Publications by authors named "Tsung-Hui Hu"

272 Publications

Elimination of Hepatitis C Virus in a Dialysis Population: A Collaborative Care Model in Taiwan.

Am J Kidney Dis 2021 Apr 30. Epub 2021 Apr 30.

Ministry of Health and Welfare, Taipei, Taiwan.

Rationale & Objective: Hemodialysis facilities are high-risk environments for hepatitis C virus (HCV). Eliminating HCV from all dialysis facilities in a community may be achieved more effectively under a collaborative care model.

Study Design: Quality improvement study of multidisciplinary collaborative care teams including nephrologists, gastroenterologists and public health practitioners.

Setting & Participants: All dialysis patients in the Changhua county of Taiwan were treated using an inter-disciplinary collaborative care model implemented within a broader Changhua-Integrated Program to Stop HCV Infection (CHIPS-C).

Quality Improvement Activities: Provision of an HCV care cascade to fill three gaps including screening and testing, diagnosis, and universal direct-acting antiviral (DAA) treatment implemented by collaborating teams of dialysis practitioners and gastroenterologists working under auspices of Changhua Public Health Bureau.

Outcomes: Outcome measures included quality indicators pertaining to six steps in HCV care ranging from HCV screening to complete treatment and cure from treatment with DAA ANALYTICAL APPROACH: A descriptive analysis.

Results: A total of 3657 patients from 31 dialysis facilities were enrolled. All patients completed HCV screening. The DAA treatment initiation rate and completion rate were 88.9% and 94.0%, respectively. The collaborative care model achieved a cure rate of 96.0% (166/173). No virologic failure occurred. The cumulative treatment ratios for patients with chronic HCV infection increased from 5.3% before interferon-based therapy (2017) to 25.6% after restricted provision of DAA (2017-2018) and then to 89.1% after universal access to DAA (2019).

Limitations: Unclear impact of this collaborative care program on incident dialysis patients entering dialysis facilities each year and on patients with earlier stages of chronic kidney disease.

Conclusions: A collaborative care model in Taiwan increased the rates of diagnosis and treatment for HCV in dialysis facilities to levels near those established by the World Health Organization.
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http://dx.doi.org/10.1053/j.ajkd.2021.03.017DOI Listing
April 2021

The role of hepatitis B virus core-related antigen in predicting hepatitis B virus relapse after cessation of entecavir in hepatitis B e antigen-negative patients.

J Viral Hepat 2021 May 1. Epub 2021 May 1.

Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

This study investigated the ability of hepatitis B core related antigen (HBcrAg) to predict hepatitis B virus (HBV) relapse in HBeAg-negative patients after cessation of entecavir therapy. A total of 301 HBeAg-negative patients without cirrhosis who had stopped entecavir therapy for at least 12 months were recruited. All patients fulfilled the stopping criteria proposed by the APASL 2012 guidelines. The five-year cumulative rates of virological relapse, clinical relapse, and HBsAg loss were 71.6%, 57.3%, and 18.7%, respectively. Serum HBsAg at end-of-treatment (EOT) was an independent predictor of virological relapse, clinical relapse and HBsAg loss; an EOT HBsAg of 150 IU/mL was the optimal cutoff value. The 5-year virological relapse rates for patients with <150 and ≥150 IU/mL HBsAg at EOT were 43.3% and 82.2% (P<.001), clinical relapse rates were 32.3% and 66.3% (P<.001), and HBsAg loss rates were 46.1% and 5.2% (P<.001), respectively. A baseline HBcrAg of 4 IU/mL was the optimal cutoff value for predicting HBV relapse. Among patients with an EOT HBsAg <150 IU/mL, the five-year virological relapse rates for patients with baseline HBcrAg levels ≤4 and >4 log U/mL were 27.9% and 59.1% (P=.006) and the clinical relapse rates were 18% and 48.1% (P=.014), respectively. EOT HBcrAg was not a significant predictor of virological or clinical relapse after cessation of entecavir. In conclusion, the combination of an EOT HBsAg of 150 IU/mL and baseline HBcrAg of 4 log U/mL can effectively predict the risk of HBV relapse after stopping entecavir therapy.
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http://dx.doi.org/10.1111/jvh.13528DOI Listing
May 2021

A novel evidence of serial changes of bone mineral density in chronic hepatitis B patients treated with entecavir.

Hepatol Int 2021 Apr 27. Epub 2021 Apr 27.

Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 83301, Taiwan.

Background And Aims: Tenofovir disoproxil fumarate (TDF) and Entecavir (ETV) are commonly used for patients with chronic hepatitis B (CHB), and renal or bone toxicity are possible concerns. This study is to evaluate the renal and bone effect of TDF compared with ETV in CHB patients.

Methods: This is a retrospective study at Kaohsiung Chung-Gung memorial hospital, Taiwan, from June 2013 to December 2018. Patients with CHB were prescribed with TDF or ETV for 3 years or above. Renal function was assessed at 12-week intervals. Dual-energy X-ray absorptiometry scans of the spine and femurs were performed at 48-week intervals. The propensity score analysis was conducted to balance the baseline characteristics of patients in both treatment groups.

Results: A total of 258 patients were included in this study: TDF (n = 135) and ETV (n = 123). The prevalence of osteopenia was much higher in the TDF group at week 48 and week 96. The TDF group showed significant mean percentage decrease from baseline in bone mineral density throughout the treatment course. Logistic regression analysis adjusted for the propensity score demonstrated that the use of TDF was the only predictive factor of significant bone density loss at week 144. The mean percentage decline of estimated glomerular filtration rate was significant in the TDF group at all time points. Renal threshold phosphate concentration was similar among both treatment groups.

Conclusions: This study suggested CHB patients treated with TDF may experience increased risks of bone loss and renal deficits compared to those treated with ETV.
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http://dx.doi.org/10.1007/s12072-021-10148-zDOI Listing
April 2021

Plasma interleukin-17 and alpha-fetoprotein combination effectively predicts imminent hepatocellular carcinoma occurrence in liver cirrhotic patients.

BMC Gastroenterol 2021 Apr 17;21(1):177. Epub 2021 Apr 17.

Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan.

Background: Predicting imminent hepatocellular carcinoma (HCC) in liver cirrhotic patients is an unmet medical need. We aimed to investigate circulatory biomarkers and their optimum combinations in a prospective study.

Methods: We investigated plasma interleukin 17 (IL-17) concentrations, quantified using enzyme-linked immunosorbent assay (ELISA), for the prediction of HCC in a large cohort of 404 HCC-naïve liver cirrhotic patients regularly followed after recruitment. Additionally, IL-17 in surgically resected tumor tissues were evaluated using immunohistochemistry staining.

