Delayed viral suppression during antiviral therapy is associated with increased hepatocellular carcinoma rates in HBeAg‐positive high viral load chronic hepatitis B

The treatment option in chronic hepatitis B (CHB) patients with persistent low‐level viremia despite entecavir or tenofovir monotherapy is unclear. This study investigated the development of hepatocellular carcinoma (HCC) or cirrhosis in hepatitis B e antigen (HBeAg)‐positive high viral load CHB patients, according to the time needed to achieve complete viral suppression. A total of 325 HBeAg‐positive CHB patients with high viral load who were recently started on antiviral therapy with entecavir or tenofovir were included. The enrolled patients were divided into 2 groups with 4 separate criteria based on the time needed to achieve complete viral suppression: within 1, 2, 3 or 4 years of therapy initiation. The outcomes were development of HCC and cirrhosis. The cumulative incidence of HCC was significantly higher in patients failing complete viral suppression within 1 year (hazard ratio (HR), 4.54; 95% confidence interval (CI), 1.03‐19.93; P = .045) or 2 years (HR, 3.38; 95% CI, 1.24‐9.23; P = .018), than patients who achieved complete viral suppression within 1 or 2 years, respectively. Cumulative incidence of cirrhosis was also significantly higher in patients failing suppression within 1 year (HR, 1.95; 95% CI, 1.04‐3.66; P = .037) or 2 years (HR, 2.44; 95% CI, 1.41‐4.22; P = .001). When the time for achieving viral suppression exceeded 2 years, the cumulative incidence of HCC or cirrhosis was not different regardless of viral suppression. Complete hepatitis B virus suppression within 2 years of antiviral therapy initiation is associated with risk reduction in HCC or cirrhosis development.     

Cumulative incidence and risk factors for the development of hepatocellular carcinoma in patients with chronic hepatitis B who achieved sustained disappearance of viremia by nucleos(t)ide analog treatment

Aim

Nucleos(t)ide analog (NA) therapy has been reported to reduce the risk of hepatocellular carcinoma (HCC). However, some patients who achieve hepatitis B virus (HBV)‐DNA disappearance from serum by NA develop HCC. In this study, we investigated the cumulative incidence and risk factors for HCC in patients with chronic hepatitis B (CHB) who achieved sustained disappearance of viremia by NA treatment.

Methods

A total of 133 CHB patients (median age, 51 years; 79 men [59%]; 28 with cirrhosis [21%]) who received NA therapy and achieved HBV‐DNA disappearance from serum were analyzed retrospectively. We evaluated the cumulative incidence of HCC and risk factors associated with HCC based on data collected at the time of HBV‐DNA disappearance.

Results

Thirteen patients developed HCC during the follow‐up period. The 1‐, 3‐, and 5‐year cumulative incidence of HCC was 0.0%, 7.8%, and 11.1%, respectively. In multivariate analysis, advanced age (hazard ratio [HR], 4.601; 95% confidence interval [CI], 1.220–17.351; P = 0.024), liver cirrhosis (HR, 5.563; 95% CI, 1.438–21.519; P = 0.013), and higher HBV core‐related antigen (HBcrAg) levels (HR, 13.532; 95% CI, 1.683–108.815; P = 0.014) at the time of HBV‐DNA disappearance were significantly associated with the development of HCC.

Conclusion

Our findings indicate the importance of continuous HCC surveillance especially in patients with advanced age, cirrhosis, and/or higher serum levels of HBcrAg, even if they achieve HBV‐DNA disappearance.     

