Clinical, biochemical, immunological and virological profiles of, and differential diagnosis between, patients with acute hepatitis B and chronic hepatitis B with acute flare

Background and Aim: In areas with high or intermediate endemicity for chronic hepatitis B virus (HBV) infection, it is difficult to distinguish acute hepatitis B (AHB) from chronic hepatitis B with an acute flare (CHB‐AF) in patients whose prior history of HBV infection has been unknown. The present study aimed to screen laboratory parameters other than immunoglobulin M antibody to hepatitis B core antigen (IgM anti‐HBc) to discriminate between the two conditions. Methods: A retrospective and prospective study was conducted in patients first presenting clinically as HBV‐related acute hepatitis to sort out acute self‐limited hepatitis B (ASL‐HB). Then, clinical and laboratory profiles were compared between patients with ASL‐HB and CHB‐AF. Parameters closely associated with ASL‐HB were chosen to evaluate sensitivity, specificity, accuracy, positive predictive values and negative predictive values for diagnosing AHB. Results: There were significant differences between patients with ASL‐HB and CHB‐AF in relation to clinical and laboratory aspects, with many outstanding differences in levels of serum HBV‐DNA, hepatitis B e antigen (HBeAg) and alpha‐fetoprotein (AFP) as well as IgM anti‐HBc. In particular, there was a greater difference between the two groups in low levels of HBeAg (ratio of the optical density of the sample to the cut‐off value [S/CO] <20) than in negativity for HBeAg (42.7% and 13.5% vs 49.3% and 45.9%). 1:10 000 IgM anti‐HBc had a sensitivity and specificity of 96.2% and 93.1%, respectively, for predicting ASL‐HB. Combining it with AFP, HBeAg or HBV‐DNA could improve diagnostic power. A combination of IgM anti‐HBc, HBV‐DNA and HBeAg had a predictive value of 98.9% and a negative predictive value of 100.0%, similar to that of a combination of IgM anti‐HBc and HBV‐DNA. Adding AFP to the combinations of IgM anti‐HBc and HBV‐DNA or HBeAg could further heighten the positive predictive value. The positive predictive value and negative predictive value of the combination of IgM anti‐HBc, HBV‐DNA and AFP were both 100.0%. Conclusions: (i) There are significant differences with respect to clinical, biochemical, immunological and virological aspects between ASL‐HB and CHB‐AF. (ii) Of several diagnostic combinations, IgM anti‐HBc jointing HBV‐DNA is most effective and most practicable in distinguishing ASL‐HB from CHB‐AF. (iii) A low HBeAg level is more useful than negative HBeAg in differential diagnosis between ASL‐HB and CHB‐AF. (iv) In those patients with a high level of IgM anti‐HBc, serum AFP level >10× upper reference limit could rule out a probability of ASL‐HB.     

Suppressive effects of entecavir on hepatitis B virus and hepatocellular carcinoma

Background and Aim: We investigated the efficacy and effectiveness of entecavir in hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) patients. Methods: We enrolled 231 nucleoside‐naïve chronic hepatitis B (CHB) patients primarily treated with entecavir 0.5 mg/day for at least 6 months in our institution. Of these, 71 patients had HCC at the start of entecavir treatment (HCC group) and 160 did not (non‐HCC group). We compared antiviral responses to entecavir in the two groups, and evaluated the effects of entecavir on the clinical outcomes of curatively‐treated HCC patients. Results: The HCC and non‐HCC groups had similar cumulative rates of HBV‐DNA negativity, alanine aminotransferase normalization, and hepatitis e antigen loss in year 2 (100% vs 95.4%, 94.7% vs 97.3%, and 40.8% vs 41.8%, respectively; P > 0.05). Entecavir treatment for 12 months decreased mean Model for End‐Stage Liver Disease scores in patients with cirrhosis and HCC (7.2 vs 5.6, P < 0.001). Of the 71 HCC patients, 16 underwent curative therapies concurrently with entecavir; hepatectomy in six and radiofrequency ablation in 10, and the 55 remaining patients received transarterial chemoembolization or conservative treatment. In a subgroup of 16 HCC patients receiving curative treatments, patients who became serum HBV DNA negative by week 24 had better overall survival (P = 0.039), but not recurrence‐free survival (P = 0.961), than those who did not. Conclusions: First‐line entecavir monotherapy is comparably effective in CHB patients with and without HCC, and improves hepatic function in HBV‐related HCC patients. An early virological response to entecavir is prognostic of improved survival following curative therapy against HBV‐related HCC.     

