New Biomarkers of Chronic Hepatitis B

Lung-Yi Mak,Wai-Kay Seto,James Fung,Man-Fung Yuen 거트앤리버 소화기연관학회협의회 2019 Gut and Liver Vol.13 No.6

Chronic hepatitis B (CHB) infection leads to clinically heterogeneous disease outcomes. Different viral markers are utilized to monitor treatment effects and predict risk of complications in patients with CHB. Hepatitis B core-related antigen (HBcrAg) is a novel serum composite viral protein whose performance has been proven to be superior to that of existing viral markers. It showed good correlation with intrahepatic covalently closed-circular DNA. Its profile differs drastically in patients in different disease phases, and the level declines with antiviral therapies. HBcrAg may be helpful for predicting hepatocellular carcinoma development and hepatitis B virus (HBV) reactivation in immunosuppressed patients. Another emerging measurable serum marker, HBV RNA, exists in the form of pregenomic RNA-containing virions. Its profile differs between patients in different disease phases in a similar manner to that of HBcrAg. HBV RNA is present in serum at lower levels than HBV DNA in treatment-naïve patients by 1–2 logs. In contrast, its level is higher than HBV DNA in patients receiving nucleos(t)ide analogues (NAs). A significant decline in serum RNA was observed in patients receiving novel antiviral therapies, including core protein allosteric modulators and RIG-1/NOD2 agonists. Both HBcrAg and HBV RNA may be helpful for predicting off-therapy sustained virological control in patients who stop long-term NA treatment.

Development of a Non-Invasive Liver Fibrosis Score Based on Transient Elastography for Risk Stratification in Patients with Type 2 Diabetes

Chi-Ho Lee,Wai-Kay Seto,Kelly Ieong,David T.W. Lui,Carol H.Y. Fong,Helen Y. Wan,Wing-Sun Chow,Yu-Cho Woo,Man-Fung Yuen,Karen SL Lam 대한내분비학회 2021 Endocrinology and metabolism Vol.36 No.1

Background: In non-alcoholic fatty liver disease (NAFLD), transient elastography (TE) is an accurate non-invasive method to identify patients at risk of advanced fibrosis (AF). We developed a diabetes-specific, non-invasive liver fibrosis score based on TE to facilitate AF risk stratification, especially for use in diabetes clinics where TE is not readily available. Methods: Seven hundred sixty-six adults with type 2 diabetes and NAFLD were recruited and randomly divided into a training set (n=534) for the development of diabetes fibrosis score (DFS), and a testing set (n=232) for internal validation. DFS identified patients with AF on TE, defined as liver stiffness (LS) ≥9.6 kPa, based on a clinical model comprising significant determinants of LS with the lowest Akaike information criteria. The performance of DFS was compared with conventional liver fibrosis scores (NFS, FIB-4, and APRI), using area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, positive and negative predictive values (NPV). Results: DFS comprised body mass index, platelet, aspartate aminotransferase, high-density lipoprotein cholesterol, and albuminuria, five routine measurements in standard diabetes care. Derived low and high DFS cut-offs were 0.1 and 0.3, with 90% sensitivity and 90% specificity, respectively. Both cut-offs provided better NPVs of >90% than conventional fibrosis scores. The AUROC of DFS for AF on TE was also higher (P<0.01) than the conventional fibrosis scores, being 0.85 and 0.81 in the training and testing sets, respectively. Conclusion: Compared to conventional fibrosis scores, DFS, with a high NPV, more accurately identified diabetes patients at-risk of AF, who need further evaluation by hepatologists.

