Search

Background/Purpose This study aims at investigating the epidemiological profile of chronic hepatitis C (CHC) regarding hepatitis C virus (HCV) genotype in Taiwan. Methods A total of 29,087 CHC patients with advanced fibrosis who received direct-acting antivirals (DAAs) therapy under Taiwan's National Health Insurance (NHI) during 2017–2018 were recruited. The HCV genotype distribution and its association with patients' demographic factors including age, gender, and geographical areas were examined. Results The most common genotypes were 1b (59.5%) and 2 (30.1%) with characteristics of older age (mean ± standard deviation (SD): 66.5 ± 10.7 years and 67.3 ± 10.9 years) and female gender predominant (57.1% and 59.4%), which were associated with iatrogenic infection decades ago. Most of patients with genotype 1a (5.9%) and 6 (3.7%) infection were relatively younger (59.2 ± 12.0 years and 60.0 ± 13.8 years) and male gender predominant (59.1% and 61.1%), except Liujia and Liuying districts in southern Taiwan. The youngest group (53.2 ± 11.8 years) and most male gender predominant (74.3%) was genotype 3 (0.37%). These genotypes with characteristics of being younger and male gender predominant were highly related to injection drug use in recent years. The number of genotype 4 patients were extremely rare (n = 25) and efficacy of genotype-4-specific-DAA was significantly poorer than non-genotype-4-specific DAA (P value = 0.0411). Conclusions The significant differences in demographic characteristics among CHC patients with different HCV genotypes found in this study suggest HCV genotype was highly associated with transmission pattern and may be used as a reference for HCV control.

Background Patients with different hepatitis C virus (HCV) genotype infections are associated with varying metabolic disorders. Although alteration of lipid metabolism has been confirmed as a virus-induced metabolic derangement in chronic hepatitis C patients, the impact of various HCV genotypes on hepatic cholesterol metabolism remains elusive. In this study, we thus investigated the HCV genotype-specific lipogenic and cholesterol metabolism profiles in an in vitro cell culture system. Methods We first conducted HCV cell culture system (HCVcc) assays by infecting Huh7.5.1 cells with multiple infection-competent HCV strains, including the genotype 2a JFH1 and JFH1-based intergenotypic recombinants 1b and 3a. We then examined the expression levels of various lipid and cholesterol-related genes. Results The data showed that infection with individual HCV genotypes exerted unique gene expression regulatory effects on lipoproteins and cholesterol metabolism genes. Of note, all HCV strains suppressed cholesterol biosynthesis in hepatocytes through downregulating the expression of HMG-CoA reductase (HMGCR) and farnesyl-diphosphate farnesyltransferase 1 (FDFT1) – two essential enzymes for cholesterol biosynthesis. These HCV-mediated inhibitory effects could be reversed by treatment with sofosbuvir, a pangenotypic NS5B inhibitor. In addition, overexpression of HCV genotype 1b, 2a or 3a core protein significantly suppressed HMGCR mRNA transcription and translation, thus diminished cellular cholesterol biosynthesis. Nonetheless, the core protein had no effect on FDFT1 expression. Conclusion Although HCV infection regulates host lipid metabolism in a genotype-specific manner, its inhibition on hepatocellular cholesterogenic gene expression and total cholesterol biosynthesis is a common effect among HCV genotype 1b, 2a and 3a.

Data regarding the efficacy and tolerability of elbasvir/grazoprevir (EBR/GZR) for East-Asian hepatitis C virus genotype 1b (HCV GT1b) patients receiving hemodialysis were limited. We prospectively recruited 40 HCV GT1b hemodialysis patients who received EBR/GZR for 12 weeks at 6 academic centers in Taiwan. The efficacy endpoints were sustained virologic response 12 weeks off-therapy (SVR12) by intention-to-treat (ITT) modified ITT (mITT) analyses. Patients’ baseline characteristics, early viral kinetics and HCV resistance-associated substitutions (RASs) at HCV non-structural 3 and 5 A (NS3 and NS5A) regions potentially affecting SVR12 were analyzed. The tolerability for EBR/GZR was also assessed. The SVR12 rates by ITT and mITT analyses were 95% (38 of 40 patients; 95% confidence interval (CI): 83.5–98.6%) and 100% (38 of 38 patients; 95% CI: 90.8–100%), respectively. Patients’ baseline characteristics, on-treatment viral decline, and baseline HCV RASs did not affect SVR12. All patients tolerated treatment well. Among 5 patients who had serious adverse events (AEs) including one death due to on-treatment suicide and the other death due to off-therapy acute myocardial infarction, none of these events were judged related to EBR/GZR. The common AEs included upper respiratory tract infection (7.5%), fatigue (5.0%) and anorexia (5.0%). Nine (22.5%) and 8 (20.0%) patients had on-treatment hemoglobin levels of 9.0–10.0 g/dL and 7.0–9.0 g/dL. Three (7.5%) patients had on-treatment elevated alanine aminotransferase (ALT) quotient > 2.5, in whom one (2.5%) had EBR/GZR-induced late ALT elevation. No patients developed hyperbilirubinemia or hepatic decompensation. In conclusion, treatment with EBR/GZR is effective and well-tolerated for East-Asian HCV GT1b patients receiving hemodialysis.

Background & Aims Acute HEV infection causes varying degrees of liver damage. Although liver-related death due to HEV infection alone is rare in healthy individuals, it is unclear whether HEV superinfection is associated with worse outcomes in patients with chronic HBV infection. Thus, we explored whether HEV superinfection was associated with increased incidence of liver-related death, cirrhosis, and hepatocellular carcinoma (HCC). Methods Serum and data were collected from 2 independent retrospective cohorts of patients with chronic HBV infection, comprising 2,123 patients without cirrhosis and 414 with cirrhosis at baseline, respectively. All the patients were negative for HEV-IgG at enrolment and HEV superinfection was defined by the presence of HEV-IgG seroconversion. Results In the non-cirrhotic cohort, 46 of 2,123 patients developed HEV superinfection. Though HEV superinfection was only associated with increased incidence of liver-related death in the overall cohort, it was a risk factor for all 3 endpoints (liver-related death, cirrhosis, and HCC) in a subgroup of 723 HBeAg-negative patients with chronic HBV infection. In addition, the 1-year mortality rate after HEV superinfection was higher in 4 patients who developed cirrhosis during the follow-up than in those who did not (50% vs. 2.4%, p = 0.001). To elucidate the perceived relationship between HEV superinfection and risk of mortality, an independent cohort of cirrhotic patients (n = 414) was further analyzed to control for the inherent increase in mortality risk due to cirrhosis. The 10 cirrhotic patients with HEV superinfection had a higher 1-year mortality rate than those without (30% vs. 0%, p Conclusions In both cohorts of patients with chronic HBV infection, acute HEV superinfection increases the risk of liver-related death, especially in those with cirrhosis. Lay summary The mortality caused by acute hepatitis E virus infection is usually low in the healthy population, but it is unclear how it affects patients with chronic hepatitis B virus infection, as they already have compromised liver function. Our data show that the 1-year mortality rate is 35.7% in patients with hepatitis B-related cirrhosis who contract hepatitis E virus. Hepatitis E may accelerate disease progression in patients with chronic hepatitis B.

Background Prophylaxis with nucleos(t)ide analogue (NA) is recommended to prevent hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)–positive patients receiving rituximab-based B-cell depletion therapy. However, little is known about the risk of clinical relapse after withdrawal of NA. Methods We retrospectively analyzed 77 noncirrhotic HBsAg carriers with hematological cancer who received rituximab-containing chemotherapy. All of them received either prophylactic entecavir or tenofovir therapy. The risk of clinical relapse and hepatic decompensation after cessation of NA was explored. Results Clinical relapse and hepatic decompensation developed in 25 (32.5 %) and 11 (14.3 %) of the patients, respectively, and 2 patients died of hepatic decompensation. Most of the hepatic events occurred within 1 year (20 of 25; 80.0%) after stopping NA. A higher pretreatment viral load (≥2000 vs Conclusions Pretreatment HBV DNA ≥2000 IU/mL is associated with increased risk of liver-related disease after cessation of prophylactic NA therapy in patients who received rituximab-containing chemotherapy.

