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Hepatitis C virus (HCV) infection is one of the major etiologies of hepatocellular carcinoma (HCC) with approximately 30% of HCC being due to HCV infection worldwide. HCV eradication by antivirals greatly reduces the risk of HCC; nevertheless, HCC remains to occur in chronic hepatitis C (CHC) patients who have achieved a sustained virological response (SVR). The proportion of post-SVR HCC among newly diagnosed HCC patients is increasing in the direct-acting antiviral (DAA) era and might be due to preexisting inflammatory and fibrotic liver backgrounds, immune dysregulation between host and virus interactions, as well as host epigenetic scars, genetic predispositions and alternations. By means of applying surrogate markers and adopting risk stratification, HCC surveillance should be consistently performed in high-risk populations. In this review, we discuss the possible molecular mechanism, risk factors, and HCC surveillance strategy for HCC development after HCV eradication in CHC patients.

Background/Aims Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P

Abstract Lifestyle modification is the standard of care for nonalcoholic fatty liver disease (NAFLD) patients. We aimed to investigate the efficacy of a short‐term lifestyle modification program in the disease course of Taiwanese nonalcoholic steatohepatitis (NASH) patients with paired biopsies. All patients received a 6‐month, strict multidisciplinary program of lifestyle modifications led by physicians, dieticians, and nursing staff. The histopathological and clinical features were assessed. The endpoints were normalization of transaminase levels, metabolic parameters, a decrease in the NAFLD activity score (NAS) ≥1, and a decrease in the fibrosis stage ≥1. We also aimed to elucidate the predictors associated with disease progression. A total of 37 patients with biopsy‐proven NASH were enrolled. The normalization of transaminase levels increased from 0% to 13.5%. There were also significantly increased proportions of patients with normal total cholesterol, triglyceride, and hemoglobin A1c levels. Fifteen (40.5%) patients had an increased NAS ≥1, whereas 10 (27.0%) patients had NAS regression. Twelve (32.4%) patients had increased fibrosis ≥1 stage. Only 2 (5.4%) patients experienced fibrosis regression. A high fasting plasma glucose (FPG) level was associated with NAS progression. Older age and higher transaminase and FPG levels were factors associated with fibrosis progression. Seven (18.9%) patients achieved a body weight reduction >3%, and 4 (57.1%) of them experienced NAS regression. No significant effect of weight reduction on the progression of fibrosis was observed. The short‐term lifestyle modification program significantly decreased liver enzymes and metabolic parameters in NASH patients. A more precise or intensive program may be needed for fibrosis improvement.

Abstract The immune response of patients with chronic liver disease tends to be lower after receiving their second coronavirus disease 2019 (COVID‐19) vaccine dose, but the effect of a third vaccine dose on their immune response is currently unknown. We recruited 722 patients without previous severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection from three hospitals. The patients received homologous (MMM) and heterologous (AZAZBNT, AZAZM) boosters, where AZ, BNT, and M denoted the AZD1222, BNT162b2, and mRNA‐1273 vaccines, respectively. Serum IgG spike antibody levels were measured at a mean 1.5 ± 0.7 (visit 1) and 5.0 ± 0.5 (visit 2) months after the third vaccine booster. A threshold of 4160 AU/mL was considered significant antibody activity. In both visits, the patients who received the MMM booster had higher anti‐S‐IgG levels than those who received the AZAZBNT and AZAZM boosters. Patients with active hepatocellular carcinoma (HCC) had lower anti‐S‐IgG levels than the control group (761.6 vs. 1498.2 BAU/mL; p = 0.019) at visit 1. The anti‐S‐IgG levels decreased significantly at visit 2. The patients with significant antibody activity had a lower rate of liver cirrhosis with decompensation (0.7% decompensation vs. 8.0% non‐decompensation and 91.3% non‐liver cirrhosis, p = 0.015), and active HCC (1.5% active HCC vs. 3.7% non‐active HCC and 94.7% non‐HCC, p

Abstract Introduction Eight-week glecaprevir/pibrentasvir (GLE/PIB) is indicated for treatment-naïve (TN) patients with chronic hepatitis C (CHC), with or without compensated cirrhosis. Given that the Taiwanese government is committed to eliminating hepatitis C virus (HCV) by 2025, this study aimed to measure real-world evidence for TN patients using 8-week GLE/PIB in the Taiwan HCV Registry (TACR). Methods The data of patients with CHC treated with 8-week GLE/PIB were retrieved from TACR, a nationwide registry program organized by the Taiwan Association for the Study of the Liver (TASL). Treatment efficacy, defined as a sustained virologic response at posttreatment week 12 (SVR12), was assessed in the modified intention-to-treat (mITT) population, which excluded patients who were lost to follow-up or lacked SVR12 data. The safety profile of the ITT population was assessed. Results A total of 7246 (6897 without cirrhosis; 349 with cirrhosis) patients received at least one dose of GLE/PIB (ITT), 7204 of whom had SVR12 data available (mITT). The overall SVR12 rate was 98.9% (7122/7204) among all patients, 98.9% (6780/6856) and 98.3% (342/348) among patients without and with cirrhosis, respectively. For the selected subgroups, which included patients with genotype 3 infection, diabetes, chronic kidney disease, people who injected drugs, and those with human immunodeficiency virus coinfection, the SVR12 rates were 95.1% (272/286), 98.9% (1084/1096), 99.0% (1171/1183), 97.4% (566/581), and 96.1% (248/258), respectively. Overall, 14.1% (1021/7246) of the patients experienced adverse events (AEs). Twenty-two patients (0.3%) experienced serious AEs, and 15 events (0.2%) resulted in permanent drug discontinuation. Only one event was considered treatment drug related. Conclusion Eight-week GLE/PIB therapy was effective and well tolerated in all TN patients, regardless of cirrhosis status.

Abstract The accuracy of noninvasive seromarkers in predicting liver fibrosis in metabolic dysfunction‐associated fatty liver disease (MAFLD) patients with or without viral hepatitis is elusive. The AST to platelet ratio index (APRI), fibrosis‐4 index (FIB‐4), and NAFLD fibrosis score (NFS) were assessed in 871 MAFLD patients who received elastography in a viral hepatitis‐endemic area. The area under the receiver operating characteristic (AUROC) curve increased substantially with increasing fibrotic stage across the three biomarkers. APRI (AUROC range 0.73–0.80) and FIB‐4 (AUROC range 0.66–0.82) performed better than NFS (AUROC range 0.63–0.75). When patients were divided into viral and non‐viral MAFLD groups, a better AUROC of APRI (range 0.76–0.80) and FIB‐4 (range 0.68–0.78) than NFS (range 0.62–70) existed only in viral MALFD but not in non‐viral MAFLD. Regarding the NFS, the AUROC was higher in non‐viral MAFLD (range 0.69–0.86) and outperformed viral MAFLD at all fibrotic stages. The accuracy in predicting liver fibrosis increased with the advancement of liver disease for the three biomarkers. NFS exerted better diagnostic accuracy in non‐viral than in viral MAFLD patients across different fibrotic stages. The best accuracy was 91.1% using the cutoff value of −9.98 for the NFS in predicting liver cirrhosis in non‐viral MAFLD patients. The APRI and FIB‐4 performed better than the NFS in predicting liver fibrosis in MAFLD as a whole. The suboptimal performance and accuracy of the NFS existed only in viral MAFLD patients. Caution should be taken when assessing the NFS in MAFLD patients with viral hepatitis.