Impact of viral hepatitis aetiology on survival outcomes in hepatocellular carcinoma: A large multicentre cohort study

While HBV and HCV are risk factors for HCC, uncertainty exists as to whether these viral infections have prognostic significance in HCC. Thus, we compared the overall survival of patients with HBV, HCV and nonviral HCC, and evaluated whether the presence of HBV and HCV predicts patient outcomes. We conducted a multicentre study of HCC cases diagnosed at six Melbourne tertiary hospitals between Jan 2000‐Dec 2014. Patient demographics, liver disease and tumour characteristics and patient outcomes were obtained from hospital databases, computer records and the Victorian Death Registry. Survival outcomes were compared between HBV, HCV and nonviral hepatitis cases and predictors of survival determined using Cox proportional hazards regression. There were 1436 new HCC cases identified including 776 due to viral hepatitis (HBV 235, HCV 511, HBV‐HCV 30) and 660 from nonviral causes. The median survival of HBV, HCV and nonviral HCC patients was 59.1, 28.4 and 20.9 months, respectively (P<.0001). On multivariate analysis, independent risk factors for survival included HCC aetiology, gender, BCLC stage, serum AFP, total number and size of lesions, and serum creatinine and albumin. After adjusting for these and method of detection, HBV remained an independent predictor of improved overall survival when compared to both nonviral (HR 0.60%, 95% CI 0.35‐0.98; P=.03) and HCV‐related HCC (HR 0.51%, 95% CI 0.30‐0.85; P=.01). In this large multicentre study, HBV is independently associated with improved overall survival compared with HCV and nonviral‐related HCC. Further studies are needed to determine the underlying factor(s) responsible.     

Effects of hepatitis B e‐antigen on recurrence of hepatitis B‐related hepatocellular carcinoma after curative resection: A meta‐analysis

Aim: The impact of hepatitis B e‐antigen (HBeAg) on recurrence of hepatocellular carcinoma (HCC) after curative resection remains controversial. This meta‐analysis aimed to determine whether the presence of HBeAg influenced the recurrence of HCC after curative resection. Methods: We performed a meta‐analysis including six studies (a total of 865 patients) to assess the effect of HBeAg on recurrence of HCC after curative resection. The pooled odds ratios (OR) were calculated using a random or fixed effects model. PUBMED, MEDLINE, EMBASE and the Cochrane Database were searched for articles published from 1990 to March 2012. Sensitivity analysis and publication bias estimate were also performed to evaluate the potential risk bias in the overall results of pooled analysis. Results: Our results showed that the presence of HBeAg significantly increased the overall HCC recurrence risk after curative resection (OR = 1.63, 95% confidence interval (CI) = 1.11–2.40; P = 0.01). Pooled data from three studies on the risk of early recurrence among HBeAg positive patients compared with HBeAg negative patients showed an increased risk of early recurrence (OR = 1.50, 95% CI = 1.02–2.19; P = 0.04). However, there was no significant difference in late HCC recurrence between HBeAg positive and negative patients (OR = 1.17, 95% CI = 0.62–2.19; P = 0.62). Conclusion: The present study suggested that HBeAg positive patients had a significantly higher risk of early recurrence after curative resection of HCC.     

Comparison between quantitative hepatitis B surface antigen,hepatitis B e‐antigen and hepatitis B virus DNA levels for predicting virological response to pegylated interferon‐α‐2b therapy in hepatitis B e‐antigen‐positive chronic hepatitis B