Factors Associated with Progression to Hepatocellular Carcinoma and to Death from Liver Complications in Patients with HBsAg-Positive Cirrhosis

Background and Aims Hepatitis B viral markers and liver tests were used as predictors for development of hepatocellular carcinoma and progression to end-stage liver disease in 128 cirrhosis patients with hepatitis B. Results During a median follow-up of 63.5 months, 28 patients (21.9%) developed HCC and 36 (28.1%) died from non-HCC liver deaths. By multivariate analysis, independent predictors of HCC development and their hazard ratios were high alfa-fetoprotein (HR2.83, 95% CI 1.60–5.00, P = 0.0003), negative HBeAg (HR2.33, 95% CI 1.04–5.29, P = 0.04), and low alanine aminotransferase value (HR1.42, 95% CI 1.08–1.89, P = 0.02). Independent predictors of non-HCC liver deaths were HBeAg positivity (HR3.39, 95% CI 1.16–9.93, P = 0.02), decrease albumin (HR1.61, 95% CI 0.99–2.63, P = 0.05), decrease platelet count (HR2.54, 95% CI 1.03–6.25, P = 0.04), high ALT value (HR1.22, 95% CI 1.03–1.43, P = 0.02), and onset of encephalopathy (HR3.34, 95% CI 1.21–9.27, P = 0.02). Concusions HBeAg negativity, elevated AFP, and low ALT values predicted HCC development, while HBeAg positivity, abnormal liver tests, and low platelet counts identified patients with non-HCC liver deaths.     

Thiazolidinediones reduce the risk of hepatocellular carcinoma and hepatic events in diabetic patients with chronic hepatitis B

Thiazolidinediones (TZDs) improve glycaemic control and ameliorate liver steatosis, inflammation and fibrosis in patients with fatty liver disease. We aimed to study the impact of TZD and glycaemic control on the risk of hepatocellular carcinoma (HCC) and hepatic events in diabetic patients with chronic hepatitis B (CHB). We performed a retrospective cohort study on diabetic patients with CHB in 2000‐2017 using a territory‐wide electronic healthcare database in Hong Kong. Diabetes mellitus was identified by use of any antidiabetic medication, haemoglobin A_1c (HbA_1c) ≥6.5%, fasting glucose ≥7 mmol/L in two measurements or ≥11.1 mmol/L in one measurement and/or diagnosis codes. Use of antidiabetic medications was modelled as time‐dependent covariates. Of 28 999 diabetic patients with CHB, 3963 (13.7%) developed liver‐related events (a composite endpoint of HCC and hepatic events) at a median (interquartile range) follow‐up of 7.1 (3.7‐11.8) years; 1153 patients received TZD during follow‐up. After adjusted for important confounders, TZD use was associated with a reduced risk of liver‐related events (adjusted hazard ratio [aHR] 0.46, 95% confidence interval [CI] 0.24‐0.88; P = .019). Similar trends were observed in HCC (aHR 0.57) and hepatic events (aHR 0.35) separately. Compared to HbA_1c of 6.5% at baseline, patients with HbA_1c ≥7% had an increased risk of liver‐related events; the risk further increased in 5795 (20.0%) patients with HbA_1c ≥9% at baseline (aHR 1.14, 95% CI 1.04‐1.26; P = .006). TZD use is associated with a lower risk of liver‐related events in diabetic patients with CHB. Liver‐related events are more common in patients with high HbA_1c levels.     

Effect of fatty liver and fibrosis on hepatocellular carcinoma development in patients with chronic hepatitis B who received nucleic acid analog therapy