Abstract We aimed to investigate the association between air pollution and advanced fibrosis among patients with metabolic associated fatty liver disease (MAFLD) and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. A total of 1376 participants who were seropositive for HBV surface antigen (HBsAg) or antibodies to HCV (anti‐HCV) or had abnormal liver function in a community screening program from 2019 to 2021 were enrolled for the assessment of liver fibrosis using transient elastography. Daily estimates of air pollutants (particulate matter ≤2.5 μm in diameter [PM2.5], nitrogen dioxide [NO2], ozone [O3] and benzene) were aggregated into mean estimates for the previous year based on the date of enrolment. Of the 1376 participants, 767 (52.8%) and 187 (13.6) had MAFLD and advanced fibrosis, respectively. A logistic regression analysis revealed that the factors associated with advanced liver fibrosis were HCV viremia (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.05–4.77; p

Abstract Elevated serum gamma‐glutamyl transferase (GGT) levels are associated with chronic hepatitis B (CHB)‐related hepatocellular carcinoma. However, their role in predicting mortality in patients with CHB treated with nucleotide/nucleoside analogs (NAs) remains elusive. Altogether, 2843 patients with CHB treated with NAs were recruited from a multinational cohort. Serum GGT levels before and 6 months (Month‐6) after initiating NAs were measured to explore their association with all‐cause, liver‐related, and non‐liver‐related mortality. The annual incidence of all‐cause mortality was 0.9/100 person‐years over a follow‐up period of 17,436.3 person‐years. Compared with patients who survived, those who died had a significantly higher pretreatment (89.3 vs. 67.4 U/L, p = 0.002) and Month‐6‐GGT levels (62.1 vs. 38.4 U/L, p 75 percentile of pretreatment GGT levels was observed with respect to the all‐cause mortality (trend p

Abstract Patients with serious mental illness have a higher risk of hepatitis C virus (HCV) infection but suboptimal HCV care. The current study aimed to facilitate HCV treatment uptake by implementing an integrated outreach care model. Multidisciplinary outreach screening followed by HCV reflex testing and onsite treatment for schizophrenia patients was accomplished through the coordination of nongovernmental organizations, remote specialists, and local care providers. The objective was microelimination effectiveness, defined as the multiplication of the rates of anti‐HCV antibodies screening, accurate HCV RNA diagnosis, treatment allocation, treatment completion, and sustained virological response (SVR12; no detectable HCV RNA throughout 12 weeks in the post‐treatment follow‐up period). A total of 1478 of the 2300 (64.3%) psychiatric patients received HCV mass screening. Seventy‐three (4.9%) individuals were seropositive for anti‐HCV antibodies. Of the 73 anti‐HCV seropositive patients, all (100%) received HCV reflex testing, and 29 (37.7%) patients had HCV viremia. Eight patients (34.8%) had advanced liver disease, including 3 with liver cirrhosis and 2 with newly diagnosed hepatocellular carcinoma. Twenty‐three of the 24 (95.8%) patients who stayed in the healthcare system received and completed 8 weeks of glecaprevir/pibrentasvir treatment and post‐treatment follow‐up without significant DDIs or adverse events. The SVR12 rate was 100%. The microelimination effectiveness in the current study was 61.6%. Individuals with serious mental illness are underserved and suffer from diagnostic delays. This patient‐centered and integrated outreach program facilitated HCV care in this marginalized population.

Background/Aims Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. Methods We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. Results The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. Conclusions Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

Abstract Unawareness of hepatitis B virus (HBV) infection and lack of surveillance may serve as major barriers to HBV control and contributors to severe hepatocellular carcinoma (HCC) at presentation. This study evaluated the risk of HBV unawareness and its relationship with HCC severity. This retrospective study was conducted in a tertiary hospital in Taiwan. Patients with HBV‐related HCC diagnosed from 2011 to 2021 were enrolled. The demographic, clinical, and HCC characteristics were collected and compared between patients with HBV unawareness and awareness with and without surveillance. Of 501 HBV‐related HCC patients enrolled, 105 (21%) patients were unaware of HBV infection at the time of HCC diagnosis. Patients with HBV unawareness were significantly younger and had poorer liver function than those with HBV awareness. Patients with HBV unawareness also had a significantly higher rate of detectable HBV DNA and an advanced stage of HCC. Ninety‐one (23%) of the HBV‐aware patients did not receive regular surveillance. Patients with HBV unawareness and awareness without surveillance shared similar clinical characteristics with more severe HCC status. Further regression analysis demonstrated that HBV awareness with periodic surveillance was associated with early stage HCC. Meanwhile, we observed that there was no change in the proportion of HBV awareness over the past 10 years. Patients with surveillance also had better HCC survival than patients without surveillance or unawareness. HBV unawareness and lack of regular surveillance correlated with advanced HCC at presentation. Efforts to improve HBV education, disease awareness, and HCC surveillance are needed.

Background: Persistent cryoglobulinemia after the completion of antiviral treatment is an important consideration of clinical management in chronic hepatitis C patients. We aimed to investigate the occurrence of serum cryoglobulinemia in chronic hepatitis C patients without cryoglobulinemia at the initiation of antiviral treatment. Methods: In total, 776 patients without cryoglobulinemia were assessed for serum cryoglobulinemia after the completion of anti-HCV treatment. Serum cryoglobulinemia precipitation was assessed upon both the initiation and the completion of the treatment and analyzed for the clinical laboratory factors associated with chronic hepatitis C. Results: One hundred eighteen (118) patients were checked for serum cryo-precipitation after the completion of the treatment, and eight patients (4.6%) were positive for serum cryoglobulinemia. The patients who tested positive for cryoglobulinemia included a higher proportion of liver cirrhosis patients (4/50%, p = 0.033) and other organ cancer patients (5/62.5%, p = 0.006) than patients who showed no signs of cryoglobulinemia after treatment. In a multivariate analysis, liver cirrhosis (odds ratio [OR]—17.86, 95% confidence interval [95% CI]—1.79–177.35, p = 0.014) and other organ cancer (OR–25.17 95% CI—2.59–244.23, p = 0.005) were independently and significantly associated with positive cryoglobulinemia 3 months after antiviral treatment. Conclusions: Three months after the antiviral DAA therapy had concluded, eight patients tested positive for cryoglobulinemia, representing a 6.7% prevalence. Liver cirrhosis and other organ cancer were independently and significantly associated with positive cryoglobulinemia after antiviral treatment. Further investigation into the causes of positive cryoglobulinemia after DAA antiviral therapy is warranted.

Objectives: Gaps in linkage-to-care remain the barriers toward hepatitis C virus (HCV) elimination in the directly-acting-antivirals (DAA) era, especially during SARS Co–V2 pandemics. We established an outreach project to target HCV micro-elimination in HCV-hyperendemic villages. Methods: The COMPACT provided “door-by-door” screening by an “outreach HCV-checkpoint team” and an “outreach HCV-care team” for HCV diagnosis, assessment and DAA therapy in Chidong/Chikan villages between 2019 and 2021. Participants from neighboring villages served as Control group. Results: A total of 5731 adult residents participated in the project. Anti-HCV prevalence rate was 24.0% (886/3684) in Target Group and 9.5% (194/2047) in Control group (P

Abstract Background/Aims Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the best policies to control COVID-19 pandemic. The serological response to COVID-19 vaccination in Taiwanese patients with different comorbidities is elusive. Methods Uninfected subjects who received 3 doses of mRNA vaccines (BNT162b2 [Pfizer-BioNTech, BNT] and mRNA-1273 [Moderna]), viral vector-based vaccines (ChAdOx1-S (AZD1222, AZ) or protein subunit vaccines (Medigen COVID-19 vaccine) were prospectively enrolled. The SARS-CoV-2-IgG spike antibody level was determined within three months after the 3rd dose of vaccination. The Charlson Comorbidity Index (CCI) was applied to determine the association between vaccine titers and underlying comorbidities. Results A total of 824 subjects were enrolled in the current study. The proportions of CCI scores of 0–1, 2–3 and > 4 were 52.8% (n = 435), 31.3% (n = 258) and 15.9% (n = 131), respectively. The most commonly used vaccination combination was AZ–AZ–Moderna (39.2%), followed by Moderna–Moderna–Moderna (27.8%). The mean vaccination titer was 3.11 log BAU/mL after a median of 48 days after the 3rd dose. Factors associated with potentially effective neutralization capacity (IgG level ≥ 4160 AU/mL) included age ≥ 60 years (odds ratio [OR]/95% confidence interval [CI]: 0.50/0.34–0.72, P