Results: IL-17 was detected in HCC tissues. The IL-17 concentrations in the peripheral blood do not have correlation with an extensive list of 31 common demographic, metabolic and liver function variables in the cohort of liver cirrhotic patients. Furthermore, patients stratified by IL-17 and alpha-fetoprotein (AFP) showed distinctive cumulative incidence of HCC. Imminent HCC, defined here as HCC occurrence within 1 year, can be predicted by IL-17 alone with an area under the receiver operating characteristic curve [AUC] of 0.762 (P = 0.002). An multivariate analysis showed that age, hepatitis C viral infection, AFP and IL-17 were four independent factors associated with imminent HCC (adjusted P = 0.03, 0.041, 0.024 and 0.008 respectively). An explicit risk score (R) combining the concentrations of two plasma biomarkers, AFP and IL-17, achieved a high AUC of 0.933 (95% confidence interval 0.893-0.972, P < 0.001) in predicting imminent HCC, with 100% sensitivity and 79.9% specificity at the optimum cutoff. The score is defined as: [Formula: see text] CONCLUSIONS: The circulatory IL-17 concentration is a predictor of subsequent HCC occurrence in liver cirrhotic patients. The combination of AFP and IL-17 is highly effective in predicting imminent HCC within 1 year.
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http://dx.doi.org/10.1186/s12876-021-01761-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052794PMC
April 2021

Letter: tenofovir versus entecavir for hepatocellular carcinoma prevention in chronic hepatitis B-related compensated cirrhosis-authors' reply.

Aliment Pharmacol Ther 2021 05;53(9):1042-1043

Division of Hepato-Gastroenterology, Department of Internal Medicine, Linko Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.

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http://dx.doi.org/10.1111/apt.16339DOI Listing
May 2021

Microalgal extract from thermotolerant Coelastrella sp. F50 retards the liver tumor progression by targeting hepatic cancer stem cells.

Phytother Res 2021 Apr 7. Epub 2021 Apr 7.

Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung, Taiwan.

Microalgae extracts have shown antitumor activities. However, the antitumor mechanism of them is not yet completely clear, especially the effect on cancer stem cells (CSCs). This study aimed to elucidate the antitumor activity and mechanism of microalgal extract from thermotolerant Coelastrella sp. F50 (F50) in hepatocellular carcinoma (HCC). Oncogenic behaviors were analyzed using cell proliferation, colony formation, invasion, sphere formation, and side population cells (SPCs) assays in HCC cells after F50 treatment. The molecular mechanism was further studied by quantitative real-time PCR, immunoblot, and immunofluorescence analyses. The chemopreventive efficacy of F50 was evaluated in rat orthotopic hepatoma, and the hepatic pathologies were investigated by immunohistochemical, immunoblot, and immunofluorescence analyses. F50 specifically suppressed hepatic CSCs (tumor spheres, drug efflux, CD133/ABCG2 CSCs markers) with no cytotoxicity in vitro. In the animal experiments, prophylactic F50 administration significantly attenuated tumor progression and improved liver function in HCC-bearing rats. In the mechanistic analysis, F50 potentially inhibited cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE ) axis in HCC cells and rat hepatoma, and exogenous PGE restored CSCs properties in F50-treated HCC cells. In summary, F50 extract inhibits hepatic CSCs by COX-2/PGE downregulation and may facilitate a novel phytotherapy for HCC prevention.
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http://dx.doi.org/10.1002/ptr.7111DOI Listing
April 2021

Combining end-of-treatment HBsAg and baseline hepatitis B core-related antigen reduce HBV relapse rate after tenofovir cessation.

Hepatol Int 2021 Mar 4. Epub 2021 Mar 4.

Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Rd, Niao-Sung 833, Kaohsiung City, Taiwan.

Background/purpose: The study investigated the role of hepatitis B core-related antigen (HBcrAg) in hepatitis B virus (HBV) relapse after stopping tenofovir disoproxil fumarate (TDF) in HBeAg-negative patients.

Methods: A total of 185 HBeAg-negative patients without cirrhosis who had stopped TDF treatment for at least 6 months were recruited. All patients fulfilled the stopping criteria proposed by the Asian Pacific Association for the Study of the Liver 2012.

Results: The 3-year cumulative incidences of virological relapse, clinical relapse, and hepatitis B surface antigen (HBsAg) loss were 72, 60.1 and 14.5%, respectively. End-of-treatment (EOT) HBsAg level was an independent predictor of virological relapse (hazard ratio (HR): 2.263; 95% confidence interval (CI): 1.779-2.887), clinical relapse (HR 1.773; 95% CI 1.367-2.298), and HBsAg loss (HR 0.179; 95% CI 0.096-0.335). Among patients who had HBsAg < 100 and ≥ 100 IU/mL, the 3-year virological relapse rates were 37.4% and 85.3% (p < 0.001), clinical relapse rates were 30.3 and 71.7% (p < 0.001), and HBsAg loss rates were 40.6 and 2.6% (p < 0.001), respectively. Among the 53 patients with EOT HBsAg level < 100 IU/mL, the 3-year virological relapse rates in patients with baseline HBcrAg levels < 4.7 and ≥ 4.7 log U/mL were 20.3 and 60.4% (p = 0.003), and the clinical relapse rates were 10.3 and 59.5% (p < 0.001) respectively. Additionally, the 3-year HBsAg loss rates in patients with baseline HBcrAg ≤ 3 and > 3 log U/mL were 42.9 and 7.9% (p < 0.001).

Conclusions: The combination of EOT HBsAg and baseline HBcrAg levels could further reduce the risk of HBV relapse after stopping TDF therapy in HBeAg-negative patients.
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http://dx.doi.org/10.1007/s12072-021-10159-wDOI Listing
March 2021

Impact of metformin use on the recurrence of hepatocellular carcinoma after initial liver resection in diabetic patients.

PLoS One 2021 4;16(3):e0247231. Epub 2021 Mar 4.

Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Background: Metformin is proposed to have chemopreventive effect of various cancer currently. However, the anti-cancer effect of metformin for diabetic patients with hepatocellular carcinoma (HCC) undergoing liver resection remains unclear. The aim of our cohort study was to assess whether metformin influence the recurrence of HCC.

Methods: We retrospectively enrolled 857 HCC patients who received primary resection from April 2001 to June 2016. 222 patients were diagnosed with diabetes mellitus (DM) from medical record. Factors influence the overall survival (OS) and recurrence-free survival (RFS) were analyzed by multivariate analysis.

Results: During the follow-up period (mean, 75 months), 471 (54.9%) patients experienced recurrence, and 158 (18.4%) patients died. Multivariate analysis revealed that DM (p = 0.015), elevated AST (p = 0.006), hypoalbuminemia (p = 0.003), tumor number (p = 0.001), tumor size (p < 0.001), vascular invasion (p <0.001), high Ishak fibrosis score (p <0.001), hepatitis B (p = 0.014), hepatitis C (p = 0.001) were independent predictors for RFS. In diabetic patients, only HbA1c>9% (p = 0.033), hypoalbuminemia (p = 0.030) and vascular invasion (p = 0.001) were independent risk factors for HCC recurrence; but the metformin use revealed no significance on recurrence. DM is a risk factor of HCC recurrence after resection. Adequate DM control can reduce the recurrence of HCC. However, the use of metformin does not reduce the risk of HCC recurrence in diabetic patient after initial resection. Hence, metformin may not have protective influences on HCC recurrence in diabetic patients who undergo initial liver resection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247231PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932176PMC
March 2021

Statin use is associated with a lower risk of recurrence after curative resection in BCLC stage 0-A hepatocellular carcinoma.