Background & Aims Data regarding the nephrotoxicity of sofosbuvir (SOF) remain controversial. We compared the evolution of estimated glomerular filtration rate (eGFR) in patients with chronic HCV infection receiving SOF-based or SOF-free direct-acting antivirals (DAAs). Methods A total of 481 patients with compensated liver diseases and eGFR ≥30 ml/min/1.73m2, receiving SOF-based (n = 308) or SOF-free (n = 173) DAAs for 12 weeks, were prospectively enrolled. The eGFR was assessed from baseline to off-treatment week 24 using the chronic kidney disease (CKD)-epidemiology collaboration equation. Differences in the evolution of eGFR between regimens were compared by a generalized linear mixed-effects model. Multivariate analysis was performed for factors affecting eGFR evolution. Results Patients receiving SOF-based DAAs experienced a significant on-treatment decline in eGFR (adjusted slope coefficient difference: −1.24 ml/min/1.73m2/month; 95% CI −1.35 to −1.13; p Conclusions Patients receiving SOF-based DAAs exhibited a quadratic trend, with eGFR worsening on treatment and improving off treatment. Increasing age, SOF-based DAAs, and more advanced baseline CKD stage are independently associated with a decline in eGFR in patients with HCV receiving DAAs. Lay summary While the efficacy of sofosbuvir for the treatment of hepatitis C virus is clear, data regarding its possible nephrotoxicity are controversial. Herein, we showed that sofosbuvir worsened on-treatment kidney function but led to an off-treatment improvement. Our findings suggest that treating physicians should be alert to risk factors for kidney dysfunction before initiating direct-acting antiviral treatment for patients with hepatitis C virus infection. Clinical trial number NCT04047680

Background & aims Large-scale data regarding the real-world effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) for patients with chronic hepatitis C virus (HCV) infection were limited in East Asia. We aimed to evaluate the clinical performance of GLE/PIB in different HCV populations in Taiwan. Methods A total of 658 chronic HCV patients with compensated liver diseases receiving GLE/PIB for 8 (n = 549), 12 (n = 103) or 16 (n = 6) weeks were retrospectively enrolled. The effectiveness was determined by sustained virologic response at off-therapy 12 weeks (SVR12 ). Patient characteristics potentially related to SVR12 and the safety profiles were also assessed. Results By evaluable population (EP) and per-protocol (PP) analyses, the overall SVR12 rate was 98.2% (95% confidence interval (CI): 96.8%-99.0%) and 99.4% (95% CI: 98.4%-99.8%). The SVR12 rates were 98.9% (95% CI: 97.6%-99.5%), 94.2% (95% CI: 87.9%-97.3%) and 100% (95% CI: 60.1%-100%) in patients receiving 8, 12 and 16 weeks of treatment respectively. A total of 656 (99.7%) patients completed the scheduled treatment. The SVR12 rates were comparable regardless of baseline characteristics or week 4 viral decline. Twenty (3.0%) patients had serious adverse events (AEs), but none were not related to GLE/PIB. The two most common AEs were pruritus (7.8%) and fatigue (5.5%). Two (0.3%) and no patients had ≥3-fold upper limit of normal (ULN) for total bilirubin and alanine aminotransferase (ALT) levels. Conclusions GLE/PIB for 8-16 weeks is effective and well-tolerated for patients with chronic HCV infection in Taiwan.

Data are limited regarding the real-world effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) in patients with chronic hepatitis C virus (HCV) infection and severe renal impairment (RI). We aimed to evaluate the performance of GLE/PIB in patients with chronic kidney disease (CKD) stage 4 or 5 in Taiwan. 108 chronic HCV patients with CKD stage 4 (n = 32) or 5 (n = 76) receiving GLE/PIB for 8-12 weeks were retrospectively recruited at 4 academic centres in Taiwan. The effectiveness was determined by sustained virologic response at off-therapy week 12 (SVR12 ) for evaluable (EP) and per-protocol populations (PP). The safety profiles were also assessed. By EP and PP analyses, the SVR12 rate was 99.1% (107 of 108 patients; 95% confidence interval (CI): 94.9%-99.8%) and 100% (107 of 107 patients; 95% CI: 96.5%-100%). The SVR12 rates were 100% (95% CI: 89.3%-100%) and 98.7% (95% CI: 92.9%-99.8%) in patients with CKD stage 4 and 5, respectively. One patient, who declined off-therapy follow-up after permanently discontinuing GLE/PIB at on-treatment week 9 due to scheduled cardiac surgery, had nonvirologic failure. Sixteen (14.8%) patients had serious adverse events (AEs), which were judged not related to GLE/PIB. The three most common AEs were pruritus (19.4%), fatigue (15.7%) and nausea (13.9%). None had ≥3-fold upper limit of normal for total bilirubin and alanine aminotransferase levels. None of the 9 patients with hepatitis B virus (HBV) coinfection developed HBV-associated hepatitis. In conclusion, GLE/PIB for 8-12 weeks is effective and well-tolerated in HCV patients with severe RI.

Background and Aims: Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel biomarker correlating with liver fibrosis stages. However, little is known about how it predicts risks of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving long-term antiviral treatment. Materials and Methods: The study contained 2 parts. The first part was to explore whether M2BPGi could be an HCC predictor in 899 CHB patients receiving long-term entecavir therapy. The second part was to validate the findings in an independent cohort of 384 on-treatment CHB patients with more severe liver disease. Results: In the discovery cohort, there were 64 patients developing HCC within an average follow-up of 7.01 years. Our data showed that M2BPGi level was positively associated with HCC development. When stratifying the patients by an M2BPGi level of 1.73 (the third quartile), the high M2BPGi group was shown to have an increased HCC risk compared to the low M2BPGi group with hazard ratio of 5.80 (95% CI 3.50–9.60). Furthermore, we found that the M2BPGi level complements PAGE-B score, a well-validated HCC prediction model, to predict HCC development. Lastly, the cutoff was validated in the independent cohort, especially those with an intermediate PAGE-B score. Conclusions: In CHB patients receiving long-term antiviral treatment, serum M2BPGi level not only serves as an independent HCC predictor but also complements PAGE-B in stratifying HCC risks.

Summary The Asia-Pacific region is home to more than half of the global population and accounted for 62·6% of global deaths due to liver diseases in 2015. 54·3% of global deaths due to cirrhosis, 72·7% of global deaths due to hepatocellular carcinoma, and more than two-thirds of the global burden of acute viral hepatitis occurred in this region in 2015. Chronic hepatitis B virus (HBV) infection caused more than half of the deaths due to cirrhosis in the region, followed by alcohol consumption (20·8%), non-alcoholic fatty liver disease (NAFLD; 12·1%), and chronic infection with hepatitis C virus (HCV; 15·7%). In 2015, HBV accounted for about half the cases of hepatocellular carcinoma in the region. Preventive strategies for viral hepatitis-related liver disease include increasing access to clean drinking water and sanitation. HBV vaccination programmes for neonates have been implemented by all countries, although birth-dose coverage is extremely suboptimal in some. Availability of screening tests for blood and tissue, donor recall policies, and harm reduction strategies are in their initial stages in most countries. Many governments have put HBV and HCV drugs on their essential medicines lists and the availability of generic versions of these drugs has reduced costs. Efforts to eliminate viral hepatitis as a public health threat, together with the rapid increase in per-capita alcohol consumption in countries and the epidemic of obesity, are expected to change the spectrum of liver diseases in the Asia-Pacific region in the near future. The increasing burden of alcohol-related liver diseases can be contained through government policies to limit consumption and promote less harmful patterns of alcohol use, which are in place in some countries but need to be enforced more strictly. Steps are needed to control obesity and NAFLD, including policies to promote healthy lifestyles and regulate the food industry. Inadequate infrastructure and insufficient health-care personnel trained in liver diseases are issues that also need to be addressed in the Asia-Pacific region. The policy response of most governments to liver diseases has thus far been inadequate and poorly funded. There must be a renewed focus on prevention, early detection, timely referral, and research into the best means to introduce and improve health interventions to reduce the burden of liver diseases in the Asia-Pacific region.

BACKGROUND Maternal anti-viral treatment prevents mother-to-infant transmission of hepatitis B virus (HBV), but the role of neonatal viremia on subsequent HBV infection is not clear. AIMS To investigate the effect of maternal anti-viral treatment on neonatal serum HBV DNA and hepatitis B surface antigen (HBsAg) in infants born to highly viremic mothers and the roles of neonatal markers in predicting chronic HBV infection in children. METHODS Serum HBV DNA and HBsAg were tested in children. Of the 201 pregnant mothers, 110 received tenofovir during the third trimester. Chronic infection in children was defined by HBsAg seropositivity at 6 or 12 months lasting more than 6 months. RESULTS The maternal HBV viral loads from baseline to delivery were 8.25 ± 0.48 to 4.29 ± 0.98 log10 IU/mL; and 8.29 ± 0.49 to 8.12 ± 0.68 log10 IU/mL in the tenofovir and control group respectively. Of the 208 children, those in the tenofovir group had a lower rate of neonatal HBV DNA seropositivity at birth (5.22% vs 30.11%, P

BACKGROUND AND AIM The NIACE score provides prognostic values for hepatocellular carcinoma (HCC) in European studies. We aim to evaluate the prognostic value of the NIACE score in Asian patients. METHODS Patients with HCC were retrospectively enrolled from a tertiary medical center in Taiwan during 2009-2014, and their clinical information were collected. The NIACE score was calculated according to the Nodular numbers, tumor Infiltration, Alpha-fetoprotein level, Child-Pugh score, and Eastern Cooperative Oncology Group score. The prognostic values of NIACE score for overall survival according to individual treatment and the Barcelona clinic liver cancer (BCLC) staging were analyzed. RESULTS A total of 468 patients were included with a median follow-up of 30 months. A greater NIACE score correlated with lower median survival and higher BCLC staging. Regardless of treatment modalities, NIACE scores (0, 1-1.5, 2.5-3, and 4-7) significantly predicted survival between groups (log-rank P