Bone and Renal Parameters Following Switch to Tenofovir Alafenamide after 96- or 144-Weeks of Tenofovir Disoproxil Fumarate Treatment in East Asians with Chronic HBV

( Ki Tae Yoon ),( Seto Wai-kay ),( Kao Jia-horng ),( Lim Seng-gee ),( Peng Cheng-yuan ),( Kwan Soo Byun ),( Inokuma Tetsuro ),( June Sung Lee ),( Flaherty John ),( Yee Leland J ),( Jump Belinda ),( Se 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Background: Tenofovir alafenamide (TAF) has shown similar efficacy to tenofovir disoproxil fumarate (TDF) with better bone and renal safety in 2 Phase 3 trials through 96 weeks. After a protocol amendment, some TDF patients received 96 weeks while others received 144 weeks of TDF treatment before rolling over to open-label (OL) TAF. Aim: To examine whether duration of prior TDF treatment impacted changes in bone and renal parameters after 48 weeks of OL TAF treatment in the subset of East Asian (EA) patients with chronic HBV. Methods: Among 190 EAs randomized to TDF, changes in bone mineral density (BMD) by DXA scans and renal parameters were assessed from OL baseline to Week 48 following switch to OL TAF. Results: At Week 48, mean (SD) percent changes from OL baseline in hip-BMD were +0.92 (2.32) and +0.79 (2.47) and in spine-BMD were +1.52 (2.68) and +2.27 (3.51) for DB-TDF-144wks and DB-TDF-96wks, respectively. Similarly, median (Q1, Q3) changes from OL baseline in creatinine clearance (eGFR_CG) were +2.4 (-4.2, +10.8) and +3.0 (-3.0, +8.4) mL/min for DB-TDF-144wks and DBTDF-96wks, respectively. Similar trends in BMD and eGFR_CG changes were seen in non-EAs. Following switching to OL TAF, improvements in bone and renal biomarkers were also observed. Conclusions: In EA patients who switched to TAF from TDF, improvements were seen in bone and renal parameters.

Correspondence on Editorial regarding “HBV pgRNA and HBcrAg reductions at week 4 predict favourable HBsAg response upon long-term nucleos(t)ide analogue in CHB”

Lung-Yi Mak,Wai-Kay Seto,Man-Fung Yuen 대한간학회 2023 Clinical and Molecular Hepatology(대한간학회지) Vol.29 No.1

Rates of metachronous adenoma after curative resection for left-sided or right-sided colon cancer

( Yuk Fai Lam ),( Wai Kay Seto ),( Teresa Tong ),( Ka Shing Cheung ),( Oswens Lo ),( Ivan Fn Hung ),( Wai Lun Law ),( Wai K Leung ) 대한장연구학회 2018 Intestinal Research Vol.16 No.4

Background/Aims: We determined the rates of metachronous colorectal neoplasm in colorectal cancer (CRC) patients after resection for right (R)-sided or left (L)-sided cancer. Methods: Consecutive CRC patients who had undergone surgical resection for curative intent in our hospital between 2001 and 2004 were identified. R-sided colonic cancers refer to cancer proximal to splenic flexure whereas L-sided cancers include rectal cancers. Patients were included only if they had a clearing colonoscopy performed either before or within 6 months after the operation. Findings of surveillance colonoscopy performed up to 5 years after colonic resection were included in the analysis. Results: Eight hundred and sixty-three CRC patients underwent curative surgical resection during the study period. Three hundred and twenty-seven patients (107 R-sided and 220 L-sided) fulfilled the inclusion criteria and had at least 1 postoperative surveillance colonoscopy performed. The proportion of patients who had polyp and adenoma on surveillance colonoscopy was significantly higher among patients with L-sided than R-sided cancers (polyps: 30.9% vs. 19.6%, P=0.03; adenomas: 25.5% vs. 13.1%, P=0.01). The mean number of adenoma per patient on surveillance colonoscopy was also higher for patients with L-sided than R-sided tumors (0.52; 95% confidence interval [CI], 0.37-0.68 vs. 0.22; 95% CI, 0.08-0.35; P<0.01). Multivariate analysis showed that L-sided cancers, age, male gender and longer follow-up were independent predictors of adenoma detection on surveillance colonoscopy. Conclusions: Patients with L-sided cancer had a higher rate of metachronous polyps and adenoma than those with R-sided cancer on surveillance colonoscopy. (Intest Res 2018;16:619-627)