BMC Cancer 2021 Jan 15;21(1):70. Epub 2021 Jan 15.

Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan.

Background: Use of statins is associated with a reduced risk of hepatocellular carcinoma (HCC). However, the effect of statin use on HCC recurrence is unclear. This study aimed to evaluate the effect of statin use on recurrence after curative resection among patients with HCC.

Methods: We retrospectively assessed 820 patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A HCC who underwent primary resection between January 2001 and June 2016 at Kaohsiung Chang Gung Memorial Hospital. Exposure to statins was defined as use of a statin for at least 3 months before HCC recurrence. Factors that influenced overall survival (OS) and recurrence-free survival (RFS) were analyzed using Cox proportional hazards models.

Results: Of the 820 patients, 46 (5.6%) used statins (statin group) and 774 (94.4%) did not (non-statin group). During the mean follow-up of 76.5 months, 440 (53.7%) patients experienced recurrence and 146 (17.8%) patients died. The cumulative incidence of HCC recurrence was significantly lower in the statin group than the non-statin group (p = 0.001); OS was not significantly different between groups. In multivariate analysis, age (hazard ratio [HR]: 1.291; p = 0.010), liver cirrhosis (HR: 1.743; p < 0.001), diabetes (HR:1.418; p = 0.001), number of tumors (HR: 1.750; p < 0.001), tumor size (HR: 1.406; p = 0.004) and vascular invasion (HR: 1.659; p < 0.001) were independent risk factors for HCC recurrence, whereas statin use (HR: 0.354; p < 0.001) and antiviral therapy (HR: 0.613; p < 0.001) significantly reduced the risk of HCC recurrence. The statin group still had lower RFS than the non-statin group after one-to-four propensity score matching.

Conclusion: Statins may exert a chemo-preventive effect on HCC recurrence after curative resection.
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http://dx.doi.org/10.1186/s12885-021-07796-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808883PMC
January 2021

Recent progress in TGF-β inhibitors for cancer therapy.

Biomed Pharmacother 2021 Feb 16;134:111046. Epub 2020 Dec 16.

Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, ROC; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ROC; Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ROC. Electronic address:

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is involved in proliferation, metastasis, and many other important processes in malignancy. Inhibitors targeting TGF-β have been considered by pharmaceutical companies for cancer therapy, and some of them are in clinical trial now. Unfortunately, several of these programs have recently been relinquished, and most companies that remain in the contest are progressing slowly and cautiously. This review summarizes the TGF-β signal transduction pathway, its roles in oncogenesis and fibrotic diseases, and advancements in antibodies and small-molecule inhibitors of TGF-β.
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http://dx.doi.org/10.1016/j.biopha.2020.111046DOI Listing
February 2021

Clinical and novel application of FibroScan, FIB-4 and aspartate aminotransferase-to-platelet ratio index in liver fibrosis evaluation in patients with hepatocellular carcinoma and their roles in oesophageal variceal prediction.

Int J Clin Pract 2021 Apr 19;75(4):e13945. Epub 2021 Jan 19.

Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan.

Background: Non-invasive techniques for liver fibrosis diagnosis are very important for clinician especially in high-risk patients for liver biopsy. We further explored the diagnostic accuracy of FibroScan, FIB-4 and aminotransferase-to-platelet ratio index (APRI) in identifying liver fibrosis and assess their predictive role for oesophageal varices in patients with hepatocellular carcinoma (HCC).

Methods: In total, 380 patients who underwent surgery for HCC were included based on retrospective study design. Liver fibrosis was pathologically diagnosed using the Ishak scoring system. Liver stiffness parameters were measured using FibroScan. APRI and FIB-4 were calculated. Among those, 121 patients who received oesophagogastroduodenoscopic examination underwent variceal evaluation.

Results: For liver cirrhosis diagnosis with FibroScan, the optimal cut-off values for the patients with HCC overall, left HCC and right HCC were 8.85, 11.75 and 8.70 kPa (the accuracy were 78.7%, 78.4% and 79.2%, respectively). They had high areas under the receiver operating characteristic curve of 0.84, 0.84 and 0.85. The combined FibroScan, APRI and FIB-4 had very high specificity (more than 92%) for cirrhosis diagnosis. The optimal cut-off liver stiffness values for the diagnosis of varices were all 11.2 kPa. For predicting varices, the optimal cut-off values of FIB-4 and APRI were 2.64 and 0.71, their accuracy were 64.3%-78.4%, 69.4% and 72.7%, respectively.

Conclusions: FibroScan, FIB-4 and APRI have moderate accuracy for liver fibrosis diagnosis and oesophageal varices prediction in patients with hepatoma. This is a study of these non-invasive techniques applied in specific hepatoma patients and with inevitable limitations and need future more studies for validation.
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http://dx.doi.org/10.1111/ijcp.13945DOI Listing
April 2021

End-of-Life-Care Quality in ICUs Is Associated With Family Surrogates' Severe Anxiety and Depressive Symptoms During Their First 6 Months of Bereavement.

Crit Care Med 2021 Jan;49(1):27-37

Department of Nursing, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan, Republic of China.

Objectives: Evidence linking end-of-life-care quality in ICUs to bereaved family members' psychologic distress remains limited by methodological insufficiencies of the few studies on this topic. To examine comprehensively the associations of family surrogates' severe anxiety and depressive symptoms with end-of-life-care quality in ICUs over their first 6 months of bereavement.

Design: Prospective, longitudinal, observational study.

Setting/participants: Family surrogates (n = 278) were consecutively recruited from seven medical ICUs at two academically affiliated medical centers in Taiwan.

Measurements And Statistical Analysis: Family surrogates' anxiety and depressive symptoms were assessed 1, 3, and 6 months postloss using the Hospital Anxiety and Depression Scale. Family satisfaction with end-of-life care in ICUs was assessed 1-month postloss by the Family Satisfaction in the ICU questionnaire. Patients' end-of-life care was documented over the patient's ICU stay. Associations of severe anxiety and depressive symptoms (scores ≥ 8 for each subscale) with end-of-life-care quality in ICUs (documented by patient care received and family satisfaction with end-of-life care in ICUs) were examined by multivariate logistic regression models with generalized estimating equation.

Main Results: Prevalence of severe anxiety and depressive symptoms decreased significantly over time. Surrogates' lower likelihood of severe anxiety or depressive symptoms 3-6 month postloss was associated with death without cardiopulmonary resuscitation, withdrawing life-sustaining treatments, and higher family satisfaction with end-of-life care in ICUs. Bereaved surrogates' higher likelihood of these symptoms was associated with physician-surrogate prognostic communication and conducting family meetings before patients died.

