Savvoula Savvidou

Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir

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.

Low serum adiponectin levels are predictive of advanced hepatic fibrosis in patients with NAFLD.

Background Adiponectin, an adipocytokine-mediating insulin action, has recently been found to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to assess possible associations between serum adiponectin levels and factors of the metabolic syndrome or histologic parameters in biopsy-proven NAFLD. Methods Patients with persistently abnormal liver function tests satisfying inclusion criteria were subjected to liver biopsy. Fibrosis stage and the NAFLD activity score were recorded for each patient. Body mass index, waist-to-hip ratio, factors of the metabolic syndrome (central obesity, hyperglycemia, hypertriglyceridemia, low high-density lipoprotein, and hypertension), and biochemical tests were also recorded. Insulin resistance was calculated by the homeostasis model assessment method. Serum adiponectin concentration was measured by an enzyme-linked immunosorbent assay. Results Forty-two NAFLD patients, including 9 with compensated cirrhosis, were included in the study. The presence of each factor of the metabolic syndrome was associated with hypoadiponectinemia. Adiponectin negatively correlated with homeostasis model assessment (r=−0.551, P=0.001). Adiponectin concentration was negatively associated with higher stages of fibrosis (one-wayanalysis of variance, P=0.007), and was not associated with NAFLD activity score. Using multivariate logistic regression, adiponectin concentration, aspartate aminotransferase/alanine aminotransferase ratio, and the presence of waist-to-hip ratio >1 were independent predictors of advanced fibrosis. The receiver operating characteristic curve for detecting advanced fibrosis using a combination of the independent variables had an area under the curve of 0.902±0.054, P<0.0001. Conclusions Low serum adiponectin levels in NAFLD patients are suggestive of advanced fibrosis. Therefore, assessment of serum adiponectin levels may be useful in clinical follow-up.

The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B

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).

P1075 PAGE-B: RISK SCORE FOR HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT IN CAUCASIAN CHRONIC HEPATITIS B (CHB) PATIENTS RECEIVING ENTECAVIR (ETV) OR TENOFOVIR (TDF)

Area under receiver operating characteristics curve (AUC) showed that HBsAg 360 IU/mL at 6 month was predictive for its clearances at EOT (PPV 86.2%, specificity 83.5%), and 10 IU/mL at 12 months was a guide to prolonged treatment (PPV 85.7%, specificity 91.4%). During follow-up, 14 of 50 patients with HBsAg clearance (28.0%) had HBsAg reversion. Among them, only three patients developed mild hepatitis, whereas convalescent status was stable in most of them. Conclusions: On-treatment HBsAg monitoring could be used to tailor the regimen and improve the HBsAg response. HBsAg seroreversion may occur even in patients with pegIFNa2a-induced HBsAg clearance.

Circulating adiponectin levels in type 2 diabetes mellitus patients with or without non-alcoholic fatty liver disease: Results of a small, open-label, randomized controlled intervention trial in a subgroup receiving short-term exenatide.

AIM Diabetes mellitus type 2 (DMT2) and non-alcoholic fatty liver disease (NAFLD) are both characterized by decreased circulating adiponectin. Recently, glucagon-like peptide-1 receptor agonists have been shown to induce adiponectins expression. However, their interaction on clinical grounds needs to be further elucidated. METHODS DMT2 patients with abnormal aminotransferases were screened for NAFLD and subjected to liver biopsy (group A, n=17). A subgroup of patients (n=110), after assessed for eligibility criteria, was blindly randomized to receive either 6-month exenatide supplementation on glargine insulin (group B) or intense, self-regulated, insulin therapy alone (group C). RESULTS Baseline patient characteristics: 49(38.6%) males, aged 63.1 ± 7.5 years-old, BMI 32.9 ± 4.9 kg/m(2), HbA1c 8.1 ± 1.2% (65 ± 14 mmol/mol), median ALT 23 U/L (range 5-126), AST 20 U/L (7-72). Group A had biopsy-proven NAFLD with a median Activity Score of 5 and fibrosis stage 3. Presence of NAFLD was accompanied by a significant decline in adiponectin (p<0.001), which was negatively correlated with the degree of ALT in all groups (Spearmans correlation, rs=-0.644, p<0.001). In the subgroup intervention trial, adiponectin was significantly raised in both groups B and C (t-Student for paired samples, p=0.001) by Δ=+24.2% (interquartile range 14.8-53.2%). This elevation was not associated with the type of intervention but with weight loss, glycemic control and reduction of C-reactive protein (one-way ANCOVA). CONCLUSION Supplementation of exenatide to glargine insulin compared to standard insulin was: (i) effective in inducing weight loss, (ii) non-inferior in lowering HbA1c and (iii) non-inferior in increasing circulating adiponectin. Higher adiponectin was associated with lower ALT, suggesting a hepato-protective role for this cytokine.

Eight-year survival in chronic hepatitis B patients under long-term entecavir or tenofovir therapy is similar to the general population

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.

A 60-year-old man with fever, cholestasis and granulomatous hepatitis

investigation is shown in Table 1. Serologictesting for viral hepatitis (hepatitis viruses A, B and C,Epstein-Barr virus, cytomegalovirus, herpes simplex virusand human immunodeficiency virus) was found negative.A high titre of anti-nuclear antibodies (ANA) 1:640, finespeckled was detected, while total immunoglobulins werewithin normal range. Anti-mitochondrial, anti-neutrophilcytoplasmic and anti-dsDNA autoantibodies were all nega-tive. The patient was subjected to chest X-ray, whole bodyimaging with computed tomography, magnetic resonance