The 58th Annual Meeting of the European Association for the Study of the Liver (EASL2023) and the EASL Congress 2023 have come to a close. During this conference, Dr. Wai-Kay Seto and his research team from The University of Hong Kong Shenzhen Hospital/ The University of Hong Kong presented several studies. Hepatology Digest had the privilege of inviting Professor Wai-Kay Seto to introduce three of the significant studies: the impact of blood sugar control on reducing the risk of digestive tract tumors in diabetes patients [1], preliminary safety and antiviral activity analysis of the Chinese-developed siRNA new drug RBD1016 in the Chinese chronic hepatitis B population [2], and a new technique for portable assessment of fatty liver [3]. The details of these studies are as follows:
Analysis of Over 270,000 People in Hong Kong: Blood Sugar Control as a Modifiable Independent Risk Factor for Liver Cancer, Biliary Tract Cancer, and Pancreatic Cancer
Diabetes mellitus (DM) is a known risk factor for liver cancer, biliary tract cancer, and pancreatic cancer. However, the impact of blood sugar control on the risk of these cancers in diabetes patients has not been well-studied.
Among 421,818 screened individuals, 273,421 diabetes patients (mean age 61.5 ± 11.7 years, 52.6% male) were included. The median follow-up time was 6.7 years (range: 4.4–10.1 years), during which 2018, 517, and 721 cases of liver cancer, biliary tract cancer, and pancreatic cancer occurred, respectively. Compared to those with an average HbA1c ≥ 7%, lower HbA1c levels (< 7%) were independently associated with reduced risks of liver cancer (aHR: 0.74; 95% CI: 0.67–0.81), biliary tract cancer (aHR: 0.67; 95% CI: 0.56–0.80), and pancreatic cancer (aHR: 0.83; 95% CI: 0.71–0.97) (Figure 1). This association remained significant after 1:2 propensity score matching (HR: 0.68–0.80), inverse probability weighting (HR: 0.71–0.85), and other sensitivity analyses.
Regardless of obesity status (aHR: 0.69–0.78), aspirin intake (aHR: 0.71–0.75), or the presence of viral hepatitis (aHR: 0.68, 95% CI: 0.59–0.79; aHR: 0.78, 95% CI: 0.69–0.88), the risk of liver cancer was lower. For biliary tract cancer, this association remained significant in individuals without smoking, normal blood pressure, and normal lipid profiles (aHR: 0.46–0.74). For pancreatic cancer, this association was significant in individuals without smoking, normal blood pressure, and no lipid abnormalities (aHR: 0.80–0.82), but it became non-significant when these metabolic risk factors were present.
In conclusion,In diabetes patients, optimal blood sugar control with an average HbA1c < 7% is independently associated with a lower risk of liver cancer, biliary tract cancer, and pancreatic cancer. These results suggest that blood sugar control is a modifiable risk factor that can influence cancer prevention strategies for the liver, gallbladder, and pancreas.
Researcher’s Remarks:
Existing evidence suggests an association between diabetes and chronic liver diseases. If diabetes occurs in patients with chronic liver diseases such as hepatitis B, hepatitis C, or fatty liver, the incidence of liver-related complications such as liver fibrosis, cirrhosis, and liver cancer increases. However, there has been no research exploring whether diabetes increases the incidence of liver-related complications in non-liver disease populations. In this study, by analyzing data from over 270,000 individuals in the Hong Kong Hospital Authority database, it was found that HbA1c is an important independent risk factor affecting liver-related complications in diabetes patients. HbA1c < 7% reduced the incidence of liver cancer by 20%. These results emphasize the importance of blood sugar control and monitoring, which not only reduces complications such as stroke and kidney disease but also lowers the risk of digestive tract tumors. (*This study was selected as “Best of EASL Congress 2023: Liver Tumors”).
Safety and Antiviral Activity of the Chinese-Made HBV siRNA New Drug RBD1016 in Chinese Chronic HBV Infected Patients
China bears one of the heaviest burdens of hepatitis B (HBV) globally, with approximately 28 million patients suffering from chronic HBV infection. Among them, only about 3.5 million are receiving treatment. According to China’s HBV treatment guidelines, the ultimate goal for chronic HBV is clinical cure (functional cure), meaning stopping treatment while maintaining hepatitis B surface antigen (HBsAg) negativity, with or without the presence of hepatitis B surface antibodies (anti-HBs), undetectable HBV DNA, normal liver biochemical parameters, and improvement in liver histology. Currently, antiviral drugs for HBV mainly include interferon and nucleos(t)ide analogs (NAs), which effectively suppress HBV replication but have no significant inhibitory effect on HBsAg.
RBD1016 is a small interfering RNA (siRNA) drug consisting of siRNA and the N-acetyl galactosamine delivery system, targeting the conserved region of the X gene of chronic hepatitis B virus (HBV). It has inhibitory effects on all four transcripts of HBV through an RNA interference mechanism, with the ability to simultaneously inhibit
both HBsAg and HBV DNA. RBD1016 is highly potent in vitro, with an EC50 of 10^-9 M. In a preclinical study, RBD1016 demonstrated potent and sustained HBsAg reduction in humanized mice and reduced HBV DNA in chimpanzees. In a Phase I clinical trial (RCT) conducted in the United States, RBD1016 was well-tolerated and showed promising early results in lowering HBsAg levels in HBV patients. The objective of this Phase IIA open-label RCT in Hong Kong is to evaluate the safety and antiviral activity of RBD1016 in Chinese chronic HBV patients.