Background: An outbreak of SARS-CoV-2 Delta variant infection occurred in Pingtung, Taiwan, in June 2021. In this study, we aimed to elucidate the clinical characteristics of the Delta-variant SARS-CoV-2 infection and the treatment outcome of antiviral agents in patients from Pingtung County in Southern Taiwan. Methods: A total of 11 patients with Delta-variant COVID-19 were consecutively admitted to a governmental hospital in June 2021. Baseline characteristics and treatment outcome were evaluated. Results: All patients were symptomatic. The most common symptoms were cough (72.7%), followed by fever (54.5%), headache (18.2%) and dysosmia/dysgeusia (18.2%). Two patients developed pneumonia without mechanical ventilation requirement. Compared to patients without pneumonia, those with pneumonia had higher aspartate aminotransferase (AST) (21.0 vs. 126.0 IU/L, P = 0.03) and lactate dehydrogenase (LDH) (143.1 vs. 409.0 IU/mL, P = 0.03), and ferritin (0.2 vs. 2.0 mg/L, P = 0.046) levels. Pneumonia improved after 2-week treatment, and no mortality occurred after 30 days of diagnosis. The median duration of viral shedding duration of viral shedding was 16.5 days (range 11–42 days) (defined by time to repeated negative real-time reverse transcriptase polymerase chain reaction (RT-PCR) or a cycle threshold (CT) value ≥ 30). Conclusion: We demonstrated the clinical characteristics of Delta-variant COVID-19 and treatment outcome of antiviral agents. The risk factors attributed to pneumonia were higher serum AST, ferritin, and LDH levels.

Abstract Hepatitis C virus (HCV) eradication through antivirals ameliorates metabolic profiles. The changes in 2‐h plasma glucose (2HPG) levels by oral glucose tolerance test (OGTT), in chronic hepatitis C (CHC) patients who receive directly acting antivirals (DAAs) was elusive. Five hundred and thirty‐three CHC patients who achieved sustained virological response (SVR, undetectable HCV RNA throughout 3 months after the end‐of‐treatment) by DAAs were consecutively enrolled. Pre‐ and posttreatment 2HPG levels and glucose status were compared. The proportion of patients with improved, worsened, and stable 2HPG was 14.4% (n = 77), 18.6% (n = 99), and 67.0% (n = 357), respectively. Compared with patients with worsening 2HPG, those with improved 2HPG had a higher proportion of cirrhosis (45.5% vs. 24.2%, p = 0.004) and higher pretreatment 2HPG levels (175.3 vs. 129.5 mg/dl, p

Background/purpose: The Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) is a nationwide registry of chronic hepatitis C patients in Taiwan. This study evaluated antiviral effectiveness of ledipasvir (LDV)/sofosbuvir (SOF) in patients in the TACR. Methods: Patients enrolled in TACR from 2017–2020 treated with LDV/SOF were eligible. The primary outcome was the proportion of patients with sustained virologic response 12 weeks after end of treatment (SVR12). Results: 5644 LDV/SOF ± ribavirin-treated patients were included (mean age: 61.4 years; 54.4% female). Dominant viral genotypes were GT1 (50.8%) and GT2 (39.3%). 1529 (27.1%) patients had liver cirrhosis, including 201 (3.6%) with liver decompensation; 686 (12.2%) had chronic kidney disease. SVR12 was achieved in 98.6% of the overall population and in 98.2% and 98.7% of patients with and without cirrhosis, respectively. SVR12 rates in patients with compensated cirrhosis treated with LDV/SOF without RBV were >98%, regardless of prior treatment experience. SVR12 was 98.6%, 98.4%, 100%, 100%, and 98.7% among those with GT1, GT2, GT4, GT5, and GT6 infections, respectively. Although patient numbers were relatively small, SVR12 rates of 100% were reported in patients infected with HCV GT2, GT5, and GT6 with decompensated cirrhosis and 98% in patients with severely compromised renal function. LDV/SOF adherence ≤60% (P

Abstract Understanding the barriers and tackling the hurdles of hepatitis C virus (HCV) care cascades is key to HCV elimination. The current study aimed to investigate the rates of disease awareness, link‐to‐care, and treatment uptake of HCV in a hyperendemic area in Taiwan. Tzukuan residents from 2000 to 2018 were invited to participate in the questionnaire‐based interviews for HCV. The rates of disease awareness, accessibility, and anti‐HCV therapy were evaluated in anti‐HCV‐seropositive participants. Among 10,348 residents, 1789 (17.3%) were anti‐HCV seropositive. Of these 1789 anti‐HCV‐seropositive participants, data of 594 participants from questionnaire‐based interviews in 2005–2018 were analyzed for HCV care cascades. Overall, 24.9% of anti‐HCV‐seropositive HCV participants had disease awareness, 53.9% of aware participants had accessibility, and 79.8% of assessed participants had received HCV treatment, with a community effectiveness of 10.7%. HCV prevalence decreased over time, from 21.2% in the early cohort to 9.3% in the recent cohort. Disease awareness increased over time, from 15.6% to 41.7%, with the community effectiveness increasing from 1.3% to 28.8%. Lower education levels and normal liver biochemistry were associated with a lower rate of disease awareness. Notably, 68% of participants with abnormal liver biochemistry and 69% of those with advanced fibrosis (FIB‐4 > 3.25) were unaware of their HCV disease. We demonstrated huge gaps in disease awareness, link‐to‐care, and treatment uptake in the HCV care cascade in an HCV‐hyperendemic area, even in the initial era of direct‐acting antiviral agents. There is an urgent need to overcome these hurdles to achieve HCV elimination.

Abstract Chronic hepatitis B (CHB) patients with low disease activity are at risk of liver fibrosis. The age‐adjusted fibrosis‐4 index (FIB4‐AA), developed in our previous publication, and was implemented to evaluate the tendency of liver fibrosis in these patients. We aimed to investigate the rate of liver fibrosis in CHB patients with low disease activity. Resuming our previous study, the FIB‐4 changes of 244 antiviral treatment‐naïve CHB patients, with a total of 1243.48 person‐years, were reviewed. Among the cohort, patients were categorized as FIB4‐AA positive or negative according to the results of their last FIB4‐AA minus their initial FIB‐4 during at least 18 months of observation time. The compound annual growth rate (CAGR) of FIB‐4 was calculated for the FIB4‐AA positive and negative groups. The assumed healthy controls had an FIB‐4 CAGR calculated to be 2.34% for both men and women, while the FIB‐4 CAGR of the whole study cohort was 2.84% ± 6.01%. FIB4‐AA positive effectively identifies CHB patients with higher mean FIB‐4 CAGR (7.11% ± 3.88% vs. −2.36% ± 3.52%, p

Background/Purpose: Switching to a tenofovir alafenamide (TAF)-containing regimen has been reported to be associated with body weight gain in human immunodeficiency virus-infected subjects. We aimed to investigate the body weight change and virological, hepatic, and renal outcomes of TAF switching among chronic hepatitis B (CHB) patients. Methods: This retrospective study included 121 CHB patients who were switched to TAF after >12 months of treatment with another nucleot(s)ide analog (NUC). All patients were monitored for 12 months. Results: The cohort was mostly Asian (96.7%) with a mean age of 55 years, 72% male, 14% cirrhosis, 21% HBeAg positive, and 75% with prior use of tenofovir disoproxil fumarate. At 12 months after TAF switching, their body weight significantly increased from 66.4 ± 11.8 to 67.8 ± 12.3 kg (p