BACKGROUND AND AIM Data regarding the efficacy and safety of paritaprevir/ritonavir, ombitasvir plus dasabuvir (PrOD) for East Asian non-cirrhotic hepatitis C virus genotype 1b (HCV GT1b) patients receiving hemodialysis were limited. METHODS Forty-six HCV GT1b non-cirrhotic patients receiving hemodialysis who received PrOD for 12 weeks were prospectively enrolled in seven academic centers in Taiwan. The primary efficacy endpoint was sustained virologic response 12 weeks off-therapy (SVR12 ). Patients' baseline characteristics, early virokinetics, and HCV resistance-associated substitutions (RASs) potentially related to SVR12 were analyzed. The safety profiles were also assessed. RESULTS The SVR12 rate was 100% (46 of 46 patients). Patients' baseline characteristics, on-treatment viral decline, and baseline HCV resistance-associated substitutions did not affect SVR12 . All patients tolerated treatment well. One patient with folliculitis temporarily discontinued treatment, and another two patients had serious adverse events (SAEs), which were considered not related to PrOD treatment. The common adverse events were pruritus (19.6%), fatigue (15.2%), and upper respiratory tract infection (6.5%). Twelve (19.6%) and one (2.2%) patients had hemoglobin levels

Overexpression of metastatic tumor antigen 1 (MTA1) was correlated with poor prognosis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC). The aim of this study was to examine the clinical significance of the expression of MTA1 and its exon 4-excluded form (MTA1dE4), the most abundant spliced variant of MTA1, in patients receiving curative resection for HBV-HCC. We collected 102 patients with HBV-HCC and received curative resection retrospectively and examined the expressions level of total MTA1/MTA1dE4 in their paired nontumor and tumor liver tissues by using RT-qPCR. The association between MTA1/MTA1dE4 expression and various tumor features as well as tumor recurrence was analyzed. During the median follow-up period of 4 years, 25 patients (24.5%) showed early recurrence (within 12 months postresection) and 42 (54.5%) showed late recurrence. In Kaplan-Meier analysis, MTA1dE4 overexpression in tumor, but not MTA1, was associated with early recurrence (P = 0.0365), but not late recurrence. In multivariate analysis, only alpha-fetoprotein (AFP) ≥200 ng/mL (P = 0.006) and large tumor size (P = 0.027) were correlated with early recurrence. In the subgroup of patients with AFP

BACKGROUND AND AIM Data regarding the comparative effectiveness and safety of sofosbuvir (SOF) in combination with ribavirin (RBV), daclatasvir (DCV), or ledipasvir (LDV) for hepatitis C virus genotype 2 (HCV-2) patients were limited. We aimed to evaluate the performance of these regimens in Taiwan. METHODS One hundred eighty-seven HCV-2 patients with compensated liver diseases receiving SOF in combination with RBV (n = 82), DCV (n = 66), or LDV (n = 39) for 12 weeks were retrospectively enrolled. The effectiveness was determined by sustained virologic response 12 weeks off therapy (SVR12 ). The patient characteristics potentially related to SVR12 were compared. The safety profiles and laboratory abnormalities were assessed. RESULTS The SVR12 rates were 93.9% (95% confidence interval [CI]: 86.5-97.4%), 98.5% (95% CI: 91.9-99.7%), and 100% (95% CI: 91.0-100%) in patients receiving SOF combined with RBV, DCV, and LDV, respectively. All patients tolerated treatment well. The stratified SVR12 rates were comparable regardless of baseline characteristics or week 4 viral decline among these regimens. Six (3.2%) patients had serious adverse events which were not related to treatment. The rates of fatigue, pruritus, and anemia tended to be higher in patients receiving RBV (22.0%, 19.5%, and 8.5%) combination than those receiving DCV (10.6%, 6.1%, and 1.5%) or LDV (10.3%, 5.1%, and 0%) combination. CONCLUSIONS Sofosbuvir in combination with RBV, DCV, or LDV for 12 weeks is effective and well-tolerated for HCV-2 patients. Compared with DCV or LDV combination, the risks of fatigue, pruritus, and anemia are higher in patients receiving RBV combination.

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 Hepatitis B virus (HBV) persistently infected about 250 million people worldwide, and a curative treatment remains an unmet medical need. Among many approaches to treat chronic hepatitis B (CHB), therapeutic vaccines have been developed for two decades, but none have yielded promising results in clinical trials. Therefore, dissection of HBV clearance mechanisms during therapeutic vaccination in appropriate models, which could give rise to new curative therapies, is urgently needed. Growing evidence indicates that prolonged and intensive exposure of antigen-specific T cells to viral antigens is a major cause of T cell exhaustion, and decreases anti-HBV immunity efficacy of therapeutic vaccination. HBV X protein (HBx) is expressed at low levels, and the understanding of its immunogenicity and potential in therapeutic CHB vaccines is limited. Methods HBV genome sequences from CHB patients were cloned into a pAAV plasmid backbone and transfected into immunocompetent mouse hepatocytes through hydrodynamic injection. Mice carrying > 500 IU/mL serum HBV surface antigen (HBs) for more than 4 weeks were considered HBV carriers mimicking human CHB and received 3 doses of weekly HBx vaccine by subcutaneous immunization. Serum HBV clearance was evaluated by monitoring serum HBs and HBV-DNA titers. Residual HBV in the liver was evaluated by western blotting for HBV core antigen. The splenic antigen-specific T cell response was quantified by a 15-mer overlapping peptide-stimulated interferon-γ enzyme-linked immunospot assay. Blood and hepatic immune cells were quantified by flow cytometric analysis. Results Our HBx-based vaccine induced systemic HBx-specific CD4+ and CD8+ T cell responses in HBV carrier mice and demonstrated significant HBs and HBV-DNA elimination. The protective effect persisted for at least 30 days without additional booster immunization. Different infiltrating myeloid cell subsets, each with distinctive roles during immune-mediated HBV clearance, were found in the liver of vaccinated mice. During vaccine therapy, inflammatory monocyte depletion resulted in sustained HBV clearance inhibition, whereas phagocytic monocyte-derived macrophage and Kupffer cell elimination resulted in only transient inhibition of vaccine-induced HBV clearance. Conclusions We report the potential role of HBx as a major immunogen in an HBV therapeutic vaccine and the significance of a liver-infiltrating monocyte subset during hepatic viral clearance.

BACKGROUND Chronic hepatitis B has been linked to lymphoma with contradictory results. AIM To investigate the association between chronic hepatitis B and lymphoma by using a nationwide population-based cohort. METHODS Records of patients diagnosed with chronic hepatitis B (hepatitis B virus [HBV] cohort) or without (non-HBV cohort) during 2004-2007 were retrieved from the Taiwan National Health Insurance Research Database. Age, sex, comorbidities, and medical visits were matched using propensity scores between both cohorts, and they were followed up longitudinally until 2012 to determine any new lymphoma development. RESULTS A total of 203 031 patients were included in each cohort with a mean follow-up of 7-9 years. The lymphoma incidence rate was significantly higher in the HBV cohort than in the non-HBV cohort (29.4 vs 15.9 per 100 000 person-years, P

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Sarcomatoid HCC is a rare histological subtype of HCC with largely unclear clinical manifestations and outcomes. We evaluated the clinical manifestations and outcomes of patients with sarcomatoid HCC. We identified 5,047 patients with histologically proven HCC from the Cancer Registry Database (1996-2016) of National Taiwan University Hospital. Among them, 40 patients with sarcomatoid HCC were identified from the pathology database of National Taiwan University Hospital. We included 160 patients with nonsarcomatoid HCC through propensity score matching according to sex, age, and Barcelona Clinic Liver Cancer stage. The majority of these patients with sarcomatoid HCC were men (75%); their median age was 58 years. Only 47.5% of the patients with sarcomatoid HCC presented with typical image patterns of HCC. The pathological grading of sarcomatoid HCC was more advanced compared with that of nonsarcomatoid HCC (42.5% vs. 23.8% in grade III and IV, P < 0.0001). The sarcomatoid group had significantly shorter median recurrence-free (13.3 vs. 84.2 months, log-rank P < 0.0001) and overall (8.3 vs. 69.3 months, log-rank P < 0.0001) survival than did the nonsarcomatoid group. The results of the multivariable Cox proportional hazard model revealed histological sarcomatoid subtype as an independent factor for all-cause mortality (hazard ratio [HR], 6.47; 95% confidence interval [CI], 3.12-13.43; P < 0.0001) and tumor recurrence (HR, 4.08; 95% CI, 1.72-9.66; P = 0.001). Conclusion: Compared with nonsarcomatoid HCC, sarcomatoid HCC was associated with more advanced histological grades and atypical image patterns. Histological sarcomatoid subtype is an independent predictor of tumor recurrence after curative treatment and all-cause mortality in patients with HCC.