Conclusions: End-of-life-care quality in ICUs is associated with bereaved surrogates' psychologic well-being. Enhancing end-of-life-care quality in ICUs by improving the process of end-of-life care, for example, promoting death without cardiopulmonary resuscitation, withdrawing life-sustaining treatments, and increasing family satisfaction with end-of-life care, can lighten bereaved family surrogates' severe anxiety symptoms and severe depressive symptoms.
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http://dx.doi.org/10.1097/CCM.0000000000004703DOI Listing
January 2021

Five-year comparative risk of hepatocellular carcinoma development under entecavir or tenofovir treatment-naïve patients with chronic hepatitis B-related compensated cirrhosis in Taiwan.

Aliment Pharmacol Ther 2020 12 27;52(11-12):1695-1706. Epub 2020 Oct 27.

Division of Hepato-Gastroenterology, Department of Internal Medicine, Linko Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.

Background: Comparative long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) for prevention of disease progression to hepatocellular carcinoma (HCC) among high-risk patients with chronic hepatitis B (CHB)-related compensated cirrhosis is controversial.

Aims: To compare the long-term efficacy of ETV and TDF in HCC prevention in patients with CHB-related cirrhosis, and to evaluate predictive risk factors for HCC development.

Methods: From January 2008 to March 2018, 894 treatment-naïve patients with CHB-related compensated cirrhosis on ETV or TDF were enrolled based on the longitudinal cohort study. Data were originally collected for 7.3 years of follow-up or after the launch of TDF in 2011. Only the 5-year cumulative incidence and risk factors of HCC were assessed.

Result: Total 678 and 216 patients received ETV and TDF, respectively. The cumulative risk of HCC at 1, 3 and 5 years of follow-up was 1.6%, 11.3% and 18.7%, respectively, in the ETV group; and 0.9%, 6.7% and 10.7%, respectively, in the TDF group (P = 0.0305). Univariate and adjusted-multivariable models revealed that platelet count, alpha-fetoprotein (AFP) levels and upper gastrointestinal (UGI) varices were independent risk factors for HCC development. TDF resulted in risk of HCC development compared to ETV with adjusted hazard ratios (aHRs) of 0.66 (95% confidence interval [CI]:0.40, 1.08; P = 0.0971), 0.69 (95% CI: 0.42, 1.14; P = 0.1488) and 0.66 (95% CI: 0.38, 1.14; P = 0.1407) under stepwise selection, propensity score adjustment, and propensity score matching multivariable models, respectively.

Conclusions: For treatment-naïve patients with CHB-related compensated cirrhosis with 5-year follow-up, after variable adjustments, propensity score approaches and subgroup analyses, TDF showed a lower rate of HCC development that did not reach statistical significance, compared to the ETV.
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http://dx.doi.org/10.1111/apt.16116DOI Listing
December 2020

Hepatoma-derived growth factor participates in concanavalin A-induced hepatitis.

FASEB J 2020 12 15;34(12):16163-16178. Epub 2020 Oct 15.

Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.

Hepatitis is an important health problem worldwide. Novel molecular targets are in demand for detection and management of hepatitis. Hepatoma-derived growth factor (HDGF) has been delineated to participate in hepatic fibrosis and liver carcinogenesis. However, the relationship between hepatitis and HDGF remains unclear. This study aimed to elucidate the role of HDGF during hepatitis using concanavalin A (ConA)-induced hepatitis model. In cultured hepatocytes, ConA treatment-elicited HDGF upregulation at transcriptional level and promoted HDGF secretion while reducing intracellular HDGF protein level and cellular viability. Similarly, mice receiving ConA administration exhibited reduced hepatic HDGF expression and elevated circulating HDGF level, which was positively correlated with serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. By using HDGF knockout (KO) mice, it was found the ConA-evoked cell death was prominently alleviated in KO compared with control. Besides, it was delineated HDGF ablation conferred protection by suppressing the ConA-induced neutrophils recruitment in livers. Above all, the ConA-mediated activation of tumor necrosis factor-α (TNF-α)/interleukin-1β (IL-1β)/interleukin-6 (IL-6)/cyclooxygenase-2 (COX-2) inflammatory signaling was significantly abrogated in KO mice. Treatment with recombinant HDGF (rHDGF) dose-dependently stimulated the expression of TNF-α/IL-1β/IL-6/COX-2 in hepatocytes, further supporting the pro-inflammatory function of HDGF. Finally, application of HDGF antibody not only attenuated the ConA-mediated inflammatory cascade in hepatocytes, but also ameliorated the ConA-induced hepatic necrosis and AST elevation in mice. In summary, HDGF participates in ConA-induced hepatitis via neutrophils recruitment and may constitute a therapeutic target for acute hepatitis.
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http://dx.doi.org/10.1096/fj.202000511RRDOI Listing
December 2020

East Asia expert opinion on treatment initiation for chronic hepatitis B.

Aliment Pharmacol Ther 2020 11 20;52(10):1540-1550. Epub 2020 Sep 20.

Hong Kong, SAR, China.

Background: Globally, chronic hepatitis B (CHB) is a major public health concern. Timely and effective management can prevent disease progression to cirrhosis and reduce the risk of hepatocellular carcinoma (HCC). Currently, there is no consensus on the clinical management of CHB in East Asia.

Aim: To establish an East Asia expert opinion on treatment initiation for CHB based on alanine aminotransferase (ALT) level, hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level, cirrhosis and HCC risk scores.

Methods: A meeting was held online with a panel of 10 experts from East Asia to discuss ALT, HBV DNA, cirrhosis and HCC risk scores. Indications for CHB treatment in the latest international guidelines were reviewed. Consensus was summarised to provide recommendations on the initiation of treatment for CHB.

Results: Anti-viral therapy is recommended for CHB patients with (a) HBV DNA ≥ 2000 IU/mL and ALT ≥ 1× upper limit of normal (ULN); (b) HBV DNA ≥ 2000 IU/mL, ALT < 1× ULN and ≥ F2 fibrosis and/or ≥ A2 necroinflammation occurs; (c) cirrhosis and detectable HBV DNA; or (d) HBV DNA ≥ 2000 IU/mL, ALT < 1× ULN and a family history of cirrhosis or HCC, extrahepatic manifestations or age > 40 years. Patients with cirrhosis and/or HCC should be treated regardless of ALT levels if HBV DNA level is detectable. Initiating anti-viral therapy or close monitoring at 3-month intervals is recommended for CHB patients with at least two HCC risk factors.

Conclusions: These expert recommendations will contribute to a new standard of daily clinical practice in East Asia.
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http://dx.doi.org/10.1111/apt.16097DOI Listing
November 2020

Chronic hepatitis B exhibited higher rate of hepatocellular carcinoma occurrence than hepatitis C in cirrhotic patients after effective antiviral treatment.

J Formos Med Assoc 2021 Jan 24;120(1 Pt 3):621-628. Epub 2020 Jul 24.

Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Taiwan. Electronic address:

Background/purpose: Effective antiviral-therapy can reduce the risk of liver cirrhosis related hepatocellular carcinoma in patients with chronic hepatitis B and hepatitis C. Yet, the difference of hepatocellular carcinoma development in chronic hepatitis B and hepatitis C patients with cirrhosis after effective antiviral therapy treatment is unknown. In this study, We comprehensive explored the difference among them.

Methods: 1363 patients with cirrhosis and hepatitis B virus treated with nucleos(t)ide analogues (NUCs) with completely suppressed virus, and patients with cirrhosis and hepatitis C virus treated with pegylated interferon (peg-IFN)/ribavirin (RBV) combination therapy who achieved sustained virologic response were enrolled.

Results: Total 261 developed hepatocellular carcinoma within a median follow-up of 4.25 years. Univariate analysis, patients developed hepatocellular carcinoma tended to be of older age, and had lower platelet counts, were chronic hepatitis B carriers, and had higher serum alfa-fetoprotein (AFP) (≥20 ng/mL), FIB-4 index and APRI scores. Subsequent multivariate analysis revealed older age, lower platelet counts, high AFP levels and chronic hepatitis B carriers were independent risk factors of hepatocellular carcinoma.

Conclusion: Our findings identify that chronic hepatitis B patients were with a higher risk of hepatocellular carcinoma compared to chronic hepatitis C patients after achieving virological response. Special attention should be paid to those patients.
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http://dx.doi.org/10.1016/j.jfma.2020.07.019DOI Listing
January 2021

Quality Assessments of End-of-Life Care by Medical Record Review for Patients Dying in Intensive Care Units in Taiwan.

J Pain Symptom Manage 2020 12 7;60(6):1092-1099.e1. Epub 2020 Jul 7.

School of Nursing, Medical College, Chang Gung University, Tao-Yuan, Taiwan, R.O.C; Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Tao-Yuan, Taiwan, R.O.C; Department of Nursing, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan, R.O.C. Electronic address:

Context/objective: Essential indicators of high-quality end-of-life care in intensive care units (ICUs) have been established but examined inconsistently and predominantly with small samples, mostly from Western countries. Our study goal was to comprehensively measure end-of-life-care quality delivered in ICUs using chart-derived process-based quality measures for a large cohort of critically ill Taiwanese patients.

Methods: For this observational study, patients with APACHE II score ≥20 or goal of palliative care and with ICU stay exceeding three days (N = 326) were consecutively recruited and followed until death.

Results: Documentation of process-based indicators for Taiwanese patients dying in ICUs was variable (8.9%-96.3%), but high for physician communication of the patient's poor prognosis to his/her family members (93.0%), providing specialty palliative-care consultations (73.3%), a do-not-resuscitate order in place at death (96.3%), death without cardiopulmonary resuscitation (93.5%), and family presence at patient death (76.1%). Documentation was infrequent for social-worker involvement (8.9%) and interdisciplinary family meetings to discuss goals of care (22.4%). Patients predominantly (79.8%) continued life-sustaining treatments (LSTs) until death and died with full life support, with 88.3% and 58.9% of patients dying with mechanical ventilation support and vasopressors, respectively.

Conclusions: Taiwanese patients dying in ICUs heavily used LSTs until death despite high prevalences of documented prognostic communication, providing specialty palliative-care consultations, having a do-not-resuscitate order in place, and death without cardiopulmonary resuscitation. Family meetings should be actively promoted to facilitate appropriate end-of-life-care decisions to avoid unnecessary suffering from potentially inappropriate LSTs during the last days of life.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.07.002DOI Listing
December 2020

On-Treatment Changes in FIB-4 and 1-Year FIB-4 Values Help Identify Patients with Chronic Hepatitis B Receiving Entecavir Therapy Who Have the Lowest Risk of Hepatocellular Carcinoma.

Cancers (Basel) 2020 May 7;12(5). Epub 2020 May 7.

Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan.

Noninvasive fibrosis indices can help stratify the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving nucleos(t)ide analogue (NA) therapy. We investigated the predictive performance of on-treatment changes in FIB-4 (△FIB-4) and 1-year FIB-4 values (FIB-4 12M) for HCC risk in patients with CHB receiving entecavir therapy. We included 1325 NA-naïve patients with CHB treated with entecavir, retrospectively, from January 2007 to August 2012. A combination of △FIB-4 and FIB-4 12M was used to stratify the cumulative risk of HCC into three subgroups each in the noncirrhotic and cirrhotic subgroups with < 0.0001 by using the log-rank test (noncirrhotic: the highest risk ( = 88): FIB-4 12M ≥ 1.58/△FIB-4 ≥ 0 (hazard ratio (HR): 40.35; 95% confidence interval (CI): 5.107-318.7; <0.0001) and cirrhotic: the highest risk ( = 89): FIB-4 12M ≥2.88/△FIB-4 ≥0 (HR: 9.576; 95% CI: 5.033-18.22; < 0.0001)). Patients with noncirrhotic CHB treated with entecavir who had a FIB-4 12M < 1.58 or FIB-4 12M ≥ 1.58/△FIB-4 < 0 exhibited the lowest 5-year HCC risk (0.6%). A combination of on-treatment changes in FIB-4 and 1-year FIB-4 values may help identify patients with CHB receiving entecavir therapy with the lowest risk of HCC.
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http://dx.doi.org/10.3390/cancers12051177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281667PMC
May 2020

Comparison of tenofovir and entecavir in the development of acute kidney injury in cirrhotic chronic hepatitis B patients with refractory ascites.

Eur J Gastroenterol Hepatol 2021 Feb;32(2):208-213

Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung.

Background And Aim: Tenofovir disoproxil fumarate (TDF) and entecavir are effective antiviral medications that are recommended as first-line monotherapies for the treatment of chronic hepatitis B (CHB) infection, including decompensated liver cirrhosis with ascites. Acute kidney injury (AKI) commonly occurs in patients with cirrhosis and ascites. The aim of this study was to compare the development of AKI during TDF and entecavir treatment of CHB patients with cirrhotic refractory ascites.

Methods: From January 2011 to April 2017, we identified patients who were diagnosed with cirrhosis with refractory ascites and received TDF or entecavir treatments at Kaohsiung Chang Gung Memorial Hospital. AKI was defined as an increase in serum creatinine of more than 0.3 mg/dL or 1.5-fold from baseline. All episodes of AKI were recorded and compared between those who received TDF and entecavir.

Results: A total of 111 patients were enrolled in this retrospective study, of which 22 patients were treated with TDF and 89 were treated with entecavir. Patients with AKI episodes had a higher proportion of TDF treatment (P = 0.01), male (P = 0.023), hepatocellular carcinoma (P = 0.007), admission (P = 0.045), and mortality (P = 0.018). Logistic regression analysis illustrated that TDF treatment of patients with comorbidity was an independent risk factor for the development of AKI [odds ratio (OR), 3.756; 95% confidence interval (CI), 1.293-10.912; P = 0.015] and hepatorenal syndrome (OR, 7.651; 95% CI, 1.697-34.508; P = 0.008).