Abstract The role of Wisteria floribunda agglutinin‐positive Mac‐2 binding protein (WFA+‐M2BP) in the prediction of disease severity in nonalcoholic fatty liver disease (NAFLD) remains elusive. This study evaluated the performance of WFA+‐M2BP in predicting fibrosis in patients with NAFLD. A total of 80 patients with biopsy‐proven nonalcoholic steatohepatitis (NASH) were enrolled. Serum WFA+‐M2BP levels were measured using standard methods. The fibrosis‐4 (FIB‐4) index was also measured. The mean values of WFA+‐M2BP were 1.0, 1.0, 0.8, and 2.2 in Metavir fibrosis stage F0, F1, F2, and F3‐4, respectively (linear trend p = 0.005). The optimal cut‐off value of WFA+‐M2BP in predicting advanced fibrosis (F3‐4) was 1.37 cut‐off index (COI), yielding the sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy of 75.0, 79.4, 39.1, 94.7, and 78.7%, respectively (p

Abstract Cancer stem cell is considered as an important cause to exacerbate the prognosis. NANOG and POU5F1 are markers for cancer stem cells. The associations between NANOG and POU5F1 expressions with the sorafenib anticancer effects in primary cultured hepatocellular carcinoma (HCC) cells were investigated. Eight primary cultured HCC parent cell lines and 13 subgroups established by flow cytometric sorting using NANOG and POU5F1 as targets were investigated with clinically achievable sorafenib plasma concentrations (5 and 10 μg/mL). Sorafenib showed obvious downregulation of RAF/MEK/ERK signaling pathways and dose‐dependent anti‐proliferative effects only on s003 parent cell line, which showed the lowest expression of NANOG among all tested cell lines except one downregulated NANOG with upregulated POU5F1 s020 subgroup. Sorafenib also inhibited proliferation in this s020 subgroup but promoted proliferation in its parent cell line. For the only one downregulated NANOG alone s015 subgroup, sorafenib which had no influence on its parent cell line inhibited proliferation in this subgroup. Only the above three cell lines could demonstrate sorafenib antiproliferative effects. On the contrary, sorafenib promoted proliferation in three (s003, s015, s071) out of four upregulated NANOG alone subgroups. On the other hand, Sorafenib showed diverse influence on proliferation among four upregulated POU5F1 alone subgroups. In conclusion, NANOG rather than POU5F1 expression is a critical marker for the anticancer effects of sorafenib on HCC. The sorafenib anticancer effects on HCC cells with high NANOG expression were limited. Sorafenib should be combined with other drug able to target cancer cells with high NANOG expression.

Abstract Background and Aims Regorafenib has demonstrated its survival benefit for unresectable hepatocellular carcinoma (uHCC) patients in a phase III clinical trial. We aimed to assess the efficacy and tolerability of regorafenib and the predictors of treatment outcomes in Taiwanese patients. Methods We analyzed the survival, best overall response, predictors of treatment outcomes, and safety for uHCC patients who had tumor progression on sorafenib therapy and received regorafenib as salvage therapy between March 2018 and November 2020. Results Eighty‐six patients with uHCC were enrolled (median age, 66.5 years; 76.7% male). The median regorafenib treatment duration was 4.0 months (95% confidence interval [CI], 3.6–4.6). The most frequently reported adverse events were hand‐foot skin reaction (44.2%), diarrhea (36.0%), and fatigue (29.1%). No unpredictable toxicity was observed during treatment. The median overall survival (OS) with regorafenib was 12.4 months (95% CI, 7.8–17.0) and the median progression‐free survival (PFS) was 4.2 months (95% CI, 3.7–4.7). Of 82 patients with regorafenib responses assessable, 4 patients (4.9%) achieved a partial response, and 33 (40.2%) had stable disease, leading to a disease control rate (DCR) of 45.1% (n = 37). Patients possessing baseline AFP 10% reduction at 4 weeks or >20% reduction at 8 weeks after regorafenib administration) exhibited comparable treatment outcomes to those with baseline AFP

Abstract The study evaluated the real-world treatment outcomes of Glecaprevir/pibrentasvir (GLE/PIB) including effectiveness, safety and healthcare resource utilization based on a nation-wide registry in Taiwan. The Taiwan HCV Registry (TACR) is a nation-wide platform organized and supervised by the Taiwan Association for the Study of the Liver. Data were analyzed for patients treated with GLE/PIB, including 3144 patients who had treatment outcome available. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA throughout 12 weeks of end-of-treatment). The overall SVR12 rate was 98.9% (3110/3144), with 98.8%, 99.4% and 100% in patients receiving 8 weeks, 12 weeks, and 16 weeks of GLE/PIB respectively. The SVR12 rate in the treatment-naïve cirrhotic patients receiving 8 weeks of GLE/PIB was 98.2% (108/110). The most common AEs were fatigue (7.5%), pruritus (6.7%) and dizziness (1.5%). The mean number of outpatient visits during the GLE/PIB was 5.94 visits for patients treated with 8 weeks, significantly different from the patients treated with 12 weeks of GLE/PIB (6.90 visits). The results support the effectiveness and safety of GLE/PIB treatment in real-world clinical practice, and provide further evidence that the shorter, 8-week GLE/PIB regimen is effective and cost-saving.

The advantage of colchicine to promote sorafenib or regorafenib anti-cancer effects on hepatocellular carcinoma (HCC) was investigated. Four primary cultured HCC cell lines (S103, S143, S160, S176) were studied by clinically achievable plasma sorafenib (5, 10 μg/mL), regorafenib (2, 4 μg/mL) and colchicine (4 ng/mL) concentrations. Sorafenib and regorafenib target genes and cancer stem cell markers (NANOG, POU5F1) were selected for experiments. Colchicine inhibited proliferation in all cell lines. Sorafenib inhibited proliferation only in S143 (5 μg/mL). Combined colchicine with sorafenib reversed the sorafenib effect on cellular proliferation from promotive to inhibitory in S103, and demonstrated anti-proliferative effects on other cell lines. Regorafenib inhibited proliferation in S103 (2 μg/mL), S176 (2 μg/mL) and S160 (4 μg/mL). Combined colchicine with regorafenib demonstrated equal or stronger anti-proliferative effects than regorafenib alone in all cell lines except S160. Combined colchicine obliterated or reduced the number of up-regulated target genes induced by sorafenib, and demonstrated equal or increased number of down-regulated target genes as compared with regorafenib alone. However, combined colchicine with regorafenib increased one up-regulated target gene in three cell lines. Colchicine obliterated or decreased the magnitude of up-regulated NANOG induced by sorafenib (S103, S143, S176) or regorafenib (S143), and combined with regorafenib could down-regulate NANOG (S160, S176). Adding colchicine to sorafenib or regorafenib showed inconsistent influence on POU5F1 expression as compared with sorafenib or regorafenib alone. The above results suggest that the anti-cancer effects of combined sorafenib with colchicine may be better than sorafenib alone. Colchicine may be added to regorafenib non-responders.

Abstract Previous in vitro and in vivo experiments had demonstrated dose‐dependent anti‐cancer effects of clinical plasma colchicine concentrations on hepatocellular carcinoma (HCC) cells. This phase IIa trial was to evaluate the potential efficiency and safety of our novel colchicine dosage schedule for the palliative treatment of advanced HCC. The dosage schedule started from oral intake of 1 mg colchicine three times per day for 4 days and discontinuation in the following 3 days (one cycle). The treatment cycle was repeated and the dosage was adjusted ranging from 3 to 1.5 mg/day according to the condition of the participant. The control group was originated from chart review of 86 HCC patients treated by sorafenib for more than 2 months. Fifteen participants signed the inform consent. Two participants were excluded due to screening failure in one and less than four treatment cycles in another. For severe adverse events, the colchicine group demonstrated higher incidence of biliary tract obstruction (p = 0.0184) than the sorafenib group. Comparison grade 1 or 2 adverse events between two groups, the colchicine group had higher incidence of diarrhea (p = 0) and the sorafenib group had higher incidence of palmar‐plantar erythrodysesthesia syndrome (p = 0.0045). There was no significant difference in mortality, median survival, and overall survival between two groups (all p > 0.2). In conclusion, our novel colchicine dosage schedule is clinically feasible and has the potential to be applied in the palliative treatment of advanced HCC especially based on the cost‐effectiveness consideration.

