chronic HCV infection. RESULTS: All patients had marginal zone lymphoma subtype and received different DAA regimens for 12-24 weeks. All four patients achieved SVR, but only three patients also had lymphoma response (one complete response, two partial responses). One patient showed progression to a high-grade lymphoma subtype after SVR. miRNA-26b expression was generally decreased in patients with HCV-NHL. Moreover, miRNA-26b expression was restored in those HCV-NHL patients with lymphoma response after 6 months (P=0.009). CONCLUSIONS: We have demonstrated that IFN-free DAA treatment of HCV can improve or even cure NHL. miRNA-26b-levels could be a potentially useful biomarker to predict lymphoma response in HCV-NHL patients.

Addressing Profiles of Systemic Inflammation Across the Different Clinical Phenotypes of Acutely Decompensated Cirrhosis.

Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients. Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5-2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF). Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating "full-blown" systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes. Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death.

Effects of Albumin Treatment on Systemic and Portal Hemodynamics and Systemic Inflammation in Patients With Decompensated Cirrhosis.

BACKGROUND & AIMS: We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections. METHODS: We performed a prospective study to assess the effects of long-term (12 weeks) treatment with low doses (1 g/kg body weight every 2 weeks) and high doses (1.5 g/kg every week) of albumin on serum albumin, plasma renin, cardiocirculatory function, portal pressure, and plasma levels of cytokines, collecting data from 18 patients without bacterial infections (the Pilot-PRECIOSA study). We also assessed the effect of short-term (1 week) treatment with antibiotics alone vs the combination of albumin plus antibiotics (1.5 g/kg on day 1 and 1 g/kg on day 3) on plasma levels of cytokines in biobanked samples from 78 patients with bacterial infections included in a randomized controlled trial (INFECIR-2 study). RESULTS: Circulatory dysfunction and systemic inflammation were extremely unstable in many patients included in the Pilot-PRECIOSA study; these patients had intense and reversible peaks in plasma levels of renin and interleukin 6. Long-term high-dose albumin, but not low-dose albumin, was associated with normalization of serum level of albumin, improved stability of the circulation and left ventricular function, and reduced plasma levels of cytokines (interleukin 6, granulocyte colony-stimulating factor, interleukin 1 receptor antagonist, and vascular endothelial growth factor) without significant changes in portal pressure. The immune-modulatory effects of albumin observed in the Pilot-PRECIOSA study were confirmed in the INFECIR-2 study. In this study, patients given albumin had significant reductions in plasma levels of cytokines. CONCLUSIONS: In an analysis of data from 2 trials (Pilot-PRECIOSA study and INFECIR-2 study), we found that albumin treatment reduced systemic inflammation and cardiocirculatory dysfunction in patients with decompensated cirrhosis. These effects might be responsible for the beneficial effects of albumin therapy on outcomes of patients with decompensated cirrhosis. ClinicalTrials.gov, Numbers: NCT00968695 and NCT03451292.

Treatment strategies for patients with decompensated liver cirrhosis due to hepatitis C virus infection eligible for liver transplantation: real-life data from five German transplant centers.

BACKGROUND: Even with highly effective direct-acting antivirals (DAAs) treatment of patients with decompensated hepatitis C (HCV) cirrhosis remains challenging. Clinical deterioration and the need for liver transplantation (LT) may arise despite previous antiviral treatment. It is unclear whether in patients with high Model for End-Stage Liver Disease (MELD) antiviral treatment is too risky and should thus be deferred until after LT. Treatment choices that are currently made in the real-world setting are unclear. METHODS: We performed a retrospective multicenter data analysis of patients with decompensated HCV cirrhosis (MELD ≥15) that presented to liver transplant centers that are part of the German Center for Infection Research when highly active DAA therapy was available. Choice of treatment strategy (DAA first vs. transplantation first) was analyzed and correlated with baseline and outcome parameters. RESULTS: Thirty-five patients fulfilled the inclusion criteria and their mean MELD score was 18.5±3.78 (median: 17, interquartile range=16-19). In the majority of patients (85.7%) DAA therapy was initiated before LT; survival rates and change in MELD were numerically better in this group compared with those where DAA therapy was withheld (82.1 vs. 40%, P=0.078; ΔMELD: -2.68±6.2 vs. 5.8±14.4, P=0.157). However, DAA treatment was more often initiated in patients with better liver function (MELD: 18±3.54 vs. 21.8±3.9, P=0.008). Three patients discontinued DAA treatment because of clinical deterioration; these patients all had a MELD score above 20 at the start of therapy. CONCLUSION: At liver transplant centers in Germany DAA before LT is attempted in the majority of cases. It appears to be associated with an improved outcome and seems safe at least in individuals with MELD below or equal to 20.

Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe.

BACKGROUND & AIMS: Antibiotic resistance has been increasingly reported in patients with decompensated cirrhosis in single-center studies. Prospective investigations reporting broad epidemiological data are scarce. We aimed to analyze epidemiological changes in bacterial infections in patients with decompensated cirrhosis. METHODS: This was a prospective evaluation of 2 series of patients hospitalized with decompensated cirrhosis. The Canonic series included 1,146 patients from Northern, Southern and Western Europe in 2011. Data on epidemiology, clinical characteristics of bacterial infections, microbiology and empirical antibiotic schedules were assessed. A second series of 883 patients from Eastern, Southern and Western Europe was investigated between 2017-2018. RESULTS: A total of 455 patients developed 520 infections (39.7%) in the first series, with spontaneous bacterial peritonitis, urinary tract infections and pneumonia the most frequent infections. Nosocomial episodes predominated in this series. Nearly half of the infections were culture-positive, of which 29.2% were caused by multidrug-resistant organisms (MDROs). MDR strains were more frequently isolated in Northern and Western Europe. Extended-spectrum beta-lactamase-producing Enterobacteriaceae were the most frequent MDROs isolated in this series, although prevalence and type differed markedly among countries and centers. Antibiotic resistance was associated with poor prognosis and failure of antibiotic strategies, based on third-generation cephalosporins or quinolones. Nosocomial infection (odds ratio [OR] 2.74; p < 0.001), intensive care unit admission (OR 2.09; p = 0.02), and recent hospitalization (OR 1.93; p = 0.04) were identified as independent predictors of MDR infection. The prevalence of MDROs in the second series (392 infections/284 patients) was 23%; 38% in culture-positive infections. A mild increase in the rate of carbapenem-resistant Enterobacteriaceae was observed in this series. CONCLUSIONS: MDR bacterial infections constitute a prevalent, growing and complex healthcare problem in patients with decompensated cirrhosis and acute-on-chronic liver failure across Europe, negatively impacting on prognosis. Strategies aimed at preventing the spread of antibiotic resistance in cirrhosis should be urgently evaluated. LAY SUMMARY: Infections caused by bacteria resistant to the main antibiotic families are prevalent in patients with cirrhosis. This study demonstrates that this healthcare problem is increasing and extends through all European regions. Infections caused by these difficult to treat bacteria resolve less frequently and often cause the death of the patient. The type of resistant bacteria varies markedly among different hospitals.

Orchestration of Tryptophan-Kynurenine Pathway, Acute Decompensation, and Acute-on-Chronic Liver Failure in Cirrhosis.

Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute-on-chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28-day follow-up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short-term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow-up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow-up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow-up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality.

Glecaprevir/Pibrentasvir in patients with chronic HCV genotype 3 infection: An integrated phase 2/3 analysis.