Conclusions: TDF treatment is a risk factor for AKI and HRS development in cirrhotic patients with refractory ascites in comparison with entecavir treatment, especially in patients with comorbidity.
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http://dx.doi.org/10.1097/MEG.0000000000001711DOI Listing
February 2021

Incidence and Factors Associated With HBV Relapse After Cessation of Entecavir or Tenofovir in Patients With HBsAg Below 100 IU/mL.

Clin Gastroenterol Hepatol 2020 11 29;18(12):2803-2812.e2. Epub 2020 Apr 29.

Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Electronic address:

Background & Aims: We investigated the incidence and factors associated with relapse of hepatitis B virus (HBV) infection in patients with levels of HB surface antigen (HBsAg) less than 100 IU/mL after cessation of entecavir or tenofovir disoproxil fumarate (TDF) treatment.

Methods: We collected data from patients with chronic HBV infection without cirrhosis treated with entecavir from 2007 through 2015 or TDF from 2011 through 2016 in Taiwan. We identified 135 patients with levels of HBsAg less than 100 IU/mL at the end of treatment (79 entecavir and 56 TDF) and collected data from them for a median of 87 weeks (interquartile range, 48-161 wk) for use as the development set. We collected data from 108 patients from separate medical centers in Taiwan, followed up for a median of 126 weeks (interquartile range, 61-214 wk), and used these as the validation group. Post-treatment virologic relapse was defined as a serum HBV DNA level greater than 2000 IU/mL, and clinical relapse was defined as an alanine aminotransferase level greater than 80 U/L and a HBV DNA level greater than 2000 IU/mL.

Results: In the development group, the 5-year incidences of virologic relapse, clinical relapse, and HBsAg loss were 40.9%, 32.5%, and 47%, respectively. The baseline HBV DNA and end-of-treatment levels of HBsAg were associated independently with relapse. In the development group, 17.3% of patients with end-of-treatment HBsAg levels less than 40 IU/mL had a virologic relapse within 5 years, whereas 67.6% of patients with a HBsAg level of 40 IU/mL or more had a virologic relapse within 5 years (P < .001); proportions of patients with clinical relapses were 10.2% (HBsAg <40 IU/mL) and 57.6% (HBsAg ≥40 IU/mL; P < .001). In the validation groups, for patients with end-of-treatment HBsAg levels less than 40 IU/mL or 40 IU/mL or more, the rates of virologic relapse at 5 years were 31.1% and 80.5% (P < .001), and rates of clinical relapse were 14.2% and 50.3% (P < .001), respectively. Rates of virologic and clinical relapse within 5 years were low (<10%) in patients with a combination of end-of-treatment HBsAg level less than 40 IU/mL and baseline HBV DNA level less than 5 × 10 IU/mL, or baseline hepatitis B core-related antigen level less than 4 log U/mL in the development group.

Conclusions: An end-of-treatment HBsAg level of 40 IU/mL or less is optimal for stopping nucleos(t)ide analog therapy. Waiting to stop therapy until patients have a combination of baseline HBV DNA level of 5 × 10 IU/mL or hepatitis B core-related antigen of 4 log U/mL and end-of-treatment HBsAg level of 40 IU/mL might reduce the risk of HBV relapse.
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http://dx.doi.org/10.1016/j.cgh.2020.04.037DOI Listing
November 2020

2020 Taiwan consensus statement on the management of hepatitis C: part (I) general population.

J Formos Med Assoc 2020 Jun 29;119(6):1019-1040. Epub 2020 Apr 29.

Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine and Hepatitis Research Center, College of Medicine, Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan.

Hepatitis C virus (HCV) infection remains a major public health issue with high prevalence in Taiwan. Recently, the advent of direct-acting antiviral (DAA) agents, with higher efficacy, excellent safety profile, and truncated treatment duration, has revolutionized the paradigm of hepatitis C treatment and made HCV elimination possible. To provide timely guidance for optimal hepatitis C management, the Taiwan Association for the Study of the Liver (TASL) established an expert panel to publish a 2-part consensus statement on the management of hepatitis C in the DAA era. After comprehensive literature review and a consensus meeting, patient-oriented, genotype-guided recommendations on hepatitis C treatment for the general and special populations have been provided based on the latest indications and scientific evidence. In the first part of this consensus, we present the epidemiology and treatment situation of hepatitis C in Taiwan, the development of DAA, pre-treatment evaluation, post sustained virologic response (SVR) monitoring, and most importantly the treatment recommendations for the general population with compensated liver disease. The second part will focus on the treatment recommendations for the special populations.
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http://dx.doi.org/10.1016/j.jfma.2020.04.003DOI Listing
June 2020

2020 Taiwan consensus statement on the management of hepatitis C: Part (II) special populations.

J Formos Med Assoc 2020 Jul 27;119(7):1135-1157. Epub 2020 Apr 27.

Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine and Hepatitis Research Center, College of Medicine, Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan.

Hepatitis C virus (HCV) infection is a silent killer that leads to rapid progression of liver cirrhosis and hepatocellular carcinoma (HCC). High prevalence of HCV infection has been reported in Taiwan, especially in high-risk populations including people who inject drugs (PWID) and patients requiring dialysis. Besides, certain populations merit special considerations due to suboptimal outcome, potential drug-drug interaction, or possible side effect. Therefore, in the second part of this 2-part consensus, the Taiwan Association for the Study of the Liver (TASL) proposes the treatment recommendations for the special population in order to serve as guidance to optimizing the outcome in the direct-acting antiviral (DAA) era. Special populations include patients with acute or recent HCV infection, previous DAA failure, chronic kidney disease, decompensated cirrhosis, HCC, liver and other solid organ transplantations, receiving an HCV viremic organ, hepatitis B virus (HBV) and HCV dual infection, HCV and human immunodeficiency virus (HIV) coinfection, active tuberculosis infection, PWID, bleeding disorders and hemoglobinopathies, children and adolescents, and pregnancy. Moreover, future perspectives regarding the management of hepatitis C are also discussed and summarized in this consensus statement.
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http://dx.doi.org/10.1016/j.jfma.2020.04.002DOI Listing
July 2020

Associations of HBV Genotype B vs C Infection With Relapse After Cessation of Entecavir or Tenofovir Therapy.

Clin Gastroenterol Hepatol 2020 12 27;18(13):2989-2997.e3. Epub 2020 Apr 27.

Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Electronic address:

Background & Aims: We compared rates of relapse of hepatitis B virus (HBV) infection between patients with HBV genotype B vs genotype C infection after cessation of entecavir or tenofovir disoproxil fumarate (TDF) therapy. All patients included in the study were HB e antigen (HBeAg)-negative.

Methods: We performed a retrospective study of 460 HBeAg-negative patients without cirrhosis in Taiwan who had stopped entecavir or TDF treatment for at least 12 months; data were collected from 2007 through 2016. All patients fulfilled the stopping criteria proposed by the APASL 2012 guidelines. Patients were evaluated every 1-3 months during the first 6 months after stopping therapy and then every 3 months until their last hospital visit; HB surface antigen (HBsAg) was measured in serum samples collected before treatment, after 12 months of treatment, and at the end of treatment. Virologic relapse was defined as a serum level of HBV DNA >2000 IU/mL after the cessation of treatment; clinical relapse was defined as increase in alanine aminotransferase more than 2-fold the upper limit of normal (40 U/L) and level of HBV DNA >2000 IU/mL after stopping treatment.