The number of patients with fatty liver has been increasing worldwide; however, the significance of fatty liver in patients with chronic hepatitis B who are receiving nucleic acid analog (NA) therapy remains unclear. Thus, we aimed to determine whether fatty liver affects the development of hepatocellular carcinoma (HCC) in patients receiving NA therapy. This study included 445 patients who received NA therapy, and the development of HCC was investigated. The primary outcome was the association between fatty liver and HCC development. During a mean follow-up period of 7.4 years, 46 patients (10.3%) developed HCC. No significant difference in the cumulative incidence of HCC was observed between patients with fatty liver and those without (p = 0.17). Multivariable analysis for age, gender, platelet count, alanine aminotransferase level at 1 year following NA therapy, and fatty liver revealed that the presence of fatty liver was not a significant factor for HCC development (hazard ratio [HR]: 0.96, 95% confidence interval [CI]: 0.5–1.9). In another multivariable analysis for advanced fibrosis, gender, and fatty liver, advanced fibrosis was found to be a significant factor for HCC development (HR: 9.50, 95% CI: 5.1–18) but not fatty liver (HR: 0.90, 95% CI: 0.5–1.7). In conclusion, in patients with chronic hepatitis B who received NA therapy, advanced fibrosis was found to be an important risk factor for HCC development but not fatty liver, suggesting the importance of providing treatment before the progression of liver fibrosis regardless of the presence of fatty liver.     

Prevalence and risk factors for viral blipping in chronic hepatitis B patients treated with nucleos (t) ide analogues

The clinical relevance of viral blipping during nucleos (t) ide analogue (NA) treatment is unclear in chronic hepatitis B (CHB). We investigated the prevalence, risk factors and clinical outcomes for those with viral blipping during NA treatment. A retrospective cohort study investigated consecutively treated CHB patients from May 2008 to February 2015 on the NAs such as entecavir (ETV), tenofovir (TDF) and lamivudine (LAM). Included patients were previously treatment naive. Viral blipping was defined as serum HBV DNA >20 IU/mL on one occasion, and not >200 IU/mL, with subsequent measurement returning to undetectable levels, that is <20 IU/mL. A total of 242 treatment‐compliant CHB patients were included with 44 (18.2%) experiencing viral blipping. In multivariable Cox regression, Asian race (HR=7.40, 95% CI 1.01–54.29, P<.049), LAM therapy (vs ETV/TDF, HR=2.53, 95% CI 1.29–4.95, P<.007), higher creatinine (per SD, HR=1.47, 95% CI 1.21–1.79, P<.001), HBeAg positivity (HR=2.68, 95% CI 1.39–5.03, P<.003) and longer time to achieve undetectable HBV DNA (per month, HR=1.05, 95% CI 1.02–1.08, P=.001) were associated with an increased risk of viral blipping. Viral blipping did not show any significant association with viral breakthrough, HBsAg loss, ALT flares or disease progression. Viral blipping is a frequent event during NA therapy; however, it did not lead to any clinically significant outcomes. Thus, it may not require more frequent blood work and patient visits in clinical practice.     

Use of cyclooxygenase inhibitor and the risk of hepatocellular carcinoma in patients with chronic hepatitis B: A nested case‐control study using a nationwide population‐based data

The study aimed to investigate the relationship between the use of COX inhibitors and the risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB) using a nationwide population‐based data. A nested case‐control study was conducted using the National Health Insurance Service–National Sample Cohort (NHIS‐NSC) from 2002 to 2013 in Korea. We compared the use of COX inhibitors between HCC cases and matched controls by categorizing 5 groups according to the cumulative defined daily dose (cDDD, <28, 28‐90, 91‐180, 181‐360, and >360) adjusting the use of antiviral agents. A total of 4980 patients with CHB were analysed as 996 HCC cases and 3984 matched controls. The number of COX inhibitor users (≥28 cDDD) was 358 patients (36%) and 1814 patients (45%) in the HCC group and control group, respectively. The use of COX inhibitors was significantly associated with a decreased risk of HCC development compared with nonusers (adjusted odds ratio [OR] 0.62, 95% confidence interval [CI] 0.52‐0.73, P < .001). There was a dose‐dependent inverse relationship between the use of COX inhibitors and the risk of HCC. The adjusted ORs were 0.75 (95% CI: 0.63‐0.90), 0.41 (95% CI: 0.31‐0.56), 0.38 (95% CI: 0.25‐0.57) and 0.49 (95% CI: 0.31‐0.79) for the 28‐90, 91‐180, 181‐360 and >360 cDDDs, respectively (P < .01). In conclusion, the use of COX inhibitors was associated with a reduced risk of HCC in CHB. COX inhibitor may have a chemopreventive role in HCC development in patients with chronic liver disease.     