Glecaprevir coformulated with pibrentasvir (G/P) is approved to treat hepatitis C virus (HCV) infection and was highly efficacious in phase 2 and 3 studies. Treating HCV genotype (GT) 3 infection remains a priority, as these patients are harder to cure and at a greater risk for liver steatosis, fibrosis progression and hepatocellular carcinoma. Data were pooled from five phase 2 or 3 trials that evaluated 8-, 12- and 16-week G/P in patients with chronic HCV GT3 infection. Patients without cirrhosis or with compensated cirrhosis were either treatment-naïve or experienced with interferon- or sofosbuvir-based regimens. Safety and sustained virologic response 12 weeks post-treatment (SVR12) were assessed. The analysis included 693 patients with GT3 infection. SVR12 was achieved by 95% of treatment-naïve patients without cirrhosis receiving 8-week (198/208) and 12-week (280/294) G/P. Treatment-naïve patients with cirrhosis had a 97% (67/69) SVR12 rate with 12-week G/P. Treatment-experienced, noncirrhotic patients had SVR12 rates of 90% (44/49) and 95% (21/22) with 12- and 16-week G/P, respectively; 94% (48/51) of treatment-experienced patients with cirrhosis treated for 16 weeks achieved SVR12. No serious adverse events (AEs) were attributed to G/P; AEs leading to study drug discontinuation were rare (<1%). G/P was well-tolerated and efficacious for patients with chronic HCV GT3 infection, regardless of cirrhosis status or prior treatment experience. Eight- and 12-week durations were efficacious for treatment-naïve patients without cirrhosis and with compensated cirrhosis, respectively; 16-week G/P was efficacious in patients with prior treatment experience irrespective of cirrhosis status.

Vitamin D deficiency is associated with hepatic decompensation and inflammation in patients with liver cirrhosis: A prospective cohort study.

BACKGROUND: Vitamin D is required to maintain the integrity of the intestinal barrier and inhibits inflammatory signaling pathways. OBJECTIVE: Vitamin D deficiency might be involved in cirrhosis-associated systemic inflammation and risk of hepatic decompensation in patients with liver cirrhosis. METHODS: Outpatients of the Hepatology Unit of the University Hospital Frankfurt with advanced liver fibrosis and cirrhosis were prospectively enrolled. 25-hydroxyvitamin D (25(OH)D3) serum concentrations were quantified and associated with markers of systemic inflammation / intestinal bacterial translocation and hepatic decompensation. RESULTS: A total of 338 patients with advanced liver fibrosis or cirrhosis were included. Of those, 51 patients (15%) were hospitalized due to hepatic decompensation during follow-up. Overall, 72 patients (21%) had severe vitamin D deficiency. However, patients receiving vitamin D supplements had significantly higher 25(OH)D3 serum levels compared to patients without supplements (37 ng/mL vs. 16 ng/ml, P<0.0001). Uni- and multivariate analyses revealed an independent association of severe vitamin D deficiency with the risk of hepatic decompensation during follow-up (multivariate P = 0.012; OR = 3.25, 95% CI = 1.30-8.2), together with MELD score, low hemoglobin concentration, low coffee consumption, and presence of diabetes. Of note, serum levels of C-reactive protein, IL-6 and soluble CD14 were significantly higher in patients with versus without severe vitamin D deficiency, and serum levels of soluble CD14 levels declined in patients with de novo supplementation of vitamin D (median 2.15 vs. 1.87 ng/mL, P = 0.002). CONCLUSIONS: In this prospective cohort study, baseline vitamin D levels were inversely associated with liver-cirrhosis related systemic inflammation and the risk of hepatic decompensation.

Effectiveness and Safety of Direct-Acting Antiviral Combination Therapies for Treatment of Hepatitis C Virus in Elderly Patients: Results from the German Hepatitis C Registry.