Despite the excellent antiviral effects of direct acting antivirals (DAAs) for hepatitis C virus (HCV) infection with subsequent decrease of morbidity and mortality, a small proportion (5%) of the treated patients do not respond to first-line DAAs and have persistent viremia. Rescue therapy for patients with DAA failures is thus mandatory from both clinical and public health perspectives. Sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX), a fixed-dose pangenotypic rescue agent, has been approved by the Food and Drug Administration (FDA) and European Medical Agency (EMA) for retreating HCV patients who fail prior DAA therapies. However, this agent has not been licensed by health authorities of Taiwan. Herein we reported two cases who successfully cleared HCV by using SOF/VEL/VOX plus ribavirin (RBV) after virologic failures to first-line pangenotypic SOF/VEL. Furthermore, we discussed the current unmet medical needs and clinical implications of SOF/VEL/VOX on the perspectives of HCV elimination in Taiwan.

Most hepatocellular carcinomas (HCCs) develop in patients with chronic hepatitis, which creates a microenvironment for the growth of hepatic progenitor cells (HPCs) at the periportal area and subsequent development of HCCs. We investigated the signal from the inflammatory liver for this pathogenic process in the hepatic conditional β-catenin knockout mouse model. Senescent β-catenin-depleted hepatocytes in aged mice create an inflammatory microenvironment that stimulates periportal HPC expansion but arrests differentiation, which predisposes mice to the development of liver tumors. The release of complement C1q from macrophages in the inflammatory niche was identified as the unorthodox signal that activated the β-catenin pathway in periportal HPCs and was responsible for their expansion and de-differentiation. C1q inhibitors blocked the β-catenin pathway in both the expanding HPCs and the liver tumors but spared its orthodox pathway in pericentral normal hepatocytes. This mechanism has been validated in human liver specimens from patients with chronic hepatitis. Taken together, these results demonstrate that C1q- mediated activation of β-catenin pathway in periportal HPCs is a previously unrecognized mechanism for replenishing hepatocytes in the inflammatory liver and, if unchecked, for promoting hepatocarcinogenesis. C1q may become a new target for blocking carcinogenesis in patients with chronic hepatitis.

Background and aims Patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are at risk of developing adverse outcomes. Coinfection with both viruses may further increase the risk. Currently, little is known about the role of fibrosis-4 (FIB-4) index, a simple liver fibrosis stage biomarker, in predicting the clinical outcomes. Methods We retrospectively enrolled 152 non-cirrhotic patients with dual chronic HCV and HBV infection: 56 patients received pegylated interferon/ribavirin therapy, while 96 patients remained untreated. The association between the FIB-4 index and the incidence of liver cirrhosis and hepatocellular carcinoma (HCC) was explored. Results After a 9.88-year follow-up, the incidence of hepatitis B surface antigen seroclearance was 4.97 (95% confidence interval: 3.13-7.89) per 100 person-years in the treated group and was 1.77 (1.10-2.85) in the untreated group. Of the treated group, only three and six patients developed HCC and liver cirrhosis, respectively, while 17 and 23 patients developed HCC and liver cirrhosis, respectively, in untreated group. Baseline FIB-4 index correlated with the development of liver cirrhosis in multivariable analysis of all subjects. High baseline FIB-4 index (per 1 point increase) in the treated groups was associated with a higher risk of developing liver cirrhosis (P = 0.001) and HCC (P = 0.038) in univariable analysis. FIB-4 index decreased only in the treated group who achieved sustained virological response (n = 34, FIB-4 index decreasing from 1.84 to 1.55). Conclusions In Taiwanese patients coinfected with HCV and HBV, FIB-4 index helps identify patients at risk of developing adverse events, even in patients receiving pegylated interferon/ribavirin therapy.

Purpose To investigate the clinical utility and longitudinal change of acoustic radiation force impulse (ARFI) ultrasonographic (US) imaging in patients with chronic hepatitis B. Materials and Methods A retrospective cohort study of patients with chronic hepatitis B who underwent serial ARFI examinations in a tertiary referral center in Taiwan between 2012 and 2016 was conducted. The clinical information and noninvasive liver stiffness measurement tests (ARFI, Fibrosis-4 index [FIB-4], and FibroScan) were collected. Serial ARFI measurements were compared in patients without antiviral therapy (nontreatment group) and during antiviral therapy (treatment group). The linear mixed-effects model with random coefficients was used to compare longitudinal repeated measurements. Results A total of 559 patients undergoing serial ARFI examinations were included. The ARFI value correlated with FIB-4 (correlation coefficient = 0.55, P.001) and FibroScan (correlation coefficient = 0.69, P.001) results. There were 314 patients with five or more ARFI measurements in more than 3 years of follow-up. The ARFI value remained unchanged in the nontreatment group (n = 189, from 1.11 to 1.11 m/sec, time trend P = .911). However, the ARFI value declined significantly in the treatment group (n = 125, from 1.63 to 1.37 m/sec, time trend P.001), both in patients with cirrhosis (n = 51, from 2.15 to 1.75 m/sec, time trend P.001) and in those without (n = 74, from 1.27 to 1.11 m/sec, time trend P.001). Conclusion ARFI US imaging is an important clinical noninvasive test for liver stiffness measurement and can be used for serial measurements in the management of chronic hepatitis B. Antiviral therapy significantly reduces liver stiffness during longitudinal follow-up.

BACKGROUND AND AIM The real-world effectiveness and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) remain limited for East Asian hepatitis C virus genotype 1b (HCV-1b) patients. The study aimed to evaluate the antiviral responses of PrOD-based regimens for HCV-1b patients in Taiwan. METHODS The study performed a retrospective analysis of 103 HCV-1b patients receiving PrOD with or without ribavirin (RBV) for 12 weeks. Data were analyzed to assess the on-treatment and off-therapy HCV viral load and on-treatment adverse events. The pre-specified characteristics related to sustained virologic response 12 weeks off therapy (SVR12 ) were compared. RESULTS At treatment week 4, 100 of 102 patients (98.0%) had serum HCV RNA level

Background & Aims The diagnostic accuracy of a novel serological panel (BioFibroScore®) to predict hepatic fibrosis in patients with chronic hepatitis C virus (HCV) infection is unknown. Methods Three markers of BioFibroScore®, including urokinase plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), and beta-2 microglobulin (β2M), were retrospectively evaluated in 635 HCV-infected patients who received percutaneous liver biopsy and FibroScan®. The formula of BioFibroScore® to predict the severity of hepatic fibrosis was developed by Adaboost algorithm. The diagnostic accuracy of hepatic fibrosis was assessed both for BioFibroScore® and FibroScan®, taking METAVIR fibrosis score as the reference standard. Results uPA and β2M were positively and MMP-9 was negatively associated with the severity of hepatic fibrosis. Thirty-five (5.5%) patients had failed FibroScan® assessment. By Adaboost model for BioFibroScore® and the established reference ranges for FibroScan®, 85.7% and 89.0% of the patients had an identical result for F0-1, F2, F3 and F4, as compared to liver biopsy. The concordance rate between BioFibroScore® and FibroScan® was 80.7%. BioFibroScore® overestimated and underestimated the stage of hepatic fibrosis in 8.3% and 6.0% patients, and most patients had one stage error. Among patients with failed FibroScan® assessment, 82.9% of them were correctly diagnosed by BioFibroScore®. Bootstrap analysis for BioFibroScore® showed the diagnostic accuracy was 80.9-88.4%. Conclusions BioFibroScore® is accurate to assess the stage of hepatic fibrosis in HCV-infected patients. Applying this noninvasive test can substantially reduce the need for invasive liver biopsy and can play a role for fibrosis evaluation when FibroScan® assessment was unavailable or unreliable.

BACKGROUND AND AIMS Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to implement salvage therapies appropriately. This study examined the feasibility of virus-host chimera DNA (vh-DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting. APPROACH AND RESULTS HBV integration in 50 patients with HBV-related HCC was determined by the Hybridization capture-based next-generation sequencing (NGS) platform. For individual HCC, the vh-DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV-related HCC. Tumor-specific ddPCR was developed to measure the corresponding vh-DNA copy number in baseline plasma from each patient immediately before surgery. vh-DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh-DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh-DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh-DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh-DNA, whereas 18.2% were from de novo HCC. CONCLUSIONS vh-DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV-related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection.

To identify the risk factors of oral cancer, we investigated the association between chronic hepatitis C (CHC) and oral cancer, and the development of oral cancer after anti-hepatitis C virus (HCV) therapy. We conducted a nationwide, population-based cohort study from 2004 to 2012 from the Taiwan National Health Insurance Research Database. CHC patients without anti-HCV therapy were matched with those non-HCV patients by age, sex and comorbidities. Moreover, CHC patients who underwent pegylated interferon and ribavirin (PegIFN/RBV) anti-HCV therapy were matched with CHC patients without anti-HCV therapy. A total of 100,058 patients were included in the HCV cohort and non-HCV cohorts, respectively. Their mean age was 59 years and 50% of these were male. CHC infection significantly increased the cumulative incidence of lichen planus and oral cancer. After adjustment for confounders and competing mortality, CHC infection significantly increased the risk of oral cancer (hazard ratio [HR]: 1.677, 95% confidence interval [CI]: 1.392-2.020, p < 0.001). Another 23,735 CHC patients without anti-HCV therapy were matched with 23,735 CHC patients in the treatment cohort. After adjustment for confounders and competing for mortality, the risk of oral cancer was significantly reduced in CHC patients receiving anti-HCV therapy (HR: 0.652, 95% CI: 0.479-0.887, p = 0.007). To minimize the inclusion of pre-existing unidentified oral cancer, we excluded oral cancer developed within the first year of CHC or anti-HCV therapy and found these associations remained statistically significant. In conclusion, CHC significantly increases the risk of oral cancer. Moreover, PegIFN/RBV antiviral therapy significantly reduces the risk of HCV-related oral cancer.