Systematic review and meta‐analysis: Development of hepatocellular carcinoma in chronic hepatitis B patients with hepatitis e antigen seroconversion

Hepatitis B e antigen (HBeAg) seroconversion is considered to have significantly favourable clinical outcomes for patients with chronic hepatitis B (CHB). However, inconsistent study results suggest that hepatocellular carcinoma (HCC) still occurs in patients with HBeAg seroconversion. We performed a systematic review and meta‐analysis to determine the incidence of HCC in patients with CHB after HBeAg seroconversion. Web of Science, PubMed and Embase databases were searched through January 2017. The incidence of HCC in CHB patients after HBeAg seroconversion was pooled using a random‐effects model or fix‐effects model. Sixteen studies were finally included, involving 4910 patients with HBeAg seroconversion. The overall pooled proportion suggested that 3.33% (95% confidence interval (CI): 2.28%‐4.58%) of patients with CHB develop HCC despite HBeAg seroconversion. In patients with HBeAg seroconversion without cirrhosis, the pooled proportion of HCC development was 0.94% (95% CI: 0.15%‐2.4%). Moreover, patients with cirrhosis, active hepatitis, or aged greater than 40 years at the time of HBeAg seroconversion were at significantly higher risk for HCC development. HBeAg seroconversion was significantly associated with a reduced risk of HCC compared with persistently positive HBeAg (RR = 0.58, 95% CI: 0.35‐0.97, P = .04). Despite the reduced risk with HBeAg seroconversion, HCC can still occur in a proportion of patients with CHB after HBeAg seroconversion. Long‐term monitoring is needed for patients with established cirrhosis, active hepatitis or those older than 40 years at the time of HBeAg seroconversion.     

Predictive score for hepatocellular carcinoma after hepatitis B e antigen loss in patients treated with entecavir or tenofovir

The risk of developing hepatocellular carcinoma (HCC) after hepatitis B e antigen seroclearance (ESC) remains unclear. We established and validated a new risk prediction model for HCC development after ESC in patients with chronic hepatitis B (CHB) receiving antiviral therapy (AVT). Between 2006 and 2016, 769 patients (training cohort) and 1,061 patients (validation cohort) with CHB who experienced ESC during AVT using entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were recruited. In the multivariate analysis, male sex (hazard ratio [HR] = 2.092; 95% confidence interval [CI] = 1.152‐3.800), cirrhosis (HR = 5.141; 95% CI = 2.367‐11.167) and fibrosis‐4 index (FIB‐4) of >3.25 (HR = 2.070; 95% CI = 1.184‐3.620) were the independent risk factors for HCC development (all P < .05). Accordingly, a novel HCC‐ESC_AVT model was developed (1x[sex: male = 1, female = 0] + 3x(cirrhosis = 1, noncirrhosis = 0) + 1x(FIB‐4: >3.25 = 1, ≤3.25 = 0). The cumulative risk for HCC development was significantly different among the risk groups based on the HCC‐ESC_AVT category (0‐1, 2‐4 and 5 for the low‐, intermediate‐ and high‐risk groups, respectively) (overall P < .001, log‐rank test). The area under the receiver operating characteristic curve (AUC) for predicting HCC development 3, 5 and 10 years after ESC was 0.791, 0.771 and 0.790, respectively (all P < .05). The predictive value of the HCC‐ESC_AVT model was similar in the validation cohort (AUC = 0.802, 0.774 and 0.776 at 3, 5 and 10 years, respectively; all P < .05). Hence, we have developed and validated a new HCC‐ESC_AVT model for HCC development, which includes male sex, cirrhosis and FIB‐4 of >3.25 as constituent variables.     