A total of 24 eligible participants were enrolled in this study. Patients received subcutaneous injections of RBD1016 at a dose of 50 mg once a week for 8 weeks, followed by a 16-week observation period (Weeks 8 to 24).
The mean age of the 24 enrolled participants was 43.6 years, with 18 males and 6 females. Twenty patients were hepatitis B e antigen (HBeAg) negative, and four were HBeAg positive. Twenty-three patients were on nucleos(t)ide analogue (NA) treatment. No serious adverse events or dose-limiting toxicities were reported throughout the study. One patient withdrew from the study due to an adverse event (AE) of headache, which was considered unrelated to RBD1016 treatment. Most reported AEs were mild or moderate, with the most common AEs being injection-site reactions (96%) and headache (21%). The proportion of patients achieving a ≥ 0.5 log10 IU/mL reduction in serum HBsAg level from baseline to Week 8 was 33.3%. Among the 14 NA-treated patients, the proportion was 42.9%. In the post-treatment evaluation at Week 24, 16.7% of patients achieved a ≥ 0.5 log10 IU/mL reduction in serum HBsAg level from baseline.
In conclusion,RBD1016 is safe and well-tolerated in Chinese chronic HBV patients, with a favorable safety profile. The preliminary results suggest that RBD1016 has antiviral activity in reducing serum HBsAg levels, with the potential to benefit a subset of chronic HBV patients. Further studies with a larger sample size and longer treatment duration are needed to confirm these findings.
Researcher’s Remarks:
HBV is a global public health concern, and China has one of the highest burdens of HBV infection. Current antiviral therapies for HBV mainly target viral replication, but they do not effectively reduce the production of HBsAg, a key viral protein. HBsAg is involved in immune evasion and the progression of liver disease. New therapeutic strategies that can effectively lower HBsAg levels are needed to achieve functional cure in chronic HBV patients. RBD1016, a Chinese-developed siRNA drug, has shown promise in early clinical trials in reducing HBsAg levels. This study is the first to evaluate the safety and antiviral activity of RBD1016 in Chinese chronic HBV patients and provides important preliminary data for its further development. (*This study was selected as “Best of EASL Congress 2023: Hepatitis B and D: New Developments in Diagnosis and Management”).
Portable Assessment of Fatty Liver Using Quantitative Ultrasound: A New Technique and Its Validation
Non-alcoholic fatty liver disease (NAFLD) patients currently have effective treatment methods through lifestyle changes to achieve weight loss. A research team has developed a wearable device using Electrical Impedance Tomography (EIT) technology for quantifying liver fat deposition (Part 1). In this pilot study, they subsequently explored the role of the EIT system in dynamically monitoring liver fat deposition (Part 2).
In Part 1, 21 healthy controls and 43 diagnosed NAFLD patients were recruited for cross-sectional assessments using Vibration-Controlled Transient Elastography (VCTE), which measures liver fat deposition through Controlled Attenuation Parameter (CAP). EIT examinations were conducted after VCTE, with 16 electrode bands worn around the waist, connected to a portable, non-ionizing, non-invasive system designed to be user-friendly even for operators with no prior experience.
Randomly assigned NAFLD subjects (n=27) underwent Magnetic Resonance Proton Density Fat Fraction (MRI-PDFF) examinations to further validate the accuracy of the wearable EIT system (Figure A). In the second part, 8 participants were recruited (2 NAFLD patients and 6 healthy controls) and underwent EIT scans at baseline and every 2 weeks. CAP values were measured using Vibration-Controlled Transient Elastography (VCTE) at baseline and in the 8th week. Significant CAP reduction was defined as a decrease of ≥40 dB/m compared to baseline.
In Part 1, the EIT system’s area under the receiver operating characteristic curve (AUROC) for predicting CAP in subjects was 0.799 (Figure B and Figure C), with a sensitivity of 86.1% and specificity of 71.4%. The EIT system’s AUROC for predicting MRI-PDFF scores was 0.782 (Figure D and Figure E), with a sensitivity of 77.8% and specificity of 80%.
In the second part, during an 8-week observation period, all 8 participants used the EIT system for dynamic monitoring at a frequency of ≥3 times, confirming the feasibility of this method. 5 out of 8 (62.5%) participants, including 2 known NAFLD patients, achieved a significant reduction in CAP (Figure F). There were 8 pairs of EIT and CAP values generated at baseline and in the 8th week, with 14 out of 16 (87.5%) maintaining consistency in liver fat categorization. Most participants found the wearable device convenient to use (87.5%), had confidence in self-administration at home (75%), and were willing to use it for the long term (62.5%). No participants experienced persistent discomfort.
In conclusion, this novel portable EIT system can predict CAP derived from VCTE and MRI-PDFF, providing a safe, well-tolerated, and cost-effective dynamic alternative for quantifying liver fat deposition.
Researcher’s Remarks:
This portable detection device was jointly developed by the University of Hong Kong and Insight Bio Limited. Its goal is to enable patients to monitor the progression of liver fat-related diseases at home through simplified and efficient detection methods, such as measuring weight, blood pressure, and other indicators. EIT operates based on the differing electrical impedance of various tissues in the human body due to their physiological and pathological characteristics. For instance, the more fat tissue present, the higher the impedance to electrical current (in a non-strict sense), leading to greater electrical resistance. The weak currents generated by EIT have no adverse effects on health. Patients only need to wear the device like a belt, which allows for the quantification of the severity of fatty liver. Higher CAP values correspond to increased EIT values. Currently, this innovative device is still under continuous development, and we look forward to seeing this technology enter clinical use soon, benefiting more patients with fatty liver.
TAG: EASL2023;Voice of China;HVB;Fatty Liver