Aim: The aim of this study was to compare the clinical applicability of quantitative serum hepatitis B surface antigen (HBsAg), hepatitis B e‐antigen (HBeAg) and hepatitis B virus (HBV) DNA for predicting virological response (VR) to pegylated interferon (PEG‐IFN) therapy. Methods: Thirty HBeAg‐positive chronic hepatitis B patients who received PEG‐IFN‐α‐2b for 48 weeks were enrolled. Quantitative HBsAg, HBeAg and HBV DNA were measured before, during and after the therapy. Paired liver biopsies were performed before and after treatment for covalently closed circular (ccc)DNA and intrahepatic HBV DNA analysis. Results: VR at 48 weeks post‐treatment, defined as HBeAg seroconversion and HBV DNA less than 10 000 copies/mL was achieved in 10 (33.3%) patients. Responders had significantly lower baseline HBsAg, HBeAg, cccDNA and intrahepatic HBV DNA levels than non‐responders. Baseline and reduced levels of log₁₀ HBsAg and log₁₀ HBeAg correlated well with those of log₁₀ cccDNA and log₁₀ total intrahepatic HBV DNA. Responders showed consistent decrease in serum HBsAg, HBeAg and HBV DNA levels during therapy. HBeAg level of 2.0 log₁₀ sample to cut‐off ratio at week 24 on therapy provided the best prediction of sustained virological response, with sensitivity and negative predictive values of 85% and 92%, respectively. One patient (3.3%) who cleared HBsAg at follow up exhibited a more rapid decline in serum HBsAg during therapy than those who developed VR without HBsAg clearance. Conclusion: Quantitative measurement of serum HBeAg during therapy may be superior to serum HBsAg and HBV DNA as a prediction of HBeAg seroconversion. Kinetics of HBsAg levels on therapy may help predict HBsAg clearance after treatment.     

Natural history of chronic hepatitis B REVEALed

Chronic hepatitis B is a worldwide public health challenge. Knowledge of natural history of chronic hepatitis B is important for the management of the disease. A community-based prospective cohort study was carried out to evaluate the risk predictors of progression of chronic hepatitis B in Taiwan. A total of 23,820 participants were enrolled in 1991-1992 from seven townships in Taiwan. Their serum samples were collected at study entry and tested for hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), antibodies against hepatitis C virus (anti-HCV), alanine aminotransferase (ALT), and α-fetoprotein (AFP). A subcohort of 3653 male and female participants who were seropositive for HBsAg and seronegative for anti-HCV was included in the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study. Newly developed cases of cirrhosis and hepatocellular carcinoma (HCC) were ascertained through follow-up examination and data linkage with profiles of the National Cancer Registry, National Health Insurance Database and Death Certification System. The incidence of both HCC and cirrhosis were significantly associated with serum HBV DNA levels in a dose-response relationship from <300 (undetectable) to ≥1,000,000 copies/mL. The biological gradients remained significant (P<0.001) after adjustment for age, sex, habits of cigarette smoking and alcohol drinking, HBeAg serostatus, and serum ALT level at cohort entry. A significant association with risk of cirrhosis and HCC was also observed for HBV genotype, precore G1896A mutant and basal core promoter A1762T/G1764A double mutant. Nomograms have been developed for the long-term risk prediction of cirrhosis and HCC for patients with chronic hepatitis B. Inactive carriers of HBV have an increased HCC incidence and liver-related mortality than HBsAg-seronegative controls. Serum HBV DNA level at study entry is a major predictor of spontaneous seroclearance of HBeAg, HBV DNA and HBsAg. These findings may inform the effective and efficient management of chronic hepatitis B.     

Evaluation of serum clusterin as a surveillance tool for human hepatocellular carcinoma with hepatitis B virus related cirrhosis

Background and Aim: Hepatocellular carcinoma (HCC) is a common human cancer worldwide. The levels of serum clusterin in HCC patients and its potential diagnostic significance is not clear. We aimed to evaluate the clinical use of serum clusterin levels as a surveillance tool for HCC with hepatitis B virus (HBV) related cirrhosis. Methods: Twenty‐two cases of healthy subjects, 31 cases of HBV carriers, 26 patients with chronic hepatitis B, 29 patients with cirrhosis, and 76 patients with HCC were enrolled in this study. Serum levels of clusterin were measured by a sandwich enzyme‐linked immunosorbent assay. Results: The serum clusterin levels in HCC patients were significantly lower than that in healthy, HBV carriers and chronic hepatitis B, but statistically higher than in cirrhosis patients. Receiver operator characteristic (ROC) curve indicated that a serum clusterin value of 50 µg/mL yielded the best sensitivity (91%) and specificity (83%) for differentiating HCC patients with HBV‐related cirrhosis from those with HBV‐related cirrhosis. The optimal alpha fetoprotein (AFP) cutoff value was 15 ng/mL and was inferior to the clusterin value of 50 µg/mL, the area under the ROC curves being 0.937 versus 0.781, respectively (P < 0.05). Conclusions: Serum clusterin was more sensitive and specific than serum AFP for differentiating HCC patients with HBV‐related cirrhosis from those with HBV‐related liver cirrhosis, and may be a useful surveillance tool of HCC based on HBV‐related cirrhosis.     

Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection

Background: Elevated serum hepatitis B virus (HBV) DNA increases the development of hepatocellular carcinoma (HCC). Rather than instantaneous DNA level, the duration of persistent HBV replication is more important in carcinogenesis. Nevertheless, most investigators evaluated the DNA level at study entry. We assessed the effects of persistently detectable serum HBV DNA on HCC recurrence. Patients and methods: We included 230 consecutive patients undergoing curative resection between 2000 and 2006. Patients who had antiviral therapy (at diagnosis or during follow‐up), fluctuating DNA (cut‐off value: 100 000 copies/ml) or recurrence within 12 months of resection were excluded. Ultimately, 157 were enrolled: 89 (non‐viraemia group) had consistently negative DNA (<100 000 copies/ml), while 68 (viraemia group) had consistently positive DNA (>100 000copies/ml). Serum DNA level, biochemical tests, α‐foetoprotein (AFP) and liver dynamic computed tomography were obtained every 3 months after surgery. Results: There were no significant differences in age, gender, liver function, histology, AFP, tumour stages or follow‐up duration between the two groups. During follow‐up (median: 35 months), patients in the non‐viraemia group had a lower 5‐year cumulative recurrence rate (54.7%) than those in the viraemia group (72.9%; P=0.043). In multivariate analysis, sustained viraemia (P=0.041) increased recurrence independently. Conclusions: Persistent viraemia increased recurrence independently after surgery. To prevent long‐term recurrences, antiviral therapy should be initiated in those with detectable serum HBV DNA.     

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.     

Intrahepatic response markers in chronic hepatitis B patients treated with peginterferon alpha-2a and adefovir

Background and Aim: We investigated whether intrahepatic markers could predict response in chronic hepatitis B virus (HBV) patients treated with peg‐interferon and adefovir for 48 weeks. Methods: Intrahepatic covalently closed circular DNA (cccDNA), total intrahepatic HBV DNA and the proportion of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) positive hepatocytes in 16 hepatitis B e antigen (HBeAg) positive and 24 HBeAg negative patients were measured at baseline and at end of treatment. Results: Baseline intrahepatic markers were not associated with sustained virological response (SVR) defined as HBV DNA < 2000 IU/mL and persistent normal alanine aminotransferase levels at the end of follow‐up (week 72). At end of treatment, intrahepatic cccDNA and total intrahepatic HBV DNA in HBeAg positive patients were significantly lower in patients with HBeAg seroconversion (P = 0.016 and P = 0.010) with positive predictive values (PPV) for SVR of 80% and 80%, respectively. In HBeAg negative patients, intrahepatic cccDNA and total intrahepatic HBV DNA had declined significantly at end of treatment (P = 0.035 and P = 0.041) and corresponding PPV for SVR was 73% and 82%. In HBeAg positive patients, median proportion of HBcAg positive hepatocytes declined significantly (P = 0.002) at end of treatment. In HBeAg negative patients, the proportion of HBsAg positive hepatocytes had declined significantly at end of treatment (P = 0.0009). Using HBsAg ≤ 7.5% as a limit, PPV for SVR in HBeAg negative patients was 83%. Conclusions: At end of treatment in HBeAg positive patients, intrahepatic cccDNA and total intrahepatic HBV DNA were predictive for SVR. In HBeAg negative patients a proportion of < 7.5% HBsAg positive hepatocytes at end of treatment was a strong predictor for SVR.     

