Lung-Yi Mak

Review article: hepatitis B core-related antigen (HBcrAg): an emerging marker for chronic hepatitis B virus infection

Chronic hepatitis B (CHB) cannot be completely eradicated due to the presence of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. While quantification of intrahepatic cccDNA requires liver biopsies, serological markers can be non‐invasive alternatives to reflect intrahepatic viral replicative activity. Recently, hepatitis B core‐related antigen (HBcrAg) has been advocated as a novel serum marker for disease monitoring and prognostication of CHB.

Body-mass index is associated with fibrosis regression during long-term nucleoside analogue therapy in chronic hepatitis B

Factors influencing changes in liver stiffness measurements during long‐term nucleoside analogue therapy for chronic hepatitis B (CHB) have not been thoroughly investigated.

Wisteria floribunda agglutinin-positive human Mac-2 binding protein predicts liver cancer development in chronic hepatitis B patients under antiviral treatment

AIM The risk factors for hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) patients with undetectable serum HBV DNA under nucleos(t)ide analogue (NA) therapy are not well defined. We aimed to examine the relationship between Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+-M2BP) and HCC development in these patients. Results There was a significant difference in the median levels of pre-treatment WFA+-M2BP between the HCC and control groups (0.67 vs 0.41 COI, respectively, p < 0.001). Among patients with cirrhosis, the median level of WFA+-M2BP was higher in HCC group than in control group (0.74 vs 0.47 COI, respectively, p = 0.014). Among patients without cirrhosis, the median level of WFA+-M2BP of HCC group was also higher (0.48 vs 0.28 COI, respectively, p = 0.002). With a cutoff value of 0.69, the AUROC of pre-treatment WFA+-M2BP to predict HCC development for the whole cohort was 0.70. With cutoff values of 0.69 and 0.34, the AUROCs to predict HCC were 0.67 and 0.77 for patients with and without cirrhosis, respectively. Materials and Methods Fifty-seven NA-treated patients with undetectable HBV DNA who developed HCC were compared with 57 controls (matched with demographics and treatment duration). WFA+-M2BP levels were measured, and expressed as cutoff index (COI). Subgroup analyses were also performed in patients with and without cirrhosis. Conclusions A higher pre-treatment WFA+-M2BP level was associated with an increased risk of HCC development in patients with undetectable HBV DNA under NA therapy. Further longitudinal studies are required to examine the role of WFA+-M2BP as an accessory risk marker for HCC development.

Seven-Year Treatment Outcome of Entecavir in a Real-World Cohort: Effects on Clinical Parameters, HBsAg and HBcrAg Levels

Objectives:We aimed to determine the levels of alanine aminotransferase (ALT), hepatitis B virus DNA (HBV DNA), HBsAg, and a novel viral marker (hepatitis B core-related antigen (HBcrAg)); hepatitis B e antigen (HBeAg) seroconversion and drug resistance rates after 7 years of entecavir treatment in chronic hepatitis B (CHB) patients.Methods:Two hundred and twenty-two Chinese CHB patients on continuous entecavir treatment were recruited. Serologic, virologic, biochemical outcomes, and the occurrence of entecavir signature mutations were determined.Results:The rates of ALT normalization, HBeAg seroconversion, and undetectable HBV DNA were 98.3%, 82.1%, and 98.7%, respectively, after 7 years of entecavir treatment. The genotypic resistance rate was 1.2%. Decline of HBsAg level was modest with a median decline rate of 0.107 log IU/ml/year. Among patients with baseline HBsAg <1,000 IU/ml and annual HBsAg decline rate of ≥0.166 log IU/ml, all have HBsAg of <200 IU/ml (a level highly predictive for HBsAg seroclearance) at year 7. In contrast, in patients with baseline HBsAg ≥1,000 IU/ml and annual HBsAg decline rate of <0.166 log IU/ml, 95.5% had HBsAg of ≥200 IU/ml at year 7. Decline of HBcrAg levels was moderate with a median decline rate of 0.244 log kU/ml/year. Forty-seven patients (32.0%) had undetectable HBcrAg level at year 7.Conclusions:Long-term entecavir therapy continued to have good responses with low drug resistance rate. However, the decline of HBsAg with treatment was suboptimal. HBcrAg level declined at a relatively better rate. Baseline HBsAg level of <1,000 IU/ml and annual decline of 0.166 log IU/ml could be used to predict HBsAg response.