Background: Glecaprevir/pibrentasvir (GLE/PIB) is a pangenotypic direct-acting antiviral agent for the treatment of chronic hepatitis C virus (HCV) infection. Real-world data of GLE/PIB in Asian patients other than Japanese are limited. We thus investigated the effectiveness and safety profile of GLE/PIB in Taiwanese patients with chronic hepatitis C (CHC). Methods: CHC patients who received 8, 12, or 16 weeks of GLE/PIB between August and October of 2018 were consecutively enrolled. The treatment duration was determined according to drug label. The hepatic fibrosis was staged according to liver histology, transient elastography, fibrosis index based on 4 factors (FIB-4), or findings of ultrasonography/endoscopy. The primary endpoint was sustained virological response at week 12 off therapy (SVR12). The safety profiles were also assessed. Results: A total of 110 CHC patients with 51% of males were enrolled. The median age was 70 years. A majority (82%) of patients were infected with HCV genotype 2. Forty-six (42%) and 64 (58%) patients had advanced hepatic fibrosis and compensated cirrhosis, respectively. Forty-five (41%) non-cirrhotic patients were treated for 8 weeks. The overall SVR12 rates were 100%, regardless of baseline clinical characteristics. The common adverse events (AEs) were pruritus (12%), anorexia (6%), and fatigue (5%). Nine (8%) serious AEs unrelated to GLE/PIB occurred. Three (2%) patients had Grade 3 elevation of total bilirubin level. None had premature treatment termination, hepatic decompensation, or death. Conclusion: Interferon-free GLE/PIB regimen is highly effective and safe for Asian chronic hepatitis C patients with advanced hepatic fibrosis or compensated cirrhosis. Keywords: Chronic hepatitis C, Direct-acting antiviral, Glecaprevir, Pibrentasvir, Taiwan

BackgroundTo investigate serum Mac-2-binding protein glycosylation isomer (M2BPGi) levels in predicting hepatocellular carcinoma (HCC) and mortality at virological remission (VR, HBV DNA MethodsThis retrospective cohort study included patients with CHB-related Child-Pugh A cirrhosis undergoing long-term antiviral therapy. Serum M2BPGi levels were quantified and multivariable Cox proportional hazards regression models were used to identify risk predictors for HCC and death.ResultsA total of 126 and 145 patients were included in the derivation and validation cohorts, respectively. The mean age was 56, and the mean M2BPGi level was 1.86 cut-off index (COI) in the derivation cohort. After adjustment for confounders, a higher M2BPGi level at VR significantly predicted HCC (hazard ratio [HR]: 1.58, 95% confidence interval [CI]: 1.19-2.10, P=0.002) and death (HR: 2.17, 95% CI: 1.02-4.62, P=0.044). The M2BPGi ³3 COI significantly increased the risk of HCC and death in the derivation and validation cohorts. Serial M2BPGi levels declined significantly (P=0.0001) in non-HCC patients only, and remained significantly lower than those who developed HCC afterwards (P=0.039).ConclusionsSerum M2BPGi levels at antiviral therapy-induced VR predict HCC development and death in patients with CHB-related Child-Pugh A cirrhosis.

The metastatic tumor antigen 1 (MTA1) protein is associated with tumor invasiveness and poor prognosis in patients with hepatocellular carcinoma (HCC), particularly in those with hepatitis B virus (HBV)-related HCC. Chronically woodchuck hepatitis virus (WHV)-infected woodchuck is an ideal animal model for studying the pathogenesis of HBV-associated liver diseases, including HCC. To investigate the roles of MTA1 in HBV-associated hepatocarcinogenesis in the woodchuck model, we cloned the woodchuck MTA1 (wk-MTA1) complementary (c)DNA and characterized its molecular functions. The sequence and organization of the wk-MTA1 protein were highly conserved among different species. Similar to its expression in human HCC, wk-MTA1 was upregulated in woodchuck HCC, as determined at RNA and protein levels. Furthermore, an MTA1-spliced variant, wk-MTA1dE4, was overexpressed in woodchuck HCC, and it was attributed to approximately 50% of the total transcripts. The percentage of wk-MTA1dE4-overexpressed woodchuck HCCs was higher than that of the total wk-MTA1-overexpressed HCCs (77.8% vs 61.1%) and wk-MTA1dE4 may represent a more sensitive marker than the total wk-MTA1 in woodchuck HCC. We overexpressed or knocked down wk-MTA1 in a woodchuck HCC cell line and demonstrated that wk-MTA1 could interact with the WHV X protein (WHx) and play indispensable roles in WHx-mediated NF-κB activation and tumor cell migration- and invasion-promoting activities. In conclusion, our results support the hypothesis that woodchuck HCC recapitulates HBV-associated HCC with respect to the molecular characteristics of MTA1 and provides new clues for conducting mechanistic studies of MTA1 in HBV-associated hepatocarcinogenesis, including the possible clinical significance of wk-MTA1dE4.

Dual hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is not rare in HBV or HCV endemic areas, and can be found in populations at risk of parenteral viral transmission. Clinical observatory studies suggest a higher risk of liver disease progression in patients with dual HCV/HBV infection than in HBV or HCV monoinfected patients. Recent trials confirmed that combination therapy of peginterferon alfa-2a or alfa-2b and ribavirin was effective and safe in dually infected patients with positive HCV RNA. Moreover, about 30% of the dually infected patients cleared hepatitis B surface antigen within 5 years after the start of peginterferon-based therapy. The optimal treatment strategies for dually infected patients with active hepatitis B, with decompensated cirrhosis, or in other clinical situations should be explored in further studies. Finally, the advent of new direct-acting antiviral-based anti-HCV therapy may lead to the development of strategies for the treatment of dually infected patients with active hepatitis C, particularly for those not tolerating or not eligible for peginterferon-based therapy. Notably, direct-acting antivirals would not have any activity against HBV infection; simultaneous or on-demand nucleos(t)ide analogs would be needed if clinically indicated.

BackgroundThe real-world data for the effectiveness and safety of sofosbuvir/ledipasvir (SOF/LDV) with or without ribavirin (RBV) in patients with hepatitis C virus genotype 1 (HCV-1) infection remain limited in Taiwan.MethodsA total of 273 chronic HCV-1 patients receiving 8, 12, or 24 weeks of SOF/LDV with or without RBV were enrolled. The sustained virologic response rate at week 12 off-therapy (SVR12) by evaluable population (EP) and per-protocol population (PP) were assessed for effectiveness. The treatment discontinuation rate due to adverse events (AEs) and serious AE rate were assessed for safety. Baseline patient characteristics and on-treatment HCV viral kinetics associated with SVR12 were analyzed.ResultsThe SVR12 rates by EP and PP analyses were 96.7% (95% confidence interval [CI]: 93.9%-98.3%) and 97.5% (95% CI: 94.8%-98.8%), respectively. The rates of treatment discontinuation due to AE and serious AE were 0.4% and 4.4%, respectively. Seven patients with true virologic failure were relapsers. In 2 patients who were lost-to follow-up, one expired at treatment week 3 due to pneumonia which was considered not related to treatment, and one declined follow-up at off-therapy week 4. The SVR12 rates were comparable in terms of baseline patient characteristics and viral decline at week 4 of treatment.ConclusionsSOF/LDV with or without RBV for 8-24 weeks is well tolerated and achieves a high SVR12 rate in patients with HCV-1 infection in Taiwan.

Real-world data regarding the effectiveness and safety of generic sofosbuvir (SOF)-based interferon-free direct acting antiviral agents (DAAs) for patients with chronic hepatitis C virus (HCV) infection remain limited. A total of 517 chronic HCV-infected patients receiving 12 or 24 weeks of SOF-based therapies were retrospectively enrolled in 4 academic centers in Taiwan. The rate of sustained virologic response at week 12 off-therapy (SVR12) and that of treatment completion were assessed. The baseline characteristics and on-treatment HCV viral kinetics to predict SVR12 were analyzed. By evaluable population (EP) analysis, the SVR12 rate was 95.4% (95% confidence interval [CI]: 93.2–96.9%). The SVR12 was achieved in 29 of 34 patients (85.3%, 95% CI: 69.6–93.6%), 130 of 139 patients (93.5%, 95% CI: 88.2–96.6%), 119 of 124 patients (96.0%, 95% CI: 90.9–98.3%) and 215 of 220 patients (97.7%, 95% CI: 94.8–99.0%) who received SOF in combination with ribavirin (RBV), ledipasvir (LDV), daclatasvir (DCV) and velpatasvir (VEL), respectively. Of 517 patients, 514 (99.4%) completed the scheduled treatment. All 15 patients with true virologic failures were relapsers. Two decompensated cirrhotic patients had on-treatment deaths which were not related to DAAs. All 7 patients who were lost to follow-up had undetectable HCV RNA level at the last visit. The SVR12 rates were comparable in terms of baseline patient characteristics and viral decline at week 4 of treatment. In conclusion, generic SOF-based regimens are well tolerated and provide high SVR12 rates in patients with chronic HCV infection.