A 7‐year study of lamivudine therapy for hepatitis B virus e antigen‐positive chronic hepatitis B patients in China

OBJECTIVE: To evaluate the long‐term efficacy and safety of lamivudine treatment for chronic hepatitis B and the impact of emergence of YMDD mutation of hepatitis B virus (HBV). METHODS: A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to receive either lamivudine 100 mg daily or a placebo in a 3:1 ratio for the first 12 weeks. Thereafter, all patients were administered with lamivudine 100 mg/d for 5 years and followed up for 2 years. RESULTS: After 12 weeks of the lamivudine treatment, serum HBV DNA levels decreased rapidly and HBV DNA negativity (<1.6 pg/mL) was 92.2%, whereas it was only 14.1% (P < 0.01) in the placebo group. At the end of 5 years, serum HBV DNA continued to be substantially suppressed. The loss of HBeAg and seroconversion were significantly correlated with baseline alanine aminotransferase (ALT) levels, in patients with baseline ALT > 2 × upper limits of normal, the loss of HBeAg was 54% and seroconversion rate was 50%, respectively. YMDD mutation developed in 70.8% of the patients at years 5. In YMDD mutant patients, HBV DNA levels were increased moderately and with mild to moderate elevations of ALT. ALT flares (ALT > 5ULN) occurred in 22 patients, 16 with YMDD variants and six with non‐variants. One year durability of seroconversion after stopping lamivudine was 80%. CONCLUSION: Lamivudine is effective and tolerable for chronic hepatitis B.     

Hepatitis B core‐related antigen levels after HBeAg seroconversion is associated with the development of hepatocellular carcinoma

Hepatitis B core‐related antigen (HBcrAg) is a novel serological marker for hepatitis B virus infection. Its clinical significance after HBeAg seroconversion has not been defined. We aimed to determine the relationship between HBcrAg levels after spontaneous HBeAg seroconversion and hepatocellular carcinoma (HCC). A total of 207 chronic hepatitis B patients with documented time of HBeAg seroconversion were enrolled. HBcrAg and HBsAg were checked within 3 years (as baseline), at 5 and 10 years after HBeAg seroconversion. HBV DNA was measured at the baseline. Multivariate Cox regression model was used to investigate the predictors for HCC development. The median follow‐up time was 13.1 (11.8‐15.5) years. Fourteen patients developed HCC (15‐year cumulative incidence: 7%). The median level of HBcrAg at baseline was significantly higher in patients who developed HCC when compared with patients without HCC (5.68 vs 4.78 log U/ml, respectively; P = .003). Cox proportional hazards model indicated that age of HBeAg seroconversion older than 40 years (hazard ratio (HR): 4.60; P = .049), presence of baseline cirrhosis (HR: 6.23; P = .003) and a higher baseline HBcrAg (HR: 1.75; P = .032) were independently associated with HCC development. A cut‐off value of baseline HBcrAg level ≥5.21 log U/mL yielded an AUROC of 0.74 with a negative predictive value of 97.7%. High HBcrAg levels within 3 years after HBeAg seroconversion were independently associated with the development of HCC in chronic hepatitis B patients.     

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.     

HBcrAg is a predictor of post‐treatment recurrence of hepatocellular carcinoma during antiviral therapy

Background/Aims: The recurrence rate of hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) is high even in patients receiving curative therapy. In this study, we analysed the risk factors for tumour recurrence after curative therapy for HBV‐related HCC while under treatment with nucleot(s)ide analogues (NAs) by measuring serum HBcrAg and intrahepatic covalently closed circular DNA (cccDNA) levels to elucidate the viral status associated with HCC recurrence. Methods: We enrolled 55 patients who developed HCC during NA therapy and underwent either curative resection or percutaneous ablation for HCC. Results: Hepatocellular carcinoma recurred in 21 (38%) of the patients over a period of 2.2 (range, 0.2–7.4) years. In multivariate analysis, serum HBcrAg levels ≥4.8log U/ml at the time of HCC diagnosis (hazard ratio, 8.96; 95% confidential interval, 1.94–41.4) and portal vein invasion (3.94, 1.25–12.4) were independent factors for HCC recurrence. The recurrence‐free survival rates of the high cccDNA group were significantly lower than those of the low cccDNA group only in patients who underwent resection (P=0.0438). A positive correlation (P=0.028; r=0.479) was observed between the intrahepatic cccDNA and the serum HBcrAg levels at the incidence of HCC. Conclusion: HBcrAg is a predictor of the post‐treatment recurrence of HCC during antiviral therapy. Serum HBcrAg and intrahepatic cccDNA suppression by NAs may be important to prevent HCC recurrence.     