DNA polymerase inhibitors for treating hepatitis B: a safety evaluation

ABSTRACT Introduction: Oral nucleoside/ nucleotide analogues (NAs) are currently the mainstay of treatment for patients with chronic hepatitis B virus (HBV) infection. They are generally safe to use. However, since their approval in the last decade and a half, the literature has reported adverse effects associated with the use of NA in HBV patients. A comprehensive review on the drug safety is lacking. Areas covered: Significant adverse effects associated with NA use in HBV patients including muscle toxicity, peripheral neuropathy, nephrotoxicity and lactic acidosis are discussed. The reported prevalence of each adverse effect, as well as their predictive factors, reversibility and their use in pregnancy and lactating mothers are covered in this review. Novel data regarding reno-protective effect of telbivudine are also discussed. Expert opinion: Use of NA in HBV is generally safe. Uncommon adverse effects can be minimized or detected early if clinicians exercise adequate precautions when using NA for at-risk populations with regular monitoring.

Hepatitis B core protein as a therapeutic target

ABSTRACT Introduction: Chronic hepatitis B virus (HBV) infection is difficult to cure, due to the presence of covalently-closed-circular DNA and virus-mediated blunting of host immune response. Existing therapies with nucleos(t)ide analogue or pegylated-interferon are not sufficient to achieve a high rate of HBV surface antigen seroclearance, a more desirable treatment outcome. Novel therapeutic agents targeting alternative viral replication steps are being developed. In this review, we will discuss the hepatitis B core antigen (HBcAg) as a therapeutic target. Areas covered: The basic structure and fundamental functions of HBcAg including nucleocapsid assembly, pre-genomic RNA encapsidation, reverse transcription, virion formation, cccDNA amplification, immune response regulation, and HBx protein interaction will be reviewed. Most of these are identified as therapeutic targets and tested in in vitro and in vivo studies, although clinical trials are scanty. Among the different components, the core protein allosteric modulators (CpAM) have been most widely investigated and appear promising in clinical trials. Expert opinion: The multiple and essential functions of HBcAg for HBV life cycle are important and attractive targets for HBV therapeutic interventions. Controlled trials involving CpAM are awaited. Apart from CpAM, drugs directed against different functions of HBcAg may be further explored to maximize the chance of cure.

A Territory-Wide Study on the Seroprevalence of Hepatitis B Virus in the General Population after Universal Hepatitis B Immunization ERA in Hong Kong, China

Poster Presentations: Viral hepatitis: Hepatitis A, B, D, E – clinical (except therapy): no. THU-162

Inverse relationship between hepatic steatosis and hepatitis B viremia: Results of a large case‐control study