Hepatitis B virus (HBV) is a hepatotropic virus that can establish a persistent and chronic infection in humans through immune anergy. Currently, 3.5% of the global population is chronically infected with HBV, although the incidence of HBV infections is decreasing owing to vaccination and, to a lesser extent, the use of antiviral therapy to reduce the viral load of chronically infected individuals. The course of chronic HBV infection typically comprises different clinical phases, each of which potentially lasts for decades. Well-defined and verified serum and liver biopsy diagnostic markers enable the assessment of disease severity, viral replication status, patient risk stratification and treatment decisions. Current therapy includes antiviral agents that directly act on viral replication and immunomodulators, such as interferon therapy. Antiviral agents for HBV include reverse transcriptase inhibitors, which are nucleoside or nucleotide analogues that can profoundly suppress HBV replication but require long-term maintenance therapy. Novel compounds are being actively investigated to achieve the goal of HBV surface antigen seroclearance (functional cure), a serological state that is associated with a higher remission rate (thus, no viral rebound) after treatment cessation and a lower rate of cirrhosis and hepatocellular carcinoma. This Primer addresses several aspects of HBV infection, including epidemiology, immune pathophysiology, diagnosis, prevention and management. Hepatitis B virus is a human hepatotropic DNA virus that can cause a lifelong chronic infection and progressive liver disease. This Primer discusses the epidemiology, mechanisms, diagnosis, prevention and management of chronic hepatitis B virus infection.

PubMed: 29599078, 2-s2.0-85044540918, Background: The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate viral hepatitis by 2030. Although no virological cure exists for hepatitis B virus (HBV) infection, existing therapies to control viral replication and prophylaxis to minimise mother-to-child transmission make elimination of HBV feasible. We aimed to estimate the national, regional, and global prevalence of HBsAg in the general population and in the population aged 5 years in 2016, as well as coverage of prophylaxis, diagnosis, and treatment. Methods: In this modelling study, we used a Delphi process that included a literature review in PubMed and Embase, followed by interviews with experts, to quantify the historical epidemiology of HBV infection. We then used a dynamic HBV transmission and progression model to estimate the country-level and regional-level prevalence of HBsAg in 2016 and the effect of prophylaxis and treatment on disease burden. Findings: We developed models for 120 countries, 78 of which were populated with data approved by experts. Using these models, we estimated that the global prevalence of HBsAg in 2016 was 3·9% (95% uncertainty interval [UI] 3·4–4·6), corresponding to 291 992 000 (251 513 000–341 114 000) infections. Of these infections, around 29 million (10%) were diagnosed, and only 4·8 million (5%) of 94 million individuals eligible for treatment actually received antiviral therapy. Around 1·8 (1·6–2·2) million infections were in children aged 5 years, with a prevalence of 1·4% (1·2–1·6). We estimated that 87% of infants had received the three-dose HBV vaccination in the first year of life, 46% had received timely birth-dose vaccination, and 13% had received hepatitis B immunoglobulin along with the full vaccination regimen. Less than 1% of mothers with a high viral load had received antiviral therapy to reduce mother-to-child transmission. Interpretation: Our estimate of HBV prevalence in 2016 differs from previous studies, potentially because we took into account the effect of infant prophylaxis and early childhood vaccination, as well as changing prevalence over time. Although some regions are well on their way to meeting prophylaxis and prevalence targets, all regions must substantially scale-up access to diagnosis and treatment to meet the global targets. Funding: John C Martin Foundation. © 2018 Elsevier Ltd, H28-kansei-ippan-001 National Academy of Sciences, NAS Novartis Roche World Health Organization, WHO Gilead Sciences Alnylam Pharmaceuticals AbbVie Meso Scale Diagnostics, MSD British Microcirculation Society, BMS Japan Society for the Promotion of Science, JSPS: 17H03589 Ministry of Health, Labour and Welfare, MHLW Vetenskapsrådet, VR Siemens Universiteit Antwerpen OLL-683801, DR-S, IGa, SB, SMB, CE, KM, HMN, KP, KR-S, SR, JDS, and HR report grants from John C Martin Foundation, during the conduct of the study, and grants from Gilead Sciences, AbbVie, WHO, National Academy of Sciences, Intercept Pharmaceuticals, and Boehringer Ingelheim, outside the submitted work. MHN reports grants and personal fees from Bristol-Myers Squibb (BMS), Gilead Sciences, and Janssen, and personal fees from Novartis, Anylam, and Dynavax, outside the submitted work. PVD acts as chief and principal investigator for vaccine trials done on behalf of the University of Antwerp, Belgium, for which the University obtains research grants from vaccine manufacturers; speaker's fees for presentations on vaccines are paid directly to an educational fund held by the University of Antwerp, and PVD receives no personal remuneration for this work. ACA reports personal fees from Mylan Pharmaceuticals, outside the submitted work. JEA reports fees paid to his hospital for participation on the advisory boards of Gilead Sciences, ViiV Healthcare, BMS, Janssen, and AbbVie, and grants from BMS, Merck Sharp & Dohme (MSD), AbbVie, and ViiV Healthcare, outside the submitted work. TB reports grants, personal fees, and non-financial support from AbbVie and Gilead Sciences; grants and personal fees from BMS, Janssen, Roche, MSD, and Sequana Medical; and personal fees from Bayer, Vertex, Tibotec, Intercept, Sirtex, and Alexion, outside the submitted work. PB reports grants and personal fees from AbbVie, Gilead Sciences, and MSD, outside the submitted work. MBr reports personal fees from BMS, Gilead Sciences, and Janssen, and grants from BMS, outside the submitted work. HLYC reports personal fees from Gilead Sciences, BMS, AbbVie, Roche, MedImmune, and Intellia, outside the submitted work. PBC reports grants from AbbVie, Gilead Sciences, and MSD, outside the submitted work. VC reports personal fees from AbbVie, BMS, Gilead Sciences, and MSD, and grants from BMS, outside the submitted work. MCor reports personal fees from AbbVie, BMS, Boehringer Ingelheim, Biogen Idec, Falk Foundation, Gilead Sciences, Janssen, MSD, Roche Diagnostics, Roche Pharma, and Siemens, outside the submitted work. SD and PJ report personal fees and non-financial support from AbbVie and Gilead Sciences, and personal fees from MSD, outside the submitted work. MHE-S is an advisory board member for Perspectum Diagnostics, and reports grants and non-financial support from Gilead Sciences, and non-financial support from AbbVie and Quadri Pharma, outside the submitted work. RF reports grants, personal fees, and non-financial support from Roche and Gilead Sciences, and personal fees and non-financial support from BMS, outside the submitted work. GBG reports grants and personal fees from Gilead Sciences, outside the submitted work. JG-S reports grants and personal fees from Gilead Sciences, and personal fees from MSD, Abbvie, Janssen, and BMS, outside the submitted work. JGer reports grants and personal fees from AbbVie, Gilead Sciences, Janssen, MSD, BMS, and ViiV Healthcare, outside the submitted work. RG reports grants from New South Wales Ministry of Health and provided project advice regarding viral hepatitis treatment to Gilead Sciences, outside the submitted work. AHa reports unrestricted grants from AbbVie, MSD, Gilead Sciences, BMS, and Novartis, and non-financial support from Gilead Sciences, outside the submitted work; he was also on advisory boards for AbbVie, Gilead Sciences, and BMS. CH reports personal fees from AbbVie, BMS, Gilead Sciences, Janssen, and MSD, outside the submitted work. JJ reports personal fees and non-financial support from Gilead Sciences and AbbVie, and personal fees from Roche and BMS, outside the submitted work. MK reports grants from Roche, Siemens, Hologic, and Boerhinger Ingleheim, outside the submitted work. JVL reports grants and personal fees from Gilead Sciences and personal fees from Cepheid, outside the submitted work. MMan reports personal fees from Roche, BMS, GlaxoSmithKline, Aevi Genomic Medicine, ENYO Pharma, and CureVac, and grants and personal fees from Gilead Sciences and Novartis, outside the submitted work. SMau reports personal fees and non-financial support from Gilead Sciences and BMS, outside the submitted work. CM reports grants and personal fees from AbbVie, Gilead Sciences, and BMS; personal fees from MSD; and grants from Roche, outside the submitted work. BM reports grants and personal fees from Gilead Sciences and personal fees from AbbVie, MSD, BMS, Bayer, Intercept, and Sigma-Tau, during the conduct of the study. FN reports personal fees and non-financial support from Gilead Sciences, during the conduct of the study. AR reports grants and personal fees from AbbVie, Gilead, and MSD, and personal fees form BMS, Celgene, Janssen, Intercept, and Lupin, outside the submitted work. HWR reports grants and personal fees from AbbVie, BMS, Boehringer Ingelheim, ENYO Pharma, Gilead Sciences, Janssen, MSD, PRA Health Sciences, Regulus, and Roche; personal fees from Alnylam and R-Pharm; and grants from Replicor, outside the submitted work. LRR reports grants from the Center for Clinical and Translational Science and the Swedish Research Council (Ghana), during the conduct of the study. LRR also reports grants from Gilead Sciences, BTG, Ariad, and Wako, outside the submitted work, and was a consultant and advisory board member for Wako, Medscape, Axis, OncLive, Bayer, Tavec, and Grail. SDR has served as an advisory board member and speaker for Gilead Sciences, AbbVie, and MSD. OS has served as a consultant and on advisory boards for MSD; received research grants from AbbVie, BMS, MSD, Boehringer Ingelheim, R-Pharm, and Hepatera; and served as a speaker for Abbott, AbbVie, BMS, Gilead Sciences, Janssen, MSD, and R-Pharm. JFS-A reports personal fees from AbbVie and grants from Gilead Sciences and Janssen, outside the submitted work. CSa reports personal fees from Gilead Sciences and BMS, outside the submitted work. PS reports grants and personal fees from Gilead Sciences, AbbVie, and BMS, and personal fees from Intercept, outside the submitted work. CSt has consulted with and served on advisory boards for Gilead Sciences, AbbVie, and MSD. VSy reports grants and personal fees from Gilead Sciences, personal fees and non-financial support from AbbVie, and personal fees from Janssen, outside the submitted work. KT reports grants and personal fees from AbbVie, Gilead Sciences, and BMS; personal fees from MSD and Alfa Wasserman; and grants from Janssen, outside the submitted work. AJvdM reports grants and personal fees from Gilead Sciences and personal fees from AbbVie, outside the submitted work. IW reports personal fees from AbbVie, Gilead Sciences, Janssen, Marcyrl, Mylan, Onxio, and Pharco, outside the submitted work. NW reports personal fees paid to her department from AbbVie, BMS, Gilead Sciences, and MSD, outside the submitted work. VWW reports personal fees from Gilead Sciences, BMS, and MSD, outside the submitted work. M-FY was a speaker or advisory board member for AbbVie, BMS, Gilead Sciences, Roche, GlaxoSmithKline, Fujirebio, Biocartis, and MSD, outside the submitted work. SZ reports consultancy and lecture fees from AbbVie, Gilead Sciences, and MSD, and consultancy fees from Intercept, outside the submitted work. All other authors declare no competing interests., This study was funded by the John C Martin Foundation through the Polaris Observatory. We thank the Research on Hepatitis group (H28-kansei-ippan-001 and H25-kanen-ippan-010; led by JT), funded by the Ministry of Health, Labour and Welfare of Japan, for their provision of country-level data for Japan, and Örebro County Council for providing ALF grants (OLL-683801) to A-SD, which allowed collection of country-level data for Sweden.