Virological and clinical implication of core promoter C1752/V1753 and T1764/G1766 mutations in hepatitis B virus genotype D infection in Mongolia

Background and Aim: The aim of the present study was to reveal virological and clinical features of hepatitis B virus (HBV) genotype D infection. Methods: One hundred and twenty‐two Mongolian chronic liver disease (CLD) patients infected with HBV were subjected for serological HBV‐markers screening and HBV‐enzyme immunoassay (EIA) genotyping. Nucleotide sequences were analyzed for 48 HBV/D strains (23 isolated from hepatocellular carcinoma (HCC) and 25 from CLD patients). Results: Prevalence of hepatitis B e antigen (HBeAg) positivity was low (25.9%) in young patients (≤30 years old) indicating early HBeAg seroclearance in HBV/D carriers. The T1764/G1766 double mutation was the most common basal core promoter (BCP) mutation (29.2%) and was frequent in HBeAg‐negative patients (39.3%). Patients harboring T1764/G1766 mutants exhibited lower HBV‐DNA and HBV core antigen (HBcAg) levels than those with wild‐type BCP strains (P = 0.024, 0.049, respectively). C1752 and/or V (not T) 1753 mutation was significantly prevalent in HCC patients (HCC vs CLD; 52.2% vs 20%, P = 0.033). T1762/A1764 mutation was detected in 75.0% of HCC patients with high viral load (≥5 log copies/mL). Precore stop codon mutation A1896 was detected in (70.8%) of HBV/D‐infected patients. Conclusions: In Mongolians infected with HBV/D, C1752 and/or V1753 mutation was associated with HCC.     

Long-term follow-up of patients with hepatitis B e antigen negative chronic hepatitis B

Background and Aim: After hepatitis B virus (HBV) e antigen (HBeAg) seroconversion, HBV‐DNA continues to replicate, and HBeAg‐negative patients still face the risk of liver disease progression. We investigated the predictive factors for alanine aminotransferase (ALT) elevation, antiviral drug use, and hepatocellular carcinoma (HCC) occurrence in HBeAg‐negative patients. Methods: Age, sex, ALT, platelet counts, HBV‐DNA levels, genotype, antidiabetic drug use, body mass index, smoking, and alcohol consumption were analyzed for a total of 244 HBV carriers who were HBeAg‐negative. Results: Of 244 HBeAg‐negative patients, 158 (64.8%) showed normal ALT levels at baseline. Multivariate Cox hazard regression analysis identified high HBV‐DNA levels and high ALT at baseline as independent risk factors for ALT elevation in the patients with normal ALT at baseline. The threshold ALT and HBV‐DNA levels were determined to be 31 IU/L and 5.3 logcopies/mL, respectively. Seventeen (7.0%) patients used antiviral drugs. Multivariate Cox hazard regression analysis identified high HBV‐DNA levels (threshold, 5.7 log copies/mL), the use of antidiabetic drugs, and daily alcohol consumption at baseline as an independent risk factor for the use of antiviral drugs in HBeAg‐negative patients. In 10 patients (4.1%), HCC was detected, and a low platelet count (threshold, 10.0 × 10⁴/mm³) was associated with the occurrence of HCC. Conclusion: This study identified predictors of future active liver disease in HBeAg‐negative patients, i.e. ALT elevation, unavoidable use of antiviral drugs, and occurrence of HCC.     

Changes in hepatitis B virus DNA levels and liver function after transcatheter arterial chemoembolization of hepatocellular carcinoma

Aim: Reports concerning changes in hepatitis B virus (HBV) status and liver function in hepatocellular carcinoma (HCC) during or after transcatheter arterial chemoembolization (TACE) have been rare and the results inconsistent. The objective of this retrospective study was to evaluate these parameters in a large cohort of HBV‐related HCC patients. Methods: One hundred and seventy‐two hepatitis B surface antigen positive HCC patients with Child–Pugh grade A or B liver disease who underwent 228 sessions of TACE were enrolled, and related clinical and laboratory data were analyzed. Results: In total, HBV reactivated in 33 (14.5%), remained stable in 152 (66.7%) and decreased in 43 (18.8%) sessions. Univariate analysis revealed that sex and HBV DNA levels correlated with changes in HBV DNA status after TACE, while hepatitis B e‐antigen (HBeAg), prothrombin time and chemotherapeutic agents were marginally significant factors. Multivariate analysis demonstrated that the major factors that influenced the HBV DNA status were baseline HBV DNA levels(P = 0.0002) and HBeAg (P = 0.0387). A comparison of the post‐TACE (30–90 days) liver function to the baseline revealed no significant differences. The reactivation group has the highest rate of exacerbation (12.1%) compared with the stable group (5.9%) and downregulation group (4.7%). Conclusion: HBV DNA changes after TACE included reactivated, decreased and stable HBV DNA levels. Although HBV reactivation did not necessarily result in exacerbation of liver damage and most HCC patients with Child–Pugh grade A and B tolerated TACE well, careful post‐procedure monitoring and managing is needed.     