The potential interaction between chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD), two of the most prevalent liver diseases worldwide, has not been well defined. We performed liver stiffness (LS) and controlled attenuation parameter (CAP) measurements using transient elastography in 1202 CHB patients. Of these, 601 steatotic patients were matched with nonsteatotic controls in a 1:1 ratio by age, gender, nucleoside analogue treatment status, and treatment duration. Severe fibrosis was defined according to EASL‐ALEH criteria, and steatosis was defined as CAP ≥222 dB m−1. Anthropometric measurements and metabolic‐related parameters were recorded. The mean age of the 1202 patients (51.4% male) was 51.8 years. 696 patients (57.9%) were on nucleoside analogues for a median duration of 76.2 months. Among treatment‐naïve patients, median serum HBV DNA was lower in steatotic individuals than in controls (3.0 vs 3.4 log IU mL−1, P < .05), with this inverse relationship remaining significant in multivariate analysis (odds ratio 0.859, 95% CI 0.743‐0.994, P < .05). With increased steatosis severity, there was a stepwise decrease in median HBV DNA levels (3.1 and 2.6 log IU mL−1 in no steatosis and severe steatosis, respectively, P = .032). Steatosis was associated with a higher median LS (5.4 kPa vs 5.0 kPa, P < .001). Severe steatosis, when compared to mild/moderate steatosis, was associated with an increased percentage of severe fibrosis (23.2% and 12.6%, respectively, P = .005). We conclude that severe steatosis was associated with increased fibrosis in CHB patients. Increasing steatosis was independently associated with lower serum HBV DNA levels, suggesting its potential negative effects on viral replication.

Pharmacokinetic evaluation of besifovir for the treatment of HBV infection

ABSTRACT Introduction: Besifovir (LB80380) is a relatively new oral acyclic nucleotide phosphonate. We reviewed the pharmacokinetic characteristics of LB80380 and discussed its role in the treatment of chronic hepatitis B infection. Areas covered: LB80380 is a prodrug of LB80331 and LB80317. It is rapidly absorbed when taken orally. Escalating doses of besifovir produce linear increase of the plasma concentration. Doses above 60mg are effective for inhibiting HBV in human. Using 60mg as an example, the maximal concentration of LB80331 in plasma is 397 ng/mL. The time required to reach maximal concentration in plasma and elimination half-life are 2.0 and 3.0 h, respectively. Besifovir and its metabolites are mainly excreted via the kidneys. Its antiviral efficacy is non-inferior to ETV 0.5mg daily. It is generally safe in terms of renal and bone toxicity. The most common adverse event is carnitine depletion which affects almost all patients on besifovir requiring carnitine supplementation. Expert opinion: Besifovir demonstrated predictable pharmacokinetic characteristics in human subjects. Few clinical studies on besifovir have been conducted. More data are expected particularly for special populations. The adverse events upon long term exposure should be monitored. Large scale head-to-head trials comparing besifovir with existing NA, especially tenofovir alafenamide, should be conducted.

Prediction of hepatocellular carcinoma development by aminotransferase to platelet ratio index in primary biliary cholangitis

AIM To investigate the usefulness of aspartate aminotransferase to platelet ratio index (APRI) in predicting hepatocellular carcinoma (HCC) risk in primary biliary cholangitis (PBC). METHODS We identified PBC patients between 2000 and 2015 by searching the electronic medical database of a tertiary center. The hazard ratio (HR) of HCC with different risk factors was determined by Cox proportional hazards model. RESULTS One hundred and forty-four PBC patients were recruited. Patients were diagnosed at a median age of 57.8 years [interquartile range (IQR): 48.7-71.5 years), and 41 (28.5%) patients had cirrhosis at baseline. The median follow-up duration was 6.9 years (range: 1.0-26.3 years). Twelve patients developed HCC, with an incidence rate of 10.6 cases per 1000 patient-years. The overall 5-, 10- and 15-year cumulative incidences of HCC were 2.3% 95%CI: 0%-4.8%), 8.4% (95%CI: 1.8%-14.5%) and 21.6% (6.8%-34.1%), respectively. Older age (HR = 1.07), cirrhosis (HR = 4.38) and APRI at 1 year after treatment (APRI-r1) > 0.54 (HR = 3.94) were independent factors for HCC development. APRI-r1, when combined with treatment response, further stratified HCC risk (log rank P < 0.05). The area under receiver operating curve of APRI-r1 in predicting HCC was 0.77 (95%CI: 0.64-0.88). CONCLUSION APRI-r1 can be used to predict the development of HCC in PBC patients. Combination of APRI-r1 with treatment response can further stratify the HCC risk.