Review : Epidemiology of Hepatocellular Carcinoma in the Asia-Pacific Region

( Ran Xu Zhu ),( Wai Kay Seto ),( Ching Lung Lai ),( Man Fung Yuen ) 대한간학회 2016 Gut and Liver Vol.10 No.3

Hepatocellular carcinoma (HCC) is the predominant primary liver cancer in many countries and is the third most common cause of cancer-related death in the Asia-Pacific region. The incidence of HCC is higher in men and in those over 40 years old. In the Asia-Pacific region, chronic hepatitis B virus and hepatitis C virus infections are the main etiological agents; in particular, chronic hepatitis B infection (CHB) is still the major cause in all Asia-Pacific countries except for Japan. Over the past two decades, the incidence of HCC has remained stable in countries in the region except for Singapore and Hong Kong, where the incidence for both sexes is currently decreasing. Chronic hepatitis C infection (CHC) is an important cause of HCC in Japan, representing 70% of HCCs. Over the past several decades, the prevalence of CHC has been increasing in many Asia-Pacific countries, including Australia, New Zealand, and India. Despite advancements in treatment, HCC is still an important health problem because of the associated substantial mortality. An effective surveillance program could offer early diagnosis and hence better treatment options. Antiviral treatment for both CHB and CHC is effective in reducing the incidence of HCC. (Gut Liver 2016;10:332-339)

A Phase 3 Study Comparing Tenofovir Alafenamide (TAF) to Tenofovir Disoproxil Fumarate (TDF) in Patients with HBeAg-positive CHB patients

( Sang Hoon Ahn ),( Kosh Agarwal ),( Scott Fung ),( Wai Kay Seto ),( Young Suk Lim ),( Ed Gane ),( Harry L. Janssen ),( Manoj Sharma ),( Wan Long Chuang ),( Ho Bae ),( Ki Tae Yoon ),( John F. Flaherty 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: In this randomized, double blind study in HBeAg- positive patients, the efficacy of TAF was demonstrated to be noninferior to that of TDF at Week 48 in the proportion with HBV DNA <29 IU/mL with improved bone and renal effects. Here we present the results after two years of treatment. Methods: 873 patients were randomized to receive TAF 25 mg QD (n=581) or TDF 300 mg QD (n=292) and treated for 144 weeks. Efficacy analyses included virologic (HBV DNA <29 IU/mL), biochemical, and serologic responses; key secondary safety endpoints Results: Baseline characteristics included: mean age 38 years, 64% males, 82% Asians, 52% genotypes C, 47% had HBV DNA ≥ 8 log10 IU/mL, and 26% were treated previously with nucleos(t)ides. Efficacy and safety end points are summarized in the Table. At Week 96, virologic response rates were similer between TAF and TDF groups. A greater percentage of TAF patients achieved normalization of serum ALT values with similar proportions of TAF and TDF patients experiencing HBeAg loss. Patients on TAF experienced smaller changes in hip and spine BMD than TDF patients through 96 weeks. The smaller decline in eGFRCG and smaller changes in renal tubular markers observed with TAF through Week 96. The rates of treatment discontinuations for adverse events (<1.5%) and serious adverse events (≤6%) were low and similar in the two arms. Conclusions: At Week 96, similar rates of virologic suppression were seen with a higher rate of ALT normalization seen in TAF patients relative to TDF and continued improved bone and renal safety with TAF compared with TDF.