Chronic hepatitis C viral (HCV) infection has been associated with non-Hodgkin's lymphoma (NHL); however, the results are inconsistent among regions with different HCV prevalence rates. The temporal relationship, risk estimates, and association between HCV and lymphoid-neoplasms remain unclear. This study investigated the temporal relationship between HCV infection and lymphoid-neoplasms using a nationwide population-based cohort. Patients with chronic HCV infection were retrieved from the Taiwan National Health Insurance Research Database during 2001-2005 and designated as the HCV cohort. Those with prior malignancies or coinfected with hepatitis B or human immunodeficiency virus were excluded. The age, sex, and comorbidities, including rheumatological disorders and diabetes, were matched by propensity scores to another non-HCV cohort. Both cohorts were followed longitudinally until 2009 for a new diagnosis of any lymphoid-neoplasms or NHL. A total of 11,679 HCV and 46,716 non-HCV patients were included and followed for 8 years. The incidence rates of any lymphoid-neoplasms and NHL were significantly greater in the HCV cohort than the non-HCV cohort (48.4 versus 22.1, and 37.0 versus 17.5 per 100,000 person-years, respectively, both P < 0.001), even after we excluded lymphoid-neoplasms developed within the first year of follow-up. Cox proportional hazards regression analysis (after adjustment for age, sex, numbers of annual medical visits during follow-up, and comorbidities) indicated that HCV infection was associated with an increased risk of either any lymphoid-neoplasms (hazard ratio = 2.30, 95% confidence interval 1.55-3.43, P < 0.0001) or NHL (hazard ratio = 2.00, 95% confidence interval 1.27-3.16, P = 0.003). Conclusion: After adjustment for confounders and biases, chronic HCV infection is temporally associated with a two-fold increased risk of lymphoid-neoplasms, especially NHL, in Asian patients; additional large studies are needed to explore whether HCV eradication can reduce the incidence of lymphoid-neoplasms. (Hepatology 2016;63:721–730)

Background & Aims Hepatitis B virus (HBV) infection poses a global public health threat. HBV vaccination has proven highly effective in preventing the infection; however, its long-term impact on the general population has not been addressed. We conducted analysis to determine the total and changing burden of chronic HBV infection and evaluate the serological status between vaccinated and unvaccinated in Taiwan. Methods Participants in "The Taiwanese Survey on Prevalence of Hyperglycemia, Hyperlipidemia and Hypertension" in 2002 (n=6602), and 4088 with follow-up survey in 2007 were included. HBsAg (including titers), anti-HBs, anti-HBc, HBeAg, anti-HBe, HBV genotypes and viral loads were assayed. Prevalence and evolving patterns of these seromarkers was compared between vaccinated and unvaccinated cohorts and predictors of persistent HBsAg positivity and negativity were examined. Results The overall prevalence of chronic HBV infection was 13·7% (95% CI, 12.9% to 14.5%) and about two thirds had past exposure (anti-HBc: 68·46%) in 2002. The vaccinated cohort tended to have lower prevalence of HBsAg and anti-HBc, and a higher proportion of anti-HBs and HBeAg positivity, genotype C and high viral load. The majority (85·42%) were consistently HBsAg negative while 12·65% were consistently positive, and 8·98% achieved seroclearance in a five-year period. In the vaccinated cohort, no subjects had acquired new exposure and became HBsAg positive, and only one (0.54%) cleared HBsAg, demonstrating the durability of vaccination through teenage and young adulthood. Conclusions This comprehensive, population-representative-survey shows that 20years after universal vaccination, the backlog still composed a substantial burden of chronic HBV infections in Taiwan.

The efficacy and safety of maternal tenofovir disoproxil fumarate (TDF) in reducing mother-to-infant hepatitis B virus (HBV) transmissions is not clearly understood. We conducted a prospective, multicenter trial and enrolled 118 hepatitis B surface antigen (HBsAg)– and hepatitis B e antigen–positive pregnant women with HBV DNA ≥7.5 log10 IU/mL. The mothers received no medication (control group, n = 56, HBV DNA 8.22 ± 0.39 log10 IU/mL) or TDF 300 mg daily (TDF group, n = 62, HBV DNA 8.18 ± 0.47 log10 IU/mL) from 30-32 weeks of gestation until 1 month postpartum. Primary outcome was infant HBsAg at 6 months old. At delivery, the TDF group had lower maternal HBV DNA levels (4.29 ± 0.93 versus 8.10 ± 0.56 log10 IU/mL, P

Summary Background Clearance of hepatitis B surface antigen (HBsAg) indicates clinical control of hepatitis B virus (HBV) infection. However, little is known about the impact of viral genomic variations on HBsAg loss. Methods We explored the association between viral genomic factors and HBsAg loss in 2121HBeAg-negative patients. HBV pre-core stop codon (1896) and basal core promoter (BCP) (1762/1764) sequences were determined in patients with HBV DNA ≥200 IU/mL (N = 1693). The effect of HBV genotype on HBsAg loss was further validated in the whole cohort of 3445 HBsAg carriers. Results The cumulative lifetime (age 28–75 years) incidence of HBsAg loss was 50.4% in 2121 HBeAg-negative patients. We found that genotype C, but not pre-core stop codon or BCP mutants, was associated with HBsAg loss. Compared to genotype B patients, genotype C patients had higher lifetime chance of HBsAg loss, with hazard ratio of 1.8 (95% confidence interval: 1.4–2.4). Multivariable analysis showed that male sex, elevated ALT levels, lower serum HBV DNA and HBsAg levels, and genotype C infection were associated with higher chance of HBsAg loss independently. We then performed sensitivity analysis, which re-included HBeAg-positive, cirrhotic and treatment-experienced patients, and confirmed the robustness of our results in 3445 HBsAg carriers. Conclusion Genotype C infection, compared to genotype B, is associated with a higher lifetime chance of HBsAg loss in Asian HBV carriers.