Early steep decline of liver stiffness predicts histological reversal of fibrosis in chronic hepatitis B patients treated with entecavir

It is unknown whether dynamic changes of liver stiffness measurement (LSM) can predict the reversibility of fibrosis. Therefore, we evaluated the utility of LSM changes in predicting histological changes of fibrosis in patients with chronic hepatitis B (CHB) on antiviral therapy. In a prospective cohort of CHB patients treated with entecavir, virological measurement and biochemical measurement along with LSM were measured at baseline and every 6 months. Liver biopsies were conducted at baseline and month 18 of treatment. Fibrosis regression was defined by the following two criteria: (a) Ishak score decrease ≥1 stage, (b) Ishak score decrease ≥1 stage or predominantly regressive by post‐treatment PIR classification. The dynamic changes of LSM and its predictive value for histological reversibility were evaluated with piecewise linear mixed‐effects model and ROC analysis. We found that at month 18 of antiviral therapy, liver fibrosis was reserved in 86 of 212 (40.6%) CHB patients by Ishak reversal criterion. Overall, a decline in LSM was associated with attenuation of Ishak score. The rate of LSM decline in the first 6 months was significantly faster in patients with fibrosis reversal (ΔLSM%_Ishak = ?2.19%/month, P = 0.0025; ΔLSM%_Ishak/PIR = ?2.56%/month, P = 0.0004). The predictive model based on baseline FIB‐4 and Ishak score as well as baseline LSM, PLT, albumin and their changes during the first 6 months could predict histological reversal (AUROC_Ishak = 0.74, 95% CI: 0.67‐0.80; AUROC_Ishak/PIR = 0.81, 95% CI: 0.74‐0.87). We conclude that in CHB patients, changes in LSM during the first 6 months of entecavir therapy can predict histological reversibility of liver fibrosis at month 18 of antiviral therapy.     

TLL1 variants do not predict hepatocellular carcinoma development in HCV cirrhotic patients treated with direct‐acting antivirals

Tolloid‐like 1 gene (TLL1) variant rs17047200 has been associated with hepatocellular carcinoma (HCC) in Japanese hepatitis C virus (HCV) patients with sustained virological response (SVR) to interferon or direct‐acting antiviral (DAA)‐based regimens. We investigated whether this holds true also in Caucasian cirrhotic patients cured by DAAs. Consecutive Caucasian HCV cirrhotics receiving DAA between December 2014 and December 2016 in a single centre were enrolled. Cirrhosis was defined histologically (METAVIR F4) or by liver stiffness measurement (LSM > 11.9 kPa). TLL1 rs17047200 was analysed by TaqMan SNP genotyping assay. 452 patients were enrolled: median age 63 (28‐87) years, 58% males, 47% HCV‐1b, LSM 19.1 (12.0‐75.0) kPa and Fibrosis‐4 (FIB‐4) score 4.9 (0.3‐46.0). 96% patients achieved an SVR. TLL1 genotype was AA in 329 (73%) and AT/TT in 123 (27%) (MAF = 0.14, HWE P > 0.05). Patients’ clinical features were similar across TLL1 genotypes. After 33 (3‐47) months from DAA start, 31 patients developed HCC, with a 3‐year estimated cumulative probability being 7.5% (95% CI: 5%‐10%). The cumulative incidence of HCC was 9% in TLL1 AA vs 7% in AT/TT patients (P = 0.55). Male sex (HR: 3.78, 95% CI: 1.4‐10.1, P = 0.008), diabetes (HR: 3.5, 95% CI: 1.68‐7.27, P = 0.001) and FIB‐4 (HR: 1.09, 95% CI: 1.03‐1.14, P = 0.001) were baseline‐independent predictors of HCC. The incidence of HCC was not influenced by TLL1 genotypes even when considering an additional group of 348 noncirrhotic patients, being 2% in AA vs 1% AT/TT patients (P = 0.58). In a large cohort of Caucasian HCV cirrhotics treated with DAA, TLL1 variants do not predict HCC development.     