Efficacy of lamivudine on hepatitis B viral status and liver function in patients with hepatitis B virus‐related hepatocellular carcinoma

Background/Aims: Treatment of patients with hepatocellular carcinoma (HCC) depends on the tumour extent and underlying liver function. Antiviral therapy with nucleoside/nucleotide analogues has been shown to be effective in improving the liver function of chronic hepatitis B (CHB) patients. We assessed whether lamivudine could induce biochemical and virological improvements in patients with hepatitis B virus‐related HCC. Patients/Methods: Of 148 CHB patients treated with 100 mg/day lamivudine for at least 6 months, 80 had HCC (CHB/HCC group) and 68 did not (CHB group). Biochemical and virological parameters were serially monitored. Results: Compared with the CHB group, the CHB/HCC group was older, had higher male predominance, bilirubin levels and liver cirrhosis rate, and lower albumin and hepatitis B virus (HBV) DNA levels and hepatitis B e antigen (HBeAg) positivity (P<0.05 each). The two groups showed similar cumulative rates of alanine aminotransferase normalization, HBV DNA seroconversion, HBeAg loss and viral breakthrough during 12 months of lamivudine treatment. After 12 months, the CHB/HCC group showed, relative to baseline, increased albumin levels (3.51±0.5 vs. 3.72±0.5 mg/ml) and decreased ascites scores (1.63±0.7 vs. 1.45±0.6) and Child–Pugh scores (6.92±1.9 vs. 6.02±1.38) (P<0.05 each). Conclusion: Lamivudine had comparable antiviral effects both in patients with CHB and CHB/HCC, and improved underlying liver function in the latter group. Treatment of HBV may increase the chance of curative treatments in patients with HBV‐related HCC.     

Intrahepatic distribution of hepatitis B virus antigens in patients with and without hepatocellular carcinoma

AIM: To study the intrahepatic expression of hepatitis B surface antigen(HBs Ag) and hepatitis B core antigen(HBc Ag) in chronic hepatitis B patients with and without hepatocellular carcinoma. METHODS: A total of 33 chronic hepatitis B patients(mean age of 40.3 ± 2.5 years), comprising of 14 HBe Ag positive and 19 HBe Ag negative patients; and 13 patients with hepatitis B virus related hepatocellular carcinoma(mean age of 49.6 ± 4.7 years), were included in our study. Immunohistochemical staining for HBc Ag and HBs Ag was done using standard streptavidin-biotin-immunoperoxidase technique on paraffin-embedded liver biopsies. The HBc Agand HBs Ag staining distributions and patterns were described according to a modified classification system. RESULTS: Compared to the HBe Ag negative patients, the HBe Ag positive patients were younger, had higher mean HBV DNA and alanine transaminases levels. All the HBe Ag positive patients had intrahepatic HBc Ag staining; predominantly with "diffuse" distribution(79%) and "mixed cytoplasmic/nuclear " pattern(79%). In comparison, only 5% of the HBe Ag-negative patients had intrahepatic HBc Ag staining. However, the intrahepatic HBs Ag staining has wider distribution among the HBe Ag negative patients, namely; majority of the HBe Ag negative cases had "patchy" HBs Ag distribution compared to "rare" distribution among the HBe Ag positive cases. All but one patient with HCC were HBe Ag negative with either undetectable HBV DNA or very low level of viremia. Intrahepatic HBc Ag and HBs Ag were seen in 13(100%) and 10(77%) of the HCC patients respectively. Interestingly, among the 9 HCC patients on anti-viral therapy with suppressed HBV DNA, HBc Ag and HBs Ag were detected in tumor tissues but not the adjacent liver in 4(44%) and 1(11%) patient respectively. CONCLUSION: Isolated intrahepatic HBc Ag and HBs Ag can be present in tumors of patients with suppressed HBV DNA on antiviral therapy; that may predispose them to cancer development.     

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.