Adipocytokines play an important role in lipid metabolism and liver disease progression. However, the interactions between hepatitis B virus (HBV) infection and adipocytokines remain largely unknown. To investigate the association of HBV infection with adipocytokines in HBV-infected and noninfected subjects. In addition, the impact of adipocytokines on serum HBV DNA, HBsAg levels and liver fibrosis stage was also examined. A case-control analysis of patients with and without chronic HBV infection was performed. The HBV group consisted of 187 patients with chronic HBV infection, and the control group consisted of 184 age-, gender- and body mass index-matched subjects without HBV infection. Fasting blood glucose, lipid profiles, adiponectin, leptin and visfatin levels were compared between the two groups. APRI and FIB-4 were calculated to estimate the severity of liver fibrosis. Most of the enrolled subjects had lower ALT levels [228 (57.7 %) ALT

BACKGROUND Fibrosis-4 index (FIB-4) is a surrogate marker for hepatic fibrosis in hepatitis B virus (HBV) carriers. AIM To investigate whether FIB-4 index stratifies the risks of adverse liver events. METHODS A total of 2075 treatment-naive, noncirrhotic the patients with chronic HBV infection were included. Most of them (82.1%) were HBeAg-negative patients and their baseline FIB-4 levels were explored to stratify the risks of cirrhosis, cirrhosis-related complications and liver-related mortality. RESULTS During a mean follow-up period of 15.47 years, we found a higher baseline FIB-4 index was associated with increased incidence rates of cirrhosis in addition to the common host and viral factors. Patients with FIB-4 >1.29, compared to those with FIB-4

BACKGROUND Chronic hepatitis C infection is linked to lymphoma development. AIM To investigate whether antiviral therapy prevents the risk of HCV-related lymphoma. METHODS Patients diagnosed with chronic hepatitis C were retrieved from the Taiwan National Health Insurance Research Database during 2004-2012. We included patients who received pegylated interferon and ribavirin (PegIFN/RBV) antiviral therapy for ≥24 weeks (PegIFN/RBV cohort) or hepatoprotectants for ≥90 days without antiviral therapy (HCV-untreated cohort). Both cohorts were matched by age, sex, and comorbidities through propensity scores and followed for newly diagnosed lymphoma or non-Hodgkin's lymphoma (NHL). RESULTS In total, 24 133 patients were included in both the PegIFN/RBV and HCV-untreated cohort. The lymphoma incidence was significantly higher in the untreated than in the treated cohort (66.48 vs 43.34 per 100 000 person-years, P = 0.029). After adjusting for confounders, the patients who received PegIFN/RBV therapy were at a lower risk of developing lymphoma compared with the untreated patients (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.43-0.96, P = 0.030). Moreover, this beneficial effect was mainly observed in patients with chronic hepatitis C

Background Data are limited regarding the effectiveness and safety of generic velpatasvir plus sofosbuvir (VEL/SOF) for hepatitis C virus (HCV) in patients with or without human immunodeficiency virus (HIV) coinfection. Aim To evaluate the effectiveness and safety of generic VEL/SOF-based therapy for HCV infection in patients with or without HIV coinfection in Taiwan. Methods Sixty-nine HIV/HCV-coinfected and 159 HCV-monoinfected patients receiving 12 weeks of generic VEL/SOF with or without ribavirin (RBV) for HCV were prospectively enrolled. The anti-viral responses and the adverse events (AEs) were compared between the two groups. The characteristics potentially related to sustained virological response 12 weeks off therapy (SVR12 ) were analysed. Results The SVR12 was achieved in 67 HIV/HCV-coinfected patients (97.1%; 95% CI: 90.0%-99.2%) and in 156 HCV-monoinfected patients (98.1%; 95% CI: 94.6%-99.4%) receiving VEL/SOF-based therapy, respectively. The SVR12 rates were comparable between HIV/HCV-coinfected and HCV-monoinfected patients, regardless of pre-specified baseline characteristics. One hundred twenty-two (53.5%) and seven (3.1%) patients had baseline resistance-associated substitutions (RASs) in HCV NS5A and NS5B regions, but the SVR12 rates were not affected by the presence or absence of RASs. One (1.4%) and five (3.1%) patients in the HIV/HCV-coinfected and HCV-monoinfected groups had serious AEs. No patient died or discontinued treatment due to AEs. The eGFR remained stable throughout the course of treatment in HIV/HCV-coinfected patients receiving anti-retroviral therapy containing tenofovir disoproxil fumarate (TDF). Conclusions Generic VEL/SOF-based therapy is well-tolerated and provides comparably high SVR12 rates for HCV infection in patients with and without HIV coinfection.

Background We investigated the patterns and predictors for virological relapse (VR), clinical relapse (CR), and sustained clinical response (SCR) and the outcomes of retreatment after nucleos(t)ide analogue (NUC) therapy discontinuation. Methods Patients with chronic hepatitis B who were discontinuing NUC therapy were prospectively enrolled. Viral and host predictors of relapse were evaluated, including hepatitis B virus (HBV) surface antigen (HBsAg) level, anti-HBV core antibody level, and presence of single-nucleotide polymorphisms in the genes encoding the receptors NTCP (rs2296651) and CTLA4 (rs231775) and in the 3' untranslated regions of the genes encoding HLA-DPA1 (rs3077) and HLA-DPB1 (rs9277535); posttherapy predictors of relapse were also investigated. Information about NUC retreatment and outcomes were recorded. Results Overall, 100 patients discontinuing 3-year entecavir (ETV) or tenofovir (TDF) therapy were enrolled. Patients discontinuing TDF exhibited significantly higher rates of VR (52.9% vs 6.1%; P < .001) and CR (15.2% vs. 1.5%, P = .007) at 3 months than those discontinuing ETV, but relapse rates at 12 months were comparable. The end-of-therapy HBsAg levels predicted VR (hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.19-2.21), CR (HR, 1.78; 95% CI, 1.13-2.81), and SCR (OR, 0.57; 95% CI, .35-.94). The CTLA4 (rs231775) non-GG genotype predicted VR (HR, 1.74; 95% CI, 1.01-3.00) and CR (HR, 2.06; 95% CI, 1.04-4.11), while the HLA-DPA1 (rs3077) AA genotype predicted SCR (OR, 10.84; 95% CI, 1.12-105). The HBV DNA 1 month after NUC treatment cessation was an early predictor of subsequent relapse. Conclusions Discontinuation of tenofovir disoproxil fumarate treatment rather than entecavir treatment is associated with earlier relapse, and NUC-specific posttherapy monitoring is necessary.

Taiwan has a fast-aging population, and it is expected to see an associated increase in the number of older adults with disabilities. We aimed to understand whether Taiwanese older adults’ disability trajectories mediated the association between disablement process factors and later long-term care (LTC) service use. Data were from the nationally representative Taiwan Longitudinal Study on Aging Survey, 1996–2007 (N = 3,429). Trajectories of disability in activities of daily living and instrumental activities of daily living were identified by using growth mixture modeling. Structural equation modeling was applied to examine the effect of disability trajectory as mediator on disablement process factors, such as demographics, number of comorbidities, depression, and leisure activities (LAs), and on later LTC service use. Three distinct disability trajectories were identified among the group of surveyed older adults: healthy (N = 2,998, 87.43 %), progressive disability (N = 363, 10.59 %), and maintained disability (N = 68, 1.98 %). These disability trajectories, either progressive disability or maintained disability trajectory, were found to have a positive mediating effect on the association between disablement process factors (older, lower educational attainment, larger number of comorbidities, and depressive symptoms) and greater use of LTC services. However, encouraging older adults to engage in LAs reduced later use of LTC services through both total and significant mediating effect of postponing development of disability trajectory in older Taiwanese adults. These findings suggest that an active lifestyle is important for older adults’ physical health and to decrease the societal burden of LTC service use.

We assessed the effectiveness and safety of sofosbuvir (SOF) combined with ledipasvir (LDV) or daclatasvir (DCV) in 12 heart transplant recipients with chronic hepatitis C virus (HCV). The sustained virologic response (SVR12) rate was 100% [95% confidence interval [CI]: 75.8%-100%]. All patients tolerated treatment well without interruption, death, or serious adverse events.

Several viral and host risk factors have been used to predict risks of hepatocellular carcinoma (HCC) in patients with chronic infection of hepatitis B virus (HBV). However, little is known whether fibrosis-4 (FIB-4) index, a liver fibrosis biomarker, helps identify non-cirrhotic patients with the lowest HCC risk.A total of 2075 treatment-naive Taiwanese patients with chronic HBV infection were followed for an average period of 16.02 years. None of them had liver cirrhosis at baseline. We explored whether a low FIB-4 index complements the favourable predictors to defines patients with the lowest HCC risk. The finding was validated in 532 non-cirrhotic patients receiving long-term nucleos(t)ide analogue (NUC) treatment with suppressed viral replication.A total of 137 treatment-naive and 10 NUC-treated patients developed HCC, respectively. We found that HCC risk started to increase when baseline FIB-4 index1.29 in the treatment-naive cohort. Patients with FIB-41.29, compared to those with FIB-41.29, were associated with a higher risk of HCC with hazards ratio of 5.56 (95% confidence interval: 3.93-7.86). More importantly, among patients with low viral load (HBV DNA level2,000 IU/ml), baseline FIB-4 index helped stratify different HCC risks such that none of 326 HBeAg-negative patients with FIB-4 index1.29, ALT level40 U/l, and HBsAg level1,000 IU/ml developed HCC. In addition, the patients with the FIB-4 index1.29 consistently had the lowest HCC risks in the validation cohort receiving long-term NUC treatment.In non-cirrhotic patients with chronic HBV infection, FIB-4 index1.29 complements the existing clinical profile to define patients with the lowest HCC risk.