Abstract Chronic hepatitis C (CHC) is a major cause of cirrhosis, hepatocellular carcinoma (HCC), and mortality. Eliminating hepatitis C virus (HCV) can greatly improve long‐term outcomes. Several direct‐acting antiviral agents (DAAs), including sofosbuvir (SOF) plus different NS5A inhibitors, as well as non‐SOF‐based DAAs, including glecaprevir/pibrentasvir (GLE/PIB), have been approved for treating CHC genotype‐2 (GT‐2) patients in Taiwan. However, there is limited real‐world effectiveness data regarding these different regimens. Thus, we aimed to evaluate the real‐world efficacy in CHC GT‐2 patients who underwent these DAA regimens. We retrospectively enrolled CHC GT‐2 patients who were treated with SOF‐based DAAs or GLE/PIB at a single medical center. A total of 704 enrolled patients were treated with either SOF + ribavirin (RBV), SOF/daclatasvir (DCV) ± RBV, SOF/ledipasvir (LDV) ± RBV, SOF/velpatasvir (VEL) ± RBV, or with GLE/PIB. The overall sustained virological response (SVR) rate was 97.9%. The SVR rate was significantly lower in the SOF + RBV group (95.6%) than in the non‐SOF + RBV (98.9%) group, especially compared to the SOF/DCV (100%) and GLE/PIB groups (99.5%). Among patients treated with SOF + RBV, cirrhotic patients had significantly lower SVR rates than noncirrhotic patients (89.4% vs 98.2%). Multivariate analysis showed that patients with a younger age, hepatitis B virus coinfection, baseline cirrhosis, or those who received SOF + RBV were less likely to achieve SVR. In conclusion, for CHC GT‐2 patients, SOF in combination with DCV, LDV, or VEL, as well as GLE/PIB, achieved similar high efficacies, regardless of cirrhosis, treatment experience, or chronic kidney disease status. Therefore, the use of DAA therapy to eradicate HCV should not be delayed in these populations.

Background/Aims Growth hormone (GH) is the main regulator of somatic growth, metabolism, and gender dimorphism in the liver. GH receptor (GHR) signaling in cancer is derived from a large body of evidence, although the GHR signaling pathway involved in the prognosis of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC, remains unclear. We aimed to explore the expression of GHR and analyze its association with clinicopathologic features and prognosis of patients with chronic hepatitis C and HCC. Methods The expression of GHR mRNA was investigated by quantitative real-time polymerase chain reaction in paired tumors and adjacent non-tumorous (ANT) liver tissues of 200 patients with chronic hepatitis C and HCC. Western blotting and immunofluorescence assays using the HCV-infected Huh7.5.1 cell model was performed. Results GHR mRNA was significantly lower in HCV-HCC tissues than in corresponding ANT liver tissues. GHR mRNA and protein levels also decreased in the HCV-infected Huh7.5.1 cell model. Notably, lower GHR expression was associated with age of >60 years (P=0.0111) and worse clinicopathologic characteristics, including alpha-fetoprotein >100 ng/mL (P=0.0403), cirrhosis (P=0.0075), vascular invasion (P=0.0052), pathological stage II–IV (P=0.0002), and albumin ≤4.0 g/dL (P=0.0055), which were linked with poor prognosis of HCC. Most importantly, the high incidence of recurrence and poor survival rates in patients with a low ratio of tumor/ANT GHR (≤0.1) were observed, indicating that low expression levels of GHR had great risk for development of HCC in patients with chronic hepatitis C. Conclusions Our study demonstrates a significant down-regulation of GHR expression as a new unfavorable independent prognostic factor in patients with chronic hepatitis C and HCC.

Abstract The spreading of viral hepatitis among injecting drug users (IDU) is an emerging public health concern. This study explored the prevalence and the risks of hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV) among IDU-dominant prisoners in Taiwan. HBV surface antigen (HBsAg), antibodies to HCV (anti-HCV) and HDV (anti-HDV), viral load and HCV genotypes were measured in 1137(67.0%) of 1697 prisoners. 89.2% of participants were IDUs and none had HIV infection. The prevalence of HBsAg, anti-HCV, dual HBsAg/anti-HCV, HBsAg/anti-HDV, and triple HBsAg/anti-HCV/anti-HDV was 13.6%, 34.8%, 4.9%, 3.4%, and 2.8%, respectively. HBV viremia rate was significantly lower in HBV/HCV-coinfected than HBV mono-infected subjects (66.1% versus 89.9%, adjusted odds ratio/95% confidence intervals [aOR/CI] = 0.27/0.10–0.73). 47.5% anti-HCV-seropositive subjects (n = 396) were non-viremic, including 23.2% subjects were antivirals-induced. The predominant HCV genotypes were genotype 6(40.9%), 1a(24.0%) and 3(11.1%). HBsAg seropositivity was negatively correlated with HCV viremia among the treatment naïve HCV subjects (44.7% versus 72.4%, aOR/CI = 0.27/0.13–0.58). Anti-HCV seropositivity significantly increased the risk of anti-HDV-seropositivity among HBsAg carriers (57.1% versus 7.1%, aOR/CI = 15.73/6.04–40.96). In conclusion, IUDs remain as reservoirs for multiple hepatitis viruses infection among HIV-uninfected prisoners in Taiwan. HCV infection increased the risk of HDV infection but suppressed HBV replication in HBsAg carriers. An effective strategy is mandatory to control the epidemic in this high-risk group.

Abstract Hepatitis D virus (HDV) infection increases the risk of hepatocellular carcinoma (HCC) in the natural course of chronic hepatitis B (CHB) patients. Its role in patients treated with nucleotide/nucleoside analogues (NAs) is unclear. We aimed to study the role of hepatitis D in the development of HCC in CHB patients treated with NAs. Altogether, 1349 CHB patients treated with NAs were tested for anti-HDV antibody and RNA. The incidence and risk factors of HCC development were analyzed. Rates of anti-HDV and HDV RNA positivity were 2.3% and 1.0%, respectively. The annual incidence of HCC was 1.4 per 100 person-years after a follow-up period of over 5409.5 person-years. The strongest factor association with HCC development was liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI] 9.98/5.11–19.46, P 50 years old (HR/CI 3.64/2.03–6.54, P

Abstract Whether patients with advanced hepatocellular carcinoma (aHCC) benefit from hepatitis C virus (HCV) eradication is uncertain. We aimed to investigate whether a survival benefit was conferred by HCV eradication in aHCC patients. This retrospective cohort study enrolled 168 HCV‐infected aHCC patients from April 2013 to January 2019. All patients were treated with sorafenib. Endpoints included overall survival (OS), progression free survival (PFS), and time to liver decompensation. Patients with undetectable HCV RNA exhibited reduced aspartate aminotransferase and alpha fetoprotein levels, as well as an attenuated proportion of aHCC at initial diagnosis but increased albumin and mean sorafenib daily dosing. Patients with undetectable HCV RNA exhibited significantly longer OS compared to patients with detectable or unknown HCV RNA, which was an independent factor of OS (HR: 0.56, 95% CI: 0.350‐0.903, P = .017). Patients with undetectable HCV RNA also presented a trend for longer PFS (HR 0.68, 95% CI: 0.46‐1.00, P = .053). The survival benefit was considered with respect to the significantly prolonged time to Child‐Pugh B scores in patients with undetectable HCV RNA (HR 0.59, 95% CI: 0.38‐0.92, P = .020). Patients with detectable HCV RNA at sorafenib initiation who further received direct acting antiviral therapy also had significantly longer OS (HR 0.11, 95% CI: 0.02‐0.81, P = .030) and PFS (HR 0.23, 95% CI: 0.06‐0.99, P = .048). In conclusion, abolishing HCV viremia preserves liver function and confers a survival benefit in advanced HCC patients on sorafenib treatment.