Results: Significantly higher proportions of patients with HBV genotype B infection had virologic and clinical relapse and retreatment than patients with HBV genotype C infection, among all patients and among patients matched by propensity sore. Patients who discontinued TDF therapy had significantly higher rates and earlier times of virologic and clinical relapse than patients who discontinued entecavir therapy, among all patients and propensity score-matched patients. Multivariate analysis showed that TDF therapy, old age, HBV genotype B, and higher end of treatment HBsAg level were independently associated with virologic and clinical relapse. Five-year rates of virologic and clinical relapse were low (19.2% and 15.4%, respectively) in patients with a combination of end of treatment level of HBsAg of 100 IU/mL or less and HBV genotype C infection. Rates of off-therapy HBsAg loss, development of hepatocellular carcinoma, and hepatic decompensation did not differ significantly between patients with HBV genotypes B vs C infection or between the entecavir vs TDF groups.

Conclusions: Higher proportions of HBeAg-negative patients with HBV genotype B infection have virologic and clinical relapse and retreatment than patients with HBV genotype C infection, after cessation of entecavir or TDF therapy.
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http://dx.doi.org/10.1016/j.cgh.2020.04.048DOI Listing
December 2020

Ability of the post-operative ALBI grade to predict the outcomes of hepatocellular carcinoma after curative surgery.

Sci Rep 2020 04 29;10(1):7290. Epub 2020 Apr 29.

Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

The albumin-bilirubin (ALBI) grade has been validated as a significant predictor for hepatocellular carcinoma (HCC). However, there is little information about the impact of postoperative ALBI grade in patients with HCC who are undergoing liver resection. We enrolled 525 HCC patients who received primary resection from April 2001 to March 2017. The impact of the pre- and post-operative ALBI grades on overall survival (OS) and recurrence-free survival (RFS) were analyzed by multivariate analysis. During the follow-up period (mean, 65 months), 253 (48.1%) patients experienced recurrence, and 85 (16.2%) patients died. Multivariate analysis revealed that diabetes mellitus (DM) (p = 0.011), alpha-fetoprotein levels (AFP) (p < 0.001), low platelet count (p = 0.008), liver cirrhosis (p < 0.001), and the first year of ALBI grade after resection (p < 0.001) were independent predictors for RFS. Additionally, old age (p = 0.006), DM (p = 0.002), AFP (p = 0.027), and ALBI grade at the first year after resection (p < 0.001) were independent risk factors for poor liver-related survival. Patients with post-operative ALBI grades II/III had older age (p = 0.019), hypoalbuminemia (p = 0.038), DM (p = 0.043), and high stages of pTNM (p = 0.021). The post-operative ALBI grade is better for predicting the outcomes in HCC patients after curative hepatectomy than the pre-operative ALBI grade.
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http://dx.doi.org/10.1038/s41598-020-64354-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190718PMC
April 2020

Real-world effectiveness of glecaprevir/pibrentasvir and ledipasvir/sofosbuvir for mixed genotype hepatitis C infection: A multicenter pooled analysis in Taiwan.

J Viral Hepat 2020 09 12;27(9):866-872. Epub 2020 May 12.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Yunlin, Taiwan.

Data on direct-acting antiviral agent (DAA) treatment for mixed genotype hepatitis C virus (HCV) infection are scant. This study examined the effectiveness of glecaprevir/pibrentasvir (GLE/PIB) and ledipasvir/sofosbuvir (LDV/SOF) for mixed HCV genotype infection in a real-world setting in Taiwan. We analysed the data from all patients with mixed HCV genotype infections treated with GLE/PIB or LDV/SOF from 2017 to 2019 in three Chang Gung Memorial Hospitals in Taiwan. The primary treatment outcome was sustained virologic response 12 weeks after treatment cessation (SVR12). Adverse events (AEs) were also evaluated. A total of 5190 HCV patients received DAA treatment during this time period. Among them, 116 patients (2.2%) had mixed infections of any 2 or 3 genotypes of 1a, 1b, 2, 3 and 6. Fifty-four patients received GLE/PIB and 62 received LDV/SOF. SVR12 rates for LDV/SOF vs GLE/PIB therapy were 96.6% (56/58) vs 100% (51/51) by the per-protocol analysis and 90.3% (56/62) vs 94.4% (51/54) by the evaluable population analysis. Two patients with 1b + 6 and 1b + 2 genotype infections in the LDV/SOF group had relapse. Evaluating the GLE/PIB vs LDV/SOF groups for the most common AEs revealed pruritus (16.7% vs 4.8%), abdominal discomfort (5.6% vs 8%) and fatigue (5.6% vs 4.8%). One patient with AE-related treatment discontinuation presented with liver decompensation after 4-week GLE/PIB therapy. DAA-related significant laboratory abnormalities occurred in two patients with >3× elevated bilirubin level in the GLE/PIB group. GLE/PIB and LDV/SOF are well tolerated and achieve high SVR12 rates for patients with mixed HCV genotype infection.
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http://dx.doi.org/10.1111/jvh.13305DOI Listing
September 2020

Incidence and predictors of hepatocellular carcinoma beyond year 5 of entecavir therapy in chronic hepatitis B patients.

Hepatol Int 2020 Jul 21;14(4):513-520. Epub 2020 Apr 21.

Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan.

Background: PURPOSE: The study compared the incidence and predictors of hepatocellular carcinoma (HCC) within and beyond year 5 of entecavir (ETV) therapy.

Methods: The study enrolled 1397 CHB patients who were naïve to nucleos(t)ide analogue (NA) treatment and had received ETV monotherapy for more than 12 months.

Results: The cumulative incidences of HCC at 3, 5, and 10 years of ETV treatment were 4%, 9.1%, and 15.8%, respectively. In the entire cohort, the annual incidence rates of HCC were 2.28% within the first 5 years and 1.34% within 5-10 years of therapy. The incidences of HCC did not differ significantly within and beyond 5 years of ETV therapy (p = 0.53), including patients with cirrhosis (p = 0.85) and without cirrhosis (p = 0.47). At year 5 of treatment, the multivariate analysis showed that the fibrosis-4 (FIB-4) index and alpha-fetoprotein (AFP) levels were independent risk factors for HCC development beyond year 5. The 10-year cumulative incidences of HCC beyond year 5 in the high-risk group (FIB-4 > 2.20 and AFP > 3.21 ng/mL) and low-risk group (FIB-4 ≤ 2.20 and AFP ≤ 3.21 ng/mL) were 48.7% and 0%, respectively. APA-B score at 12 months and year 5 had a higher C-index for the prediction of HCC beyond year 5 than the PAGE-B at baseline and year 5 (p = 0.003 and p = 0.039, respectively) CONCLUSIONS: The HCC incidence tended to decrease but did not change significantly within and beyond 5 years of ETV therapy. The FIB-4 index and AFP levels at year 5 were predictive of HCC development beyond year 5 of ETV therapy.
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http://dx.doi.org/10.1007/s12072-020-10031-3DOI Listing
July 2020

Serial changes of renal function after directly acting antivirals treatment for chronic hepatitis C: A 1-year follow-up study after treatment.