BACKGROUND: With the aging of the hepatitis C virus (HCV)-infected patient cohort and the availability of highly effective and tolerable treatment regimens, an increasing number of elderly patients are now eligible for HCV therapy. This study investigated clinical and epidemiologic characteristics of elderly HCV-infected patients as well as the effectiveness and safety of available therapies. METHODS: Patients were enrolled into the German Hepatitis C Registry (DHC-R), a prospective, multicenter, real-world cohort study. Patients were treated at the discretion of the physician, and data were collected by a web-based system. RESULTS: Of 7133 patients who initiated treatment, 686 (9.6%) were > 70 years of age. In patients > 70 years, intent-to-treat (ITT) SVR12 was 92.6% (514/555) compared to 90.7% (4521/4985) in patients ≤ 70 years of age. Overall, adverse events (AEs) were reported in 374 (54.5%) and 3435 patients (53.3%) > 70 or ≤ 70 years of age; 7.6% (52) and 3.6% (235) in the respective age groups had a serious AE. Twenty-two (3.2%) and 62 (1.0%) of the patients > 70 or ≤ 70 years discontinued treatment due to AEs. Death was reported in 34 patients, of whom eight were > 70 years of age. Frequent comorbidities in patients > 70 years of age were cardiac disease, renal disease and diabetes. Psychiatric disorders, substance abuse and viral co-infection were more frequent in younger patients. CONCLUSION: Direct-acting antiviral therapies were well tolerated in patients older than 70 years. SVR12 rates in the elderly patient group were similar to those observed in younger patients. Differences in the prevalence of comorbidities between age groups warrant individualized attention with respect to drug-drug interactions and therapy adherence. The study was registered in the German Clinical Trials Register, DRKS-ID: DRKS00009717.

Interferon-free treatment choice according to baseline RASs leads to high SVR rates in HCV genotype 1 infected patients.

AIM: Different combinations of direct antiviral agents (DAA) lead to high SVR rates in HCV genotype 1 infected patients. However, presence of baseline resistance-associated substitutions (RASs) represents a major risk factor for treatment failure. It is unknown whether choice of treatment based on RASs has the potential to decrease virologic failure rates. METHODS: Population-based sequencing of NS3 and NS5A genes was performed in HCV genotype 1 infected patients at a German university hospital. Treatment was individually selected based on resistance analyses. RESULTS: In total, 319 patients (50% treatment-experienced and 30% with cirrhosis) were included. With the treatment choice based on the baseline NS3 and NS5A resistance profile SVR rates between 96 and 100% were observed in all subgroups, including treatment-experienced patients with cirrhosis and HCV genotype 1a infected cirrhotic patients. CONCLUSIONS: The choice of treatment based on the RASs status at baseline may be beneficial for optimizing treatment efficacy in patients with HCV genotype 1 infection and risk factors for treatment failure.

Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.

Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival. PATIENTS: 407 patients with ACLF and 235 patients with acute decompensation (AD). RESULTS: 152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90-day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%). CONCLUSION: Bacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies.

Liver transplantation for chronic hepatitis C virus infection in the United States 2002-2014: An analysis of the UNOS/OPTN registry.

Chronic hepatitis C virus (HCV) infection is a leading cause for orthotopic liver transplantation (OLT) in the U.S. We investigated characteristics of HCV-infected patients registered for OLT, and explored factors associated with mortality. Data were obtained from the United Network for Organ Sharing and Organ Procurement and Transplantation network (UNOS/OPTN) registry. Analyses included 41,157 HCV-mono-infected patients ≥18 years of age listed for cadaveric OLT between February 2002 and June 2014. Characteristics associated with pre- and post-transplant survival and time trends over the study period were determined by logistic and Cox proportional hazard regression analyses and Poisson regressions. Most patients were white (69.1%) and male (70.8%). At waitlist registration, mean age was 54.6 years and mean MELD was 16. HCC was recorded in 26.9% of the records. A total of 51.2% of the patients received an OLT, 21.0% died or were too sick; 15.6% were delisted and 10.4% were still waiting. Factors associated with increased waitlist mortality were older age, female gender, blood type 0, diabetes, no HCC and transplant region (p<0.001). OLT recipient characteristics associated with increased risk for post OLT mortality were female gender, age, diabetes, race (p<0,0001), and allocation MELD (p = 0.005). Donor characteristics associated with waitlist mortality included age, ethnicity (p<0.0001) and diabetes (p<0.03). Waitlist registrations and OLTs for HCC significantly increased from 14.4% to 37.3% and 27.8% to 38.5%, respectively (p<0.0001). Pre- and post-transplant survival depended on a variety of patient-, donor-, and allocation- characteristics of which most remain relevant in the DAA-era. Still, intensified HCV screening strategies and timely and effective treatment of HCV are highly relevant to reduce the burden of HCV-related OLTs in the U.S.

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.