Background: The biochemical response is a crucial indicator of prognosis in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues (NAs). The impact of hepatitis D virus (HDV) infection on alanine aminotransferase normalization is elusive. Methods: The longitudinal study recruited 1185 CHB patients who received NAs. These patients were tested for anti-HDV antibody and HDV RNA at the initiation of anti-hepatitis B virus (HBV) therapy and annually for patients who were HDV-seropositive. ALT levels were examined at the first and second year of anti-HBV therapy. ALT abnormality was defined as ALT levels above 40 IU/mL in both male and female, and the risk factors associated with ALT abnormality were analysed. Results: Rates of seropositivity for anti-HDV and HDV RNA were 2.0% and 0.8% among 1185 NA-treated CHB patients, respectively. The strongest factor associated with ALT abnormality (>40 IU/mL) after first year treatment with NAs was HDV RNA seropositivity at year 1 (odds ratio [OR]/95% confidence interval [CI]: 31.44/3.49–283.56, P = 0.002), followed by liver cirrhosis (2.18/1.51–3.15, P

Background/Aims Obstacles exist in facilitating hepatitis C virus (HCV) care cascade. To increase timely and accurate diagnosis, disease awareness and accessibility, in-hospital HCV reflex testing followed by automatic appointments and a late call-back strategy (R.N.A. model) was applied. We aimed to compare the HCV treatment rate of patients treated with this strategy compared to those without. Methods One hundred and twenty-five anti-HCV seropositive patients who adopted the R.N.A. model in 2020 and another 1,396 controls treated in 2019 were enrolled to compare the gaps in accurate HCV RNA diagnosis to final treatment allocation. Results The HCV RNA testing rate was significantly higher in patients who received reflex testing than in those without reflex testing (100% vs. 84.8%, P

Background/Aims Direct‐acting antivirals (DAAs) have been approved for hepatitis C virus (HCV) treatment in patients with end-stage renal disease (ESRD) on hemodialysis. Nevertheless, the complicated comedications and their potential drug-drug interactions (DDIs) with DAAs might limit clinical practice in this special population. Methods The number, class, and characteristics of comedications and their potential DDIs with five DAA regimens were analyzed among HCV-viremic patients from 23 hemodialysis centers in Taiwan. Results Of 2,015 hemodialysis patients screened in 2019, 169 patients seropositive for HCV RNA were enrolled (mean age, 65.6 years; median duration of hemodialysis, 5.8 years). All patients received at least one comedication (median number, 6; mean class number, 3.4). The most common comedication classes were ESRD-associated medications (94.1%), cardiovascular drugs (69.8%) and antidiabetic drugs (43.2%). ESRD-associated medications were excluded from DDI analysis. Sofosbuvir/velpatasvir/voxilaprevir had the highest frequency of potential contraindicated DDIs (red, 5.6%), followed by glecaprevir/pibrentasvir (4.0%), sofosbuvir/ledipasvir (1.3%), sofosbuvir/velpatasvir (1.3%), and elbasvir/grazoprevir (0.3%). For potentially significant DDIs (orange, requiring close monitoring or dose adjustments), sofosbuvir/velpatasvir/voxilaprevir had the highest frequency (19.9%), followed by sofosbuvir/ledipasvir (18.2%), glecaprevir/pibrentasvir (12.6%), sofosbuvir/velpatasvir (12.6%), and elbasvir/grazoprevir (7.3%). Overall, lipid-lowering agents were the most common comedication class with red-category DDIs to all DAA regimens (n=62), followed by cardiovascular agents (n=15), and central nervous system agents (n=10). Conclusions HCV-viremic patients on hemodialysis had a very high prevalence of comedications with a broad spectrum, which had varied DDIs with currently available DAA regimens. Elbasvir/grazoprevir had the fewest potential DDIs, and sofosbuvir/velpatasvir/voxilaprevir had the most potential DDIs.

Abstract Hepatitis C virus (HCV) eradication deteriorates lipid profiles. Although HCV eradication may reduce the risk of vascular events as a whole, whether deteriorated lipid profiles increases the risk of cardio‐cerebral disease in certain patients is elusive. Serial lipid profiles were measured before, during, at and 3 months after the end of direct‐acting antivirals (DAAs) therapy, and annually thereafter in chronic hepatitis C patients who achieved a sustained virological response (SVR, undetectable HCV RNA at posttreatment week 12). The primary end‐point was the occurrence of the events. A total of 617 patients were included, with a mean follow‐up period of 26.8 months (range: 1‐65 months). The total cholesterol and low‐density lipoprotein cholesterol (LDL‐C) levels increased significantly from treatment week 4 to 2 years after treatment. Logistic regression analysis revealed that the factors independently associated with a significant cholesterol increase included age (odds ratio [OR]/95% confidence intervals [CIs]:1.02/1.006‐1.039, P = .007) and smoking (OR/CI:3.21/1.14‐9.02, P = .027). Five patients developed cardio‐cerebral diseases during 1376 person‐years follow‐up period. Compared to patients without vascular events, a significantly higher proportion of those with vascular events experienced an LDL‐C surge >40% (80% vs 19.9%, P = .001). Cox‐regression analysis revealed that an LDL‐C surge >40% was the only factor predictive of vascular events (HR/CI: 15.44/1.73‐138.20, P = .014). Dyslipidemia occurred after HCV eradication, and it was associated with the risk of cardio‐cerebrovascular diseases. Attention should also be paid to the extrahepatic consequence beyond liver‐related complications in the post‐SVR era.

Abstract The utility of primary culture originated from the residual aspiration specimens to predict outcomes of hepatocellular carcinoma patients receiving curative treatment was investigated. A total of 105 American Joint Committee on Cancer TNM stage I or II patients were included. The culture results were determined at the 28th of culture and were divided into rapid proliferation of cancer cells alone, rapid proliferation of both cancer cells and cancer‐associated fibroblasts, rapid proliferation of cancer‐associated fibroblasts alone, slow proliferation, and no outgrowth of plating specimens. Our results showed that outgrowths of cultured cells from plated particles were achieved in 98.1% of patients. Sixty‐nine patients (65.7%) showed rapid proliferation of cultured cells (11 rapid proliferation of cancer cells alone, 17 rapid proliferation of both cancer cells and cancer‐associated fibroblasts, and 41 rapid proliferation of cancer‐associated fibroblasts alone). There was no significant difference in the incidence of recurrence or survival between patients with normal and abnormal serum alpha‐fetoprotein levels, chronic hepatitis B and chronic hepatitis C, TNM stage I and stage II, histological high‐grade and low‐grade hepatocellular carcinoma, and between patients treated by operative resection and local abrasion. Only patients with rapid proliferation of cancer cells ± rapid proliferation of cancer‐associated fibroblasts showed significantly higher incidence of recurrence than patients with other growth types (P = .0482), but there was no significant difference in survival between two groups. In conclusion, primary culture using this method is clinically feasible and can be applied to predict recurrence of hepatocellular carcinoma patients receiving curative treatment.

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.