The latest evidence on the impact of fatty liver on liver-related outcomes and mortality in chronic hepatitis B

Xianhua Mao,Lung Yi Mak,Wai-Kay Seto 대한간학회 2023 Clinical and Molecular Hepatology(대한간학회지) Vol.29 No.3

RNA interference as a novel treatment strategy for chronic hepatitis B infection

Rex Wan-Hin Hui,Lung-Yi Mak,Wai-Kay Seto,Man-Fung Yuen 대한간학회 2022 Clinical and Molecular Hepatology(대한간학회지) Vol.28 No.3

Chronic hepatitis B (CHB) is a major cause of liver-related morbidity and mortality. Functional cure of CHB, defined as sustainable hepatitis B surface antigen (HBsAg) seroclearance, is associated with improved clinical outcomes. However, functional cure is rarely attainable by current treatment modalities. RNA interference (RNAi) by small-interfering RNA (siRNA) and anti-sense oligonucleotide (ASO) has been studied as a novel treatment strategy for CHB. RNAi targets post-transcriptional messenger RNAs and pregenomic RNAs to reduce hepatitis B virus (HBV) antigen production and viral replication. By reducing viral antigens, host immune reconstitution against HBV may also be attained. Phase I/II trials on siRNAs have demonstrated them to be safe and well-tolerated. siRNA is effective when given in monthly doses with different total number of doses according to different trial design, and can lead to sustainable dose-dependent mean HBsAg reduction by 2–2.5 log. Incidences of HBsAg seroclearance after siRNA therapy have also been reported. ASOs have also been studied in early phase trials, and a phase Ib study using frequent dosing regimen within 4 weeks could achieve similar HBsAg reduction of 2 log from baseline. Given the established efficacy and safety of nucleos(t) ide analogues (NAs), future RNAi regimens will likely include NA backbone. While the current evidence on RNAi appears promising, it remains undetermined whether the potent HBsAg reduction by RNAi can result in a high rate of HBsAg seroclearance with durability. Data on RNAi from phase IIb/III trials are keenly anticipated.

Safety and Efficacy at 1-Year after Switching from TDF to TAF in CHB Patients with Risk Factors for TDF Use

( Byoung Kuk Jang ),( Edward Gane ),( Wai Kay Seto ),( Harry La Janssen ),( Florin A Caruntu ),( Hyung Joon Kim ),( Dzhamal Abdurakhmanov ),( Shuhei Nishiguchi ),( Andrzej Horban ),( Ho Bae ),( John F 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Tenofovir alafenamide (TAF), a new prodrug of tenofovir (TFV), is now a preferred treatment in the 2017 EASL HBV Guidelines, and may be particularly useful in patients with risk factors for TDF associated renal and bone effects. We assessed the 1 year safety and efficacy in CHB patients with TDF risk factors who were switched from TDF to TAF. Methods: In two identically-designed Phase 3 studies, HBeAg(+) and HBeAg(-)patients were randomized 2:1 to TAF 25 mg or TDF 300 mg and treated in a double- blind fashion for 96 weeks; all patients received open-label (OL) TAF for an additional 48 weeks (through Week 144). Renal and bone safety parameters, and antiviral efficacy (HBV DNA < 29 IU/mL) and ALT normalization were assessed in the subset of switch patients with baseline risk factors for TDF use: Age >60 years, osteoporosis of hip or spine, ³Stage 2 CKD (GFRCG < 90 mL/ min), albuminurina (UACR >30 mg/g), hypophosphatemia (PO4 <2.5 mg/dL), or presence of comorbidities (e.g. HTN, DM). Results: Of 1298 patients randomized and treated in the 2 studies, 540(42%) switched to open- label TAF at Week 96 (TAF^®TAF 360; TDF^®TAF 180), of which 284(53%) patients had at least 1 TDF risk factor at baseline; 123(23%) patients had ³2 risk factors. Baseline demographics and disease characteristics were similar between treatment groups. At Week 144, significant improvements in renal (sCr, eGFRCG) parameters, hip and spine BMD were observed and summarized in the table. Antiviral efficacy was maintained at Week 144 in both groups and in TDF patients who switched to TAF, increased rates of ALT normalization were seen. Conclusions: In CHB patients with risk factors for potential TDF toxicity, switching from TDF to TAF resulted in improved bone and renal safety parameters while efficacy was maintained in this subgroup at one year.