Validation of risk prediction scores for hepatocellular carcinoma in patients with chronic hepatitis B treated with entecavir or tenofovir

Several prediction scores for the early detection of hepatocellular carcinoma (HCC) are available. We validated the predictive accuracy of age, albumin, sex, liver cirrhosis (AASL), RESCUE‐B, PAGE‐B and modified PAGE‐B (mPAGE‐B) scores in chronic hepatitis B (CHB) patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF). Between 2007 and 2014, 3171 patients were recruited (1645, ETV; 1517, TDF). The predictive accuracy of each prediction score was assessed. The mean age of the study population (1977 men; 1194 women) was 48.8 years. Liver cirrhosis was present in 1040 (32.8%) patients. During follow‐up (median, 58.2 months), 280 (8.8%) patients developed HCC; these patients were significantly older; more likely to be male; had significantly higher proportions of liver cirrhosis, hypertension and diabetes; and had significantly higher values for the four risk scores than those who did not develop HCC (all P < .05). Older age (hazard ratio [HR] = 1.048), male sex (HR = 2.142), liver cirrhosis (HR = 3.144) and prolonged prothrombin time (HR = 2.589) were independently associated with an increased risk of HCC (all P < .05), whereas a higher platelet count (HR = 0.996) was independently associated with a decreased risk of HCC (P < .05). The predictive accuracy of AASL score was the highest for 3‐ and 5‐year HCC predictions (areas under the curve [AUCs] = 0.818 and 0.816, respectively), followed by RESCUE‐B, PAGE‐B and mPAGE‐B scores (AUC = 0.780‐0.815 and 0.769‐0.814, respectively). In conclusion, four HCC prediction scores were assessed in Korean CHB patients treated with ETV or TDF. The AASL score showed the highest predictive accuracy.     

Association of suppressor of cytokine signalling 3 polymorphisms with insulin resistance in patients with chronic hepatitis C

Suppressor of cytokine signalling 3 is thought to be associated with insulin resistance in patients with chronic hepatitis C. We evaluated the role of suppressor of cytokine signalling 3 polymorphisms in determining insulin resistance in patients with chronic hepatitis C. Two hundred and ninety untreated hepatitis C virus‐infected patients without diabetes and cirrhosis were genotyped for the SNPs rs4969168, rs4969170 and rs12952093 of suppressor of cytokine signalling 3 using the TaqMan Genotyping Assay. We found that the rs4969170 AA genotype and rs4969170 A allele frequency were significantly more common in the insulin‐resistant group than the non‐insulin‐resistant group (89.5% vs 76.1%, OR = 2.693, 95% CI: 1.221‐5.939, P = 0.012 and 94.8% vs 88.0%, OR = 2.463, 95% CI: 1.151–5.271, P = 0.017, respectively). Haplotype G‐C was likely associated with non‐insulin resistance (adjusted P = 0.011). Multiple logistic regression analysis indicates that the independent risk factors for insulin resistance are the SNP rs4969170 AA genotype (OR = 3.005, 95% CI: 1.194–7.560, P = 0.019), HCV genotype 1 (OR = 2.524, 95% CI: 1.099–5.794, P = 0.029) and BMI (OR = 0.514, 95% CI: 0.265–0.999, P = 0.05).     