PLoS One 2020 14;15(4):e0231102. Epub 2020 Apr 14.

Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.

Background: Our preliminary data showed a slight decrease of estimated glomerular filtration rate (eGFR) after direct-acting antivirals (DAAs) treatment in chronic hepatitis C (CHC). However, long-term outcome of renal evolution after DAAs has not been well documented.

Aim: To assess the renal function under DAAs treatment in CHC patients of an Asian population at 6 months and 1 year after complete treatment.

Methods: A cohort of 1536 CHC patients who received therapies with DAAs were analyzed. Serial eGFR levels at 24 weeks after treatment (SVR24) and 48 weeks after treatment (SVR48) were evaluated. We compared eGFR at baseline, SVR12, SVR24 and SVR48, and defined renal function deterioration as decrease of eGFR >25% from baseline to SVR24 and SVR48.

Results: Overall, there was decline of eGFR from SVR12 to SVR48 in all patients (84.30 ± 27.00 -> 73.20 ± 28.67 mL/min/1.73m2, p<0.001). This trend of decline was similar in all groups. Multivariate analysis for deterioration in renal function from baseline to SVR24 showed liver transplantation, hypertension and baseline eGFR < 60 mL/min/1.73m2 were independent risk factors. Multivariate analysis for persistent deterioration in renal function from baseline to SVR48 showed liver transplantation, baseline eGFR < 60 mL/min/1.73m2 and DCV/ASV use were independent predictive factors.

Conclusions: There is a trend of decline in eGFR at 1-year after DAAs treatment regardless of baseline renal function or DAAs. Liver transplantation and baseline eGFR < 60 mL/min/1.73m2 were independent predictive factors of persistent deterioration in renal function from baseline to SVR48. Close monitoring renal function in these patients was suggested.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231102PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156075PMC
July 2020

Gut Microbiota Dysbiosis in Patients with Biopsy-Proven Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study in Taiwan.

Nutrients 2020 Mar 19;12(3). Epub 2020 Mar 19.

Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.

The gut microbiota plays a role in nonalcoholic fatty liver disease (NAFLD), but data about gut dysbiosis in Asians with NAFLD remains scarce. We analyzed the differences in fecal microbiota between adults with and without NAFLD. This cross-sectional study examined adults with histology-proven NAFLD (25 nonalcoholic fatty liver (NAFL) patients, 25 nonalcoholic steatohepatitis (NASH) patients, and 25 living liver donors (healthy controls)). The taxonomic composition of the gut microbiota was determined by 16S ribosomal RNA gene sequencing of stool samples. The NAFL and NASH groups showed lower total bacterial diversity and richness than the controls. NAFLD patients had higher levels of the phylum Bacteroidetes and lower levels of Firmicutes than controls. The genus , family , order , and class were less abundant in patients with NAFL or NASH than healthy individuals. The lipopolysaccharide biosynthesis pathway was differentially enriched in the NASH group. This study examined the largest number of Asian patients with biopsy-proven NAFL and NASH in terms of dysbiosis of the gut microbiota in NAFLD patients. NAFLD patients had higher levels of Bacteroidetes and lower levels of Firmicutes These results are different from research from western countries and could provide different targets for therapies by region.
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http://dx.doi.org/10.3390/nu12030820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146257PMC
March 2020

Combined Chibby and β-Catenin Predicts Clinical Outcomes in Patients with Hepatocellular Carcinoma.

Int J Mol Sci 2020 Mar 17;21(6). Epub 2020 Mar 17.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.

Chibby is an antagonist of β-catenin and is considered a potential tumor suppressor protein, but the role of Chibby in hepatocellular carcinoma (HCC) has not been characterized. The expression patterns of Chibby and β-catenin in HCC specimens and paired adjacent noncancerous tissues were measured by Western blotting and immunohistochemistry. The correlations between Chibby expression and clinicopathological parameters were analyzed. Then the biological functions of Chibby were analyzed in vitro. The Chibby protein was significantly downexpressed in human primary HCC tissues compared to that in matched adjacent normal liver tissue and is a risk factor for HCC recurrence and shorter survival. Furthermore, we found that in HCC tissues the high expression of β-catenin with low expression of Chibby in the nuclei was an independent predictor for disease-free survival (DFS) ( = 0.012) and overall survival (OS) ( = 0.005). Subsequent genetic manipulation in vitro studies revealed that Chibby knockdown induced the expression of β-catenin and C-myc, cyclin D1 protein, which promoted cell proliferation and invasiveness. In contrast, overexpression of Chibby decreased β-catenin expression and inhibited the cell proliferation and invasiveness. Our results suggest that low expression of Chibby was associated with advanced tumor-node-metastasis (TNM) stage and poor differentiation. Furthermore, the combination of Chibby and β-catenin can predict poor prognosis in patients with HCC. Chibby inhibited HCC progression by blocking β-catenin signaling in vitro. Chibby is a biomarker and may be a potential therapeutic target for HCC.
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http://dx.doi.org/10.3390/ijms21062060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139567PMC
March 2020

Real world clinical practice in treating advanced hepatocellular carcinoma: When East meets West.

PLoS One 2020 12;15(3):e0230005. Epub 2020 Mar 12.

Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Background And Aims: The Barcelona Clinic Liver Cancer (BCLC) stage C (BCLC C) of hepatocellular carcinoma (HCC) includes a heterogeneous population for which sorafeninb is one of the recommended therapies. We aim to evaluate the real world clinical treatment and survival of BCLC stage C patients in an Asian cohort.

Methods: This is a retrospective cohort study that enrolled 427 consecutive BCLC stage C patients diagnosed between 2011 and 2017 by using the HCC registry data for our hospital. All patients were managed via a multidisciplinary team (MDT) approach.

Results: Hepatitis B surface antigen positive was noted in 50.6% of the patients. The patients were classified as performance status (PS)1 alone (n = 83; 19.4%), PS2 alone (n = 23; 5.4%), or macrovascular invasion (MVI) or extrahepatic spread (EHS) (n = 321; 75.2%). The median overall survival (OS) was 11.0 months in the whole cohort. The most frequent treatments were transcatheter arterial embolization (TAE) in the PS1 (45.8%) and PS2 patients (52.2%) and sorafenib (32.4%) in the MVI or EHS patients. The independent prognostic factors were the PS, Child-Pugh class, MVI or EHS, alpha fetoprotein levels, and treatment type.

Conclusions: We reported the real world management in BCLC stage C patients in an Asian cohort through the use of personalized management via a MDT approach.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230005PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067409PMC
June 2020