The treatment of chronic hepatitis C (CHC) has been revolutionized in an era of all-oral direct-acting antivirals (DAAs) since 2014. Satisfactory treatment efficacy and tolerability can be provided by novel DAAs. Nevertheless, there are still some unmet needs and emerging issues in the treatment of CHC in the DAA era. Certain hard-to-cure populations are prone to have inferior treatment responses, including patients with severe liver decompensation, active hepatocellular carcinoma (HCC), and hepatitis C virus (HCV) genotype 3 (HCV-3) infection and those who experience multiple DAA treatment failures. Hepatitis B virus (HBV) reactivation during and after DAA treatment has raised concern regarding the use of prophylactic antivirals against HBV throughout DAA treatment. However, the standard strategy for the use of prophylactic antivirals is not uniform across regional guidelines. In the post-sustained virological response (SVR) period, HCC still occurs in a substantial proportion of patients. Due to the relatively short follow-up period, the net benefit of the achievement of an SVR by DAAs in the reduction of extrahepatic manifestations has not yet been determined. Attention must also be paid to HCV reinfection, particularly in high-risk populations. The most critical and unmet need for HCV elimination is the large gap in the HCV care cascade at the population level. To accomplish the World Health Organization (WHO)’s goal for HCV elimination by 2030, the expansion of access to HCV care requires a continuous effort to overcome practical and political challenges.

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.

Abstract Results of fine‐needle aspiration of hepatic nodules may be equivocal to confuse clinical judgment. The utility of primary culture of aspiration residual specimens to improve the accuracy in differential diagnosis between hepatocellular carcinoma and benign lesions was investigated. A total of 337 patients (hepatocellular carcinoma proven by aspiration 277, by other modalities 35, benign nodules 25) were included. The growth patterns of cancer cells at the 14th day of primary culture from aspiration proven hepatocellular carcinoma patients were applied as criteria for analysis. Hepatocellular carcinoma proven by aspiration showed higher incidence of outgrowth of cancer cells than those not proven by aspiration or the incidence of outgrowth of hepatocyte antigen positive cells in benign lesions (all P 2 cm. Using at least one positive result of growth patterns or aspiration as item for differential diagnosis increased the sensitivity, negative predictive value and accuracy, but little decreased the specificity and positive predictive value as compared with aspiration results alone in nodules measuring either ≤ or >2 cm. In conclusion, the growth patterns at the 14th day of primary culture can be applied for dynamic interpretation of the specimens to improve the diagnostic accuracy of fine‐needle aspiration between hepatocellular carcinoma and benign lesions.

Background: The features and risk analysis of non-alcoholic fatty liver disease (NAFLD) in a community-based setting remain elusive. The predictors between obese and lean subjects need further clarification. We aimed to assess the characteristics of NAFLD during a community screening. The associated metabolic abnormalities and cardiovascular risk assessment were also analyzed. Methods: A total of 2483 subjects receiving multi-purpose health screening at 10 primary care centers were recruited. They received clinical assessment, including demographic data, laboratory examination, and abdominal sonography. Results: The prevalence of NAFLD and metabolic syndrome were 44.5%, and 15.8%, respectively. Among those NAFLD subjects, 1212 (48.8%) subjects were obese (BMI≥ 24 kg/m2). There was an increasing trend of NAFLD according to age, ranging from 25.8% of those aged 27 kg/m2 (P for trend< 0.0001). Conclusion: IR is predictive of NAFLD irrespective of BMI. The cardiovascular risk may exist in lean NAFLD subjects. Keywords: Non-alcoholic fatty liver disease, Metabolic syndrome, Insulin resistance, Risk assessment, Community screening

BackgroundHigh dosage and longer duration of antiviral treatment has been suggested to treat cryoglobulinemia patients. We aimed to investigate the efficacy of antiviral treatment in cryoglobulinemia patients and analyze the associated factors of persistent cryoglobulinemia.MethodsTotally 148 patients after completion of anti-HCV treatment were enrolled in our study. Serum cryoglobulinemia precipitation was assessed and analyzed for the associated factors after antiviral therapy.ResultsFifty-one (34.5%) out of 148 patients were positive for serum cryoglobulinemia after completion of antiviral therapy. In multivariate analysis, advanced fibrosis (Odds Ratio [OR]- 4.13, 95% Confidence Interval [95% CI]- 1.53-11.17, p = 0.005) and platelet counts (OR-0.98, 95% CI- 0.97-0.99, p = 0.010) were independently and significantly associated with persistent cryoglobulinemia. The factors associated with the persistent cryoglobulinemia in SVR patients were advanced fibrosis (OR-1.93, 95% CI- 1.02-3.65, p = 0.041) and platelet count (OR-0.98, 95% CI- 0.96-0.99, p = 0.041) by multivariate analysis. Multivariate logistic regression analysis showed persistent (OR-4.83, 95% CI- 1.75-13.36, p = 0.002) was significantly associated with advanced fibrosis in patients with cryoglobulinemia follow up after antiviral therapy.ConclusionsThe prevalence of the persistent cryoglobulinemia is 34.5% after completing antiviral therapy and it is associated with advanced fibrosis, also HCV clearance.

Background and aims The itemization difference of patient-reported outcome (PRO) in hepatitis patients with different etiologies remains elusive in Asia. We aimed to assess the characteristics and the difference of health-related quality of life (HRQoL) in chronic hepatitis B (CHB), chronic hepatitis C (CHC), and non-alcoholic fatty liver disease (NAFLD) patients. Methods We conducted the study in an outpatient setting. The 36-Item Short Form Health Survey (SF-36) was completed by the patients upon the initial diagnosis and recruitment for a long-term follow-up purpose. The PRO results were also assessed by disease severity. Results There were 244 patients (198 males) of CHB, 54 patients (29 males) of CHC, and 129 patients (85 males) of NAFLD, respectively. CHC patient had the mean score of 67.1 ± 23.3 in physical component summary (PCS) of the SF-36 health survey, which was significantly lower than CHB patients (76.4 ± 19.5), and NAFLD patients (77.5 ± 13.7), respectively (p = 0.001). The significantly lower performance of PCS in CHC patients was mainly attributed to the lower performance in physical functioning and bodily pain components. Higher fibrosis 4 index scores were significantly associated with lower PCS scores in all patient groups. There was no significant difference of mean mental component summary (MCS) between groups. However, NAFLD patients had significantly lower mental health scores than other groups (p = 0.02). Conclusions The significant difference of HRQoL exists in hepatitis patients with different etiologies. Disease severity leads to a lower PCS performance.

The regulatory role of microRNAs (miRNAs) in HBV-associated HCC pathogenesis has been reported previously. This study aimed to investigate the association between serum miR-125b and liver fibrosis progression in chronic hepatitis B (CHB) patients after nucleos(t)ide analog (NA) treatment. Baseline serum miR-125b levels and other relevant laboratory data were measured for 124 patients who underwent 12-month NA therapy. Post-12-month NA therapy, serum miR-125, platelet, AST, and ALT levels were measured again for post-treatment FIB-4 index calculation. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for a higher post-treatment FIB-4 index. Results showed that baseline miR-125b levels were inversely correlated with the post-treatment FIB-4 index (ρ = −0.2130, p = 0.0082). In logistic regression analyses, age (OR = 1.17, p < 0.0001), baseline platelet level (OR = 0.98, p = 0.0032), and ALT level (OR = 1.00, p = 0.0241) were independent predictors of FIB-index > 2.9 post-12-month treatment. The baseline miR-125b level was not significantly associated with a higher post-treatment FIB-4 index (p = 0.8992). In 59 patients receiving entecavir (ETV) monotherapy, the alternation of serum miR-125b in 12 months and age were substantially associated with a higher post-treatment FIB-4 index (>2.9), suggesting that miR-125b is a reliable biomarker for detecting early liver fibrosis under specific anti-HBV NA treatments (e.g., ETV).