A novel index using routine clinical parameters for predicting significant liver inflammation in chronic hepatitis B

Identifying the degree of liver inflammation is critical for therapeutic judgement of patients with chronic hepatitis B (CHB). However, we lack indexes which can accurately predict significant liver inflammation in patients with CHB. This study aimed to develop a simple predictive index for liver inflammation in CHB using routine clinical parameters. A total of 519 patients with CHB who underwent liver biopsy were enrolled and randomly divided into training (n = 346) and validation cohorts (n = 173). Based on routine clinical parameters, gamma‐glutamyl transpeptidase (GGT; P = 0.031) and platelets (PLT; P < 0.001) were identified as independent predictors of significant inflammation by multivariable analysis in the training cohort. Accordingly, the GGT to PLT ratio (GPR) was developed to amplify the opposing effects for predicting liver inflammation. In the training cohort, the AUCs of GPR in predicting significant inflammation were 0.791 (95% CI: 0.742‐0.839), 0.783 (95% CI: 0.717‐0.849) and 0.791 (95% CI: 0.716‐0.867) in the entire patients with CHB, HBeAg‐positive CHB patients and HBeAg‐negative CHB patients, respectively. The diagnostic performance of GPR for significant inflammation was significantly superior to that of alanine aminotransferase (ALT), aspartate transaminase (AST) and GGT in all patients with CHB and HBeAg‐positive CHB patients, but was comparable with ALT, AST and GGT in HBeAg‐negative CHB patients. In the validation cohort, the diagnostic performance of GPR in assessing significant liver inflammation was also superior to other indexes in all patients with CHB and HBeAg‐positive CHB patients, but was comparable with GGT in HBeAg‐negative CHB patients. Thus, GPR can be a novel and simple index for predicting significant liver inflammation in CHB, especially for HBeAg‐positive CHB.     

Influence of hepatitis B virus reactivation on the recurrence of HBV‐related hepatocellular carcinoma after curative resection in patients with low viral load

It is unclear whether the reactivation of hepatitis B virus (HBV) influences the prognosis of hepatocellular carcinoma (HCC) after resection in patients with chronic hepatitis B. The aim of this study was to identify the influence of HBV reactivation on the recurrence of hepatitis B‐related HCC after curative resection in patients with low viral load (HBV DNA <2000 IU/mL). We retrospectively analysed a total of 130 patients who underwent curative resection for HBV‐related early stage HCC (single nodule; <5 cm/two or three nodules; <3 cm) with pre‐operative HBV DNA levels <2000 IU/mL with serial HBV DNA tests. The predictive factors including HBV reactivation for the recurrence of HBV‐related HCC after curative resection were investigated. Fifty‐three patients (41%) had HBV reactivation after resection among 130 patients. HBV reactivation was observed in 22 of 53 patients with undetectable baseline HBV DNA and in 31 of 77 patients with detectable baseline HBV DNA. Cumulative recurrence rates after resection at 1, 2 and 3 years were 17.0%, 23.3% and 31.4%, respectively. The multivariable analysis demonstrated that the risk factors for the recurrence were the presence of microvascular invasion (hazard ratio (HR) 2.62, P = 0.003), multinodularity (HR 4.61, P = 0.005), HBV reactivation after resection (HR 2.03, P = 0.032) and HBeAg positivity (HR 2.06, P = 0.044). HBV reactivation after curative resection is associated with the recurrence of HBV‐related HCC in patients with low viral load.     

Higher risk of hepatocellular carcinoma in chronic hepatitis B vs chronic hepatitis C after achievement of virologic response

It is unclear whether the achievement of virologic response modifies the risk of hepatocellular carcinoma (HCC) differently in chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Our aim was to compare the risk of HCC between patients with CHB and CHC who achieved virological response. We analysed data from patients with CHB treated with entecavir (n=2000) or CHC treated with peg‐interferon and ribavirin (n=733) at a tertiary hospital from 2004 to 2011. Virological response was defined as serum HBV DNA<15 IU/mL at 1 year of treatment for CHB or the achievement of sustained virologic response for CHC. Virological response was achieved in 1520 patients with CHB (76.0%) and 475 patients with CHC (64.8%). During the median follow‐up period of 6 years, 228 patients with CHB (11.4%) and 59 patients with CHC (8.0%) developed HCC. Among patients with virological response, CHB was independently associated with a significantly higher incidence of HCC (hazard ratio, 2.17; 95% CI, 1.30‐3.63; P=.003) than CHC. Among patients without virological response, there were no differences in HCC incidence between the two cohorts (P=.52). In patients with cirrhosis at baseline, the incidence of HCC did not differ between the two cohorts even after achieving virological response (P>.99). In conclusion, patients with CHB treated with entecavir were associated with a higher risk of HCC compared to patients with CHC treated with peg‐interferon and ribavirin after achieving virological response. However, the risk of HCC did not differ between the two cohorts if the patients had cirrhosis at baseline, even if virological response was achieved.     