The high accessibility to healthcare and increasing awareness of hepatocellular carcinoma (HCC) surveillance after sustained virologic response (SVR) to HCV treatment allow early detection of operable HCC in Taiwan. However, the effects of achieving SVR on patient characteristics and surgical outcomes after curative resection remain elusive. We aimed to compare the clinical presentation and postoperative prognosis among patients with early-stage HCV-related HCC and different viral status. We retrospectively analyzed 208 patients with BCLC stage 0 or A-HCC, including 44 patients who remained HCV viremic, 90 patients who developed HCC after achieving SVR (post-SVR HCC), and 74 patients who subsequently achieved SVR after resection. Patients with post-SVR HCC had a lower degree of hepatitis and better liver function than those who achieved SVR or remained viremic after resection. Notably, 75.6% of patients with post-SVR HCC did not have cirrhosis. Patients with post-SVR HCC and those achieving SVR after resection exhibited comparable recurrence rates and recurrence-free survival, while patients with persistent viremia had the worst surgical outcomes. We concluded that patients with post-SVR HCC had a better liver function but similar surgical outcomes compared with patients who achieved SVR after resection. The low prevalence of cirrhosis in patients with post-SVR HCC highlights the importance of regular surveillance after SVR.

Abstract Sorafenib is currently the first‐line therapy for advanced hepatocellular carcinoma (aHCC) patients. However, the outcomes and prognostic factors of sorafenib therapy have not been well investigated. We aimed to investigate the pretreatment factors and outcomes among Taiwanese aHCC patients receiving sorafenib treatment. A total of 347 patients with aHCC and well‐compensated liver cirrhosis (Child‐Pugh A) status receiving sorafenib were consecutively enrolled from March 2013 through December 2016. Pre‐treatment clinical data and viral hepatitis markers were collected and analyzed with their outcomes. The primary endpoint of the study was overall survival. The factors associated with overall survival were also investigated. The median overall survival of all the patients was 238 days (range, 9‐1504 days) with a 1‐year overall survival of 43.2%. Positive hepatitis B surface antigen and absence of portal vein thrombosis (PVT) were independent factors associated with better overall survival. The median duration of sorafenib therapy was 93.0 days (range, 4‐1504 days). After stopping sorafenib, the median survival was 93.0 days (range, 1‐1254 days). The 1‐year survival after stopping sorafenib was 21.2%. In chronic hepatitis B patients, total bilirubin level was the only factor associated with overall survival. Hepatitis C antibody RNA negativity, tumor size, PVT, and white blood cell count were the independent factors associated with survival among those chronic hepatitis C patients. There were different prognostic factors stratified by viral etiologies in aHCC patients receiving sorafenib. Viral eradication increased survival in chronic hepatitis C patients.

Abstract The majority of patients undergoing methadone maintenance treatment (MMT) are neither examined nor treated for hepatitis C virus (HCV) infection. We aimed to evaluate an integrated referral model in the management of HCV among MMT patients. This retrospective study included 390 HCV‐infected MMT patients between April 2015 and May 2017. Patients who tested positive for HCV antibodies were referred to a liver clinic by MMT case managers or psychiatrists. Patients who agreed to receive anti‐HCV treatment were treated with pegylated interferon and ribavirin. The rate of patient engagement at a liver clinic increased from 14.1% to 58.2% after integrated care. Multiple logistic regression analysis showed that higher education level (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.01‐2.60) and elevated ALT level (OR, 4.30; 95% CI, 2.70‐6.85) were independently associated with patients who accepted referral. Active drug use (OR, 0.52; 95% CI, 0.31‐0.85) was inversely associated with referral acceptance. Of the 112 patients who met the criteria for anti‐HCV therapy, 66 (58.9%) were treated with pegylated interferon and ribavirin. Finally, the rate of treatment completion and sustained virological response (SVR) was 65.2% and 54.5%, respectively, among the 66 patients. Treatment completion (OR, 39.67; 95% CI, 7.80‐201.62) was found to be the only independent factor associated with SVR achievement. Although integrated care by psychiatrists and hepatologists significantly increased the rates of engagement and acceptance of antiviral treatment for HCV‐infected MMT patients, only a minority of MMT patients achieved successful treatment.

During the clinical trial development of directly acting antivirals (DAAs), evidence regarding the treatment efficacy in chronic hepatitis C patients with hepatocellular carcinoma (HCC) was scarce because these patients have always been excluded. Apart from the clinical trials, more HCC patients are currently being treated in daily practice, given that these treatments are highly effective and involve well-tolerated regimens. Large scale, real-world studies have demonstrated potentially suboptimal antiviral treatment efficacy in HCC patients who received DAAs. It is postulated that the impairment of the bioavailability of DAAs may account for the inferior treatment response. However, the results could not be generalized across all studies. The differing results were attributed to diverse patient characteristics, suboptimal regimens or imprecise definitions of active cancer statuses at the time of treatment initiation. Additional large-scale studies that utilize the treatment of choice in clearly defined HCC patients with different disease severities are warranted to clarify the issue.

Background/Purpose: Treatment with daclatasvir plus asunaprevir (DCV + ASV) for 24 weeks provided a sustained virologic response (SVR) rate of over 90% in hepatitis C virus genotype 1b (HCV-1b) infected patients without non-structural 5A (NS5A) resistance-associated substitutions (RASs) at the L31 and Y93 sites. In this study, we investigated whether adding ribavirin to the DCV + ASV combination could shorten the original treatment regimen to 12 weeks without compromising the treatment efficacy for HCV-1b patients without NS5A RASs. Methods: In the prospective, open-label, single-arm, nationwide multi-center phase III study, a total of 70 interferon-naïve or interferon-experienced HCV-1b patients without baseline L31/Y93 RASs received daclatasvir (60 mg/day) and asunaprevir (100 mg twice daily) plus weight-based ribavirin (1000–1200 mg/day) for 12 weeks, with a 12-week post-treatment follow-up. The primary end-point was the rate of undetectable HCV RNA 12 weeks post-treatment (SVR12). Results: The SVR12 rate was 97.1% (68/70) and 100% (68/68) in the full-analysis-set and the per-protocol population, respectively. None of the 68 patients who completed the 12-week treatment experienced relapse during post-treatment follow-up. Two patients withdrew from the study at treatment days 21 and 34 due to anorexia and fatigue, which were considered ribavirin-related and resolved post medication cessation. A total of 4 serious adverse events were reported and considered treatment-unrelated. No deaths or grade 4 adverse events requiring hospitalization was observed throughout the study. Conclusion: Truncated regimen of DCV + ASV plus ribavirin for 12 weeks was highly effective and safe in HCV-1b patients without NS5A L31/Y93 RAS. Keywords: DCV, ASV, RBV, CHC, Abbreviated treatment

Background and aimsHepatitis C virus (HCV) genotyping is a pivotal tool for epidemiological investigation, guiding management and antiviral treatment. Challenge existed in identifying subtypes of genotype-1 (G-1) and genotype (GT) of indeterminate. Recently, the Abbott HCV RealTime Genotype Plus RUO assay (HCV GT Plus) has been developed aiming to overcome the limitations. We aimed to evaluate the performance of the assay compared with 5' UTR sequencing in clinical samples.Materials and methodsEligible individuals were treatment chronic hepatitis C patients that were enrolled consecutively in a medical center and two core regional hospitals in southern Taiwan from Oct 2017 through Aug 2018. The patient with genotype 1 without subtype and indeterminate previously genotyped by Abbott RealTime HCV GT II will further determinate by Abbott HCV RealTime HCV GT Plus. All of the genotype results were validated by 5' UTR sequencing as a reference standard.ResultsA total of 100 viremic CHC patients were recruited, including 63 G-1 patients (male: 28), and 37 patients (male: 15) of indeterminate genotyped by Abbott RealTime HCV GT II assay (HCV GT II), respectively. The detection rate of 63 GT1 samples without subtype were 93.7% (59/63), 37 indeterminate samples without genotype were 62.2 (23/37) by HCV GT Plus. 5' UTR sequencing confirmed HCV GT Plus characterized results for 84.7% (50/59) of type1, with 100% (4/4), 82.8 (24/29) and 84.6% (22/26) for 1a, 1b and type6; 65.2% (15/23) of indeterminate with 100% (3/3) and 60% (12/20) for 1b and type 6 samples, respectively.ConclusionsThe Abbott RealTime HCV GT Plus RUO assay provides additional performance in GT detection.