Hepatocellular carcinoma risk in HBeAg‐negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet.Greece cohort

Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients treated with lamivudine. Whether HCC rates are comparable in patients treated with the current first‐line antivirals remains uncertain. We estimated the incidence and evaluated predictors of HCC in a large nationwide prospective cohort (HepNet.Greece) of HBeAg‐negative CHB patients treated with entecavir. HBeAg‐negative CHB patients from the same cohort who were initially treated with lamivudine were used as controls. We included 321 patients treated with entecavir for a median of 40 months and 818 patients treated initially with lamivudine for a median of 60 months. In the entecavir group, HCC developed in 4 of 321 (1.2%) patients at a median of 1.5 (range: 1.0–4.5) years, while the cumulative HCC incidence was significantly higher in cirrhotics than noncirrhotics (1, 3, 5 years: 0%, 3%, 9% vs 1%, 1%, 1%; P = 0.024) and in older patients (P = 0.026). Entecavir compared with lamivudine group patients had lower HCC incidence (1, 3, 5 years: 0.3%, 1.2%, 2.8% vs 0.7%, 3.8%, 5.6%; P = 0.024). However, in multivariable Cox regression analysis, the HCC risk was independently associated with older age (P < 0.001), male gender (P = 0.011) and cirrhosis (P = 0.025), but not with the initial agent. In conclusion , our large nationwide study indicates that the HCC risk remains increased in entecavir‐treated HBeAg‐negative CHB patients with cirrhosis, particularly of older age, at least for the first 5 years. The HCC risk does not seem to be significantly reduced with entecavir compared with antiviral therapy starting with lamivudine.     

Expression level of glutamine synthetase is increased in hepatocellular carcinoma and liver tissue with cirrhosis and chronic hepatitis B

Studies have suggested that glutamine synthetase (GS) is a potential marker of hepatocellular carcinoma (HCC). We aimed to evaluate the expression of GS in non-malignant liver tissue and serum GS levels in HCC, liver cirrhosis (LC), chronic hepatitis B (CHB), five kinds of extrahepatic diseases patients and healthy subjects. Immunohistochemistry (IHC) was used to assess GS expression in 260 liver tissue samples (from 120 HCC, 90 CHB stage 4, and 50 CHB stage 1–3 patients). Enzyme-linked immunosorbent assays of 325 samples (from 100 healthy donors, 33 CHB stage 1–3, 43 CHB stage 4, 111 HCC, and 45 extrahepatic diseases patients) were used to further analyze GS levels in serum. IHC studies showed the expression of GS in 70% of HCC patients, 46.7% of CHB stage 4 patients and 38% of CHB stage 1–3 patients. The χ² tests showed significant difference between HCC samples and non-tumor tissues (P = 0.001 for HCC vs. CHB stage 4, P = 0.000 for HCC vs. CHB). Consistent with this, serum GS levels are increased in HCC and CHB stage 1–4 patients. There are significant differences among all samples (P = 0.000 for all), except CHB stage 1–3 versus CHB stage 4 (P = 0.552). Based on multiple linear regressions, HCC, CHB stage 1–4 and AFP were significantly associated with serum GS levels. In addition, in HCC group, TNM and Child-Pugh were significantly associated with GS levels. Expression of GS is increased in HCC, LC, and CHB. It may be a new serum marker for liver disease.